Natural anti-cancer products: insights from herbal medicine.

Introduction

Cancer remains a global public health crisis, with over 20 million new cases and 9.7 million deaths around the world [ 1 , 2 ]. It is caused by internal factors such as genetics [ 3 – 5 ], endocrine [ 6 ], and immunity [ 7 ], as well as external factors like chemicals [ 8 ], physics [ 9 ], unhealthy lifestyles [ 10 ], and aging-related factors [ 11 ]. Herbal medicine offers a multifaceted strategy for cancer therapeutics, emphasizing both tumor suppression and improving general health conditions [ 12 , 13 ]. This includes the improvement of immune system function, reduction of side effects associated with conventional cancer treatments such as chemotherapy and radiation, and the holistic management of patient health [ 14 , 15 ]. For example , research showed that the ethanol extract of Marchantia polymorpha L. (Common liverwort) suppressed the growth of liver cancer cells by triggering apoptosis via intrinsic and endoplasmic reticulum (ER) stress-associated pathways [ 16 ]. Besides, another study published in Chinese Medicine explored the effects of Cucurbitacin B on inhibiting transforming growth factor-beta 1 (TGF- β 1)-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC), revealing that Cucurbitacin B modulates ROS production and the phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) signaling pathways [ 17 ]. Despite these promising advancements, the precise molecular targets of many phytochemicals in herbal medicine remain poorly defined, representing a significant barrier to their broader acceptance and integration into mainstream cancer treatment protocols.

This review provides an overview of the 12 most frequently studied natural anti-cancer products, including terpenoids [Artemisinin, Ginsenosides, Triptolide, and Ursolic acid (UA)], flavonoids (Apigenin, Icariin, and Silibinin), phenols [Curcumin, Epigallocatechin gallate (EGCG), and Resveratrol], alkaloids (Berberine), and anthraquinone (Emodin). Figure 1 illustrates the structure of natural products and their origination from herbal medicine. These compounds have demonstrated promising anti-cancer properties, including tumor immunity enhancement, reversal of multidrug resistance, regulation of autophagy and ferroptosis, and antiproliferative, pro-apoptotic, and anti-metastatic effects, both in vitro and in vivo (Fig. 2 ). Additionally, this review delineates the commonly employed disease models (in silico, in vitro, ex vivo, and in vivo models), pharmacological research methodologies (efficacy assays, omics technologies, and target validation), and modification strategies (including drug modification and drug delivery systems) utilized in anticancer research involving natural compounds (Fig. 3 ).

This review explores the intersection of shinning compounds from Chinese medicine and cancer research, focusing on the synthesis of experimental findings and scholarly conclusions mostly drawn from academic publications since 2019. These compounds have been reported in over 100 research publications, with studies conducted in both preclinical and clinical settings. The literature review was performed using several reputable databases, including PubMed, Web of Science, Medline, Scopus, and Clinical Trials. Search terms utilized included “Natural product”, “Herbal medicine”, “Chinese medicine”, “Chinese medicinal herb”, “Cancer”, “Tumor”, and “Neoplasm”. Our study synthesizes recent advances in herbal medicine-derived anti-cancer compounds by critically analyzing their pharmacological mechanisms, therapeutic potential, and integration challenges within oncology, aiming to provide clear insights.

Apigenin

Apigenin, a flavonoid predominantly derived from Matricaria chamomilla (Chamomile), has garnered significant attention in recent years due to its broad spectrum of pharmacological properties such as anti-inflammatory, antioxidative, antidepressant effects, and cardiovascular protection [ 18 – 21 ]. Remarkably, apigenin has demonstrated efficacy against a diverse array of cancer types, including lung, breast, colon, bladder, head and neck, melanoma, prostate, kidney, cervical, thyroid, oral, pancreatic, and leukemia cancers [ 22 – 30 ]. It impedes cancer progression through various mechanisms, including modulation of tumor immunity, reversal of drug resistance, promotion of autophagy and ferroptosis, induction of apoptosis, and inhibition of invasion and metastasis [ 31 – 34 ]. In silico model employs advanced computational techniques, such as molecular docking, dynamics simulation, quantitative structure–activity relationship (QSAR), and quantum calculation, to assess apigenin derivatives as potential inhibitors of HPV-associated cervical cancer and DNA polymerase theta [ 35 ]. Apigenin is categorized under the biopharmaceutical classification system (BCS) class II, characterized by low solubility and high permeability [ 36 – 38 ]. Recent advancements in drug delivery, such as the application of the self-microemulsifying drug delivery system (SMEDDS) and microwave solid dispersion techniques, have significantly enhanced the bioavailability of Apigenin [ 39 , 40 ]. Moreover, there is growing evidence that co-administration of Apigenin with other pharmacological agents may yield synergistic effects, enhancing therapeutic outcomes [ 41 – 43 ]. To serve as a guide for future research and clinical use, the following sections will briefly review the mechanisms, routes, and molecular targets through which Apigenin produces its anti-cancer actions.

Apigenin improves tumor immunity

Apigenin demonstrates potent immunomodulatory effects across various cancer types through interactions with diverse immune cells, including dendritic cells (DCs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and T lymphocytes [ 44 – 47 ]. Some recent studies show that high doses of apigenin can inhibit the proliferation of DCs, and can also reduce the protein expression of programmed death-ligand 1 (PD-L1) in DCs by inhibiting the phosphorylation of STAT1, thus inducing anti-cancer immunity [ 48 , 49 ]. Apigenin also works by stimulating NK-92 cell proliferation [ 50 ]. Apigenin is also shown to reduce M2-like macrophage populations and promote M1 macrophage polarization in murine models, a mechanism potentially mediated by Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) upregulation. Furthermore, evidence indicates that apigenin suppresses C–C motif chemokine ligand 2 (CCL2) secretion, thereby inhibiting MDSCs infiltration into pancreatic tumors. This anti-invasive effect may be attributed to nuclear factor kappa-B (NF- κ B) signaling downregulation [ 45 ]. Therefore, apigenin exhibits promising potential as an immunotherapeutic agent in cancer treatment through its multi-target modulation of immune components. Key mechanisms include the inhibition of PD-L1 expression and the modulation of NF- κ B/SHIP-1 signaling pathway, which collectively enhance the efficacy of cancer immunotherapy (Table 1 ).

Apigenin reverses cancer drug resistance

Apigenin has demonstrated significant potential in overcoming drug resistance across multiple cancer types through diverse molecular mechanisms. In nasopharyngeal carcinoma (HONE1 and CNE2) cells, apigenin inhibits drug resistance by suppressing epidermal growth factor receptor (EGFR) signaling [ 51 ]. In head and neck squamous cell carcinoma (HNSCC), apigenin reverses resistance to cetuximab by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) and blocking RAS-Mitogen-activated protein kinase (MAPK) pathway [ 52 ]. Apigenin’s role in modulating drug resistance is further supported by its interaction with key pathways such as GLUT-1 and PI3K/AKT. Overexpression of GLUT-1, a marker for hypoxia, and the hyperphosphorylation of AKT are critical contributors to cisplatin resistance in laryngeal cancer cells, including HEp-2 cells. Apigenin is hypothesized to enhance cisplatin sensitivity in these cells by down-regulating GLUT-1 protein expression and AKT phosphorylation [ 53 – 55 ]. In ovarian cancer (SK-OV-3 and SK-OV-3/DDP) cells, apigenin reduces myeloid cell leukemia-1 (Mcl-1) mRNA and protein levels, a member of the anti-apoptotic Bcl-2 family, thereby reversing cisplatin resistance [ 32 , 56 , 57 ]. In doxorubicin-resistant liver cancer (BEL-7402/ADM) cells, apigenin restores drug sensitivity by reducing nuclear factor erythroid 2-related factor 2 (NRF2) expression at both RNA and protein levels through PI3K/AKT pathway inhibition, thereby increasing intracellular doxorubicin [ 58 , 59 ]. In doxorubicin-resistant human uterine sarcoma (MES-SA/Dx5), apigenin reduces intracellular glutathione (GSH) levels by inhibiting ATP-binding cassette subfamily B member 1 (ABCB1) [ 60 ], while in prostate cancer, it reverses doxorubicin resistance by down-regulating ABCB1 protein expression [ 61 ]. Additionally, apigenin re-sensitizes Adriamycin-resistant breast cancer (MCF-7/ADR) cells by inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway [ 62 ]. And in hypoxic tumor models, apigenin overcomes paclitaxel resistance by suppressing AKT and heat shock protein 90 (HSP90) signaling, which hinders the production of hypoxia-inducible factor-1 α (HIF-1 α ) [ 63 ]. These findings highlight apigenin’s multifaceted role in overcoming drug resistance through interactions with drug efflux transporters and key signaling pathways.

Apigenin suppresses cancer growth by regulating the processes of autophagy and ferroptosis

Autophagy is a cellular process that facilitates the transport of cytoplasmic macromolecules and organelles to lysosomes, where they undergo degradation and subsequent recycling [ 64 , 65 ]. It has been demonstrated that the autophagy process is closely linked to a large number of proteins expressed by autophagy-related genes (ATGs). At the same time, the process of autophagy is also subject to regulation by the mTOR. For instance, the activation of its complex, mammalian target of rapamycin complex 1 (mTORC1), can impede the autophagic process [ 66 ]. Apigenin exhibits inhibitory effects on mTOR and p70S6K, leading to increased LC3-II conversion and GFP-LC3 puncta formation, hallmarks of autophage induction. Additionally, apigenin suppresses the mTOR/PI3K/AKT signaling pathway, thereby promoting autophagy in erythroid subtype leukemia (TF-1), liver cancer (Hep G2), and colon cancer (HT-29) cells [ 67 – 70 ]. Under hypoxic conditions, apigenin treatment in gastric cancer (AGS and SNU-638) cells enhances phosphorylation of ATG5, LC3-II, AMP-activated protein kinase (AMPK), and unc-51 like autophagy activating kinase 1 (ULK1), while simultaneously down-regulating p62, collectively driving autophagy-mediated cell death [ 71 ]. The process of ferroptosis is characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation [ 72 ], represents another mechanism by which apigenin exerts its anti-cancer effects. Apigenin induces ferroptosis in multiple myeloma (NCI-H929) cells [ 73 ]. It mitigates myeloperoxidase (MPO)-mediated oxidative stress and inhibits ferroptotic cell death in neurons, while also enhancing glutathione peroxidase 4 (GPX4) activity [ 74 , 75 ]. Thus, apigenin suppresses cancer growth through its regulation of autophagy and ferroptosis. By inhibiting the mTOR signaling pathway, apigenin promotes autophagy-mediated cell death, thereby limiting cancer cell survival under metabolic or oxidative stress. Additionally, its ability to induce ferroptosis in cancer cells further amplifies its therapeutic potential as an anti-cancer agent. These findings underscore apigenin’s multifaceted role in targeting distinct cellular processes, positioning it as a promising candidate for cancer therapy.

Apigenin suppresses cancer progression via classical modalities

Apigenin has been found to influence multiple phases of the cell cycle in a variety of cancers, including skin, liver, breast, and colon cancers, primarily by causing G0/G1 phase arrest, blocking the transition from G0/G1 to S phase, and disrupting progression through the G2/M phase, thereby inhibiting cell proliferation [ 76 ]. Specifically, in colon cancer (HCT 116), apigenin induces G0/G1 phase arrest cells by up-regulating miR-215-5p , which modulates the expression of E2F transcription factors, key regulators of cell cycle progression [ 77 ]. Similarly, in prostate cancer (22Rv1 and PC-3) cells, apigenin treatment is shown to induce cell cycle arrest at the G0/G1 phase in a dose-dependent manner [ 78 ]. In breast cancer (MDA-MB-468) cells, apigenin partially extends the duration of the S phase [ 79 ]. Apigenin also modulates apoptosis in cancer cells through multiple pro-apoptotic pathways, including the mitochondrial pathway, Caspase activation, and oxidative stress induction. In cervical cancer (HeLa) cells, apigenin induce apoptosis via two distinct pathways: one involves down-regulating Bcl-2 protein expression, while the other activates p53 to varying degrees, leading to the induction of p21, fatty acid synthase (Fas) expression and ultimately apoptosis [ 80 ]. In lung cancer (A549) cells, apigenin increases cytochrome C levels, which in turn inhibits mitochondrial function, thereby leading to Caspase-9 and Caspase-3 activation and subsequent apoptosis [ 81 ]. Moreover, apigenin also inhibits tumor by modulating EMT and related protein expression. In human liver cancer (BEL-7402) cells, apigenin decreases Snail1 and NF- κ B protein levels while influencing cancer cell EMT [ 82 ]. In human melanoma (A375) cells, apigenin down-regulates STAT3 target genes matrix metalloproteinase 2 ( MMP-2 ) and MMP-9 , thereby suppressing tumor growth and invasion [ 83 ]. Collectivelly, apigenin suppresses cancer progression through a multifaceted mechanisms that includes cell cycle regulation, apoptosis induction, and metastasis inhibition. Apigenin arrests cancer cells in the G2/M phase or the G0/G1 phase, thereby halting their proliferation. It also modulates critical proteins like Bcl-2 and p53 to induce apoptosis, promoting cell death in various cancer types. Additionally, apigenin inhibits metastasis by down-regulating proteins involved in EMT and tumor cell invasion, such as Snail1, MMP-2, and MMP-9.

Investigating apigenin anti-cancer effects through drug delivery system

Despite its promising anti-cancer effects, apigenin’s clinical application is limited by its poor water solubility. To address this challenge, advanced DDS have been developed to enhance its bioavailability, stability, and therapeutic efficacy. Emulsions, such as W/O/W formulations (water-in-oil-in-water), has been shown to significantly improve the oral bioavailability of apigenin [ 84 , 85 ]. Moreover, the development of liposomal delivery systems presents a promising approach for the efficient administration of apigenin. The cytotoxicity of apigenin nanoliposomes in colon cancer (HCT-15 and HT-29) cells is stronger than that of free apigenin [ 86 ]. Apigenin and tocopherol derivative-containing D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) liposomes shows inhibitory effects in A549 tumor-bearing nude mice [ 87 ]. This combination leverages the unique properties of TPGS, which not only enhances the solubility and stability of apigenin but also prolongs its circulation half-life, thereby improving its bioavailability and therapeutic efficacy. The apigenin-loaded lipid nanocapsules (AP-LNC) are prepared using a phase transformation method, demonstrating a significant enhancement in the inhibition rate of Hep G2 and MCF-7 cells [ 88 ]. Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) have been extensively utilized as polymeric carriers for DDS due to their biocompatibility, biodegradability, and ability to enhance drug solubility and stability. In melanoma (A375) cells, PLGA NPs prepared via the solvent replacement method exhibit a concentration-dependent inhibitory effect on tumor growth [ 89 ]. Similarly, PLGA NPs prepared through nanoprecipitation have been shown to effectively block p53 production in ovarian cancer (OVCAR4) cells, thereby exerting a more potent anti-tumor effect compared to free apigenin [ 90 ]. Additionally, multi-emulsion solvent evaporation technique has been use to create nanoparticles that effectively maintain hepatocyte structure and restore normal cellular function in Hep G2 cells [ 91 ].

In summary, apigenin exerts multi-target anti-cancer effects by modulating immune components, reversing multidrug resistance, regulating autophagy and ferroptosis, and inducing cell cycle arrest and apoptosis. Its poor solubility, however, necessitates the development of advanced drug delivery systems, such as liposomes and nanoparticles, which enhance its therapeutic potential across various cancer types. These systems improve solubility, control release, and target specific cancer types more effectively, positioning apigenin as a promising candidate for cancer therapy.

Artemisinin

Artemisinin is a sesquiterpene lactone compound derived from Artemisia annua L., a traditional Chinese medicinal herb (Qinghao in Chinese) [ 92 , 93 ]. Genetic analysis has demonstrated that amorpha-4,11-diene synthase (ADS), encoded by the ADS gene, functions as the first committed enzyme and plays a critical role in the artemisinin biosynthesis pathway in Artemisiae annuae [ 94 ]. Artemisinin has been demonstrated to possess multiple pharmacological activities, such as antimalarial, antiviral, antibacterial, anti-inflammatory, and anti-cancer properties [ 95 – 98 ]. To assess its safety profile, a machine learning-based toxicity prediction platform was developed, integrating in in vitro cardiotoxicity screening using cardiomyocyte cell lines and in vivo validation in zebrafish models. This approach accurately predicts the cardiotoxicity and other adverse effects of artemisinin derivatives, highlighting its utility in preclinical drug safety evaluation in cancer therapy [ 99 , 100 ]. Moreover, efficacy study has demonstrated that artemisinin suppresses the proliferation and growth of diverse cancers, such as cervical, lung, prostate, bladder, ovarian, and breast cancers [ 101 – 105 ]. Its anti-cancer mechanisms are multifactorial, involving immunomodulation, induction of autophagy and ferroptosis, and suppression of tumor metastasis and angiogenesis [ 106 , 107 ]. Furthermore, artemisinin synergizes with conventional chemotherapeutic agents, selectively targeting cancer cells while enhancing treatment efficacy [ 108 – 111 ]. Clinically, the therapeutic potential of artemisinin derivatives is under investigation in several trials: artesunate in the treatment of cervical intraepithelial neoplasia ( NCT04098744 ), metastatic breast cancer ( NCT00764036 ), and stage II/III colon cancer ( NCT02633098 ). The following section reviews the pharmacological effects, intricate mechanisms, and specific biological targets of artemisinin across cancer type.

Artemisinin regulates tumor immunity

Artemisinin modulates the immune response in liver, breast, colon, and leukemia cancers through enhancing the activity of NK and T cell function and decreasing regulatory T (Tregs) and MDSCs [ 112 – 114 ]. It attenuates lymphoma (K-562, Raji and YAC-1) cells by enhancing NK cell activity with low adverse effects [ 113 ]. Artemisinin suppresses tumor growth by enhancing the immunosuppression of Tregs and MDSCs, effectively reversing the immunosuppressive tumor microenvironment, inducing robust immunogenic cell death, and boosting anti-cancer immunity in 4T1 cells in vitro and in vivo [ 115 ]. Therefore, artemisinin holds significant promise as an immune-modulating agent in cancer therapy. It enhances the function of NK and T cells while simultaneously reducing immunosuppressive cells, such as Tregs and MDSCs. These dual effects reverse the immunosuppressive tumor microenvironment, thereby facilitating enhanced immune surveillance and a more robust antitumor immune response. Additionally, artemisinin induces immunogenic cell death, which not only directly eliminates cancer cells but also stimulates the body's inherent anti-cancer immune response, further amplifying its therapeutic effects.

Artemisinin reverses multidrug resistance

Research suggests that artemisinin and its derivatives can modulate the activity of P-glycoprotein (P-gp), plasmodium falciparum multidrug resistance protein 1 (PfMDR1), and breast cancer resistance protein (BCRP) in breast, liver, colon and leukemia cancers [ 116 , 117 ]. In the context of liver cancer, artemisinin has been demonstrated to reduce the protein expression of actin filament associated protein 1-like 2 (AFAP1L2) and reverses sorafenib resistance in specific liver cancer cell lines (Hep G2, Hep3B, MHCC-97 H, and Huh-7) [ 118 ]. Furthermore, artemisinin has been shown impair lysosomal function in lung cancer (A549/TAX) and breast cancer (MCF-7/ADR) cells, while subsequently improves the sensitivity of cancer cells to paclitaxel [ 119 ]. In addition, artemisinin, through mechanisms such as increasing drug loading, enabling rapid reactive release, and optimizing drug delivery sequence, can efficiently and precisely address the multidrug resistance in breast cancer (MCF-7 and LCC9) cells [ 117 , 120 ]. Moreover, dihydroartemisinin has been found to overcome dexamethasone and oxaliplatin resistance in multiple myeloma (ARP1 and H929) and colon cancer (HCT 116 and SW620) cells by enhancing the sensitivity of these cells to dexamethasone and oxaliplatin [ 121 , 122 ]. Furthermore, dihydroartemisinin damages heme metabolism in osimertinib-resistant EGFR mutant NSCLC (PC9-OR3, PC9-OR5, PC9-GR1-AZD2, and PC9-GR4-AZD1) cells, thereby inhibits cell proliferation with relatively low toxicity [ 123 ]. Thus, artemisinin and its derivatives exhibit a broad spectrum of activities against multidrug resistance in cancer treatment. They operate through multiple mechanisms, including modulating drug efflux proteins, reversing specific drug resistances, impairing lysosomal functions, optimizing drug delivery, and enhancing the sensitivity of cancer cells to chemotherapy agents. These multifaceted mechanisms position artemisinin as a promising candidate for incorporation into combination therapy regimens designed to overcome drug resistance in diverse cancer types.

Artemisinin suppresses cancer growth by regulating the processes of autophagy and ferroptosis

Artemisinin and its derivatives exert its anti-cancer effects through the regulation of autophagy and ferroptosis via multiple distinct pathways. These pathways include mitochondrial autophagy, iron homeostasis regulation, and lipid peroxidation induction and ROS production. Such pathways have demonstrated to possess significant anti-tumor effects across a diverse range of cancer types, including liver, bladder, breast, endometrial, myeloma, and acute myeloid leukemia cancers [ 124 ]. Artemisinin regulates autophagy markers (LC3B and p62) to stimulate autophagy [ 125 ]. Artesunate induces ATG5 associated autophagy in bladder cancer (T24 and EJ) and endometrial cancer (Ishikawa and AN3 CA) cells [ 103 , 126 ]. Moreover, artesunate regulates autophagy and ferroptosis by inhibiting STAT3 activation in non‑Hodgkin lymphoma (U2932, SU-DHL4, and Jurkat) cells [ 127 ]. Dihydroartemisinin has been found to inhibit cell proliferation in liver cancer (HepG2.2.15) cells in a dose- and time-dependent manner through the induction of autophagy [ 128 ]. Additionally, artemisinin plays a role in regulating the cancer progression, particularly in liver cancer, by inducing ferroptosis [ 129 , 130 ]. Artesunate suppresses myeloma (MM1S) cell progression through inducing ferroptosis [ 131 ]. In lymphoma (U2932 and SU-DHL-4) cells, artesunate promotes ferroptosis by impairing the STAT3 pathway [ 132 ]. In primary liver cancer, dihydroartemisinin increases the level of lipid ROS and malondialdehyde, while simultaneously decreasing the protein expression of GPX4. These alterations trigger ferroptosis in primary liver cancer (Hep G2 and Hep3B) cells [ 133 , 134 ]. Dihydroartemisinin also regulates iron metabolism to induce ferritin autophagy and subsequent ferroptosis in acute myeloid leukemia (MOLM-14 and OCI/AML-2) cells [ 135 ]. Furthermore, dihydroartemisinin has been demonstrated to increase the unstable iron pool, promote ROS accumulation, induce ferroptosis, and inhibit the proliferation of leukemia (HL-60, KG-1, and THP-1) cells [ 136 ]. Novel 1,3, 4-oxadiazol-artemisinin hybrids has been found to induce ferroptosis in breast cancer (MCF-7) cells in a dose-dependent manner [ 137 ]. Briefly, artemisinin and its derivatives exert anti-tumor effects on a variety of cancer cells through multiple mechanisms. These mechanisms involve reducing protein expression, promoting mitochondrial autophagy, inducing apoptosis, enhancing cytotoxicity, activating specific pathways, regulating iron metabolism and ROS production, and ultimately inducing autophagy, apoptosis, and ferroptosis. Moreover, these effects can lead to an improvement in the sensitivity of cancer cells to chemotherapy drugs.

Artemisinin and its derivatives suppress cancer progression via classical modalities

Artemisinin and its derivatives have been demonstrated to exert inhibitory effects on cancer progression through multiple well-established mechanisms. For instance, artesunate inhibits colon cancer cell proliferation by inducing cell cycle arrest at G0/G1 phase and subsequent cell senescence [ 138 ]. Artemisinin down-regulates the mRNA levels of proliferation-related genes ( c-Myc , N-cadherin , Vimentin , Snail , E-cadherin ) in renal cancer (UMRC-2 and Caki-2) cells to attenuate cancer progression [ 139 ]. Dihydroartemisinin inhibits the growth and invasion of sgastric cancer (SGC-7901, MKN-28 and MGC-803) cells through the modulation of key signaling pathways such as the Cyclin D1-CDK4-Rb and STAT1/KDR/MMP-9 pathways [ 140 – 142 ]. Moreover, artemisinin modulates the expression of apoptotic proteins in a dose-dependent manner in salivary gland cancer (A-253/HTB-41) cells. Specifically, it increases the pro-apoptotic protein (Bax, Bim, Bad and Bak) expression, while decreasing anti-apoptotic protein (Bcl-2 and Bcl-xL) expression, and activates Poly (ADP-ribose) polymerase 1 (PARP1) and Caspase-3, ultimately triggering cell death [ 143 ]. Dihydroartemisinin induces apoptosis of breast cancer (4T1) cells by enhancing ROS release, increasing p53 protein expression and activating Caspase-3 [ 144 ]. Artesunate significantly inhibits the growth of lung cancer (A549) cells by interfering with cell cycle progression, reducing the protein expression of Bcl-2 and MMP-9, and increasing the protein expression of Bax [ 145 , 146 ]. In ovarian cancer (IOSE144, A2780, OVCAR3, and SK-OV-3) cells, dihydroartemisinin downregulates Bcl-2 and upregulates Bax, which inhibits cancer cell proliferation and leads to cell cycle arrest at the S phase [ 104 , 147 , 148 ]. To sum up, artemisinin and its derivatives inhibit the proliferation, migration, and invasion of various cancer cells through multiple distinct mechanisms. They also exhibit diverse effects such as anti-inflammatory activity, enhanced cell cycle arrest, and induction of apoptosis in specific cancer types. Furthermore, they possess broad anti-tumor potential, as evidenced by their ability to inhibit angiogenesis in relevant animal models.

Artemisinin and its derivatives combined with other medications for cancer treatment

The combination of artemisinin or its derivatives with different chemotherapeutic agents (e.g., Oxaliplatin, carboplatin) and other natural compounds (e.g., Resveratrol) has been demonstrated to yield synergistic anti-tumor effects. For example, when artemisinin is combined with oxaliplatin, the anti-tumor effect of oxaliplatin on esophageal cancer (EC109) cells is enhanced [ 149 ]. Artesunate and carboplatin, when used in combination, promote cell cycle arrest and induce the expression of cell cycle and apoptosis-related proteins, thereby exerting synergistic anti-tumor effects on NSCLC (A549) cells [ 150 ]. When artemisinin and resveratrol are encapsulated into nano-sized liposomes, HT-29 cell growth is inhibited in a time- and dose-dependent manner [ 151 ]. Additionally, combination studies have revealed that trastuzumab inhibits breast cancer (HCC1569, HCC1954, and BT-474) cell proliferation more effectively when combined with dihydroartemisinin compared to single drug treatment [ 152 ]. Dihydroartemisinin plays a significant anti-tumor role in multiple cancers and has been shown to enhance the anti-tumor efficacy of cisplatin in NSCLC (A549) cells [ 153 ]. Dihydroartemisinin and capecitabine have a synergistic effect on human colon cancer (HCT 116, DLD-1, SW620, and HCT-15) cells and mitigate the side effects induced by capecitabine [ 154 ]. Dihydroartemisinin has been demonstrated to suppress the proliferation, migratory abilities, and invasive capacity of various breast cancer (MCF-7, MDA-MB-231, and BT-549) cells [ 155 ]. The combination of dihydroartemisinin and resveratrol synergistically inhibits the migration of liver cancer (Hep G2) and breast cancer (MDA-MB-231) cells [ 156 ]. The 1:1 combination of sulfampyridine and dihydroartemisinin exhibits high efficacy against glioma (TN22) cells [ 157 ]. Artemisinin, in conjunction with sorafenib and venettok, has been shown to display a collaborative inhibitory action on the proliferation and trigger cell death in diverse acute leukemia cell lines under laboratory conditions [ 158 ]. The combination of dihydroartemisinin and cisplatin synergistically inhibits the proliferation of pancreatic ductal adenocarcinoma (PANC-1 and SW1990) cells and induces ferroptosis by modulating iron metabolism [ 159 ]. Additionally, when dihydroartemisinin and sorafenib are combined, they can inhibit Hep G2 cell proliferation and induce ferroptosis. This combination generates high levels of ROS, promoting cancer cell apoptosis and demonstrating synergistic anti-cancer effects in hepatoma (Hep G2) cells [ 160 , 161 ]. The combination of artesunate and sorafenib shows synergistic antitumor activity in hepatocellular cancer (Hep G2) cells [ 162 ]. Overall, the combination of artemisinin with different chemotherapy agents and other natural compounds demonstrates significant anti-tumor effects, including enhancing the anti-proliferation, pro-apoptotic, and cell cycle regulation effects of oxaliplatin, metformin, and carboplatin on various cancer cell lines. Such combination treatments hold great potential in both clinical and experimental settings, as they enhance anti-tumor activity and exhibit synergistic effects.

Investigating artemisinin anti-cancer effects through drug delivery system

To enhance the bioavailability and enable more specific targeting of artemisinin for tumors treatment, researchers have been actively exploring diverse drug delivery systems. These include nanoparticles, liposomes, polymer micelles, dendrimers, hydrogels. Such system can improve the efficacy of artemisinin and present a promising strategy in the treatment of lung, colon, and breast cancers [ 163 – 165 ]. For instance, when artemisinin is combined with metformin within co-carrier nanoparticles, it exhibits superior anti-proliferative effects on lung cancer (A549) and breast cancer (T-47D) cells compared to its free form [ 163 , 166 ]. Additionally, artemisinin loaded into manganese oxide within a co-delivery system has been shown to possess the ability to penetrate deeply into solid tumors, enabling precise diagnostic and targeting capabilities, especially for breast cancer (T-47D) cells [ 167 ]. The oral administration system using heme lipid artemisinin nanoparticles demonstrates remarkable stability with the gastrointestinal tract and during blood circulation. However, these nanoparticles can dissociate in the tumor microenvironment, which significantly augments their accumulation within tumors. In mouse models, this property has led to the complete suppression of colon cancer (MC38) cells within 30 days [ 168 ]. Copper artemisinin nanoparticles can achieve cascade amplification of ROS production and have a high tumor inhibition rate in breast cancer (4T1) xenograft model [ 169 ]. The use of tween 80 micelles for artemisinin-loaded micelles effectively prevents premature drug release during circulation, and this system has shown a significant tumor inhibitory effect, with inhibition rates reaching up to 85% [ 170 ]. Biodegradable dihydroartemisinin nanoparticles, employing a MPEG-PCL micelle carrier, ensure a sustained release of the drug in aqueous solutions. These nanoparticles have shown to be more effective and less toxic in vivo compared to free dihydroartemisinin [ 171 ]. To sum up, the development of novel drug delivery systems has significantly enhanced the bioavailability, stability, and targeting efficiency of artemisinin, thereby improving its potential as an anti-cancer agent. Systems such as nanoparticles, liposomes, and micelles play crucial roles in ensuring that artemisinin is delivered effectively to tumors, which in turn enhances its therapeutic effects while minimizing potential side effects. Approaches like co-carrier nanoparticles, manganese oxide-based co-delivery, copper-based ROS amplification, and biodegradable nanoparticles have all yielded promising results in preclinical models of lung, colon, and breast cancers. These advancements suggest that artemisinin, when delivered through optimized drug delivery systems, holds great promise as a more effective treatment for a variety of cancers.

Artemisinin derivatives inhibit cancer progression

Artemisinin derivatives have been shown to exert inhibitory effects on cancer progression through multiple mechanisms. Dihydroartemisinin has been demonstrated to modulate cytotoxic T lymphocyte (CTL) function by influencing Treg cell inhibition, thereby enhancing anti-cancer immunity in mice and inhibiting the growth of melanoma (B16-F10) cells [ 172 , 173 ]. Artesunate effectively reduces the protein expression of PD-L1 in NSCLC (NCI-H1975, NCI-H460, A549, and PC-9) cells [ 174 ]. Dihydroartemisinin augments the responsiveness of colon cancer (HCT 116 and RKO) cells to oxaliplatin [ 175 ]. When artesunate and chloroquine are combined, they can regulate macrophages, inhibit the proliferation of colon cancer (HCT 116 and CT26) cells, and reverse the immunosuppressive tumor microenvironment [ 176 ]. The concurrent delivery of dihydroartemisinin and pyrophosphorus-iron induces increased production of ROS, thereby triggering ferroptosis. This process not only leads to cancer cell death but also enhances tumor immunogenicity, rendering previously non-immunogenic colon tumors susceptible to anti-PD-L1 checkpoint blockade immunotherapy [ 177 ]. Dihydroartemisinin promotes anti-programmed death-1 (PD-1) action in liver cancer (HepG2.2.15) cells [ 178 ]. The combination of oxaliplatin and dihydroartemisinin has a strong synergistic effect on ROS generation. The combination of ROS generation and immunostimulant using nanomedical drugs works synergistically with checkpoint blocking immunotherapy to treat colon cancer (CT26 and MC38) in mice [ 179 ]. In glioblastoma multiforme, the combination of artesunate with lower doses of metformin demonstrates antitumor effects by activating the AMPK/mTOR pathway and inducing autophagy in human glioblastoma (U251 and U118-MG) cells [ 180 ]. Artemisinin derivatives with piperazine and fluorophore suppresses the cell cycle at the G0/G1 phase, increases Bax expression, decreases Bcl-2 protein expression, induces concentration-dependent apoptosis, and inhibits cell migration via E-cadherin and N-cadherin pathways in colon cancer (HCT 116) cells [ 181 ]. Artemisinin and its derivatives inhibit the migration and invasion of cancer cells, and have anti-tumor and anti-angiogenic effects on tumor xenografts in nude mice [ 182 – 185 ]. Dihydroartemisinin influences colitis-associated colon cancer (CACC) at multiple stages. Artesunate and sorafenib synergically induce lipid peroxidation and ferroptosis in liver cancer (Hep G2, SNU-182 and SNU-449) cells [ 186 ]. Dihydroartemisinin also causes lipid peroxidation and ROS generation, which leads to ferroptosis in glioma (U251 and U373) cells [ 187 ]. Dihydroartemisinin@MIL-101 nanoreactor produces ROS and consumes GSH, resulting in the accumulation of lipid peroxide and induction of ferroptosis in lung cancer (Lewis) cells [ 188 ]. Overall, artemisinin derivatives, including dihydroartemisinin and artesunate, exhibit a wide range of anti-cancer effects by modulating immune responses, enhancing chemotherapy efficacy, inducing ferroptosis, and inhibiting cancer cell proliferation, migration, and invasion across various cancer types.

To sum up, artemisinin and its derivatives exemplify the potential of a single phytochemical to modulate immunity, overcome drug resistance, and induce cell death pathways such as ferroptosis and autophagy. Continued investigations into synergistic regimens, targeted drug delivery, and clinical safety profiles are of utmost importance for fully realizing artemisinin’s therapeutic potential in cancer treatments.

Berberine

Berberine is an isoquinoline alkaloid, mainly extracted from Coptis chinensis or Coptidis Rhizoma (Huanglian in Chinese). Berberine has been long-term used for its anti-inflammatory, antioxidant, anti-diabetic, cardioprotective, hepatoprotective, and neuroprotective effects [ 189 , 190 ]. Regarded as a promising anti-tumor candidate, berberine has diverse pharmacological properties [ 191 – 193 ]. Berberine modulates cancer immunity, reduces drug resistance, promotes apoptosis and autophagy, inhibits cell cycle progression, and curtails invasion and metastasis in a range of cancers such as lung, breast, colon, liver, gastric, prostate, ovarian, and leukemia [ 194 , 195 ]. In silico studies shows that berberine interacts with key oncogenic proteins such as p53, EGFR, AKT, p38, and ERK1/2, while in vitro experiments validated its ability to decrease the phosphorylation of these proteins, highlighting its potential as an effective treatment for oral squamous cell carcinoma and breast cancer [ 196 , 197 ]. Ex vivo studies demonstrate that berberine and its eight analogs inhibit cancer cell viability in a canine mammary carcinoma cell line and transgenic zebrafish models through apoptosis induction, while zebrafish embryo toxicity experiments are conducted to assess the in vivo safety of berberine [ 198 , 199 ]. In clinical studies, berberine has been tested in various cancers, including lung cancer ( NCT03486496 ), colon cancer ( NCT03281096 ), and gastric cancer ( NCT03609892 ). However, the clinical application of berberine is restricted because of its poor water solubility and low bioavailability. To avoid these disadvantages, advanced delivery systems such as nanoparticles and liposomes are developed to improve the solubility and stability of berberine [ 200 – 202 ]. This section is dedicated to discussing the current investigations into the anti-tumor efficacy of berberine, both as a standalone and as part of combination therapies.

Berberine improves tumor immunity

Berberine has indicated significant immunomodulatory actions in regulating tumor microenvironment by modulating various immune cells, inflammatory mediators, and immune checkpoint pathways [ 203 ]. For breast cancer, by modifying the inflammatory cytokine network and immune cell infiltration, berberine has been shown to inhibit tumor growth and metastasis in hypoxic environments [ 204 , 205 ]. Berberine enhances the activation of NK cells, DCs, and CTLs, while reducing the populations of MDSCs and TAMs [ 206 , 207 ]. Moreover, berberine suppresses the growth of liver cancer by reducing the number of MDSCs in tumor tissues and inhibiting angiogenesis [ 208 ]. Additionally, berberine protects liver cancer progression by modulating intrahepatic T cell heterogeneity, potentially improving the efficacy of cancer immunotherapy [ 194 , 209 ]. Berberine has been shown to reprogram TAMs from M2 to M1 phenotype, thereby enhancing the anti-tumor immune response [ 210 ]. Regarding inflammatory mediators, berberine significantly reduces the levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF- α ), interleukin-6 (IL-6), and IL-1 β , and downregulates their protein expression [ 210 ]. In a breast cancer model, berberine inhibits tumor growth under hypoxic conditions by modulating the inflammatory cytokine network and immune cell infiltration [ 210 , 211 ]. Berberine exerts antitumor effects by inhibiting PD-L1 activity, improving T-cell-mediated immunity. It is achieved by suppressing the deubiquitinating of CSN5 and leads to PD-L1 ubiquitination and degradation, reactivating cytotoxic T-cells and reducing immunosuppressive cells in the tumor microenvironment [ 210 ]. Therefore, berberine shows great promise as a multi-target agent capable of modulating the tumor microenvironment to promote anti-tumor immunity. Its ability to enhance immune cell function, reduce immunosuppressive cells, reprogram TAMs, decrease inflammatory mediators, and inhibit immune checkpoints, positions it as a valuable compound for cancer therapy.

Berberine reverses tumor drug resistance

Berberine has been reported to reverse drug resistance in various cancer types by targeting multiple drug resistance mechanisms. One of the key mechanisms through which berberine combats multidrug resistance is its ability to inhibit drug efflux pumps, particularly in regulating the ABC transporter family, including P-gp and Multidrug resistance protein 1 (MRP1). Berberine has been shown to downregulate the expression of these transporters, thereby increasing the intracellular retention and potency of drugs like doxorubicin. Experimental evidence indicates that berberine, combined with doxorubicin, significantly reduces the efflux of chemotherapeutics, and enhances their cytotoxic effects in breast cancer [ 212 , 213 ]. Additionally, berberine can reverse drug resistance by activating AMPK, which is involved in cellular energy homeostasis. It is a potential therapeutic target in drug-resistant cancers. Berberine can cause a change in the metabolism of cancer cells by activating AMPK. It can reverse the Warburg effect. This metabolic reprogramming disrupts the energy supply of drug-resistant cancer cells. It leads to increased sensitivity to chemotherapy. Moreover, the activation AMPK can downregulate HIF-1 α , which is a hypoxia-inducible factor that promotes P-gp expression, and further enhances chemosensitivity. Studies also demonstrated that berberine sensitizes drug-resistant breast cancer cells to doxorubicin by the modulation of the AMPK-HIF-1 α -P-gp pathway [ 214 ]. Berberine can also target mitochondria, which are critical organelles in energy production and apoptosis regulation. Due to its delocalized positive charge, berberine can disrupt mitochondrial membrane potential and upregulate the content of ROS. These mitochondrial perturbations can stimulate intrinsic apoptosis pathways. It can effectively result in cell death in drug-resistant cancer cells. Furthermore, mitochondrial targeting by berberine is increased if combined with nanomedicine platforms, such as GSH-responsive paclitaxel-berberine conjugates, which can achieve simultaneous drug release and targeted delivery. This approach has shown superior efficacy in reversing resistance in lung and breast cancer models [ 215 ]. For the synergistic effects with chemotherapeutics, berberine can increase the efficacy of conventional chemotherapeutic agents. It has been indicated across various cancer types, including breast, liver, lung, and colon cancers. Its synergistic effects are attributed to multiple mechanisms, including enhanced drug uptake, efflux transporters inhibition, and cancer cell metabolism disruption. For instance, berberine can improve doxorubicin uptake in tumor tissues while simultaneously down-regulate the protein expression of P-gp and MRP1 in breast cancer. This dual action not only improves chemotherapeutic efficacy but also reduces the likelihood of multidrug resistance development [ 212 ]. Berberine can reverse the multidrug resistance of breast cancer via the suppression of the efflux function of ABC transporters. In vivo experiments have shown that berberine can treat Adriamycin-resistant breast cancer patient as well [ 216 ]. Therefore, berberine shows promise as a treatment for tumors that are resistant to various drugs. Upon targeting efflux transporters, reprogramming cancer metabolism, inducing mitochondrial apoptosis, and synergizing with chemotherapeutic agents, berberine exhibits the multi-faceted nature of drug resistance. The integration of innovative delivery systems further augments its potential. It paves the way for its translation from bench to bedside. Continued research and clinical trials are recommended to fully identify the therapeutic potential of berberine.

Berberine suppresses cancer growth by regulating the processes of autophagy and ferroptosis

Berberine could apoptosis and autophagy in cancer cells through various mechanisms. Berberine can also act as an autophagy regulator to regulate physiological and pathological conditions and reduce drug resistance in cancer treatment [ 217 ]. Regarding apoptosis, berberine primarily upregulates pro-apoptotic proteins while down-regulating anti-apoptotic proteins. In liver cancer cells, berberine induces apoptosis by activating Caspase-3 and Caspase-9 through the miR-221 / SRY-related HMG-box 11 (SOX11) axis [ 218 ]. Similarly, in renal cell carcinoma, berberine treatment increases ROS levels and apoptosis rates, accompanied by the protein upregulation of Bax, Bad, Bak, Cytochrome, the downregulation of Bcl-2c and activating Caspase-3, and Caspase-9 [ 219 ]. Berberine can significantly suppress the proliferation of human glioma (U-87 MG) cells and induce the apoptosis of U-87 MG and LN-229 cells by down-regulating the protein expression of Bcl-2, up-regulating that of Bax and activating Caspase-3 [ 220 ]. In a study on the anti-cancer effect of berberine on Peripheral blood mononuclear cells (PBMCs) from patients with chronic lymphocytic leukemia, berberine is found to promote apoptosis by reducing Bcl-2, ROR1, and mir-21 gene levels [ 221 ]. Berberine suppresses EMT and promotes apoptosis of colonic epithelial cells induced by tumor-associated fibroblasts by regulating TGF- β signaling [ 222 ]. Self-assembled mitochondria-targeted nano drugs (HA/PEG/BD NDs) from 9-O-octadecyl-substituted berberine derivatives exhibit significant mitochondrial targeting of tumor cells and remarkable anti-tumor efficacy in A549 genetically engineered tumor models. HA/PEG/BD NDs induce apoptosis through dissipation of the mitochondrial membrane potential, release of cytochrome C, and increase in Caspase-9/3 activity, activation of pro-apoptotic Bax, inhibition of anti-apoptotic Bcl-2 and up-regulation of ROS levels to induce apoptosis [ 223 ]. Based on these reports, the anti-cancer properties of berberine can be regarded by stimulating both endogenous and exogenous apoptosis via increasing the protein expression of pro-apoptotic molecules Bax, Bad, Bak, and activating Caspase-3, Caspase-8 and Caspase-9. Berberine also induces autophagy in cancer cells, although the effects appear to be context-dependent and involve multiple signaling pathways. In melanoma cells, berberine induces autophagic cell death by inactivating the AKT/mTOR signaling pathway [ 224 ]. Similarly, in acute lymphoblastic leukemia cells, berberine induces autophagy and cell death by inhibiting the AKT/mTORC1 signaling pathway [ 225 ]. In gastric cancer cells, berberine induces autophagy inhibition through the regulation of MAPK/mTOR/p70S6K and AKT pathways, leading to the suppression of cancer cell growth both in vitro and in vivo [ 226 ]. Berberine has been reported to act as a naturally occurring MET inhibitor that synergizes with ositinib to overcome acquired resistance to ositinib caused by MET amplification [ 227 ]. Berberine synergistically and selectively reduced the survival of several MET-amplified Ositinib-resistant EGFR-mutant NSCLC cells when used in combination with Ositinib. It may enhance the induction of apoptosis through Bim elevation and Mcl-1 reduction [ 228 ]. Therefore, berberine's broad spectrum of action against cancer cells through the regulation of autophagy and ferroptosis highlights its potential as a powerful anticancer agent. Its ability to target multiple cellular mechanisms responsible for cancer progression and survival offers a promising avenue for developing more effective cancer treatments.

Berberine suppress cancer progression via classical modalities

Berberine can block the progression of the cell cycle at the G0/G1 phase, preventing the transition to the S phase, thereby inhibiting cancer cell proliferation. Additionally, it can interfere with the S phase and G2/M phase, disrupting DNA synthesis and mitosis. In breast cancer cells, berberine and its derivatives arrested the G2/M phase by inhibiting HIF-1 α activity and regulating its downstream targets through non-coding RNAs [ 205 , 229 ]. Moreover, berberine induced S phase arrest in breast cancer (MDA-MB-231) cells. It enhances their chemosensitivity to conventional therapies [ 230 , 231 ]. The molecular mechanisms underlying berberine-induced cell cycle arrest include the increase of cyclin-dependent kinase (CDKs) inhibitors, such as p21 and p27, and the decrease of Cyclin D1 [ 215 ]. Interestingly, berberine has been found to promote the ubiquitination of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) through the E3 ubiquitin ligase TRIM21. It leads to S phase arrest in colon cancer cells [ 232 – 234 ]. Berberine can arrest the cell cycle of lymphocytic Jurkat cells at G0/G1 phase, suggesting that it may play a positive role in the treatment of leukemia [ 235 ]. Studies have shown that for Tca8113 and MCF-7, the maximum arrest occurred after 12 h of berberine treatment, and for Hela, CNE2 and HT-29, the maximum arrest was observed at 24, 36 and 24 h, respectively. The results showed that Berberine could induce different cancer cells to arrest at G2/M phase [ 236 ]. Mitochondria-targeted nanomedicines self-assembled from GSH-responsive paclitaxel-SS-berberine conjugates can upregulate ROS levels in cancer cells, arrest cells in the G2/M phase, induce cancer cell apoptosis, and inhibit tumor growth [ 237 ]. Berberine could suppress bladder cancer (BIU-87 and T24) cells in a dose- and time-dependent manner. It can promote cell cycle arrest at G0/G1 site, and induce cell apoptosis in a dose-dependent manner [ 231 ].

Recent studies have revealed that berberine can regulate cell cycle depending on the cancer type. In bladder cancer (T24 and 5637) cells, berberine inhibited cell proliferation and cell cycle progression by down-regulating the HER2/PI3K/AKT signaling pathway [ 238 ]. Berberine inhibits cyclin activity by regulating PI3K/AKT, MAPK, and Wnt signaling pathways at the colon prelesion stage, thereby slowing down the cell cycle progression of polyp or adenoma cells [ 239 ]. In addition, berberine affected the expression of several proteins important in tumor cell cycle progression, These proteins include Cyclin-D1, Cyclin-B1, Cdc25, CDK1, Epidermal Growth Factor (EGF), Raf/MEK/ERK, and Platelet-derived growth factor (PDGF), activated enhancer-binding protein-1 (AP-1), AP-2, and CD147 [ 240 ]. Thus, berberine could arrest the cell cycle at different stages, thereby inhibiting the growth and proliferation of cancer cells, and is a promising potential anti-cancer drug.

Berberine has demonstrated significant anti-invasive and anti-metastatic effects in various cancer types by modulating multiple signaling pathways. In glioma cells, berberine suppresses cell proliferation, migration, and invasion by inhibiting the TGF- β 1/SMAD2/3 signaling pathway [ 220 ]. Similarly, in osteosarcoma (MG-63 and U-2 OS) cells, berberine inhibits tumor cell migration and invasion by regulating the MMP/NM-23 and MAPK/ c-Jun N-terminal kinase (JNK) signaling pathways [ 241 ]. Advanced drug delivery systems have further enhanced the anti-metastatic potential of berberine. In a breast cancer xenograft model (MDA-MB-231), mitochondria-targeted nanomedicines co-assembled from berberine and doxorubicin effectively repairs mitochondrial protein defects (Mfn1/Drp1) and inhibits the activity of MMP-2 and MMP-9, resulting in significant suppression of tumor cell proliferation and lung metastasis [ 242 ]. Moreover, berberine can inhibit glioma cell migration and invasion by suppressing the TGF- β 1/COL11A1 activity and regulating the actin cytoskeleton arrangement [ 243 ]. The anti-metastatic effects of berberine are mediated through the regulation of multiple signaling cascades, including MAPK, PI3K-AKT, and NF- κ B pathways [ 205 , 220 , 229 , 231 , 238 , 241 , 244 , 245 ]. Therefore, berberine demonstrates remarkable anti-invasive and anti-metastatic properties by modulating multiple signaling pathways. It can effectively inhibit tumor cell migration and invasion by targeting MMPs, regulating cytoskeletal dynamics, and repairing mitochondrial protein defects. Furthermore, advanced delivery systems, such as mitochondria-targeted nanomedicines, further improve their therapeutic potential for combating cancer progression.

Synergistic effects of berberine with other drugs

Recent studies have highlighted the potential of combining berberine with conventional cancer therapies to enhance treatment efficacy and reduce side effects [ 246 ]. Berberine-loaded nanoparticles, such as chitosan/pectin nanoparticles, have shown enhanced cytotoxicity against gastric cancer cells by modulating epigenetic factors ( miR-185-5p and KLF7 ) [ 247 ]. Berberine, combined with cisplatin, has a synergistic anti-cancer effect on the MG-63 osteosarcoma cell line. It can significantly promote osteosarcoma cell death by the inhibition of the protein expression of MMP-2, Bcl-2, Cyclin D1, and CDK4, and up-regulating Bax expression [ 248 ]. Berberine is a regulator of the HMGB1- Toll-like receptor 4 (TLR4) axis and can inhibit breast cancer metastasis aggravated by chemotherapy. Doxorubicin and berberine can be assembled into nanomedicines without the help of additional carriers. This nanomedicine not only effectively inhibits tumor growth with fewer side effects, but also significantly inhibits lung metastasis by blocking the HMGB1-TLR4 axis [ 249 ]. Janus nanocarrier for doxorubicin and berberine (HA-MSN@DB) can be delivered to liver cancer cells via CD44 receptor-mediated targeting effect. Berberine significantly reduces adriamycin-triggered repopulation of liver cancer cells in vitro and in vivo by inhibiting the Caspase-3-iPLA2-COX-2 pathway. Thus HA-MSN@DB co-delivery attenuates chemotherapy-exacerbated liver cancer recurrence [ 250 ]. Moreover, berberine has also been reported to improve the sensitivity of cancer cells to radiotherapy. In ovarian cancer (SK-OV-3) cells, berberine significantly increases the radiosensitizing effect, potentially improving the outcomes of radiotherapy [ 251 ]. Therefore, berberine demonstrates significant potential as an adjunct to conventional cancer therapies, including enhancing treatment efficacy, overcoming drug resistance, and reducing side effects. Berberine has been identified as a flexible and attractive candidate for enhancing the results of cancer treatment across a range of cancer types due to its capacity to work in concert with chemotherapeutics, targeted treatments, and radiation therapy, when combined with sophisticated delivery systems.

Application of multi-omics techniques to investigate the anti-cancer properties of berberine

The combination of omics technologies, such as transcriptomics, proteomics, metabolomics, and multi-omics methods, could greatly improve the understanding of multifaceted activity of berberine [ 252 ]. It may aid in the development of berberine-based treatments for various disorders.

For transcriptomics, high-throughput RNA sequencing is useful for determining the effect of berberine on gene expression patterns. Berberine has been demonstrated to change the expression of critical regulatory genes in the liver. It can result in hypolipidemic consequences. This modulation includes the activation of genes related to lipid catabolism and the downregulation of lipid synthesis-associated genes. It could lead to a lower risk of metabolic diseases. Furthermore, transcriptome investigations have demonstrated that berberine modulates the expression of genes associated with inflammation and glucose homeostasis. It highlights its therapeutic potential in metabolic illnesses [ 253 ]. For the proteomics, mass spectrometry-based proteomics has been critical in the determination of the protein targets and signaling cascades impacted by berberine treatment. Berberine can regulate the expression of proteins involved in mitochondrial activity and oxidative stress in colon cancer cells. Berberine has been shown to increase mitochondrial respiration and energy generation while decreasing oxidative stress and apoptosis. These proteome alterations aid in promoting cell death and inhibiting cancer cell proliferation. It may highlight berberine's potential as an anti-cancer medication [ 254 ]. For metabolomics, metabolomic profiling has shed information on the metabolic changes caused by Berberine treatment. Significant variations in bile acid composition have been detected. It suggests that berberine plays a role in modulating gut flora and metabolic health. Berberine affects the intestinal environment via changing bile acid synthesis and composition, promoting the growth of beneficial bacteria communities. This alteration of the gut microbiota is related with improved metabolic parameters, such as increased insulin sensitivity and lower inflammation, highlighting the relevance of the gut-liver axis in the therapeutic effects of berberine [ 255 ]. For the lipidomic, lipidomic investigations have shown that berberine changes lipid profiles. It contributes to the therapeutic benefits in metabolic diseases. Berberine affects cellular membrane composition and function by regulating the amounts of various lipid species such as cholesterol esters, phospholipids, and sphingolipids. These alterations can have an impact on signaling pathways related to lipid metabolism, inflammation, and insulin sensitivity, potentially improving disorders including hyperlipidemia and nonalcoholic fatty liver disease. Furthermore, lipidomic analysis has discovered lipid biomarkers that can be regarded as indications of berberine efficacy. It can help customize personalized treatment regimens [ 256 ]. For epigenomics, according to research, berberine effects epigenetic alterations such as DNA methylation and histone acetylation. It can influence gene expression patterns linked to cancer progression. Berberine can regulate the shape of chromatin and the accessibility of transcriptional apparatus to certain genes by regulating the activation of enzymes involved in various epigenetic pathways. It can inhibit cancer cell proliferation and spread. These findings indicate that berberine may function as an epigenetic modulator with potential uses in cancer therapy. According to research, berberine can affect epigenetic alterations such as DNA methylation and histone acetylation. It can influence gene expression patterns for cancer progression. Berberine can change chromatin structure via altering the activity of enzymes in these epigenetic processes [ 257 ]. For pharmacogenomics, scientists identified genetic variants that can regulate berberine metabolism, transport, and target interactions. This information allows for adjusting berberine dose regimens and the selection of appropriate patient demographics. It may improve therapeutic outcomes while reducing the likelihood of treatment failure [ 258 ]. For glycomics, scientists have provided insights into the role of berberine in modulating immune responses and inflammation. By altering the glycosylation patterns of immune signaling-related proteins, berberine can influence the recognition and response of immune cells to pathogens and damaged tissues. This modulation of glycan structures could affect processes such as cell adhesion, migration, and cytokine production. It can contribute to the anti-inflammatory and immunomodulatory effects of berberine [ 259 ]. For the toxicogenomic, assessments of gene expression alterations associated with toxicity could contribute to a better knowledge of the safety of berberine. Toxicogenomic studies can predict probable side effects and determine safety dose ranges by assessing the expression of genes involved in detoxification, oxidative stress response, and apoptosis. For chemogenomic techniques, which combine chemical and genomic data, can predict interactions between berberine and other proteins. It can explain its mode of action. For example, research has found that berberine interacts with enzymes involved in lipid metabolism and inflammatory processes. It explains the molecular foundation for its therapeutic benefits. Such information is crucial for the rational creation of berberine compounds with increased efficacy and fewer adverse effects [ 260 ]. Therefore, these integrative Omics-related approaches have not only advanced our understanding of berberine's therapeutic benefits, but also paved the path for personalized medicine tactics and the creation of innovative therapeutic agents.

Overall, berberine exemplifies how a single phytochemical can orchestrate complex anti-cancer effects, extending from reprogramming the tumor microenvironment and reversing multidrug resistance to reshaping metabolic and epigenetic landscapes. Future directions lie in harnessing multi-omics insights and advanced delivery platforms to optimize berberine’s translational potential, aiming to integrate it effectively into personalized cancer therapies. However, it is easy to produce false positive data due to the overlap between the emission wavelengths of berberine and those of most experimental fluorescent probes, so this requires special attention from researchers during future studies on berberine.

Curcumin

Curcumin, a phenolic compound extracted from Curcumae longae rhizoma (Jianghuang in Chinese) and Curcumae rhizoma (Ezhu in Chinese) [ 261 , 262 ], demonstrates a broad array of pharmacological activities. These include anti-inflammatory, antioxidant, antibacterial, antiviral, and antidepressant qualities, as well as cardioprotective, hepatoprotective, and neuroprotective benefits [ 263 , 264 ]. Additionally, curcumin exhibits a wide range of anti-tumor properties, proving effective against various types of cancer, such as lung, breast, colon, bladder, head and neck, prostate, kidney, cervical, thyroid, pancreatic cancer cells, and even melanoma, non-Hodgkin lymphoma, and leukemia [ 265 , 266 ]. In silico studies show that curcumin, when combined with chemotherapy drugs, exhibit strong interactions with target proteins, with curcumin achieving the highest interaction scores with marker proteins, and curcumin derivatives fitting well in the active site of target proteins, suggesting their potential as effective anticancer agents for breast cancer [ 267 , 268 ]. It restrains cancer progression by modulating the host immunity, promoting autophagy and ferroptosis, eliciting apoptosis, and inhibiting invasion and metastasis. Curcumin affects cancer cells by modulating several immune mediators, including cytokines, ROS, and cyclooxygenase-2 (COX-2). It also contributes to diminishing the activity of oncogenic molecules, protein kinases, growth factors, and critical signaling pathways, including NF- κ B, JNK, and STAT3 [ 269 ]. Although curcumin holds promise as an anti-cancer agent, its practical application is hindered by its limited water solubility and stability in vitro environments as well as its low bioavailability in vivo studies [ 270 – 272 ]. To face these challenges, the use of nanocarriers to deliver curcumin to the targeted tissue is suggested as a promising solution in vivo experiment [ 273 – 276 ]. In clinical practices, combining conventional anti-tumor medications with adjuvant treatments has shown complementary and supplementary role that enhanced the safety and effectiveness while minimizing adverse effects of the applied therapeutic strategies, as evidenced by numerous clinical trials [ 277 – 279 ], namely on breast cancer ( NCT03980509 ), prostate cancer ( NCT03769766 ), cervical cancer ( NCT04294836 ) and advanced pancreatic cancer ( NCT00094445 ). The following section provides a concise summary of the intricate mechanisms and specific targets through which curcumin acts against various types of cancer.

Curcumin improves immunity

Curcumin exhibits promising immunomodulatory effects by interacting with a range of immune cell types (e.g., macrophages, DCs, MDSCs, NK cells, and T cells) in lung, breast, colon, liver, head and neck, ovarian, and tongue carcinoma [ 280 , 281 ]. Curcumin enhances the activities of NK cells, DC cells, and B cells, and increases the quantity of cytotoxic T cells to eliminate cancer cells [ 282 ]. It also stimulates the proliferation of T cells, restores CD8 + T cells function, and revitalizes the defective T cells to kill cancer cells in colon carcinoma (HCT 116 and SW620) and head and neck cancer cells [ 283 , 284 ]. Curcumin suppresses the development of liver cancer and lung cancer by decreasing MDSCs quantity in Hep G2 and Lewis lung cancer xenograft models, thereby reducing angiogenesis process [ 285 , 286 ]. Furthermore, curcumin inhibits colon cancer (HCT 116 and SW620) and oral squamous cell carcinoma (CAL 27) cells by shifting TAMs from a M2 phenotype to M1 phenotype [ 287 , 288 ]. In conclusion, curcumin improves immunological activity in cancer treatment or increases the number of immune cells, which strengthens innate immunity.

Cytokines play a complex role in tumor microenvironment, working as mediators of cancer progression and therapeutic agents [ 289 , 290 ]. Curcumin inhibits tumor growth by reducing the levels of pro-inflammatory cytokines (e.g., TNF- α , IL-8, IL-6, and IL-1) [ 291 – 293 ], also down-regulating the protein expressions of these cytokines [ 294 ]. Additionally, curcumin suppresses the secretion of pro-cancer cytokines including stromal cell-derived factor 1 (SDF-1) and TGF- β 1, which inhibits tongue fibroblasts from developing into squamous cell carcinoma [ 295 ].

Curcumin exerts immunomodulatory effects by modulating various immune checkpoints (PD-1, CTLA-4, and CD47, and PD-L2) facilitating the recognition and elimination of cancer cells by immune cells [ 283 ]. Curcumin enhances T lymphocyte activity to inhibit colon cancer (HCT 116 and SW620) and head and neck carcinomas (SNU1041 and SCC-15) cell growth by down-regulating PD-L1 protein expression [ 296 , 297 ]. It also lowers CTLA-4 protein expression in CD4 + CD25 + Tregs, thereby enhancing the effectiveness of cancer immunotherapy [ 298 ].

Curcumin's impact on immunological responses is commonly evaluated using in vitro and in vivo assays in the above cases. Nevertheless, enhancing the bioavailability and drug delivery of curcumin continues to be a crucial matter that needs to be resolved prior to its practical implementation.

Curcumin reverses multidrug resistance

Curcumin could reverse multidrug resistance in cancer cells by inhibiting the function or expression of proteins such as P-gp, BCRP, multidrug resistance-related protein (MRP), and EGFR. This action helps counter resistance to first-line molecular drugs (Doxorubicin, Oxaliplatin, Paclitaxel, 5-Fluorouracil, and Cisplatin), or monoclonal antibodies (Cetuximab, Gefitinib, and Erlotinib), and immunotherapy drugs (Pembrolizumab and Atezolizumab) in various cancers including lung, colon, liver, breast, ovarian, myeloid leukemia, and osteosarcoma [ 299 – 302 ].

Specifically, curcumin sensitizes resistant cells of the lung (A549/Cisplatin), colon (SW620/DOX) and myeloid leukemia (K-562/DOX) to Doxorubicin and Cisplatin through inhibiting the transport function and protein expression of P-gp [ 303 – 305 ]. By preventing the accumulation of anti-cancer drugs within the cell, P-gp promotes resistance by preventing their cytotoxic or apoptotic effects. Its capacity to promote ATP-dependent drug translocation across the plasma membrane against significant concentration gradients allows it to accomplish this. Thus, P-gp inhibition would promote the influx of anti-cancer drugs inside the cell and result in cell cytotoxicity. Alternatively, the addition of a P-gp substrate in conjunction with the anti-cancer drug may have a comparable impact by competing for the transport pathway [ 306 ]. Furthermore, curcumin augments the effectiveness of Doxorubicin and Paclitaxel in overcoming MDR in lung cancer (A549), ovarian cancer (SK-OV-3), and colon cancer (HCT-8) cells by inhibiting both the protein function and expression of P-gp [ 307 , 308 ]. Besides, curcumin conjugated with anti-P-gp antibody significantly improve the capability of targeting P-gp protein, thereby overcoming MDR in cervical cancer (KB-V1/DOX) cells [ 309 ].

In addition, curcumin also suppresses MRP in Oxaliplatin (L-OHP) resistance pancreatic cancer (PANC-1 and MIA PaCa-2) cells through its impacts on miR-409-3p , its curcumin-related mode of action increases L-OHP sensitivity and regulates the expression of ERCC1. This approach increases the drug's sensitivity by decreasing the colon cancer cells' release of L-OHP and colon cancer (HCT 116) cells and inhibits BCRP in mice model. BCRP is an ATP-binding cassette (ABC) transporter that actively extrudes medication into the intestinal lumen, hence decreasing the drug's oral bioavailability. Curcumin boosted Sulphasalazine's systemic exposure in a dose-dependent way [ 310 – 312 ].

Growth of human malignancies is commonly connected with abnormal cellular communication by inappropriate activation of receptor tyrosine kinases (RTK) following mutation, overexpression or ectopic ligand synthesis. RTK, including human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), and EGFR, can be overexpressed or upregulated in cancer cells. This can lead to various effects, including altered cell cycle regulation, increased cell proliferation, blocked apoptosis, increased motility and invasive capacity, metastasis-associated growth, and angiogenesis promotion [ 313 ].

Gefitinib and Erlotinib are oral tyrosine kinase inhibitors (TKIs) that are particularly effective in patients with specific mutations in the EGFR gene. Curcumin significantly augments the suppressive efficacy of gefitinib on H157, H1299, IEC-18, and NCI-H1975 cancer cells by facilitating the degradation of EGFR receptor [ 314 , 315 ]. Curcumin can be used as an EGFR-TKI sensitizer to treat NSCLC with wild-type EGFR and a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation.

Furthermore, curcumin reduces EGFR protein expression in Erlotinib-resistant NSCLC (H1650) cells, hence enhancing the efficiency of Erlotinib, the recommended drug to combat lung cancer [ 299 , 316 ]. The low response rate of lenvatinib, which is mostly caused by resistance development, limits its practical utility in treating patients with advanced liver cancer, even though it is the recommended initial treatment for this condition. Significant EGFR activation was seen in lenvatinib-resistant cell lines, and a genome-wide transcriptome profiling investigation linked lenvatinib resistance to the PI3K-AKT pathway. The EGFR-PI3K-AKT pathway's gene and protein expression were significantly inhibited by the combination therapy of curcumin and Lenvatinib. So, curcumin is shown to overcome Lenvatinib resistance and strengthens the anti-liver cancer efficacy in Huh-7 and PLC cells [ 317 ].

Besides, curcumin can enhance the therapeutic effect of pembrolizumab and atezolizumab by reversing the drug resistance [ 318 ]. Combining curcumin with an anti-PD-1 monoclonal antibody enhances the therapy efficacy in melanoma (B16-F10) and colon cancer (MC38) xenograft models [ 300 , 319 ]. The findings indicate that curcumin has the capacity to regulate the function and expression of these transportation proteins, hence playing a key role in counteracting MDR of cancer cells.

Curcumin suppresses cancer growth by regulating the processes of autophagy and ferroptosis

Autophagy and ferroptosis are two different forms of cell death that have attracted considerable attention in the realm of cancer treatment. Growing evidence shows that curcumin induces autophagy and ferroptosis in lung, liver, colon, breast, cervical, and renal cell carcinoma, which lead to cell death and tumor growth inhibition [ 320 , 321 ].

Autophagy, a key form of cancer cell death, involves the breakdown and recycling of the cell's internal components. Multiple studies have shown that curcumin either induces or inhibits autophagy in a variety of in vitro or in vivo settings. Autophagy is frequently triggered by curcumin and its derivatives; However, this depends on the cellular environment and the stimulus. Furthermore, certain research has connected curcumin's potential to its iron-chelating properties. Curcumin has also been demonstrated to protect renal function by reducing ROS, reduce cancer by inhibiting rather than activating autophagy (an effect that may be mediated by the stimulation of miR-143 ), and lessen hypoxia/reoxygenation injury by controlling the activity of certain proteins [ 322 ].

Curcumin suppresses renal cell carcinoma (ACHN) and cervical cancer (SiHa) cells through the up-regulation of autophagy-related proteins, including p62, LC3B and Beclin-1 [ 323 , 324 ]. Moreover, curcumin diminishes cancer stemness in triple negative breast cancer (MCF-7 and MDA-MB-231) cells by up-regulating gene and protein expression of ATG5 and ATG2B [ 325 ]. Additionally, curcumin causes cytotoxicity in thyroid and ovarian cancers [ 326 , 327 ]. Furthermore, curcumin suppresses autophagy flux in breast cancer (MCF-7) and glioblastoma (A172 and U-87 MG) cells by decreasing the proportion of LC3-II/LC3-I and up-regulating p62 protein expression [ 328 , 329 ].

Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation. Curcumin can regulate the ferroptosis-related gene (e.g., MYC , IL-1β , EZH2 , SLCA5 , and CAV1 ) expression to inhibit colon cancer (SW480) cell progression [ 330 , 331 ]. Moreover, curcumin down-regulates the protein expression of GPX4 and Solute carrier family 7 member 11 (SLC7A11) to induce ferroptosis in colon cancer (HCT-8) and follicular thyroid cancer (FTC-133 and FTC-238) cells [ 332 , 333 ]. Additionally, curcumin suppresses tumor growth in osteosarcoma (Saos-2 and U-2 OS) and breast cancer (MCF-7 and MDA-MB-453) cells by producing malondialdehyde (MDA), elevating ROS levels, and enhancing Fe 2+ accumulation within cells [ 334 ]. Furthermore, curcumin decreases the expression of the NCOA4, FTH1 , and p53 genes, which causes ferroptosis in clear cell renal cell carcinoma (A-498-DR and 786-O-DR) cells [ 335 ]. Through the promotion of lipid peroxidation, disruption of iron homeostasis, and inhibition of antioxidant defenses, curcumin pushes cancer cells towards ferroptosis. The impact of curcumin on ferroptosis and autophagy offers substantial potential for improving cancer therapy approaches.

Curcumin suppresses cancer progression via classical modalities

In the field of cancer research, the conventional exploration of anti-cancer strategies has primarily centered around studying cellular processes involved in cell cycle, apoptosis, and metastasis. In this regard, curcumin has been found to induce cell cycle arrest in G0/G1, S, and G2/M phases in various cancer types [ 336 ]. For example, curcumin treatment induces cell cycle arrest at the G0/G1 phase in liver cancer (SK-HEP-1 and Hep G2) and breast cancer (MCF-7) cells [ 337 , 338 ]. In addition, curcumin treatment leads to cell cycle arrest at the S or G2/M phase in colon cancer (MC38 and HCT 116) cells, accompanied by a reduction in the protein expression of cell cycle-related markers (e.g., cyclin A2, cyclin E1, CDK2, and p21) [ 339 , 340 ].

Curcumin reduces Cyclin D1 protein expression, inhibiting cell cycle, particularly at the G0/G1 phase, in colon, breast, and prostate cancers. Additionally, curcumin enhances p27 and p21 protein expression, thereby obstructing cell cycle advancement at the G0/G1 and S phases. Notably, curcumin elicits cell cycle arrest in several solid malignancies, including lung, colon, and neuroblastoma, predominantly affecting the G2/M phase [ 341 – 343 ]. Conversely, hematological cancers, including lymphoma and leukemia, often demonstrate cell cycle arrest at the G0/G1 phase [ 344 – 346 ]. Curcumin causes cell cycle arrest at the G2/M phase in both estrogen receptor (ER)-negative breast cancer (MDA-MB-231 and SKBR3) and (ER)-positive breast cancer (T-47D and MCF-7) cells [ 347 – 350 ]. Furthermore, HER-2 positive breast cancer (SKBR3 and 435eB) undergoes cell cycle arrest in the G0/G1 phase [ 351 ], while HER-2 negative breast cancer (MCF-7) cells mainly undergo cell cycle arrest at the S phase [ 352 ]. In addition, curcumin triggers cell cycle arrest at G0/G1 and S phases in triple negative breast cancer (BT-549 and MDA-MB-231) cells [ 353 – 355 ].

Curcumin triggers cell apoptosis in lung, colon, liver, cervical, and pancreatic cancers by up-regulating pro-apoptotic protein expression (Bax and Bad) or by inhibiting anti-apoptotic proteins (Bcl-xL and Bcl-2), as well as activating Caspase pathway [ 340 , 356 – 359 ]. Specifically, it induces apoptosis in colon cancer (HCT 116) and lung cancer (A549) cells by activating apoptotic proteins, notably PARP, Caspase-3, and Caspase-8 [ 357 , 360 ]. Furthermore, it reduces the protein expression of Bcl-2 and increases that of Bax, triggering apoptosis in cervical cancer (Ca Ski and Hela) and pancreatic cancer (BxPC-3) cells [ 356 , 361 ].

The main Caspases implicated in cancer cell death through apoptosis include Caspase-8, Caspase-9, and the executioner Caspases, specifically Caspase-3 and Caspase-7. Curcumin activates Caspase-3 in several cancer types, resulting in the breakdown of cellular substrates and the successful initiation of programmed cell death (apoptosis). Caspase-8 is triggered by death receptors in the extrinsic pathway, while Caspase-9 is activated as a result of mitochondrial damage in the intrinsic pathway. Hence, curcumin suppresses cancer progression by inducing cell cycle arrest at various phases and promoting apoptosis through the modulation of key regulatory proteins, such as cyclins, CDKs, Bax, and Caspases. As for lung, liver, colon, breast, ovary, and nasopharyngeal tumors, curcumin inhibits migration and invasion [ 362 – 368 ]. It decreases the metastasis-related proteins (Vimentin, MMP-9, and E-cadherin) in breast cancer (MDA-MB-231) and lung cancer (A549) cells [ 362 , 363 ]. These results suggest that curcumin demonstrates anti-tumor properties through the regulation of the cell cycle and the modulation of proteins associated with apoptosis and metastasis, hence effectively impeding cancer progression.

Curcumin combined with other medications for cancer treatment

Curcumin has shown great potential for synergistic effects, reversing drug resistance, and enhancing sensitivity when combined with chemotherapeutic agents. In recent years, there has been an increasing interest in exploring this promising immunotherapy approach [ 369 ]. Studies have demonstrated that curcumin enhances the activity of PD-1/PD-L1 antibodies in murine colon cancer (MC38 and CT26) and liver cancer (Hep3B) cells by effectively preventing immune evasion [ 370 , 371 ]. Growing evidence supports the potential effectiveness of curcumin combined with various chemotherapeutic agents, including Lenvatinib, Doxorubicin, Rapamycin, Paclitaxel, and Cisplatin, in treating diverse cancers such as breast, liver, colon, oral, and osteosarcoma [ 317 , 372 – 377 ]. Besides, a synergistic approach utilizing curcumin and doxorubicin demonstrates enhanced anti-tumor efficacy against colon cancer (CT26), breast cancer (MCF-7), osteosarcoma (K-7), and head and neck cancer (HSC-3) cells [ 378 – 381 ] . A phase II clinical trial ( NCT01490996 ) has shown that daily Folinic acid/5-fluorouracil/Oxaliplatin chemotherapy, when used alongside oral curcumin treatment, is safe and tolerable in patients with metastatic colon cancer [ 382 ]. Additionally, coadministration of supplemental curcumin with other first-line chemotherapy drugs (Avastin/FOLFIRI/Paclitaxel/Bioperine) demonstrates efficacy in treatment of breast cancer ( NCT00852332 ), cervical cancer ( NCT05947513 ), and myeloma ( NCT00113841 ). The combination of Doxorubicin (0.4 mg/mL) and curcumin (5 µM) shows a higher additive impact by lowering the growth of Hodgkin lymphoma (L-540) cells by 79%. According to the pharmacokinetic analysis, curcumin (5 mg/kg) may also improve Doxorubicin (5 mg/kg) absorption and reduce drug efflux in vivo [ 383 , 384 ]. For metastatic and advanced bladder cancer, Cisplatin-based combination therapy has become the accepted standard of care. In comparison to curcumin or Cisplatin alone, co-treatment with curcumin (10 µM) and cisplatin (10 µM) has demonstrated a strong synergistic effect by up-regulating ERK1/2 phosphorylation and activating Caspase-3 in bladder cancer cell lines [ 385 ]. It has been demonstrated that Celecoxib (selective COX-2 inhibitor) with curcumin together inhibits cancer cell progression in vitro more than Celecoxib solely. Curcumin (10–15 µmol/L) andCelecoxib (5 µmol/L) at physiological dosages showed a synergistic inhibitory effect against human colon cancer (HT-29) cells [ 386 ]. In both pre-clinical and clinical trials, these findings suggest that curcumin has substantial synergistic effects in inhibiting multiple types of cancer.

Curcumin exerts its anti-cancer effects via regulating gut microbiota

The gut microbiota is crucial in the development and progression of various cancers including colon, liver, cervical cancers, and myeloid leukemia [ 387 , 388 ]. Curcumin increases the abundance of beneficial bacteria like Bifidobacteria and Lactobacillus . Moreover, curcumin strengthens the gut barrier function, preventing the leakage of harmful substances that can induce systemic inflammation, thereafter, causing apoptosis in colon cancer (HT-29 and HCT 116) cells [ 389 , 390 ]. In addition, curcumin sensitizes liver cancer (H22) cells to 5-fluorouracil cytotoxic effects by reducing the abundance of harmful bacteria ( Helicobacter and Campylobacteria) [ 274 ]. Clinical research has been undertaken to investigate the physiological effects of curcumin on the microbiota of children with colon cancer and acute lymphoblastic leukemia ( NCT05472753 and NCT05045443 ). Overall, the way curcumin interacts with the gut microbiota offers a potentially effective way to treat cancer. By modulating microbial composition, enhancing beneficial metabolites, and improving immune function, curcumin contributes to cancer prevention and treatment.

Application of multi-omics techniques to investigate the anti-cancer properties of curcumin

Omics technologies encompass a broad range of fields including genomics, proteomics, metabolomics, and transcriptomics, each offering insights into the molecular and cellular processes of organisms. In cancer research, these technologies are invaluable because they provide comprehensive data about the genetic mutations, protein dysregulations, and metabolic changes associated with cancer [ 391 – 394 ]. Curcumin inhibits tumor growth in 4T1 xenograft model by regulating the breast cancer metabolism of amino sugars and nucleotide sugars [ 395 ]. Moreover, curcumin exerts its anti-lung cancer actions on A549 cells by regulating 25 differential metabolites that influence the fatty acid metabolism, sphingolipid metabolism, and glycerophospholipid catabolism in cancer cells [ 396 ]. Furthermore, curcumin selectively alters miRNA and mRNA expression, inducing apoptosis in ovarian cancer (A2780 and PA1) and breast cancer (MCF-7 and MDA-MB-231) cells, as demonstrated through mRNA and miRNA library sequencing [ 397 , 398 ]. Furthermore, curcumin triggers cell death in pancreatic (BxPC-3) and breast cancer (MDA-MB-231) cells, disrupting 227 and 453 proteins, respectively, as identified through proteomics [ 356 , 399 ]. Overall, omics technologies provide a holistic view of the cellular changes induced by curcumin, highlighting its potential as a versatile and effective anti-cancer agent.

Curcumin derivatives inhibit cancer progression

Derivatives such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC), and curcumin difluorinated (CDF) are fascinating advancements that expand curcumin's potential in fighting lung, colon, ovarian, cervical, and bladder cancers [ 400 – 402 ]. DMC induces apoptosis in lung cancer (A549) and bladder cancer (RT4 and TCCSUP) cells by activating Caspase-3 and Caspase-9 activity, and inhibiting the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) [ 402 , 403 ]. In addition, BDMC suppresses breast cancer (BT-549, MDA-MB-231, and MCF-7) progression through down-regulating cancer metastasis-related proteins (MMP-9 and TWIST1) and inducing pro-apoptotic proteins (p53) expression [ 404 , 405 ]. Besides, a clinical trial ( NCT06063486 ) has been performed to assess the efficacy of DMC and BDMC in reducing tumor markers and improving patient survival rates following treatment therapy. In summary, curcumin derivatives have the potential to both improve curcumin's overall efficacy and rectify its disadvantages.

Investigating curcumin anti-cancer effects through drug delivery system

The therapeutic efficacy of curcumin, however, is restricted by its poor solubility, low absorption from the gut, rapid metabolism, and systemic elimination. To overcome these challenges, researchers have been exploring various drug delivery systems such as nanoparticle encapsulation, liposomes, polymeric micelles, dendrimers, hydrogels that can enhance curcumin's bioavailability and therapeutic efficacy [ 406 – 413 ]. Nanoparticle-based curcumin drug delivery systems (DDS) enhance apoptosis and inhibit cell migration in breast cancer (MDA-MB-231) and lung cancer (A549) cells [ 413 , 414 ]. Moreover, curcumin-encapsulated micelles induce cancer cell apoptosis, initiate a halt in the cell cycle, and enhance cellular uptake of curcumin in gastric cancer (BGC-823 and SGC-7901), colon cancer (HT-29 and HCT 116), breast cancer (MCF-7), and glioblastoma multiforme (GL261) cells [ 407 , 412 , 415 , 416 ]. In addition, nanogel loaded with curcumin such as AuNP@Ng/Cur, hyaluronic acid-grafted poly(N-isopropylacrylamide), and PVAS@PEG nanogels shows better targeting and low toxicity in breast cancer (MDA-MB-231) and melanoma (B16-F10) cells [ 417 – 419 ]. Besides, when compared to free curcumin, curcumin-loaded liposomes exhibit enhanced cytotoxicity to cancer cells in liver cancer (H22 and Hep G2) and breast cancer (SKBR3 and MCF-7) cells [ 420 , 421 ]. Taking together, these innovative carrier materials not only address the limitations associated with curcumin's natural properties but also enhance its targeting and intake into cancer cells.

Exosomes released by numerous types of cells and contain a vast spectrum of bioactive components including proteins, lipids, and nucleic acids. Exosomes can deliver their payload through direct cell-to-cell contact or without it. Exosomes have garnered significant interest for medication delivery in clinical settings due to their ability to operate as intracellular communication vehicles, transferring content to targeted destination [ 422 ]. Since most exosomes are hydrophobic and lipid-enriched, they can be used to deliver therapeutic substances like curcumin. Curcumin's plasma concentration and bioavailability were both enhanced by the in vivo injection of curcumin via exosomes. When 100 mg/kg body weight curcumin is administered orally or intraperitoneally, a plasma concentration of 1,250 ng/ml is reached after 30 min (5–10 times greater than when curcumin is administered alone), and this concentration lasts for 12 h [ 423 ]. The solubility, stability, and bioavailability of curcumin are all increased when it is incorporated into exosomes [ 424 ]. Curcumin loaded exosomes (Exo-CUR) was administered orally to nude mice containing the cervical Ca Ski-tumor xenograft to assess its in vivo anti-cancer efficacy. Curcumin diet, exosomes by themselves, and PBS were used as controls. Exosomes demonstrated a slight (25–30%) reduction of tumor growth, whereas dietary curcumin had no impact. On the other hand, the cervical tumor xenograft growth was significantly inhibited by Exo-CUR (61%; p < 0.01). Rats given Exosomes or Exo-CUR did not exhibit any signs of gross or systemic toxicity [ 424 ]. Exo-CUR extracted from lung cancer (H1299) cells treated with curcumin (10 μM) produced a slowdown in proliferation, colony formation, migration, and invasion. By down-regulating DNMT1, curcumin via exosomes is able to upregulate TCF21 expression and function as a tumor suppressant [ 425 ]. Curcumin treatment of chronic myelogenous leukaemia (CML) cells resulted in a dose-dependent rise in phosphatase and tensin homolog (PTEN), the miR-2 1 target. Moreover, curcumin therapy reduces VEGF expression and releases AKT phosphorylation. Assays for colony formation show that curcumin had an impact on CML cells' ability to survive. Certain observations imply that exosomes may be involved in the cellular disposal of miRNAs. To determine whether curcumin led to a reduction in miR-21 in CML cells and its exosome packaging, authors examined the content of miR-21 in K-562 and LAMA-84 cells as well as exosomes following curcumin treatment. Additionally, authors demonstrated that adding curcumin to CML cells resulted in an increase in miR-196b cellular expression and a downregulation of Bcr-Abl expression [ 426 ]. Moreover, curcumin-encapsulated grapefruit exosomes can alleviate colitis and boost mouse survival. When curcumin-encapsulated grapefruit exosomes are administered to DSS-induced colitis-affected mice, colon tissue extracts showed lower levels of TNF- α , IL6, and IL-1 β in comparison to other groups, according to ELISA analysis [ 427 ].

In sum, curcumin can engage multiple anti-tumor pathways, spanning immunity, autophagy, ferroptosis, and classical cell cycle arrest. It underscores the broad therapeutic scope, yet its real-world impact depends on overcoming poor pharmacokinetics through innovative delivery strategies (nanoparticles and exosomes) and synergistic combinations. Emerging multi-omics insights reveal how curcumin fine-tunes cancer cell metabolism, immune checkpoints, and even microbial ecosystems, positioning it as a uniquely adaptable agent in the quest for personalized oncology solutions.

Emodin

Emodin is a naturally occurring anthraquinone found in the roots and barks of various plants, which is an active constituent in medicinal herbs, such as Rhei radix et rhizoma (Dahuang in Chinese) and Polygoni cuspidati rhizoma et radix (Huzhang in Chinese) [ 428 – 430 ]. Additionally, emodin is synthesized as a secondary metabolite by molds and lichens [ 431 , 432 ]. Emodin possesses a myriad of pharmacological effects including anti-oxidant, anti-inflammatory, anti-tumor, anti-ulcer, hepatoprotective, renal-protective, neuroprotective, antidiabetic, antibacterial, antiviral, muscle relaxant, immunosuppressive and antifibrotic activities, and therapeutic effects on hypertrophic scar [ 433 – 435 ]. Emodin also demonstrates a broad spectrum of anti-cancer characteristics, showing promise against a number of cancers, including melanoma, pancreatic, thyroid, nasopharyngeal, cervical, endometrial, gastric, prostate, lung, breast, colon, kidney, liver, ovarian, and leukemia [ 436 ]. The related molecular mechanisms corresponding to the anti-cancer activities of emodin are involved in the modulation of tumor immunity, induction of apoptosis, inhibition of cell proliferation, and induction of autophagy, necroptosis, ferroptosis and uncoupling, mitigation of drug resistance [ 437 ]. In addition, in silico methods are employed to predict the pharmacological properties of emodin based on its interaction with carbonic anhydrase IX, and these predictions are subsequently validated through in vitro experiments on the HCT 116 and HeLa cell lines [ 438 , 439 ]. In addition, zebrafish are utilized to assess the antiangiogenic effects of emodin, which effectively inhibited vascular development and tumor angiogenesis in vivo, highlighting its potential for cancer treatment [ 440 ]. To address the challenges of poor intestinal absorption, rapid elimination, and low bioavailability of emodin, and to enhance its cellular uptake and anti-cancer efficacy, various drug delivery systems have been employed to encapsulate emodin, resulting in improved antitumor efficacy against multiple cancer types [ 441 – 444 ]. The following section provides a concise summary of the intricate mechanisms and specific targets through which emodin acts against various types of cancer.

Emodin regulates tumor immunity

Emodin emerges as a promising anti-cancer agent through its multifaceted mechanisms that target neutrophils, macrophages [ 445 ]. Neutrophil extracellular traps (NETs) have emerged as key effectors in neutrophil responses to diverse stimuli, which play a pivotal role in cancer progression and associated thrombosis. This underscores the intricate interplay between neutrophils, hypercoagulation, and carcinogenesis [ 446 ]. Emodin exhibits a novel anti-cancer mechanism by suppressing N2 neutrophils, thereby mitigating hypercoagulation and preventing lung carcinogenesis. In the urethane-induced lung carcinogenic model, emodin reduces hypercoagulation and tumor lesions, accompanied by a decrease in N2 neutrophils and modulated cytokine profiles (IFN- γ , IL-12 up; IL-6, TNF- α , TGF- β 1 down). Immunohistochemical and network pharmacology data further supported multi-target effects of emodin on N2 neutrophils, inhibiting tumor growth and promoting lung health [ 445 ]. TAMs, an essential subset of immune cells infiltrated in the tumor microenvironment, is found affected EMT and cancer stem cell formation [ 447 ]. Furthermore, it inhibits EMT and cancer stem cell formation in breast cancer cells to halt metastatic recurrence by disrupting TGF- β 1-mediated interactions between TAMs and breast cancer cells [ 448 ]. Emodin exerts anti-tumor effects against liver cancer by modulating M2 macrophage polarization towards M1 phenotype via the miR-26a /TGF- β 1/AKT axis, thereby inhibiting cancer cell proliferation and invasion [ 449 ]. Furthermore, emodin reduces the population of M2-like protumorigenic macrophages within the tumor microenvironment. Moreover, emodin may act by antagonizing the P2X7 receptor, thereby decreasing the activation of M1 macrophages and potentially inhibiting their recruitment to the tumor microenvironment [ 450 ]. Emodin, targeting neutrophils and macrophages, exhibits anti-cancer potential by mitigating hypercoagulation and modulating cytokine profiles in lung cancer. It also disrupts the tumor-promoting loop between tumor cells and TAMs, inhibiting tumor growth, EMT, cancer stem cell formation, and metastatic recurrence in breast cancer. Emodin also has anticancer effects by lowering M2-like macrophage numbers and altering macrophage polarization.

Emodin suppresses cancer growth by regulating the processes of necroptosis, autophagy, ferroptosis and uncoupling

Emodin demonstrates anti-cancer activity against prostate, renal, glioma, liver, colon cancers, and melanoma by inducing necroptosis, autophagy, and ferroptosis through various signaling pathways [ 451 , 452 ]. Emodin significantly reduces viability in prostate cancer (PC-3 and DU 145) cells. Emodin activates the necroptosis pathway, enhancing MLKL and HSP90AA1 expression and activating the PGAM pathway, leading to mitochondrial fission and ROS generation [ 453 ]. Emodin can effectively kill renal cancer cells. It induces necroptosis via a ROS-mediated activation of the JNK signaling pathway and also inhibits glycolysis by down-regulating glucose transporter 1 (GLUT1) through ROS-mediated inactivation of the PI3K/AKT signaling pathway [ 451 ]. Emodin effectively inhibits glioma (U251) cell proliferation, inducing apoptosis and necroptosis via the TNF- α /RIP1/RIP3 signaling axis. Its ability to upregulate TNF- α , RIP1, RIP3, and MLKL both in vitro and in vivo suggests emodin as a potential anti-cancer agent targeting glioma through necroptosis [ 454 ]. Emodin inhibits liver cancer progression by modulating autophagy through the miR-371a-5p /PTEN axis, down-regulating miR-371a-5p and up-regulating PTEN, thereby enhancing autophagy markers LC3-II and reducing p62 [ 455 ]. Emodin-induced autophagy promoted Snail and β -catenin protein degradation, inhibiting EMT partly through the PI3K/AKT/mTOR and Wnt/ β -catenin pathways. Therefore, emodin plays a significant role in inhibiting liver cancer (HepG2) cell metastasis via the interplay between autophagy and EMT [ 456 ]. Emodin inhibits proliferation and induces ferroptosis in colon cancer (HT-29, RKO, HCT-15 and SW620) cells by inactivating the NF- κ B pathway and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Emodin decreases GSH content, xCT and GPX4 expression, increases ROS generation, MDA, and lipid peroxidation, effects reversed by ferroptosis inhibitors and autophagy inhibitors, iron chelator DFO, ferostatin-1, and NCOA4 silencing. Emodin is expected to be a promising candidate for anti-cancer therapy [ 452 ]. Emodin exerts antiproliferative effects on melanoma (B16-F10) cells by reducing ATP levels and functioning as a mitochondrial uncoupler [ 457 ]. Emodin stands out as a versatile and promising candidate for anticancer therapy due to its capacity to engage multiple cell death pathways and interfere with cancer cell metabolism and survival. The depth of its impact on cellular mechanisms such as necroptosis, autophagy, ferroptosis, and mitochondrial function underscores its potential in the clinical setting.

Emodin inhibits tumor recurrence, and cancer-related cachexia

Emodin halts nasopharyngeal carcinoma recurrence, and alleviates lung cancer-related cachexia symptoms, demonstrating potential as a chemopreventive and therapeutic agent in nasopharyngeal carcinoma and lung cancer [ 458 , 459 ]. Emodin inhibits SP1 protein expression, suggesting its role in suppressing Epstein-Barr virus (EBV) reactivation. Furthermore, emodin inhibits the tumorigenic properties induced by repeated EBV reactivation. Emodin administration also restrains tumor growth in mice induced by EBV activation, collectively supporting its potential as a chemopreventive agent against EBV reactivation and nasopharyngeal carcinoma recurrence [ 459 ]. Emodin inhibits transcription Factor 4 (TCF4)- Twist family bHLH transcription factor 1 (TWIST1) complex formation, thereby suppressing parathyroid hormone-like hormone (PTHLH) protein expression, which are implicated in lung cancer cachexia. In lung cancer (A549) tumor-bearing mice, emodin-containing extract alleviates cachexia symptoms by down-regulating fat browning-related genes and skeletal muscle atrophy, highlighting its potential as a therapeutic agent for lung cancer-related cachexia [ 458 ]. Emodin shows promise as a chemopreventive and therapeutic agent against cancer-related complications such as tumor recurrence and cachexia. Its ability to inhibit EBV reactivation and tumor growth in nasopharyngeal carcinoma, as well as alleviating cachexia symptoms in lung cancer, underscores its multifaceted therapeutic potential.

Emodin suppresses cancer progression via classical modalities

Emodin, a versatile natural compound, exerts its antitumor effects through multiple mechanisms, including cell cycle arrest, apoptosis induction, angiogenesis inhibition, migration, and invasion suppression and tumor metastasis inhibition in NSCLC, breast, ovarian, endometrial, liver, cervical, colon, endometrial cancers, as well as melanoma, and papillary thyroid carcinoma [ 448 , 460 ]. Emodin can suppress cell growth through inducing cell cycle arrest at G0/G1, S and G2/M stages, such as G0/G1 arrest in NSCLC cells via hyaluronan synthase 2 (HAS2)-mediated signaling [ 461 ], and S and G2/M phases arrest in liver cancer (Hep G2) cells [ 456 ]. This cell cycle inhibition is further supported by its ability to induce mitotic catastrophe and G2/M phase arrest in cervical cancer (HeLa) cells. It highlights its efficacy in disrupting cell division [ 462 ]. Furthermore, emodin promotes apoptosis through multiple pathways. It increases ROS levels, leading to DNA damage and apoptosis in NSCLC (NCI-H520, NCI-H460, and A549) cells [ 463 ]. In endometrial cancer (KLE) cells, emodin regulates MAPK and PI3K/AKT signaling to enhance ROS production and apoptosis [ 464 ]. Similarly, in liver cancer, emodin upregulates oxidative stress defense and tissue homeostasis [ 465 ]. Emodin exhibits pro-apoptotic effects in melanoma (B16-F10 and A375) cells by increasing the Bax/Bcl-2 ratio, and suppressing the Wnt/ β -catenin pathway [ 466 ]. Emodin effectively suppresses the viability and migration of B16-F10 cells and may induce apoptosis via the mitochondrial pathway or the death receptor-mediated pathway [ 467 ]. Moreover, emodin exhibits anti-cancer activity in breast, colon, and liver cancers by targeting various pathways and suppressing VEGF-related angiogenesis and tumorigenesis. In triple-negative breast cancer (MDA-MB-231 and 4T1) cells, emodin targets nuclear receptor corepressor 2 (NCOR2) to upregulate seryl-tRNA synthetase (SerRS), suppressing VEGFA transcription and angiogenesis [ 440 ]. In colon cancer (HCT 116) cells, emodin reduces VEGF secretion and VEGFR1/2 protein expression by down-regulating Acyl-CoA synthetase long chain family member 4 (ACSL4) [ 468 ], while in liver cancer, emodin inhibits tumorigenesis through concurrently suppressing the VEGFR2-AKT-ERK1/2 signaling pathway, and inhibiting the protein expression of SMAD2/4 by enhancing miR-34a level in Hep G2 cells [ 469 ].

In addition, emodin demonstrates anti-migratory, anti-invasive and anti-metastasis properties. In ovarian cancer (SK-OV-3, A2780 and PA1) cells, it hinders migration and invasion by inhibiting EMT and altering cadherin protein expression [ 470 ]. In melanoma (B16-F10 and A375) cells, emodin decreases MMP-2 and MMP-9 protein expression, suppressing migration and invasion [ 466 ]. Emodin downregulates proliferation, invasion markers in liver cancer in vivo [ 465 ]. Emodin inhibits tumor metastasis in breast cancer by disrupting TGF- β 1-mediated TAM-cancer cell interactions to halt EMT and stem cell formation [ 448 ], and modulating AKT/ERK signaling to attenuate metastatic potential in obesity/hyperlipidemia [ 471 ]. Furthermore, emodin modulates signaling pathways critical for tumor growth and progression. Emodin inhibits breast cancer (MCF-7) cell proliferation in a time- and dose-dependent manner. Elevated AhR and CYP1A1 protein expression post emodin treatment suggests the antitumor activity of emodin via AhR-CYP1A1 pathway activation [ 472 ]. In NSCLC (A549, H1650, H460, H1975, PC-9, H1299, and CCD-19Lu) cells, it inhibits KRAS mutant cell lines by reducing secretory phospholipase A2-IIa (sPLA2-IIa) and NF- κ B pathway activity, while inhibiting mTOR and AKT while activating AMPK [ 473 ]. Emodin inhibits endometrial cancer (KLE) cell proliferation by regulating MAPK and PI3K/AKT signaling pathways [ 464 ]. Emodin demonstrates efficacy in suppressing liver cancer (Hep G2 and Huh7) cell growth, metastasis, and CD44 + hepatoma cell proliferation [ 474 ]. In papillary thyroid carcinoma (TPC-1 and IHH4) cells, emodin downregulates NF- κ B and TLR4 signaling, inhibiting cell proliferation, invasion, and migration [ 475 ].

Emodin has the potential to be used as a photosensitizer in photodynamic therapy of skin cancer. Emodin mediates photodynamic therapy effectively and distinctly on skin cancer cells (SCC-25, MUG-Mel2) and normal keratinocyte (HaCaT) cells [ 476 ]. In melanoma (B16-F10 and A375) cells, its ability to decrease MMP-2 and MMP-9 protein expression and suppress the Wnt/ β -catenin pathway suggesting a therapeutic strategy for highly metastatic tumors [ 466 ].

Emodin inhibits breast cancer metastasis by reducing lipid synthesis through the downregulation of triglyceride synthesis-related genes, including Fas , glycerol-3-phosphate acyltransferase 1 ( Gpat1 ), and stearoyl-CoA desaturase 1 ( Scd1 ). Additionally, emodin attenuates the high metastatic potential to the liver in the context of obesity and hyperlipidemia through modulation of the AKT and ERK signaling pathways, involving interaction with CSNK2A1 in breast cancer [ 471 ].

Therefore, emodin demonstrates antitumor effects through mechanisms such as cell cycle arrest, apoptosis induction, and angiogenesis and metastasis inhibition. In a variety of cancer types, it alters the expression of biomarkers and targets different signaling pathways.

Emodin combined with other medications for cancer treatment

Emodin, when combined with various medications, demonstrates synergistic anti-cancer effects by enhancing apoptosis, inhibiting proliferation, migration, and invasion, and reversing drug resistance, and mitigating chemotherapy-induced testicular toxicity in breast, lung, colon, cervical, liver, pancreatic cancers, as well as chronic myeloid leukemia and multiple myeloma [ 477 , 478 ]. Emodin in combination with berberine significantly inhibits salt-inducible kinase 3 (SIK3) activity, reducing cell growth and inducing cell cycle arrest and apoptosis in breast cancer cells. Mechanistically, the combination treatment attenuates SIK3-potentiated mTOR-mediated aerobic glycolysis and suppresses AKT signaling, leading to G0/G1 phase cell cycle arrest and apoptosis in a SIK3-dependent manner. These findings suggest that the emodin-berberine combination may serve as a novel SIK3 inhibitor for the prevention and treatment of breast cancer (MDA-MB-231, BT-20, and AU565) cells [ 479 ]. Thymoquinone and emodin synergistically inhibit breast cancer (MCF-7) cell proliferation, enhancing cytotoxicity, and inducing apoptosis while curtailing migration and stemness [ 480 ]. Emodin synergistically enhanced the antiproliferative effects of paclitaxel in NSCLC (A549) cells, augmenting apoptosis through up-regulating the protein expression of Bax, Bcl-2, as well as activating the phosphorylation of AKT, and ERK, as well as activating Caspase-3. In vivo, emodin potentiated the antitumor effects of paclitaxel in A549 xenografts without significant side effects, suggesting a promising combinational strategy for NSCLC treatment [ 481 ]. Emodin inhibits proliferation and drug efflux, enhances Cisplatin (DDP)-induced apoptosis and DNA damage, and decreases P-gp protein expression in a dose-dependent manner in NSCLC (A549 and H460) cells. These findings suggest emodin as a potential adjuvant to enhance DDP sensitivity in NSCLC [ 482 ]. Meanwhile, emodin synergizes with DDP to enhance lung cancer A549/DDP cell apoptosis and impede migration/invasion, likely via inhibiting NF- κ B signaling and down-regulating drug resistance proteins (P-gp, MRP, and GST), thereby reversing DDP resistance and augmenting intracellular drug accumulation [ 483 ]. Emodin enhances anti-proliferation of 5-fluorouracil and inhibits invasion and migration of 5-fluorouracil-resistant colon cancer (SW480) cells. The combination induces apoptosis by regulating the protein expression of Bcl-2 and Bax, activating Caspase-3, and reversing 5-fluorouracil resistance through downregulation of the PI3K/AKT pathway. In vivo, emodin reverses 5-fluorouracil resistance in colon cancer xenografts, indicating its potential as a molecular therapy for 5-fluorouracil-resistant colon cancer (SW480/5-FU) cells [ 484 ]. In vivo, emodin and tetrahydropalmatine synergistically reduces colon cancer (HT-29) tumor size, increasing F4/80 expression, decreasing IL-6 and TGF- β levels, promoting tumor oxidation, and down-regulating p53 and STAT3 protein expression. These findings suggest a synergistic mechanism involving cytokine regulation and p53 pathway inhibition for the treatment of colon cancer [ 485 ]. The combination of emodin and vinblastine has been demonstrated to enhance the sensitivity of cervical cancer (HeLa) cells to the latter. This combination has been shown to potentiate the cytotoxic effect of vinblastine, disrupt mitosis and block cells in the G2/M phase. Furthermore, it has been shown to raise ROS production and oxidative stress, which causes edema and mitochondrial damage. Additionally, the combination of emodin and vincristine enhances cell apoptosis by activating Caspase-3 and Caspase-7, and decreasing Bcl-2 protein expression [ 486 ]. Meanwhile, emodin enhances the sensitivity of liver cancer (Hep G2) cells to DDP by inhibiting EMT [ 487 ]. Emodin inhibits cell activity across cell lines, enhancing apoptosis synergistically with gemcitabine in pancreatic cancer. Emodin potentiates the anti-cancer effects of EGFR inhibitor on pancreatic cancer (PANC-1 and BxPC-3) cells by inhibiting STAT3 signaling, promoting apoptosis. The combination of emodin and EGFR inhibitor synergistically inhibits cancer cell proliferation in vitro and in vivo, modulating STAT3 protein expression [ 488 ]. Emodin and berberine combination exhibits synergistic anti-tumor effects, inhibiting cell proliferation, clonogenicity, migration, and invasion in pancreatic ductal adenocarcinoma (BxPC-3 and MIA PaCa-2) cells. This synergism has significant anti-cancer effects on pancreatic ductal adenocarcinoma via targeting EGFR-signaling through Laminin subunit beta 3 (LAMB3) regulation [ 489 ].

Emodin and 3'‑azido‑3'‑deoxythymidine (AZT) exerts the synergistic antitumor effects on human chronic myeloid leukemia (K-562) cells. Emodin-AZT combination reduces toxicity, improving efficacy, and modulating growth, apoptosis, and Wnt/ β -catenin signaling via EGR1 [ 490 ]. Emodin suppresses imatinib resistance in chronic myeloid leukemia (K-562/ADM) cells via Bcr-Abl and STAT5 downregulation, alongside allosteric inhibition mechanisms [ 491 ]. Emodin significantly mitigates cyclophosphamide-induced testicular toxicity in rats by improving sperm function and reproductive hormones levels, reversing oxidative stress and inflammation, and increasing testicular antioxidant enzymes, demonstrating its potential to counteract chemotherapy-related testicular damage [ 492 ]. Emodin synergized with carfilzomib to reduce proliferation and viability in multiple myeloma cells, increasing ROS production and inducing apoptosis and autophagy pathways via activating Caspase-3 and PARP [ 493 ]. Emodin combined with telomerase inhibitor BIBR1532 synergistically enhances telomere dysfunction and inhibits 4T1 xenograft tumor growth, highlighting a potential strategy for cancer treatment [ 494 ]. The combination of emodin with various pharmacological agents holds significant promise in cancer therapy, offering synergistic effects that enhance apoptosis, overcome drug resistance, and improve therapeutic outcomes. By targeting multiple pathways involved in cancer cell proliferation, migration, and resistance mechanisms, emodin enhances the efficacy of conventional and targeted therapies.

Emodin derivatives inhibit cancer progression

Emodin derivatives, particularly aloe-emodin, demonstrate broad-spectrum anti-cancer activity against multiple tumor types. Emodin derivatives inhibit cancer cell proliferation, promotes apoptosis, and disrupts oncogenic signaling pathways in prostate, breast, lung, colon, melanoma, nasopharyngeal, pancreatic, and glioma cancers [ 495 , 496 ]. It achieves this through mechanisms such as oxidative stress induction, modulation of apoptotic proteins, inhibition of telomerase activity, and disruption of cell cycle progression. Moreover, β -Dihydroartemisinin-emodin and emodin-8-O-glucoside can inhibit anti-cancer potential in liver cancer, neuroblastoma, and glioblastoma [ 497 , 498 ], underscoring the therapeutic promise of emodin derivatives in cancer treatment.

Emodin and aloe-emodin share an isomeric relationship, with their sole distinction lying in the placement of a single hydroxyl group. Aloe-emodin demonstrates broad-spectrum anti-cancer activity against various tumor types, including prostate, breast, lung, colon, cervical cancer, melanoma, nasopharyngeal, liver, pancreatic cancers and glioblastoma [ 499 – 510 ]. In prostate cancer, aloe-emodin exhibits anti-cancer effects against DU 145 cells by inducing ROS-mediated oxidative stress, apoptosis, mitochondrial dysfunction, and inhibiting Wnt/ β -catenin signaling [ 500 ]. Similarly, in breast cancer (MCF-7 and MDA-MB-231) cells, aloe-emodin selectively inhibits proliferation and promotes apoptosis by modulating Bcl-2 protein levels through miR-15a / miR-16–1 upregulation [ 501 ], competitively inhibiting telomerase and stabilizing G-quadruplex structure, suppressing hTERT transcription in breast cancer (MDA-MB-453, MDA-MB-231, and MCF-7) cells through E2F1 upregulation and c-Myc downregulation, as well as promoter demethylation [ 502 ]. At the same time, aloe emodin can also inhibit the metastasis of breast cancer (MCF-7) cell [ 503 ]. Aloe-emodin reverses adriamycin (ADR) resistance in MCF-7/ADR cells by inhibiting P-gp efflux, altering energy metabolism, and inducing autophagy while enhancing apoptosis via DNA damage, ROS generation, and Caspase-3 activation [ 504 ]. Furthermore, aloe-emodin exhibits anti-cancer activity against NSCLC (A549 and NCI-H1299) through Caspase-dependent apoptosis, autophagy induction via MAPK activation and AKT/mTOR inhibition, and ROS-mediated autophagy-triggered apoptosis, demonstrating its potential as a therapeutic candidate and synergize with gemcitabine [ 505 ]. In colon cancer (HCT 116) cells, aloe-emodin inhibits cancer cell proliferation and induces apoptosis via the mitochondria-mediated pathway, involving Bax/Bcl-2 modulation, Caspase activation, and cytochrome C release [ 506 ]. Additionally, aloe-emodin potently inhibits melanoma (A375 and SK-MEL-28) growth and metastasis by enhancing apoptosis, inducing G2 arrest, and modulating Wnt/beta-catenin signaling [ 507 ]. Aloe-emodin inhibits nasopharyngeal carcinoma cell (5-8F and CNE1) proliferation, migration, and promotes apoptosis by regulating Dual specificity phosphatase 1 (DUSP1), blocking ERK-1/2, AKT, and p38-MAPK pathways, and stabilizing DUSP1 via ubiquitin–proteasome inhibition [ 508 ]. Aloe emodin exerts dose-dependent cytotoxicity in pancreatic carcinoma (MIA PaCa-2 and PANC-1) cells, inducing apoptosis and autophagy, arresting cell cycle, and disrupting mitochondrial membrane potential, thereby inhibiting cancer cell growth [ 509 ]. Lastly, in drug-resistant glioma, aloe-emodin enhances the anti-cancer effects of temozolomide (TMZ) in drug-resistant glioma (NULU and ZAR) cells by restoring drug sensitivity, inhibiting colony formation, and slowing migration, indicating the potential of aloe-emodin as a natural adjuvant in glioblastoma treatment [ 510 ].

β -Dihydroartemisinin-Emodin exhibits potent anti-cancer activity in liver cancer (Hep G2) cells by inhibiting proliferation, promoting apoptosis via cell cycle arrest and Caspase-mediated pathways, and inhibiting migration [ 498 ]. Emodin-8-O-glucoside inhibits viability and proliferation of neuroblastoma and glioblastoma cells (SK-N-AS, T98G, and C6) in a dose-dependent manner [ 497 ]. The therapeutic potential of these derivatives in the treatment of cancer is shown by the strong action of β -Dihydroartemisinin-Emodin in liver cancer and the inhibition of neuroblastoma and glioblastoma cell growth by Emodin-8-O-glucoside. Therefore, aloe-emodin’s ability to reverse drug resistance, inhibit metastasis, and enhance the effectiveness of other chemotherapeutic agents, such as gemcitabine and temozolomide, underscores its potential as a valuable adjuvant in cancer therapy. Their mechanisms of action, which include the induction of oxidative stress, modulation of apoptosis, inhibition of telomerase, disruption of cell cycle progression, and interference with oncogenic signaling pathways, make them attractive candidates for cancer treatment.

Application of multi-omics techniques to investigate the anti-cancer properties of emodin

Emodin significantly reduces the viability of lung cancer cells and triggers apoptosis. After treatment with emodin, the analysis of the transcriptome using RNA-seq reveals that 65 genes showed a significant change in expression in A549 and H1650 cells. In vitro qRT-PCR results confirm the up-regulation of 4 genes and the downregulation of 9 genes in A549 and H1650 cells. In vivo qRT-PCR results shows similar gene expression changes in tumor tissues compared to the control group: up-regulation of 3 genes; down-regulation of 6 genes [ 511 ].

Aloe emodin and emodin inhibit breast cancer metastasis by suppressing adhesion, invasion, and angiogenesis, and inducing anoikis in a co-culture model of MCF-7 and HUVEC cells. Metabolomics analysis identifies 27 and 13 biomarkers for aloe emodin and emodin, respectively, implicating pathways such as polyamine metabolism, the methionine cycle, the TCA cycle, purine metabolism, GSH metabolism, and aspartate synthesis. Quantitative analysis confirmed that the inhibitory effect of aloe emodin is better than that of emodin, suggesting distinct mechanisms for each compound against breast cancer metastasis [ 503 ]. Cell metabolomics is used to investigate emodin's toxicity and mechanism, revealing differences in 33 and 23 metabolites in Hep G2 cells extracts and media, respectively, affecting 8 pathways. The results demonstrate the potential of cell metabolomics in clarifying emodin's toxic effects, mechanisms, and biomarkers, aiding in the discovery of drug toxicity targets and signal network changes [ 512 ]. Therefore, omics approaches enhance understanding of emodin's antitumor effects. RNA-seq in lung cancer cells shows altered gene expression post-emodin treatment. The qRT-PCR confirms differential gene regulation both in vitro and in vivo.

Emodin exerts its anti-cancer effects through the drug delivery system

Emodin, when encapsulated in various drug delivery systems, demonstrating enhanced cancer cell killing efficiency, suppressed tumor cell metastasis, and improved antitumor efficacy. effectively improve bioavailability, cellular uptake, and anti-cancer mechanisms of emodin. These drug delivery systems include magnetic liposomal nanocomposites, targeted liposomes, polymer lipid hybrid nanoparticles, pH/ion-responsive hydrogels, EGF-modified micelles, hybrid membrane-coated nanoparticles, and Fe 3 O 4 -PEG-Cy7-coated formulations. These systems demonstrate enhanced antitumor efficacy against diverse types of cancer, such as breast cancer, lung cancer, ovarian cancer, melanoma, pancreatic cancer, and gastric cancer [ 441 – 444 , 513 – 517 ].

At low concentrations, the magnetic liposomal emodin nanocomposite containing ferromagnetic iron oxide nanocubes dramatically increases the effectiveness of killing MCF-7 cancer cells [ 441 ]. A targeted liposome is developed through the modification of arginine-8-glycine-aspartic acid (R 8 GD) to encapsulate emodin and daunorubicin separately. The combination of these R 8 GD modified liposomes demonstrated potent toxicity against highly invasive breast cancer (MDA-MB-435S) cells, effectively suppressing the formation of vasculogenic mimicry (VM) channels, and inhibiting tumor cell metastasis by down-regulating HIF-1 α , MMP-2, TGF- β 1 and VE-cad [ 442 ]. Emodin-loaded polymer lipid hybrid nanoparticles (E-PLNs) exhibited superior anti-cancer efficacy against breast cancer (MCF-7) cells by enhancing uptake, promoting early apoptosis via Bax/Bcl-2 pathway, and inhibiting tumor growth by over 60% in mice. The therapeutic effect of E-PLNs surpasses that of free emodin, highlighting their potential as an effective anti-breast cancer agent [ 514 ]. The γ -irradiated bovine albumin nanoparticle, functionalized with folic acid and carrying emodin, demonstrates enhanced activity against MCF-7 cancer cells and induced an immune response in macrophages [ 443 ].

Emodin encapsulated in micelles, surface-modified with EGF as a targeting ligand, and formulated in a compound preparation. EGF-modified emodin micelles are characterized for their physical and chemical properties, showing enhanced uptake and antiproliferative effects in ovarian cancer (SK-OV-3) cells. The compound formulation inhibits ovarian cancer cell invasion and metastasis by down-regulating the protein expression of HIF- α , MMP-2, MMP-9, and E-cadherin, demonstrating significantly in vivo pharmacodynamic effects. These findings suggest a novel strategy for ovarian cancer treatment using EGF-targeted paclitaxel and emodin micelles [ 516 ]. Emodin-encapsulated stearic acid-g-chitosan oligosaccharide (CSO-SA/EMO) enhances antitumor potential of emodin through micelle delivery. CSO-SA/EMO exhibits distinct physicochemical characteristics and efficient cellular uptake in gastric cancer (MGC803 and BGC823) cells, enabling passive enhanced permeability and retention (EPR) targeting in vivo. Compared to free emodin, CSO-SA/EMO significantly inhibits tumor growth, arrests cell cycle, and exhibits substantial antitumor activity in vivo [ 513 ]. Emodin-loaded, Cy7-functionalized, polyethylene glycol (PEG)-coated Fe 3 O 4 (Fe 3 O 4 -PEG-Cy7-Emodin) exhibits enhanced magnetic susceptibility, excellent biocompatibility, passive targeting to pancreatic cancer (BxPC-3 and hTERT-HPNE), capability for dual-modal FI/MR imaging, controlling drug loading and release, minimal side effects, and potent antitumor efficacy. These characteristic positions it as a promising drug delivery system for pancreatic cancer [ 444 ].

Hydrogels with different reactivity can enhance the targeting properties of emodin [ 515 , 518 ]. Emodin encapsulated in pH/ion responsive self-assembling peptide (RADA16-I) hydrogels demonstrates enhanced immunotherapeutic potential by significantly inhibiting lung cancer (Lewis) cell survival, increasing the uptake, promoting cell apoptosis and inducing cell cycle arrest at G2/M phase, and reducing migration, invasion, and clonogenicity, while mitigating toxicity to normal cells [ 515 ]. Emodin encapsulated with glycyrrhizin in hybrid membrane (erythrocyte and macrophage to form a hybrid membrane)-coated nanoparticles enhanced solubility and antitumor efficacy, achieving an IC 50 half that of free emodin. Photodynamic therapy using the hybrid membrane-derived nano-formulation enhanced ROS levels and promoted early death of B16 melanoma cells via the Bax/Bcl-2 pathway [ 517 ]. Therefore, emodin encapsulated in various nanocomposites, liposomes, and micelles significantly enhances cancer cell killing efficiency and exhibits potent anti-cancer activity. Targeted modifications improve uptake and efficacy, outperforming free emodin in inhibiting tumor growth and metastasis. Hydrogel encapsulation and hybrid membrane-coated nanoparticles further enhance targeting and solubility, with photodynamic therapy increasing ROS levels and inducing apoptosis.

In sum, emodin emerges as a multi-dimensional agent that aligns a range of cell death pathways (necroptosis, autophagy, and ferroptosis) with immune reprogramming to thwart tumor progression and metastasis. It tackles difficult challenges such as cancer recurrence and cachexia, reshapes the tumor microenvironment by modulating macrophages and neutrophils, and overcomes drug resistance via synergistic combinations with both conventional chemotherapeutics and molecularly targeted interventions. Through advanced delivery systems and omics-guided mechanistic insights, emodin exemplifies a sophisticated approach to cancer therapy that bridges robust biological activity with the promise of clinical translation.

Epigallocatechin gallate (EGCG)

Epigallocatechin gallate (EGCG) is a polyphenolic compound that is extracted from Camellia sinensis , widely consumed in China and also across the globe [ 519 ]. EGCG has been demonstrated to possess multiple therapeutic benefits. For instance, it exhibits cardioprotective, hepatoprotective, and neuroprotective effects, and is characterized by antioxidant, anti-inflammatory, antibacterial, antiviral, antidepressant properties [ 520 ]. Furthermore, it exhibits a broad spectrum of anti-cancer activities against various types of cancers, such as lung, breast, and colon cancers. It exerts its anti-tumor effects through multiple mechanisms, which include the modulation of tumor immunity, reversal of drug resistance, and the induction of apoptosis [ 521 ]. Several studies have investigated the combination of EGCG with conventional anti-cancer treatments. These investigations aim to optimize the safety and effectiveness of chemoradiotherapy regimens while simultaneously reducing the associated side effects [ 522 ].Additionally, in silico and in vitro studies have provided evidence that EGCG targets NF- κ B pathway, highlighting its potential as a therapeutic alternative for pancreatic cancer treatment by reducing cell growth, inducing apoptosis, and repressing NF- κ B target genes [ 523 ]. Besides, an ex vivo study has been conducted to develop high-performance microgel assembly bioinks using EGCG-modified hyaluronic acid and phenylboronic acid grafted hyaluronic acid. The developed bioinks facilitate the high-fidelity 3D bioprinting of complex structures, owing to their excellent rheological properties. They also hold potential applications in drug testing, particularly when using breast cancer organoids [ 524 ]. In clinical study, EGCG is utilized in the context of colon cancer ( NCT02891538 ), esophageal cancer ( NCT05039983 ), breast cancer ( NCT02580279 ), and lung cancer ( NCT02577393 ) to evaluate its supportive and chemo preventive effects in cancer patients. The following section provides a concise summary of the intricate mechanisms and specific targets through which EGCG acts against various types of cancer.

EGCG improves tumor immunity

EGCG has been shown to exert an impact on various immune cells, including neutrophils, macrophages, cytotoxic T-cell, and tumor-infiltrating lymphocytes (TILs), within the context of multiple cancer types such as colon, breast, bladder cancers, as well as melanoma, leukemia, and renal cell carcinoma [ 525 , 526 ]. For instance, EGCG can stimulate T cell and NK cell activity, enhancing the function of Tregs to maintain immune tolerance and prevent autoimmune reactions in melanoma and colon cancer [ 527 , 528 ]. Furthermore, when combined with the inhibitor fragment 1 (FRA), EGCG can directly target PD-L1 dimers exerting more effective anti-cancer immunity [ 529 , 530 ]. Notably, EGCG reduces the accumulation of MDSCs by inhibiting the secretion of cytokines such as inducible nitric oxide synthase (iNOS), Nox2, NF- κ B, and STAT3. It also blocks ECM-receptor interactions and upregulates critical genes including Cxcl3 , Met , Col8a1 , Oasl2 , and Mmp12 . As a result, this leads to an increase in the proportion of CD4 + and CD8 + T cells in tissue and tumor sites in mice bearing 4T1 mammary tumors [ 531 ]. Overall, EGCG exerts a multifaceted influence on tumor immunity. It enhances the activity of immune cells like T cells and NK cells, promote immune tolerance through the regulation of Tregs, and reduces the accumulation of MDSCs while up-regulating critical immune genes. This property underscores its potential as a potent immunomodulatory agent in cancer therapy.

EGCG reverses tumor drug resistance

EGCG has been shown to delay the onset of multidrug resistance and enhance the efficacy of anti-cancer therapies across multiple malignancies, such as lung, breast, leukemia, ovarian, head and neck, and skin cancers. It achieves this by altering P-gp, MRP, BCRP, and EGFR, which play crucial roles in oncological treatment [ 532 – 534 ]. Specifically, EC31 reverses drug resistance in breast cancer (LCC6/MDR), leukemia (P388/ADR and K-562/P-gp) and human oral epidermal cancer (KB-A1) cells by inhibiting P-gp-mediated drug efflux and restoring intracellular drug accumulation [ 535 , 536 ]. Furthermore, EGCG augments the effectiveness of doxorubicin and paclitaxel in overcoming MDR in NSCLC (H1975), human oral epidermal cancer (KB-A1), and lung cancer (H460/PT) cells by inhibiting both the protein function and expression of P-gp [ 537 – 539 ]. Moreover, EGCG modulates some signaling pathways (e.g., Hedgehog and AMPK/AKT/MAPK pathways) in human rhabdomyosarcoma cells and NSCLC to overcome drug resistance [ 534 , 540 , 541 ]. Pivotally, the assembled EGCG and daunorubicin nanocomplex-mediated disassembly enhances the treatment effect by synergistically reversing chemoresistance in leukemia (HL-60 and HL-60/MX2) and lung cancer (A549) cells [ 542 , 543 ]. Overall, EGCG represents a promising therapeutic agent for overcoming drug resistance in cancer treatment. Its ability to inhibit key drug efflux pumps, modulate resistance-related signaling pathways, and restore the effectiveness of standard chemotherapies highlights its potential as an adjuvant in cancer therapy.

EGCG suppresses cancer progression via classical modalities

EGCG has been shown to regulate the cell cycle in various cancer types, including breast, prostate, lung, and colon cancers [ 544 , 545 ]. Its primary mechanism of action involves inducing cell cycle arrest at different phases, thereby impeding cancer cell proliferation. Specifically, EGCG can trigger cell cycle arrest at the G2/M phase, preventing the transition to the S phase. Additionally, it is capable of inducing G2/M phase arrest, which disrupts mitotic progression and ultimately leads to apoptosis. For instance, in liver cancer cells (Hep G2 and Huh7), EGCG induces G2/M phase arrest by up-regulating the protein expression of p21 waf1/Cip1 and down-regulating cell cycle-related genes such as CDC25A , CCNB , CCNB2 , and CCND [ 546 , 547 ]. Studies have provided evidence that EGCG can block DNA replication in prostate cancer (DU 145) and colon cancer (HCT 116) cells through the targeting of multiple cell cycle regulators [ 548 – 552 ]. Moreover, EGCG induces G0/G1 phase arrest in oral squamous cell carcinoma (HSC-3) cells [ 553 ]. In gastric carcinoma (CRL-1739 and TSGH 9201) cells, EGCG induces G2/M arrest by activating the CDK1/cyclin B1 complex [ 554 ]. Notably, EGCG modulates WEE1 kinase, which is overexpressed in numerous cancers including lung, colon, breast, liver cancer, bladder, and brain cancers, and plays a crucial role in the G2/M DNA repair checkpoint [ 555 – 557 ]. Furthermore, EGCG suppresses key signaling pathways such as the PI3K/AKT/mTOR and AMPK pathways, and also inhibits factors like ROS, iNOS, Cox-2, NF- κ B, Senescence-associated secretory phenotype (SASP), and p53-mediated cell cycle regulation in preadipocytes [ 558 ]. In ovarian cancer (SK-OV-3 and OVCAR3) and esophageal squamous cell carcinoma (KYSE150 and KYSE510) cells, EGCG induces apoptosis by increasing the levels of pro-apoptotic proteins (Bax and Cytochrome c), activating Caspase-3 and Caspase-9, and stimulating tumor suppressor genes ( PTEN and SERPINB2 ), while simultaneously decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) [ 559 , 560 ]. EGCG also demonstrates enhanced growth inhibition and apoptosis induction in SK-OV-3 cells, accompanied by the upregulation of PTEN protein expression [ 561 , 562 ]. In human melanoma cell line A375, EGCG induces apoptosis via mitochondrial signaling pathway and downregulates autophagy through the AMPK/mTOR and PI3K/AKT/mTOR signaling pathway [ 563 ]. EGCG also disrupts the STAT3/CXCL8 signaling pathway, thereby inhibiting the formation of NETs and reducing motility and invasion in colon cancer (SW480) cells [ 564 ]. Moreover, it curtails VEGF-dependent angiogenic pathways and significantly reduces endoglin/pSmad1 levels, which inhibits tumor growth in human liver cancer (PMECs) and gastric cancer (SGC7901) cells and alleviates asthma symptoms [ 565 – 567 ]. Furthermore, EGCG inhibits TGF- β -induced EMT in human cervical cancer (Hela and SiHa) and anaplastic thyroid carcinoma (8505C) cells via the ROS/Smad signaling [ 568 – 570 ]. Additionally, in glioblastoma (U87), EGCG can inhibit the induction of EMT [ 570 – 572 ]. Overall, EGCG suppresses cancer progression through a diverse array of classical mechanisms, encompassing cell cycle arrest, apoptosis induction, inhibition of angiogenesis, and disruption of EMT. By precisely targeting key cell cycle regulators, apoptosis-related proteins, and signaling pathways that are integral to tumor progression and metastasis, EGCG exhibits significant potential as a therapeutic agent for various malignancies.

Investigating EGCG anti-cancer effects through drug delivery system

Due to its inherent chemical instability, EGCG is frequently combined with metals or other substances to form nanoparticles, which enhances its applicability in cancer treatment [ 573 , 574 ]. For example, MXene@EGCG can inhibit the expression of HSPs in tumor cells [ 575 ]. Moreover, EGCG-encapsulated micelles induce cancer cell apoptosis, trigger cell cycle arrest, and enhance the cellular uptake of EGCG in multiple cancer cell lines, including gastric cancer (BGC-823 and SGC-7901), colon cancer (HT-29 and HCT 116), breast cancer (MCF-7), and glioblastoma multiforme (GL261) cells [ 407 , 412 , 415 , 416 ]. Additionally, EGCG-loaded liposomes have been demonstrated to enhance cytotoxicity compared to free EGCG in breast cancer (SKBR3 and MCF-7) and liver cancer (H22 and Hep G2) cells [ 420 , 421 ]. These innovative carrier materials not only effectively overcome the limitations associated with the natural properties of EGCG but also significantly enhance its therapeutic efficacy against diverse forms of cancer, thereby representing a promising approach for improving cancer treatment outcomes.

EGCG regulates cytotoxicity for its anti-cancer activity

The term "cytotoxic" refers to a cell that is eliminated by chemicals or other cells rather than necrosis or apoptosis. Cytotoxicity has been demonstrated to be correlated with EGCG's anti-cancer activity [ 576 , 577 ]. In various cancer cell lines such as human pancreatic cancer (PANC-1, MIA PaCa-2, and BxPC-3), human colon cancer (SW480, HCT-15, and HT-29), and human lung cancer (HT1975, H358, and A549) cells, EGCG has been demonstrated to increase the cytotoxicity of chemotherapy drugs [ 578 , 579 ]. Through mechanisms such as promoting the elevation of oxidative stress within diseased cells [ 580 ] and the enhancing cytotoxic T-cell responses, EGCG palmitate exhibits specific cytotoxicity towards cancer cells. At higher dosages (≥ 125 μg/mL), EGCG exhibits a cytotoxic effect, leading to the death of approximately 30% of J774A.1 cells while simultaneously inducing the production of substantial amounts of lysozyme and IL-1 β , which can contribute to the reduction of inflammation [ 568 , 581 ]. By exploiting the vulnerability of cancer cells to the accumulation of toxic metabolites, cytotoxicity mediated by EGCG can effectively prevent cancer cells from surviving under the burden of harmful byproducts. This approach holds the potential to precisely and effectively eradicate tumors while minimizing damage to healthy and non-cancerous cells. Future research on EGCG may focus on identifying and inhibiting enzymes that are responsible for eliminating harmful byproducts of cancer cell metabolism, thereby further enhancing its anti-cancer potential.

EGCG exerts its anti-cancer effects through combining with other medications

Recent investigations into the synergistic effect of EGCG in combination with various agents have yielded significant findings. Specifically, when combined with monoclonal antibodies, first-line chemotherapy (such as doxorubicin, oxaliplatin, paclitaxel, 5-fluorouracil, and cisplatin), targeted drugs (including cetuximab, gefitinib, and erlotinib), immunotherapy drugs (like pembrolizumab and atezolizumab) and other natural products (e.g., curcumin), EGCG has demonstrated its potential in inhibiting multiple cancer types. For instance, studies have shown its inhibitory effects on pancreatic cancer (PANC-1), cervical cancer (HeLa and C-33A), and colon cancer (HCT 116) cells, primarily by reducing drug resistance and enhancing treatment sensitivity [ 582 – 585 ]. In addition, the combination of high-dose celecoxib and EGCG has been found to decrease the number of tumor cells induced by cisplatin [ 586 ]. Of note, it has been observed that EGCG in combination with other natural products exhibits enhanced efficacy in tumor treatment compared to its use alone [ 587 – 590 ]. For example, when cilantro is combined with EGCG, it can reduce the proliferating cell nuclear antigen at both mRNA and protein levels, thereby inhibiting the activity of human uterine fibroid cells [ 591 ]. Moreover, a conjugate composed of curcumin, EGCG and resveratrol has demonstrated a potent killing effect on head and neck cancer (TU212) cells [ 592 ]. In recent years, the combination of vitamins and EGCG has also played an important role in tumor treatment, especially in female patients [ 593 , 594 ]. The ability of EGCG to synergize with a diverse range of therapeutic agents—spanning from conventional chemotherapies to targeted therapies, immunotherapies, and natural products, underlines its potential as an adjunct in cancer treatment. By mitigating drug resistance and augmenting treatment sensitivity, EGCG could potentially play a pivotal role in improving the outcomes of existing therapies. Its combinations with other natural products, such as curcumin, resveratrol, and cilantro, suggest that integrating EGCG into multi-modal treatment regimens may offer greater therapeutic benefits than using it as a standalone agent.

Application of multi-omics techniques to investigate the anti-cancer properties of EGCG

Through the integration of transcriptomics and metabolomics investigations, it has been revealed that EGCG can interfere with glycerophospholipid metabolism and thereby inhibit the growth of colon cancer (HT-29) cells [ 595 ]. Metabolomics studies have further demonstrated that EGCG exerts anti-lung cancer benefits by regulating 33 differential metabolites in A549 cells, which are involved in various metabolic processes including glucometabolic, amino acid metabolism, nucleotide metabolism, and vitamin metabolism [ 596 , 597 ]. Moreover, mRNA and miRNA library sequencing studies have indicated that EGCG specifically modifies mRNA and miRNA expression, leading to cell death in lung cancer and breast cancer (MCF-7) cells [ 598 , 599 ]. However, the precise mechanism through which EGCG alters miRNA expression remains elusive, which presents an interesting area for further research [ 600 ]. By influencing key metabolic pathways, such as glycerophospholipid metabolism and glucometabolism, EGCG alters the metabolic profile of cancer cells, contributing to its anti-cancer properties. Additionally, EGCG’s capacity to modulate mRNA and miRNA expression highlights its potential in regulating gene expression networks that are implicated in cancer progression. While much has been uncovered, the exact mechanism by which EGCG influences miRNA expression still requires further in-depth investigation.

Overall, EGCG is notable for its capacity to modulate tumor immunity, overcome drug resistance, and orchestrate classical anti-cancer pathways, ranging from cell cycle arrest to apoptosis. By bridging multi-omics insights with advanced formulation techniques and synergistic regimens, EGCG exemplifies a promising model of how a single polyphenol can exert multifaceted control over tumor while minimizing the associated toxicities.

Ginsenosides

Ginsenosides, characterized by their triterpenoid nature, constitute one of the active constituents within Ginseng radix et rhizoma or Panax ginseng (Renshen in Chinese) [ 601 , 602 ]. Among these ginsenosides, ginsenoside Rg3, ginsenoside Rh2 and ginsenoside compound K have demonstrated potent and diverse pharmacological activities, particularly in the context of breast cancer treatment [ 603 , 604 ]. Rg3 is a saponin compound with two distinct enantiomers: 20 (S)-ginsenoside Rg3 and 20 (R)-ginsenoside [ 605 ]. This compound exhibits a broad spectrum of pharmacological characteristics, among which its antioxidant and anti-inflammatory effects are especially prominent. Ginsenoside Rg3 is capable of diminishing lung inflammation, averting damage to liver and kidney functions, lessening neuroinflammation, averting cerebral and myocardial ischemia–reperfusion injury, and ameliorating symptoms of hypertension and diabetes [ 606 ]. Ginsenoside Rg3 has a wide range of anti-cancer properties, which are related to its functions in immune regulation, anti-angiogenesis, induction of mitochondrial autophagy, induction of tumor cell apoptosis, and inhibition of metastasis and invasion [ 605 , 607 ]. The anti-inflammatory, antioxidant and anti-cancer properties of ginsenoside Rg3 have been validated through numerous in vivo and in vitro studies. It has been shown to be effective in the treatment of various diseases, including colon, breast, gastric, and liver cancers, as well as atherosclerosis, liver fibrosis, Huntington's disease, cardiac hypertrophy, heart failure and various skin diseases [ 608 – 612 ]. In silico analysis shows that ginsenoside Rg3 and ginsenoside Rh1 exert anticancer effects through different mechanisms: Ginsenoside Rg3 activates miR-424-5p by down-regulating ATXN8OS, while Rh1 inhibits metastasis by targeting RhoA and ROCK1, with both showing cytotoxic and pro-apoptotic effects in breast and lung cancers [ 613 , 614 ]. And in vivo study shows that ginsenoside Rg1 exhibits strong cytotoxicity against lung cancer cells and suppresses oncogene expression in a zebrafish model [ 615 ]. In clinical trials, ginsenoside Rg3 is used to treat liver cancer ( NCT01717066 and NCT04523467 ) and gastric cancer ( NCT01757366 ). Ginsenoside Rh2, which is the predominant bio-active ginsenoside derived from the root of Panax ginseng, has been demonstrated to possess a diverse range of pharmacological activities [ 616 ]. These activities encompass antitumor effects, enhancement of cardiac function, mitigation of fibrosis, anti-inflammatory actions, antidepressant effects, and thus exhibit remarkable medicinal potential [ 617 – 621 ]. In cancer treatment, ginsenoside Rh2 shows multiple activities against tumor cells, such as influencing tumor immunity and autophagy [ 621 , 622 ]. Compound K, which is one of the metabolites of ginsenoside Rb1, exhibits antioxidant, anti-inflammatory, anti-cancer, and hypolipidemic properties [ 623 – 625 ]. Compound K exerts an inhibitory effect on tumor growth through ferroptosis as well as the delay of cell cycle [ 626 , 627 ]. The subsequent part presents an overview of the mechanisms and molecular targets through which ginsenoside exerts its actions against diverse forms of cancer.

Ginsenosides improve tumor immunity

The anti-cancer efficacy of ginsenoside Rg3 is closely related to its immunomodulatory function. In clinical studies, ginsenoside Rg3 has been demonstrated to effectively increase the counts of CD3 + T, CD4 + T, and CD8 + T lymphocytes. It also enhances the activity of NK cells, thereby augmenting the treatment effectiveness for NSCLC patients [ 628 ]. In vivo experiments regarding gliomas (C6), Rg3 induces the transformation of TAMs from the protumor M2 phenotype to the antitumor M1 phenotype. This alteration activates the immune microenvironment, promotes the T cell immune response, elevates the M1/M2 ratio, and simultaneously reduces the proportion of Tregs and myeloid suppressive cells [ 629 ]. In tumor microenvironment, ginsenoside Rg3 exerts regulatory effects on immune inflammatory cells, cytokines, as well as relevant signaling pathways. Specifically, it has been demonstrated that ginsenoside Rg3 regulates STAT3 and suppresses the secretion of CCL2 by tumor cells. As a result, the recruitment of MDSCs and TAMs is decreased. This facilitates the immune system in recognizing circulating tumor cells, thereby impeding their colonization and proliferation [ 630 ]. Moreover, ginsenoside Rg3 also regulates TGF- β /Smad signaling pathway and inhibits the secretion of TGF- β by tumor cells. Consequently, cancer-related fibroblasts are inactivated and revert to a dormant state, which weakens the robustness of the matrix barrier [ 631 ]. Ginsenoside Rh2 also exhibits remarkable effects in the tumor microenvironment. In colon cancer (MC38) cells, it initiates the infiltration, multiplication and activation of T cells. For breast cancer (MDA-MB-231 and 4T1) cells, it enhances the immune surveillance of NK cells. In pancreatic cancer (Panc02 and PANC-1) cells, it promotes the infiltration of DCs [ 621 , 632 , 633 ]. Meanwhile, compound K can regulate the balance between Tregs and T helper cell in lung cancer (A549 and Lewis) cells, modulate the tumor microenvironment by means of targets, such as STAT3 and PD-L1 in prostate cancer (DU 145, PC-3, and LNCaP) cells [ 634 , 635 ]. Thus, ginsenosides, including ginsenoside Rg3, ginsenoside Rh2, and compound K, significantly enhance tumor immunity through a variety of mechanisms, including the activation of T cells, modulation of macrophage phenotypes, regulation of immune pathways and cytokines, and reprogramming of the tumor microenvironment. By shifting immune cells towards more potent anti-cancer phenotypes, inhibiting immunosuppressive factors, and strengthening the immune system’s ability to detect and eliminate tumor cells, these compounds effectively promote anti-tumor immune responses.

Ginsenosides reverse tumor drug resistance

Ginsenoside Rg3 has been the subject of extensive investigations regarding its potential to counteract the multidrug resistance of cancer cells. This encompasses the resistance of first-line chemotherapeutic agents such as paclitaxel, temozolomide, tamoxifen, osimertinib, gemcitabine, and icotinib in various malignancies including breast, lung, pancreatic cancers, as well as glioblastoma multiforme [ 636 – 638 ]. The resistance to paclitaxel, whether inherent or acquired during the course of treatment, represents a significant hurdle in breast cancer chemotherapy. Ginsenoside Rg3 exerts its effects in two aspects: it directly targets tumor cells and simultaneously participates in the remodeling of the tumor microenvironment. When combined with paclitaxel, this treatment suppresses the activation of the IL-6/STAT3 pathway. Moreover, it facilitates the transformation of the initial tumor M2 macrophages into an anti-tumor M1 type, suppresses MDSCs, reduces tumor related fibroblasts and collagen fibers in tumor microenvironment, promotes tumor cell apoptosis, and effectively reverses the MDR of breast cancer (MCF-7/PTX) xenograft model [ 639 ]. Tamoxifen is a commonly used first-line drug for clinical treatment of breast cancer. Enhanced glycolysis has been identified as a crucial factor contributing to tamoxifen resistance, and ginsenoside Rg3 can effectively address this issue. The presence of ginsenoside Rg3 leads to an elevation in the levels of 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer (MCF-7/TamR and T-47D/TamR) cells [ 640 ]. Additionally, ginsenoside Rg3 also attenuate the resistance of NSCLC cells to osimertinib by suppression of the stemness that relies on the Hippo pathway [ 637 ]. In lung cancer cells, ginsenoside Rg3 inhibits ROS production, leading to NF- κ B and HIF-1 α -mediated downregulation of PTX3, and inhibits gemcitabine induced MDR of lung cancer cells [ 638 ]. In glioma cells, 20 (S)-Rg3 effectively downregulates O6-methylguanine DNA-methyltransferase expression through the Wnt/ β -catenin pathway, significantly reversing MDR [ 636 ]. In pancreatic cancer cells, ginsenoside Rg3 upregulates the expression levels of long noncoding RNA cancer susceptibility candidate 2 ( CASC2 ) and PTEN , leading to the suppression and programmed cell death of pancreatic cancer cells that are resistant to gemcitabine [ 641 ]. Ginsenoside Rh2 also demonstrated significant effects in overcoming drug resistance. In pancreatic cancer (MIA PaCa-2 GR) bearing mice, it overcomes the resistance to gemcitabine by restraining LAMC2-Modulated ABC transporters. In paclitaxel-resistant breast cancer (MCF-7/PTX) cells, it suppresses cell proliferation by inhibiting the protein expression of P-gp [ 642 ]. Overall, ginsenosides, particularly ginsenoside Rg3 and ginsenoside Rh2, play a critical role in reversing tumor drug resistance through various mechanisms. By targeting key signaling pathways such as IL-6/STAT3, autophagy, glycolysis, and Wnt/ β -catenin, as well as by modulating the tumor microenvironment, ginsenosides enhance the efficacy of chemotherapy drugs in cancer types that exhibit resistance, including breast, lung, pancreatic cancers, and glioblastoma. Their capacity to regulate drug resistance proteins, metabolic pathways, and immune cell phenotypes renders them promising candidates for combination therapies aimed at overcoming MDR and improving the outcomes of cancer treatment.

Ginsenosides suppress cancer growth by regulating the processes of autophagy and ferroptosis

In the existing body of research, ginsenoside Rg3 has been shown to affect cellular autophagy, which constitutes one of the underlying mechanisms for its tumor suppressive effects. Specifically, studies have shown that 20 (S)-Rg3 blocks the late stage of autophagy (lysosomal fusion and autophagic lysosomal degradation) in cervical cancer cells, preventing them from maintaining a stable state through autophagy and inducing apoptosis in cervical cancer (HeLa) cells [ 643 ]. Moreover, ginsenoside Rg3 has been found to inhibit the protective autophagy of breast cancer (MCF-7) cells under hypoxic conditions [ 644 ]. In addition, in certain cancers, the tumor inhibitory effect of ginsenoside Rg3 is related to its ability to promote autophagy. For instance, ginsenoside Rg3 suppresses the growth, infiltration, and motility of osteosarcoma (MG-63 and U-2 OS) cells, while boosting their apoptosis and autophagy processes [ 645 ]. In human colon cancer cells, ginsenoside Rg3 induces mitochondrial autophagy. The action of ginsenoside Rg3 triggers the PINK1-Parkin signaling pathway, which leads to the recruitment of Parkin and ubiquitin proteins to the mitochondria, thereby initiating mitochondrial autophagy. During this process, GAPDH is involved and plays a role in regulating Parkin translocation to mitochondria [ 607 ]. Apart from autophagy, ginsenoside Rg3 influences ferroptosis, which is another form of programmed cell death. The dynamic nano-catalyst protected by ginsenoside Rg3 can activate apoptosis pathways, resulting in the elimination of pancreatic cancer (L3.6pl) cells [ 646 ]. However, ginsenoside Rh2 inhibits autophagy and promotes apoptosis of cervical cancer (HEK 293 T, HeLa, and C-33 A) cells under starvation conditions [ 647 ]. Meanwhile, ginsenoside compound K triggers the apoptosis of human cervical cancer (HeLa) cells by modulating autophagy, and induces ferroptosis through the FOXO pathway in liver cancer (Hep G2 and SK-HEP-1) cells [ 648 ]. Overall, ginsenosides, particularly ginsenoside Rg3, ginsenoside Rh2, and compound K, exhibit versatile and potent anti-cancer effects through the regulation of autophagy and ferroptosis. These compounds can either promote or inhibit autophagy depending on the specific cancer type and cellular conditions, such as the presence of hypoxia or nutrient starvation.

Ginsenosides suppress cancer progression via classical modalities

In terms of classic pathways for anti-cancer, ginsenoside Rg3 triggers a halt in the cell cycle across different cancer types. A common manifestation is that ginsenoside Rg3 increases the ratio of cancer cells at the G0/G1 phase. In detail, research has revealed that ginsenoside Rg3 disrupts the cell cycle at G0/G1 phase via the EGFR/Ras/Raf/MEK/ERK pathway in lung cancer (A549), liver cancer (Hep G2) cells, and the formation of Cyclin D1, CDK2, and CDK4 in colon cancer (SW620 and LoVo) cells [ 649 , 650 ]. Furthermore, ginsenoside Rg3 interferes with the G1/S transition in prostate cancer (PC-3) cells by modulating ROS [ 651 ], triggers a halt in the melanoma (B16) cell cycle during the S phase, and reduces the levels of the proliferating cell nuclear antigen [ 652 ]. In lung cancer (A549 and NCI-H1299) cells, ginsenoside Rg3 increases the ratio of cells at G2/M phase [ 653 ]. Similarly, ginsenoside Rh2 induces cell cycle arrest at G0/G1 phase in oral cancer (YD10B and Ca9-22), colon cancer (HCT-15, HCT 116, and DLD-1) and melanoma (A375 and B16-F10) cells [ 654 – 656 ]. Compound K blocks the G0/G1 phase in liver cancer (Hep G2, SMMC-7721, BEl-7404, and Huh7) and cervical cancer (HeLa) cells [ 648 , 657 ].

Ginsenoside Rg3 triggers cell death through apoptosis in a range of cancer cells, which involves the regulation of various proteins by ginsenoside Rg3. For example, ginsenoside Rg3 triggers cell death and suppresses cell growth by reducing TIGAR protein levels in rat gastric precancerous areas [ 658 ]. In NSCLC cells, ginsenoside Rg3 may increase Bax level and activate Caspase-3 in cells and decrease the expression of the anti-apoptotic protein (Bcl-2) [ 659 ]. Caspase-3 is a commonly studied pro-apoptotic protein in the context of the pro-apoptotic mechanism of ginsenoside Rg3. When administered in combination with 5-fluorouracil, ginsenoside Rg3 can significantly increase the apoptosis rate in colon cancer (SW620 and LoVo) cells through the activation of the Apaf1/Caspase-9/Caspase-3 pathway [ 650 ]. In addition, the pro-apoptotic effect of ginsenoside Rg3 on cancer cells has also been studied in models of liver, ovarian, gastric cancers, as well as renal cell carcinoma and melanoma [ 660 – 664 ]. Through miR-429 , Rg3 regulates genes associated with apoptosis in gastric cancer (AGSR-CDPP) cells resistant to cisplatin [ 662 ], regulates cancer cell apoptosis via the MEK signaling pathway in melanoma (A375.S2) cells [ 663 ], and promotes p53 demethylation and histone acetylation of p21 and p16 to enhance apoptosis of renal cell carcinoma cells [ 664 ]. Ginsenoside Rh2 can affect the expression of apoptotic proteins such as Bcl-2 in osteosarcoma (U-2 OS) and esophageal cancer (ECA109 and TE-13) cells, thereby inhibiting tumor progression [ 665 , 666 ]. In addition, compound K can promote the activities of Caspase-3 and Caspase-9 in prostate cancer (PC-3) cells [ 667 ].

Ginsenoside Rg3 primarily inhibits cell migration by reducing the protein levels of MMPs such as MMP-2, MMP-7, and MMP-9, and by obstructing the EMT process in cancer cells [ 652 , 668 – 670 ]. Specifically, ginsenoside Rg3 inhibits Notch-Hes1-EMT signaling to suppress the cell migration and metastasis in colon cancer [ 668 ]. In osteosarcoma cells, the mechanism underlying ginsenoside Rg3's inhibition of migration is also related to the Wnt/ β -catenin pathway [ 669 ]. Furthermore, ginsenoside Rg3 plays a key role in preventing liver cancer cells from migrating and invading by increasing the protein levels of ARHGAP9 [ 671 ]. Ginsenoside Rh2 inhibits tumor growth via ER β -TNF α pathway in breast cancer (MCF-7) cells [ 672 ]. Compound K inhibits the proliferation and invasion of esophageal cancer (ECA109) cells through the VEGF-A/PI3K/AKT pathway [ 625 ]. Therefore, these compounds modulate key signaling pathways such as EGFR/Ras/Raf/MEK/ERK, ROS, MEK, and PI3K/AKT, thereby exerting control over cancer cell proliferation, survival, and metastasis.

Ginsenosides combined with other medications for cancer treatment

The combined application of PD-L1 has demonstrated notable anti-cancer outcomes, which can be attributed to the activation of memory T cells and the reduction in adaptive PD-L1 enrichment within breast cancer (4T1) cells [ 673 ]. At present, ginsenoside Rg3, recognized for its multifunctional anti-tumor properties, has also received attention for its combined application with first-line anti-cancer drugs. When ginsenoside Rg3 is combined with 5-fluorouracil, a significant enhancement the suppression of multiple aspects related to cancer progression, including proliferation, invasion, migration, and angiogenesis, is observed in both lung and colon malignancies. In lung cancer (A549 and SPC-A-1) cells, this combination achieves its effects through the suppression of the NF- κ B signaling pathway's functionality and the downregulation of VEGFA expression [ 674 ]. In colon cancer (SW620 and LoVo) cells, the dual treatment of ginsenoside Rg3 and 5-fluorouracil triggers the Apaf1/Caspase-9/Caspase-3 pathway, leading to a marked increase in apoptosis, elevating the levels of Cyclin D1, CDK2, and CDK4 levels to halt G0/G1 cell cycle, and suppresses the PI3K/AKT signaling pathway [ 650 ]. Within liver cancer (SMMC-7721) cells, ginsenoside Rg3 potentiates oxaliplatin's anti-cancer properties, curbing liver cancer growth and facilitating cell death through the control of PCNA and Cyclin D1 expression [ 675 ]. Ginsenoside Rg3 combined with sorafenib exhibits a synergistic effect. Administering ginsenoside Rg3 and sorafenib together markedly reduces the survival, glucose uptake, and lactate concentrations in liver cancer (Hep G2 and BEL7404) cells, a process linked to the glycolysis mediated by HK2 and the PI3K/AKT signaling pathway [ 676 ]. Ginsenoside Rg3 is also capable of augmenting the cancer-fighting properties of gefitinib and doxorubicin. In NSCLC (A549 and H1299) cells, ginsenoside Rg3 enhances gefitinib's cytotoxic effect, with variations depending on the dosage and treatment duration. Moreover, it significantly inhibits the migration of these cells [ 659 ]. When combined with doxorubicin, ginsenoside Rg3 suppresses tumor expansion and lung cancer metastasis in an osteosarcoma (143B and U-2 OS) xenograft model. This is achieved through their combined ability to regulate mTOR/HIF-1 α /VEGF and EMT signaling pathways [ 677 ]. In addition, ginsenoside Rg3 can also be used in combination with certain active natural products to achieve a more potent anti-cancer effect. For instance, 20 (S)-Rg3 and curcumin suppress the proliferation of breast cancer (MDA-MB-231) cells in a dose- and time-dependent manner and enhance the radiosensitivity of cancer cells [ 678 ]. Ginsenoside Rh2 enhances anti-PD-L1 immunotherapy by promoting the infiltration, proliferation, and activation of CD8 + T cells in colon cancer (MC38) cells [ 621 ]. Ginsenoside Rh2 combined with EGFR-targeted liposomes can inhibit tumor growth and metastasis in breast cancer [ 679 ].Thus, the combination of ginsenosides with other therapeutic agents, including chemotherapy drugs, targeted therapies, natural products, and immunotherapies, significantly enhances their anti-cancer effects. These combinations work through various mechanisms, such as modulation of signaling pathways (e.g., NF- κ B, PI3K/AKT, and mTOR/HIF-1 α /VEGF), induction of apoptosis, inhibition of metastasis, and enhancement of immune responses.

Ginsenosides exert its anti-cancer effects through regulating gut microbiota

The occurrence and progression of cancer are associated with an imbalanced gut microbiota. For instance, a nanoparticle coupling of ginsenoside Rg3 reshapes the imbalanced gut microbiota in vivo and interferes with metabolism processes, thereby inhibiting the occurrence and metastasis of liver cancer [ 680 ]. Although there are reports in the literature regarding the regulatory effects of ginsenoside Rh2 and compound K on gut microbiota, the research focusing on their specific roles in cancer remains relatively limited [ 681 – 683 ].

Investigating ginsenosides anti-cancer effects through drug delivery system

Ginsenosides inherently possess limitations in terms of bioavailability and typically require special delivery systems to be developed with other carriers to function effectively. The process of encapsulating Rg3 within PLGA nanoparticles (Ginsenoside Rg3-PLGA) and enveloping them in a membrane made of microcapsules from tumor cells results in Ginsenoside Rg3-PLGA@TMVs, which is notably capable of stimulating CD86 and CD80 DCs in a laboratory setting [ 684 ]. In comparison to cholesterol liposomes (C-LPs), ginsenoside Rg3-LPs not only markedly enhance cellular uptake and the capacity to penetrate glioma spheroids (C6) cells, but also significantly strengthen the active targeting of glioma and the intertumoral diffusion ability in vivo [ 629 ]. The self-micro emulsifying drug delivery system (RGO-SMEDDS) incorporating ginsenoside Rg3, ganoderma lucidum polysaccharides, and oridonin A restores immune functions by suppressing immunosuppressive cytokines and M2 polarized macrophages. Moreover, it can reduce angiogenesis through the downregulation of vascular endothelial growth factor and its receptors, and delay cell growth by obstructing the EGFR/AKT/protein kinase B/GSK3 signaling pathway in liver cancer (Huh7 and Hep G2) cells [ 685 ]. A ginsenoside Rg3-based nanoparticle formulated with folate, polyethylene glycol, and cyclodextrin has been validated to induce the transformation of immunosuppressive tumor microenvironment [ 608 ]. Polyethylene glycol-ginsenoside ginsenoside Rh1 and ginsenoside Rh2 conjugates as well as self-assembled micelles loading with ginsenoside Rh2 enhance water solubility and enable passive targeted delivery in lung cancer (A549) cells [ 686 , 687 ]. Ginsenoside Rh2-irrigated nano-in-thermogel can also reduce the multidrug resistance of breast cancer (MCF-7/PTX) cells [ 688 ]. Micelles modified with homing peptides derived from chitosan, gold nanoparticles and multifunctional liposomes can effectively deliver compound K to cancer cells, thereby enhancing the anti-cancer effects [ 689 – 691 ]. Overall, the development of advanced drug delivery systems (DDS) is crucial for optimizing the therapeutic potential of ginsenosides in cancer treatment. Encapsulation within nanoparticles, liposomes, self-emulsifying systems, and conjugation with targeting ligands such as folate and PEG significantly enhance the bioavailability, solubility, and targeted delivery of ginsenosides to tumor sites. These systems not only improve the anti-cancer efficacy of ginsenosides but also assist in overcoming challenges like poor solubility and multidrug resistance. The combination of DDS with ginsenosides represents a promising strategy for enhancing the outcomes of cancer treatment.

In summary, ginsenosides exert multifaceted anti-cancer effects through various mechanisms. They modulate immune cell polarization, reverse drug resistance by targeting key signaling and metabolic pathways, and regulate cell death processes such as apoptosis, autophagy, and ferroptosis. Ginsenosides can also reshape the tumor microenvironment through remodeling of TAMs and TGF-β–related fibroblast activation. By integrating ginsenosides into advanced DDS, researchers have successfully overcome challenges like low bioavailability and multidrug resistance, thereby amplifying therapeutic outcomes. These attributes position ginsenosides as versatile candidates for combination therapies, leveraging immunomodulatory, metabolic, and signaling crosstalk to elicit robust anti-tumor responses across multiple malignancies.

Icariin/icaritin

Icariin is one of flavonoids derived from Epimedii folium or Epimedium brevicornu (Yinyanghuo in Chinese) [ 692 , 693 ]. Icaritin, a bioactive metabolite of icariin hydroxylated at the 3,7-positions, is the main metabolite of icariin in the body. Both icariin and icaritin are used for the treatment of sexual dysfunction, osteoporosis, Alzheimer's disease, and exhibit anti-inflammatory and anti-cancer effects [ 694 , 695 ]. They demonstrate powerful inhibitory effects on many cancers such as liver, prostate, breast, cervical, breast, pancreatic cancers, as well as leukemia and melanoma [ 696 – 699 ]. Icariin and icaritin achieve their anti-cancer effects by inducing autophagy and apoptosis, disrupting the cell cycle, modulating tumor immunity, and inhibiting cell invasion and metastasis. To improve extraction rates, whole-cell catalysis demonstrates superior production performance, with Aspergillus sp.y 848 being used to isolate purer icaritin [ 700 , 701 ]. Additionally, the combination of icaritin with chemotherapy drugs can inhibit NK cell or T cell lymphoma growth in vivo [ 702 ]. In China, combination therapies involving icaritin are the subject of numerous ongoing clinical trials for the treatment of hepatocellular cancer ( NCT03236636 , NCT03236649 , ChiCTR2300077991, and ChiCTR2300077987) and pancreatic ductal adenocarcinoma (ChiCTR2300077907). It is noteworthy that the China National Medical Products Administration has granted approval for the use of icaritin (trade name acoradine) as a treatment option for patients with advanced liver cancer, emphasizing its safety, efficacy, and broad therapeutic potential in 2022 [ 703 ]. In summary, icariin and icaritin possess a wide range of pharmacological effects and show great promise in future anti-cancer treatments.

Icariin and icaritin improve tumor immunity

Icariin and icaritin both enhance the anti-cancer response by modulating the function of CD4 + and CD8 + T cells, macrophages, and MDSCs in melanoma, breast, prostate, pancreatic and liver cancers [ 698 , 704 , 705 ]. Icariin increases the proportion of tumor-infiltrating CD4 + and CD8 + T cells, reduces the number of MDSCs, and induces their differentiation into macrophages and DCs, restores CD8 + T cell function in 4T1 breast cancer xenograft model in vivo [ 697 , 706 ]. Furthermore, icariin exhibits dual anti-cancer mechanisms by decreasing polymorphonuclear-MDSCs and inhibiting macrophage differentiation from the M1 to M2 phenotype in pancreatic cancer (Panc02) cells [ 698 , 704 ]. However, icaritin suppresses liver cancer by reducing hematopoietic stem cells and PMN-MDSCs in liver cancer (Hepa1-6) cells and exerts anti-cancer effects by reducing the proportion of MDSCs and restoring CD8 + T cell function in breast cancer (4T1) cells as well [ 706 , 707 ].

Icariin enhances macrophage phagocytosis, reduces spleen and thymus indices, downregulates pro-inflammatory cytokines (IL-6, IL-8, IL-1 β ) in cervical cancer (SiHa) cells, and inhibits TGF- β 1 protein expression in breast cancer (MDA-MB-231) cells, suggesting its immunomodulatory effects [ 708 , 709 ]. In contrast, icaritin inhibits the release of TNF- α and IL-6 in lung cancer (A549) cells, preventing bone metastasis [ 710 ]. Icaritin downregulates the mRNA and protein expression of PD-L1 in liver cancer (SMMC-7721) and melanoma (B16-F10) cells, enhancing anti-cancer immune responses and prolonging patient survival [ 699 , 711 , 712 ]. In addition, icaritin upregulates CXC chemokines (e.g., CXCL9 and CXCL10) and T cell marker factors (e.g., CD8 and IFN- γ ), facilitating the recruitment of immune cells to tumors, and formed a "hot" tumor microenvironment in lung cancer (Lewis) cells [ 713 ]. Therefore, icariin and icaritin promote the infiltration of immune cells, inhibit various immune checkpoints, reduce the levels of inflammatory cytokines and enhance anti-cancer immunity.

Icariin and icaritin reverse tumor drug resistance

Icariin and icaritin enhance the sensitivity of resistant liver, breast, ovarian, and osteosarcoma to first-line chemotherapy drugs (doxorubicin, tamoxifen and cisplatin) by inhibiting P-gp, MDR1 or MRP1 [ 714 , 715 ]. Icariin specifically improves breast cancer (MCF-7/ADR and MCF-7/TAM) cells response to adriamycin and tamoxifen by blocking P-gp and autophagy [ 714 , 716 ]. In contrast, icaritin targets MDR1 and downregulates the protein expression of P-gp in liver cancer (Hep G2/ADR) cells, meanwhile, it decreases the mRNA and protein levels of MDR1 and MRP1 in osteosarcoma (MG-63/DOX) cells to sensitize them to adriamycin and doxorubicin, respectively [ 717 , 718 ]. Therefore, icariin and icaritin hold significant promise in overcoming tumor drug resistance by targeting and inhibiting key drug efflux pumps, including P-gp, MDR1, and MRP1. These compounds enhance the sensitivity of cancer cells to first-line chemotherapy drugs, such as adriamycin, tamoxifen, and cisplatin, by blocking the mechanisms that facilitate drug resistance.

Icariin and icaritin suppress cancer growth by regulating the processes of autophagy

Both icariin and icaritin can prevent breast, liver, cervical, colon and oral squamous cancer through autophagy [ 696 , 719 ]. Icariin induces the emergence of autophagosomes and modulates autophagy-related proteins (e.g., p62, Beclin-1, LC3-I, and LC3-II) in breast cancer (MDA-MB-468 and 4T1), cervical cancer (Hela) and ovarian cancer (SKVCR) cells [ 720 – 722 ]. Aside from autophagic vesicles, icaritin degrades mitochondrial proteins (e.g., MNF1, MNF2, HSP60, TOM20, and TiM23) in liver cancer (SK-Hep1) cells [ 696 ]. It also causes the accumulation of endogenous LC3 dots, modulates autophagy-related proteins, and subsequently increases autophagy flux in breast cancer (MDA-MB-468 and MCF-7), oral squamous cell carcinoma (CAL 27 and SCC-9) and liver cancer (Hepa1-6 and Huh7) cells [ 723 – 725 ]. Thus, icariin and icaritin exert anti-cancer effects by regulating the process of autophagy in various tumor types. Icariin enhances autophagy by inducing autophagosome formation and modulating key autophagy-related proteins, leading to the inhibition of cancer cell proliferation and promoting cell death. On the other hand, icaritin promotes mitochondrial autophagy and increases autophagy flux, inducing cell death in cancer cells.

Icariin and icaritin suppress cancer progression via classical modalities

Icariin and icaritin have been identified to induce cell cycle arrest at G0/G1, S, and G2/M phases in breast, liver, prostate, ovarian, lung, colon, retinal pigment epithelial, nasopharyngeal, gallbladder, nasopharynx, multiple myeloma and NK/T-cell lymphoma [ 715 ]. Icariin triggers cell cycle arrest at the G0/G1 phase in multiple cancer types, including ovarian cancer (SK-OV-3), lung cancer (A549), cervical cancer (SiHa), breast cancer (MDA-MB-468 and 4T1), retinal pigment epithelial and gallbladder cancer (GBC-SD) cells [ 708 , 721 , 726 – 729 ]. Meanwhile, icariin downregulates the protein expression of Cyclin D1, further inducing G1/S phase arrest in ovarian cancer (SK-OV-3) cells [ 730 ]. In contrast, icaritin upregulates the protein expression of p21, causing in G0/G1 arrest in liver cancer (Hep G2 and Huh7) cells [ 731 ], induces G0/G1 or S phase arrest via regulating cell cycle markers (p27 Kip1 , p16 Ink4a , and pRb) in prostate cancer (PC-3), endometrial carcinoma (RL95-2 and Ishikawa), nasopharyngeal carcinoma (HONE1 and HNE1) and multiple myeloma (U266), liver cancer (PLC/PRF/5) and colon cancer (HT-29) cells [ 732 – 734 ]. Additionally, icaritin demonstrates inhibitory effects on cell cycle arrest at G2/M phase in endonodal NK/T-cell lymphoma (SNT-8 and SNK-10) cells and cervical cancer (Hela) cells [ 735 , 736 ]. Icariin and icaritin induce apoptosis in multiple cancers, such as breast, liver, ovarian, lung, colon, cervical, neuroblastoma and NK/T-cell lymphoma by enhancing pro-apoptotic proteins and reducing anti-apoptotic proteins [ 697 , 708 , 735 – 745 ]. Icariin activates Caspase-3, Caspase -9, PARP, DR4 and DR5, inducing apoptosis through the death receptor pathway in colon adenocarcinoma (HCT 116) cells [ 745 ]. It also modulates mitochondrial proteins to trigger apoptosis in lung adenocarcinoma (A549 and H1975) cells [ 741 ]. Additionally, icaritin demonstrates pro-apoptotic effects in extranodal NK/T-cell lymphoma (SNT-8 and SNT-10), cervical cancer (Hela), liver cancer (Hep G2) cells and neuroblastoma (TDP-43-transfected SH-SY5Y) cells [ 735 , 736 , 742 – 744 ]. In order to trigger apoptosis through the mitochondrial pathway, icariin and icaritin can both release Cytochrome C from mitochondria, triggering the Caspase cascade. Moreover, they activate death receptors (e.g., TNFR-1, DR4, and DR5), and Caspase-8, thereby initiating apoptosis via the death receptor pathway. Icariin suppresses migration and invasion in breast cancer (4T1, Hs 578 T, and MDA-MB-468), lung cancer (A549), and ovarian cancer (SK-OV-3) cells [ 721 , 726 , 739 , 746 ]. It upregulates E-cadherin and downregulates Vimentin, inhibiting cell migration and invasion of cervical cancer (SiHa) cells [ 708 ]. Besides, icariin inhibits osteoclast generation and significantly suppresses the bone metastasis of prostate cancer (RM-1) cells [ 704 ]. Similarly, icaritin modulates metastasis-related proteins (e.g., MMP-9, E‐cadherin, N‐cadherin, and Vimentin) and exhibits inhibitory effects in multiple myeloma (RPMI 8226 and OPM-2), ovarian cancer (A2780), esophageal cancer stem cells (ECA109) and endometrial cancer (RL95-2 and Ishikawa) cells [ 732 , 747 – 749 ]. Icariin and icaritin exert potent anti-cancer effects through classical mechanisms, including regulation of the cell cycle, induction of apoptosis, and inhibition of migration and invasion. By modulating key proteins involved in these processes, such as cyclins, Caspases, death receptors, and metastasis-related proteins, both compounds significantly suppress tumor growth and metastasis across a range of cancer types.

Icariin and icaritin combined with other medications for cancer treatment

Studies have shown that combinations of icariin and icaritin can enhance the treatment of prostate, liver, breast, and nasopharyngeal cancers by boosting efficacy and reducing side effects [ 750 – 752 ]. The icariin and P815AB peptide combination notably enhances the activity index of CTLs in mastocytoma (P815)-bearing mouse model, boosts CD8 + T cell cytotoxicity against prostate cancer (PC-3, DU 145, and RM-1) cells, upregulates immune-related proteins for lymphoma protection, and inhibits autophagy in ovarian cancer (SKVCR) cells, sensitizing it to cisplatin [ 720 , 753 ]. Moreover, icaritin, combined with anti-PD-1 antibodies notably amplifies the immune response and suppresses melanoma (B16-F10 and B16) and liver cancer (Hepa1-6) bearing models in vivo [ 699 , 707 ]. Icaritin also synergizes with doxorubicin to induce immunogenic cell death in liver cancer (Hepa1-6) cells, enhances the anti-cancer immune response with unmethylated cytosine-guanine oligodeoxynucleotide in melanoma (B16-F10), overcomes drug resistance in breast cancer (4T1) cells with epigenetic drugs (JQ1), and induces ferroptosis in nasopharynx cancer (HONE1 and HNE1) cells with gamma irradiation [ 724 , 752 , 754 , 755 ]. Thus, the combination of icariin and icaritin with other medications or treatment modalities significantly enhances the immune system, sensitize tumors to chemotherapy, overcome drug resistance, and promote cell death through mechanisms such as autophagy inhibition, immunogenic cell death, and ferroptosis.

Icariin and icaritin derivatives inhibit cancer progression

Icariin can be rapidly metabolized in the body into a variety of active ingredients like icariside I and icariside II, making impressive progress in treating a wide range of bladder, lung, prostate and breast cancers [ 756 – 759 ]. Icariside I enhances beneficial gut bacteria, upregulates immune cells, and inhibits melanoma (B16-F10) cell growth [ 760 , 761 ]. In contrast, icariside II targets various cancer types, including bladder cancer (BIU-87 and T24), cervical cancer (Hela), lung cancer (A549 and Lewis), prostate cancer (DU 145), colon cancer (SW620), and melanoma (A2058 and A375R) cells resistant to BRAF inhibitors, by blocking cell cycles, inducing autophagy and apoptosis, and modulating the tumor microenvironment when combined with anti-PD-1 [ 756 – 758 , 762 – 766 ]. Notably, icariside II also induces ferroptosis in renal cell carcinoma (ACHN and Caki-1) and promotes differentiation in acute myeloid leukemia (HL-60 and THP-1) cells [ 767 , 768 ]. Distinct from icariin, icaritin and its derivatives demonstrate unique anti-cancer mechanisms. Icaritin derivative IC2 triggers autophagy and apoptosis by targeting the SCD1 enzyme in breast cancer (MCF-7) cells in vitro and in vivo [ 759 , 769 ]. Additionally, the modified icaritin isopentenyl derivative C3 induces cell apoptosis and cell cycle arrest at S phase in multiple myeloma (RPMI 8226), while another semi-synthetic derivative 11c inhibits the proliferation of liver cancer (Hep G2 and SMMC-7721) cells by inducing cell apoptosis and cell cycle arrest at G0/G1 phase [ 770 , 771 ]. Therefore, icariin, icariside I, icariside II, and icaritin derivatives demonstrate broad-spectrum anti-cancer activity particularly effective in overcoming drug resistance and enhancing the therapeutic outcomes of existing treatments. Icariside II, in particular, shows promise in combination with immunotherapies, such as anti-PD-1, while other derivatives, such as IC2, C3, and 11c, offer new strategies for targeting specific cancer pathways, such as lipid metabolism, the cell cycle, and apoptosis.

Icariin and icaritin exert anti-cancer effects through regulating gut microbiota

Although its entire potential in cancer treatment has not yet been investigated, it has been discovered that icariin regulates the human intestinal microbiota. Specifically, icariin treatment group leads to a significant increase in beneficial bacteria (e.g., bifidobacterium and lactobacillus) counts, while decreasing harmful bacteria (e.g., enterococcus and enterobacteriaceae) counts, thereby improving the intestinal flora imbalance of cervical cancer (U14) bearing mice [ 708 ].

Application of multi-omics techniques to investigate the anti-cancer properties of icariin and icaritin

Transcriptomic analysis reveals distinct roles for icariin and icaritin in cancer regulation. Icariin downregulates NF- κ B-related genes in breast cancer (MDA-MB-231) cells [ 697 ]. Icariin emerges as a pivotal anti-cancer agent in liver cancer (Hep G2 and SMMC-7721) cells, with metabolomics suggesting arachidonic acid and other metabolites may contribute to its mechanisms [ 772 ]. Meanwhile, icaritin regulates PLK1 and induces apoptosis in NK or T-cell lymphoma (SNT-8, SNK-10, and NK-92 MI) cells, while activating the PI3K/AKT pathway to inhibit endometrial cancer (HEC-1-A) cell proliferation [ 702 , 773 ]. Proteomic studies identify 1024 differential proteins enriched in autophagy and mitochondrial apoptosis pathways in liver cancer (SK-Hep1) cells [ 696 ]. Transcriptomic and metabolomic results show that icaritin increases white blood cells, alleviating cancer-induced leukopenia [ 774 ]. Pharmaco-omics and proteomics indicate that icaritin exerts its anti-lung cancer (Hep G2) cells by up-regulating FYN protein [ 775 ]. Therefore, the integration of multi-omics techniques has significantly advanced the understanding of the anti-cancer mechanisms of icariin and icaritin.

Investigating icariin and icaritin anti-cancer effects through drug delivery system

The utilization of various delivery platforms, including phospholipid complexes, cyclodextrin complexes, micellar formations, nano-carriers, and solid materials, significantly enhance the bioavailability of icariin and icaritin, exhibiting remarkable potential in the treatment of breast, lung and gastric cancers [ 776 – 778 ]. Nanomaterials coated with icariin facilitated drug release, induce apoptosis, and show strong cytotoxicity against ovarian cancer (SK-OV-3 and Caov-3) cells [ 776 ]. A novel gelatin/polylactic acid (PLA) coaxial fiber membrane containing icariin enhances osteogenic effect and effectively suppresses the activity of human osteosarcoma (MG-63) cells [ 779 ]. The IRGD-functionalized RBCM-mimicking nanoparticles carrying icariin exhibits potent inhibitory effects on lung cancer (A549) cell proliferation [ 777 ]. Furthermore, nano-micelles formulated with icariin, curcumin and carrier material notably suppress the proliferation of breast cancer (MCF-7) cells in vitro and in vivo [ 780 ]. The optimized icariin-loaded bilosome-melittin (ICA-BM) formulation markedly enhances the anti-pancreatic cancer efficacy of icariin in PANC-1 cells [ 781 ]. In contrast, icaritin-based nanoparticle DDS demonstrate significant substantial promise in cancer treatment. For instance, the system FLA@GNPs induces apoptosis in lung cancer (A549) cells [ 782 ]. Co-loaded with icaritin and JQ1, within ARNP nanoparticles, the system inhibits breast cancer (4T1) cells and alleviates bone and lung metastasis [ 755 ]. Icaritin-laden micelles efficiently deliver the drug to oral squamous cell carcinoma (CAL 27) cells, inducing apoptosis and inhibiting proliferation in liver cancer (HCCLM3) in vitro and in vivo [ 783 , 784 ]. Micelles containing icaritin and doxorubicin reshape the immune microenvironment and hinder the growth of liver cancer (Huh7 and Hepa1-6) cells [ 724 ]. Notably, the heat-sensitive IC-ML complex, supported by icaritin and Coix seed oil, triggers cell apoptosis and cycle arrest, enhancing the therapeutic efficacy against liver cancer (Hep G2) in vitro and in vivo [ 785 ]. Furthermore, PLGA@icaritin activates anti-cancer immune response, elicits immunogenic cell death in gastric cancer (MFC) cells [ 778 ]. The development of advanced DDS for icariin and icaritin has significantly improved the bioavailability, targeting, and therapeutic efficacy of these compounds in cancer treatment. By utilizing various platforms such as nanomaterials, micelles, and nanoparticles, these delivery systems enhance the controlled release of icariin and icaritin, promote apoptosis, and increase cytotoxicity in a range of cancers.

In sum, Icariin and its metabolite icaritin offer multiple anti-tumor mechanisms, including immunomodulation, drug resistance reversal, induction of autophagy and apoptosis, and cell cycle arrest. Icariin can also synergize with chemotherapy agents or immunotherapies to enhance efficacy and reduce toxicity. Across various malignancies—breast, liver, cervical cancers, and more—icariin and icaritin demonstrate a notable ability to inhibit tumor proliferation and metastasis. Advanced drug delivery platforms (e.g., nanoparticles, microcapsules, and microspheres) further improve their solubility and bioavailability. Additionally, derived compounds such as icariside I/II excel at triggering ferroptosis and boosting immune responses, while multiple ongoing clinical trials (particularly for liver cancer) continue to confirm their safety and therapeutic promise.

Resveratrol

Resveratrol, a naturally produced polyphenolic molecule, has garnered considerable amounts of interest in recent decades due to its possible medicinal uses [ 786 ]. Resveratrol can be extracted from more than 70 plant species and is particularly abundant in grape, blueberry and raspberry, as well as Polygoni cuspidati rhizoma et radix (Huzhang in Chinese) [ 787 ], and several synthetic routes are also available to provide high quality and yield of resveratrol [ 788 , 789 ]. Resveratrol is known for its antioxidant, anti-inflammatory and cardioprotective properties [ 790 – 792 ] and has a wide range of anti-cancer properties in oral, gastric, liver, pancreatic, breast, prostate, colon, lung, and skin cancers [ 793 ]. Resveratrol enhances tumor immunity, reverses tumor drug resistance, and regulates autophagy and cell cycle [ 794 – 796 ]. It can be used as a chemo preventive agent as well as a therapeutic agent involved in inhibiting the developmental stages of tumors [ 797 , 798 ]. Thus, resveratrol can function as a complementary drug to conventional chemotherapy [ 799 ]. Besides, it can also be used as a combination of other therapies, acting synergistically with other anti-cancer drugs [ 800 , 801 ]. In silico analysis investigates the binding of resveratrol to tumorigenic proteins, providing the first in silico characterization of its interactions with HIF-1 α , and offering detailed insights into their structural configurations and potential therapeutic roles in NSCLC and pancreatic cancers [ 802 , 803 ]. Additionally, the organoid-based ex vivo model is emerging as an innovative technology for assessing the efficacy and toxicity in bladder cancer treatment [ 804 ]. Moreover, clinical studies have evaluated the safety, pharmacokinetics, and pharmacodynamics of resveratrol in subjects with colorectal cancer and multiple myeloma, as well as its potential for cancer prevention in healthy participants ( NCT00920803 , NCT00920556 , and NCT00098969 ). This section summarizes the complex mechanisms and specific targets of resveratrol against various types of cancer in the following sections.

Resveratrol enhances tumor immunity

Resveratrol has a critical role in modulating the immune system and enhancing its ability to recognize and attack cancer cells. It affects various immune cells, including B cells, TAMs, MDSC, T cells and NK cells, and regulates the tumor immune microenvironment and exerts anti-tumor effects in lung, breast, and oral cancers by increasing the number and activity of immune cells [ 805 , 806 ]. Resveratrol inhibits cancer proliferation by reversing the 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced increase in the number and the immunosuppressive function of MDSCs in mice [ 807 ]. Also, resveratrol acts on TAMs, promoting the M1/M2 macrophage polarization ratio, inhibiting the conversion of TAMs from M1 to M2 subtype, and exerting an inhibitory effect in the microenvironments of tumor cells in lung, breast, and oral cancers [ 808 – 810 ]. Resveratrol also affects T cell function by inhibiting tumor growth through activation of effector T cells [ 811 ], as well as influencing T cell function by increasing the proliferation of cytotoxic CD8 + T cells and enhancing their ability to produce cytokines, such as IFN- γ , to kill tumor cells [ 812 – 814 ]. NK cells are also crucial for targeting and destroying tumor cells and are suitable targets for cancer immunotherapy. Resveratrol enhances the cytotoxic activity of NK cells, upregulates the expression of NK cell activation receptors to improve their ability to recognize and kill cancer cells [ 815 , 816 ]. Resveratrol can modulate the tumor immune microenvironment by altering cytokine production. It reduces the levels of pro-inflammatory cytokines (e.g., IL-6 and TNF- α ) [ 817 ] and pro-carcinogenic cytokines (TGF- β 1, TNF- β , and CXCL12) [ 818 ] which exerts an inhibitory effect on pancreatic cancer associated fibroblasts (CAF) and colon cancer (HCT 116) cells [ 819 , 820 ]. Resveratrol exerts immunomodulatory effects by acting on multiple immune checkpoints (PD-L1, PD-1, CTLA-4, NKG2A, TIM-3, and BTLA). It includes altering the tumor immune microenvironment to inhibit the value-added of ovarian and oral cancer cells [ 821 , 822 ], as well as weakening the inhibitory function of Tregs on effector T-cells [ 823 ], to promote the killing of cancer cells. Therefore, resveratrol plays a multifaceted role in enhancing anti-cancer immunity by modulating various immune cells, cytokine production, and immune checkpoints. By promoting the activity of cytotoxic T cells, NK cells, and macrophages, while simultaneously inhibiting the immunosuppressive functions of MDSCs and Tregs, resveratrol creates a more favorable immune microenvironment for anti-tumor immunity. Additionally, its ability to regulate cytokines and immune checkpoints further strengthens its potential as an immune-modulatory agent in cancer treatment.

Resveratrol reverses tumor drug resistance

Resveratrol has been shown to inhibit drug transporters, thereby increasing the intracellular concentration of chemotherapeutic drugs. Also, resveratrol can inhibit prostate cancer and of oral squamous cell carcinoma drug resistance by down-regulating EGFR. This property allows it to participate in the therapeutic process of various anti-cancer drugs (paclitaxel, celastrol, adriamycin, rapamycin, and cetuximab) [ 824 – 827 ]. Specifically, resveratrol reduces the protein expression levels of P-gp, MRP1, BCRP, CYP3A4, GST and mRNA expression of hPXR to restore the sensitivity of NSCLC and colon cancer cells to polyphenols. The combination of quercetin-resveratrol can reduce the levels of EGFR, EGR3 and IL6, and increase the levels of IGFBP7 and NKX3.1, which can play an anti-prostate cancer role [ 825 ]. Resveratrol administration also increases the sensitivity of oral squamous cell carcinoma to cetuximab by decreasing the protein expression of uPAR, which inhibits the signaling molecule ERK1/2 downstream of EGFR [ 828 ]. Thus, resveratrol plays a crucial role in reversing tumor drug resistance by targeting drug transporters, down-regulating EGFR expression, and enhancing the efficacy of chemotherapeutic agents. By inhibiting drug efflux pumps and modulating key signaling pathways, resveratrol restores the sensitivity of cancer cells to chemotherapy and targeted therapies, improving treatment outcomes.

Resveratrol inhibits cancer progression by regulating the process of autophagy and ferroptosis

Resveratrol has been shown to induce autophagy and ferroptosis in lung, breast, pancreatic, ovarian cancers, as well as myeloma, leading to cell death and tumor growth inhibition [ 829 , 830 ].It activates key autophagy-associated proteins, such as Beclin-1 and LC3, which promote the degradation of damaged organelles and proteins [ 831 – 833 ], as well as increasing the phosphorylation of AMPK and decreasing the phosphorylation of mTOR and its downstream substrates in a dose-dependent manner, leading to autophagy [ 832 ]. Resveratrol targets neuroblastoma by inducing intrinsic apoptosis, which is mediated by the intracellular ROS axis and ER stress [ 834 ]. In the context of autophagy as a survival mechanism, resveratrol can sensitize cancer cells to chemotherapy by inducing lysosomal membrane permeabilization (LMP) which attenuates the fusion of autophagosomes and lysosomes [ 835 ]. Resveratrol induces iron death in carcinoma cells by regulating the expression of iron death-related genes [ 836 , 837 ]. In the lung squamous cell carcinoma (LUSC) tumor immune microenvironment, resveratrol regulates SLC7A11-HMMR interaction, activates iron death and potentiates the cytotoxicity of CD8 + T cells to exert antitumor effects. In addition, RSV can induce iron death in colon cancer cells by promoting lipid peroxidation and inhibiting the protein expression of SLC7A11 and GPX4 [ 838 ]. Thus, resveratrol’s ability to regulate both autophagy and ferroptosis plays a critical role in its anti-cancer effects. By inducing autophagy, resveratrol promotes the degradation of damaged cellular components, leading to cell death and inhibition of tumor growth. Moreover, its ability to induce ferroptosis through lipid peroxidation and the regulation of ferroptosis-related genes makes resveratrol a potent therapeutic agent in cancers that are susceptible to this form of cell death.

Resveratrol inhibit cancer in classical modalities

Resveratrol exerts its anti-cancer effects in colon, breast, and liver cancers by disrupting cell cycle and preventing proliferation of cancer cells [ 839 – 844 ]. For instance in colon cancer and lymphoma, it induces cell cycle arrest at G0/G1 phase [ 813 , 845 ], and in cervical cancer and melanocytoma, it stops in G1 phase [ 846 , 847 ]. This effect is mediated by the regulation of cyclin and CDK, which are important regulators of cell cycle progression. Resveratrol increases the protein expression of CDK inhibitors (p15), which block cell cycle progression and induce growth arrest [ 848 ]. Resveratrol's ability to regulate the cell cycle involves several molecular targets: In cells with functional p53, resveratrol enhances p53 activity, leading to cell cycle arrest and apoptosis [ 849 ]. Resveratrol also affects the checkpoint kinase Chk2, which is involved in the DNA damage response and cell cycle regulation and plays a crucial role in maintaining the stability of the tumor microenvironment [ 850 ]. Resveratrol activates Caspase-3 and Caspase-8, and up-regulates the protein expression of Bax [ 851 – 853 ], while inhibiting anti-apoptotic proteins like Bcl-2 [ 854 ], in order to induce apoptosis in luminal squamous cell carcinoma, cervical carcinoma, colon carcinoma, ovarian carcinoma, and uterine leiomyoma cells. Specifically, it activates Caspase-3 to exert anti-tumor effects in luminal squamous cell carcinoma and ovarian cancer [ 855 , 856 ]. In colon cancer and uterine leiomyoma, it promotes apoptosis through Bcl-2 protein expression and increases Bax protein expression [ 853 , 857 ]. Resveratrol can activate Caspase-3 in breast cancer (MCF-7) cells, leading to the breakdown of cellular substrates and successful initiation of apoptosis [ 858 ]. Moreover, resveratrol has been shown to inhibit the protein expression of fibronectin, N-calmodulin, waveform protein and increase the protein expression level of E-calmodulin in breast and colon cancer cells to inhibit tumor cell invasion or migration [ 798 , 834 , 859 ]. Therefore, resveratrol exerts its anti-cancer effects through the regulation of the cell cycle, induction of apoptosis, and inhibition of tumor cell migration and invasion. By arresting the cell cycle at various stages and enhancing the expression of pro-apoptotic proteins while inhibiting anti-apoptotic ones, resveratrol effectively suppresses cancer cell proliferation and induces cell death.

Resveratrol exhibits synergistic effects in cancer treatment

Resveratrol can significantly boost the anti-cancer impact when combined with a range of chemotherapeutic drugs. Studies have shown that resveratrol and curcumin have emerged as effective chemopreventive and chemoprotective compounds [ 860 ]. Their combination can effectively reduce bladder cancer (T24-GCB), colon cancer cell survival induced stronger ER stress and upregulation of the pro-death UPR molecule CHOP and exerted stronger cytotoxic effects [ 795 , 800 , 861 ]. Besides, resveratrol in combination with 5-fluorouracil induced S-phase cell cycle arrest and apoptosis of CD133 + colon cancer stem cells by regulating Bax gene [ 862 ]. Resveratrol also sensitizes colon cancer (Caco-2) and lung cancer (NSCLC) cells to paclitaxel by inducing apoptosis. This combination leads to increased cytotoxicity by increasing ROS levels, inducing oxidative DNA damage and decreasing cellular antioxidant defenses, resulting in effective apoptosis induction in cancer cell lines [ 863 ]. In various cancer cell lines and in vivo tumor models, resveratrol enhances the antitumor efficacy of rapamycin (An inhibitor of the autophagy inducer of mTORC1) by reducing the autophagy induced by AKT phosphorylation in thyroid cancer (KTC-1 and TPC-1) cells [ 801 ]. Thus, resveratrol’s ability to enhance the effects of various chemotherapeutic drugs provides a compelling rationale for its use in combination therapies. By inducing oxidative stress, modulating apoptosis pathways, and regulating the cell cycle and autophagy, resveratrol synergistically enhances the efficacy of drugs like curcumin, 5-fluorouracil, paclitaxel, and rapamycin.

Resveratrol derivatives in cancer treatment

Derivatives of resveratrol exhibit strong anti-cancer potential, and some of them have been used in colon and breast cancer therapy. Astragalus is a dimethylated derivative of resveratrol, which inhibits Top1 enzyme activity and treats colon cancer through the Top1/Tdp1-mediated DNA repair pathway with low toxicity [ 864 ]. Moreover, astragalus achieves its inhibitory effect on the tumor ball formation and migratory capacity of HeLa cancer stem-like cells by inhibiting the protein expression levels of stemness markers (e.g., CD133, Oct4, Sox2, and Nanog), as well as STAT3 signaling [ 865 ]. Besides, resveratrol derivatives inhibits human topoisomerase II and induces apoptotic cell death, and shows antitumor activity in different types of breast cancer (ER-positive MCF-7 and ER-negative SKBR3) cells [ 866 ]. Overall, these classes of derivatives have been designed to be more readily absorbed and retained in the body, thereby increasing their effectiveness in reaching and acting on target tissues, as well as the need for smaller doses sufficient to achieve the desired therapeutic effect [ 867 , 868 ]. Thus, resveratrol derivatives, including astragalus, demonstrate strong anti-cancer potential by targeting critical molecular pathways involved in DNA repair, cancer stem cell maintenance, and apoptosis. These derivatives exhibit enhanced bioavailability and tissue targeting, making them more effective in treating cancers such as colon and breast cancer. By improving pharmacokinetics and reducing toxicity, resveratrol derivatives offer a promising avenue for developing more efficient and less toxic cancer therapies.

Application of multi-omics techniques to investigate the anti-cancer properties of resveratrol

Thirty-eight target proteins are identified by proteomics analysis, which shows that the targets are mainly involved in cytoskeletal remodeling and EMT. It shows that resveratrol can inhibit A549 cell migration by binding to multiple targets to regulate cytoskeletal remodeling and inhibit EMT in order to exert anti-cancer effects [ 869 ].

Investigating resveratrol anti-cancer effects through drug delivery system

Pharmacokinetic studies have demonstrated that despite being absorbed after oral administration, resveratrol undergoes rapid and extensive Phase I and Phase II metabolism in rodents and humans. Therefore, researchers have designed novel DDS (nanoparticles, micelles, gels, and liposomes) to improve the bioavailability and therapeutic efficacy of resveratrol in cancer. Nanoparticle-based resveratrol delivery systems include resveratrol-loaded nanocrystals (NANO-RSV), silica mesoporous nanoparticle (MSN)-based DDS, and biocompatible resveratrol-conjugated gold nanoparticles (Res-AuNPs) [ 870 – 872 ]. Their advantages are commonly demonstrated by the prolonged release of resveratrol at the tumor site and significant in vitro therapeutic effects [ 871 , 873 ]. Besides, hydrogels co-doped with dopamine-reduced graphene oxide (DOPA-rGO; a photothermal nano-agent) and resveratrol exhibit injectability and in situ gelation, along with suitable physicochemical properties and good cytocompatibility. Chemo-photothermal therapy (RES + DOPA-rGO@Gel + NIR light) of the hydrogel was able to reduce the viability of breast cancer cells to only 31% [ 874 ]. In addition, resveratrol-loaded cationic liposomes (RLs) achieved specific delivery in liver cancer cells, as evidenced by a significant reduction in liver marker enzymes [ 875 ]. Therefore, resveratrol-loaded nanocrystals, silica mesoporous nanoparticles, gold nanoparticles, hydrogels, and cationic liposomes represent promising DDS platforms that can be further optimized for clinical use. These systems not only overcome the pharmacokinetic limitations of resveratrol but also enable targeted and controlled drug release at tumor sites, enhancing the drug's anti-cancer effects.

Overall, resveratrol exerts multi-faceted anti-cancer effects by modulating tumor immunity (e.g., boosting cytotoxic T cells and NK cells), reversing drug resistance (via down-regulating EGFR and P-gp), inducing autophagy and ferroptosis, and arresting cell cycle progression while promoting apoptosis. It also enhances the efficacy of standard chemotherapies (e.g., 5-fluorouracil and paclitaxel) through synergistic mechanisms involving oxidative stress and apoptosis pathways. Furthermore, resveratrol derivatives (e.g., astragalus) show improved bioavailability and strengthen anti-cancer outcomes by inhibiting DNA repair or stemness markers in tumor cells. Leveraging multi-omics findings and advanced DDS (nanoparticles, hydrogels, and liposomes) further increases its therapeutic impact and addresses pharmacokinetic limitations.

Silibinin

Silibinin, a flavonolignan derived from the seeds and fruits of Silybi fructus or Silybum marianum (Shuifeiji in Chinese), exhibits a diverse array of pharmacological effects, including hepatoprotective, anti-inflammatory, antioxidative, anti-fibrotic, and anti-tumorigenic properties [ 876 – 878 ]. Research indicates that silibinin effectively inhibits tumor growth across a broad spectrum of cancers such as breast, ovarian, lung, colon, pancreatic, liver, renal cell, endometrial, and bladder cancers [ 879 ]. Silibinin has multi-anticancer effects in vitro and in vivo, it inhibits cancer progression through regulating tumor immunity, overcoming drug resistance, boosting autophagy and ferroptosis, triggering apoptosis, inducing cell cycle arrest, and so on. It achieves these effects through targeting various cellular molecules—including TNF- α , IL-6, and VEGF—and impacting several signaling pathways such as the Wnt/ β -catenin and PI3K/AKT/mTOR pathways [ 880 – 882 ]. Moreover, silibinin shows potential as an adjuvant in mitigating numerous side effects of anti-cancer therapies, such as hepatotoxicity and neurotoxicity [ 883 , 884 ]. In silico analysis reveals ENO1, GLUT4 and ID3 as potential targets for disrupting the metabolic network in breast cancer cells, with silibinin promoting cytotoxicity, apoptosis, and lipid metabolism reprogramming [ 885 , 886 ]. In clinical studies, silibinin shows promising anti-cancer activity with minimal toxicity in conditions including colon and head and neck cancers [ 887 , 888 ]. Recent clinical research focus on its efficacy in treating brain metastases from cancers like leptomeningeal carcinomatosis, lung cancer, and breast cancer ( NCT05793489 , NCT05689619 ). The following section is a summary of the relevant pharmacological mechanisms of the anti-cancer effect of silibinin.

Silibinin improves tumor immunity

Silibinin inhibits tumor growth through immunomodulatory activities, such as regulating immune cells (Tregs, macrophages, DCs, NK cell), inhibiting inflammatory cytokines (IFN- γ , IL-2, IL-6, IL-10, IL-12, TNF- α , and TGF- β ), and modulating immune check points (PD-L1 and PD-1) [ 889 – 893 ]. Silibinin can regulate the proliferation, differentiation, and function of immune cells. Silibinin improves cancer immunity by promoting T cell proliferation, increasing the quantity of T cells, and enhancing T cell responses and function [ 894 , 895 ]. Silibinin effectively remodels the tumor microenvironment by enhancing the activation of NK cells, which boosts their ability to recognize and eradicate breast cancer (4T1, MCF-7, and MDA-MB-231) cells [ 890 ]. Additionally, it facilitates the polarization of macrophages towards the M1 phenotype, augmenting their phagocytic and antigen-presentation capabilities, thereby strengthening the body's antitumor immune response [ 891 , 896 ]. Silibinin also regulates cytokine secretion, increasing IL-12 and IFN- γ levels while reducing TGF- β , SDF-1, IL-6, and TNF- α , all of which play crucial roles in immune regulation and anti-cancer immunity in 4T1 breast cancer bearing mice [ 890 ]. Moreover, silibinin mitigates immunosuppression and inhibits tumor progression by limiting PD-L1 protein expression in lung cancer (A549, H292, and H460), papillary thyroid cancer (TPC-1), and nasopharyngeal carcinoma (C666-1) cells [ 889 , 892 , 897 ]. It also induces immunogenic cell death (ICD) in colon cancer (CT26) and melanoma (B16-F10) cells by elevating the protein expression of CRT, HSP70, and HMGB1, which are important in anti-tumor responses [ 895 ]. Furthermore, silibinin may modulate immunity by suppressing HIF-1 α in colon cancer (CT26) and ovarian clear-cell carcinoma (HAC-2, OVISE, and RMG-1) cells, influencing the tumor immune landscape [ 878 , 898 ]. Thus, silibinin demonstrates significant potential as an immune-modulatory agent in cancer therapy. By enhancing T cell proliferation, NK cell activation, and macrophage polarization, silibinin strengthens the body’s immune response against tumors. Additionally, its ability to regulate cytokine secretion, inhibit immune checkpoints, and induce immunogenic cell death further supports its potential in cancer treatment. Silibinin’s effects on HIF-1 α also suggest that it can modulate the tumor microenvironment, improving immune cell function and tumor recognition.

Silibinin reverses tumor drug resistance

Emerging evidence suggests that silibinin can reverse tumor drug resistance through blocking P-gp and MRP1 and inhibiting transcriptional activation in prostate, ovarian, lung, and liver cancers [ 899 ]. Silibinin augments the efficacy of cisplatin and paclitaxel by diminishing cell adhesion to the extracellular matrix in ovarian cancer (A2780) and colon cancer (CT26) cells, thereby increasing drug sensitivity [ 900 , 901 ]. Furthermore, silibinin modulates lung cancer (H3122 and H2228) cells by enhancing the therapeutic effects of nintedanib, brigatinib, and lorlatinib through the inhibition of STAT3 activity [ 902 , 903 ]. Additionally, silibinin improves radiosensitivity in prostate cancer (DU 145) cells by mitigating DNA damage, particularly following EGFR knockdown [ 904 ]. Therefore, silibinin offers significant promise as a therapeutic agent in reversing tumor drug resistance through various mechanisms, including inhibition of drug efflux pumps, modulation of cell adhesion, and regulation of key signaling pathways like STAT3. Its ability to enhance the efficacy of both conventional chemotherapy and targeted therapies, as well as improve radiosensitivity.

Silibinin inhibits cancer progression by regulating the process of autophagy and ferroptosis

Silibinin has been shown to induce autophagy in several cancer types by modulating various molecular pathways. Specifically, silibinin decreases phosphorylated mTOR protein levels, which in turn induces autophagy and inhibits the progression of liver cancer, breast cancer, and glioma [ 905 – 907 ]. Notably, silibinin also influences the autophagic degradation of YAP in castration-resistant prostate cancer (PC-3 and C4-2) and breast cancer (MCF-7 and MDA-MB-231) cells, highlighting its potential in autophagy modulation [ 882 , 908 ]. Additionally, it down-regulates the Wnt/ β -catenin signaling pathway, a key regulator of autophagy, and prevents EMT in renal cell carcinoma (786-O and ACHN) and liver cancer (Hep G2) cells [ 909 , 910 ]. In breast cancer (MCF-7) cells, silibinin triggers nuclear translocation of apoptosis-inducing factor (AIF), mediated by the inhibition of the ER α pathway and enhanced autophagy [ 911 ]. Moreover, silibinin's interaction with PINK1 and Parkin promotes mitophagy, reduces ROS levels, and enhances cellular resilience in liver cancer (Hep G2) and breast cancer (MCF-7 and MDA-MB-231) cells [ 912 , 913 ]. Silibinin also impacts the process of ferroptosis by modulating various signaling pathways and molecular mechanisms, including NF- κ B and STING pathways [ 914 , 915 ]. It regulates intracellular oxidative stress and iron metabolism, influencing the occurrence of ferroptosis by decreasing the protein expression of ACSL4 [ 915 ]. Thus, by modulating the mTOR pathway, inducing autophagic degradation of YAP, and inhibiting the Wnt/ β -catenin signaling pathway, silibinin suppresses tumor growth and metastasis in various cancers. Furthermore, silibinin's ability to regulate mitophagy and ferroptosis enhances cellular resilience and modulates oxidative stress, further contributing to its anti-cancer effects.

Silibinin inhibits cancer progression via classical modalities

Silibinin exerts cell cycle arrest across various phases including G0/G1, S, or G2/M, across multiple cancer types such as endometrial carcinoma, cervical, and lung cancer [ 916 ]. Substantial evidence confirms silibinin's predominant action in inducing G2/M phase arrest in a range of cancers including endometrial, cervical, bladder, prostate, renal, and colon cancers [ 917 ]. Specifically, in human epithelial colon adenocarcinoma (Caco-2) cells, silibinin decreases S phase populations and inhibits mitosis (G2/M) [ 918 ]. Furthermore, it suppresses cell proliferation and enforces G0/G1 phase arrest by targeting Cyclin D, cyclin E, and CDK4 in cholangiocarcinoma (HuCCT-1 and CCLP-1) and NSCLC (A549, H292, and H460) cells [ 889 , 919 ]. Numerous researches have reported that silibinin can promote the apoptosis by regulating apoptotic-related proteins (e.g., Bax, Bcl-2, and Bcl-xL) and activating Caspases in lung, colon, renal, oral, pancreatic cancers, as well as endometrial carcinoma [ 920 , 921 ]. It effectuates tumor cell apoptosis through the activation of the JNK/c-Jun and JNK/SAPK pathways, leading to reduced Bcl-2 levels and elevated Bax, as well as activated Caspase-3 and PARP in oral cancer (YD10B and Ca9-22) and pancreatic cancer (SW1990) cells [ 922 , 923 ]. Additionally, silibinin induces apoptosis in oral cancer (YD10B, Ca9-22, and SCC-25) cells and renal tissues from carcinogenesis models by releasing Cytochrome c [ 922 , 924 , 925 ], and triggers mitochondrial damage in human epidermal cancer (A-431) cells [ 926 ]. Silibinin also modulates mitochondrial dynamics by up-regulating DRP1, and down-regulating OPA1, MFN1, ATP content, and mitochondrial biogenesis regulatory factors (TFAM, PGC1 α , and NRF2), which promotes both extrinsic and intrinsic pathways of apoptosis in breast cancer (MCF-7 and MDA-MB-231) cells [ 927 ].

Silibinin's capacity to inhibit tumor progression is further demonstrated through its anti-angiogenic and anti-metastatic effects in colon, rectal, lung, prostate, bladder, breast, oral, and papillary thyroid cancers [ 928 ]. It obstructs the nuclear translocation of YAP/TAZ, leading to apoptosis in breast cancer (MCF-7 and MDA-MB-231) cells [ 908 ], and mitigates migration and invasion in breast cancer (MDA-MB-231) cells by reducing oxidative stress, suppressing NLRP3 inflammasome activation, enhancing mitochondrial fusion, and down-regulating RAC1 mRNA [ 927 , 929 ]. Moreover, silibinin curtails migration and invasion in oral and prostate cancer cells by inhibiting EMT and modulating the protein level of N-cadherin, vimentin, and E-cadherin [ 882 , 922 ]. It also reduces proliferation and migration in lung cancer (A547) cells by targeting RHBDD1 [ 930 ]. Therefore, silibinin exerts its anti-cancer effects through multiple classical mechanisms, including cell cycle arrest, apoptosis induction, and the inhibition of angiogenesis and metastasis. By targeting key molecular pathways such as cyclin/CDK complexes, JNK/c-Jun signaling, and mitochondrial dynamics, silibinin effectively suppresses tumor growth and progression. Furthermore, its ability to modulate tumor cell migration and invasion, particularly through the regulation of EMT and mitochondrial fusion.

Silibinin combined with other medications for cancer treatment

The combination of silibinin with first-line chemotherapy drugs has shown potential to enhance the efficacy of cancer treatments while mitigating drug-related side effects [ 931 , 932 ]. Silibinin combined with neratinib or etoposide significantly promotes apoptosis in breast cancer (4T1, MCF-7, and MDA-MB-231) cells by up-regulating the protein expression of p53 and p21 [ 932 , 933 ]. Furthermore, the combination of silibinin with paclitaxel or metformin enhances anti-cancer effects in lung cancer (A549) in vitro and in vivo by increasing chemotherapy sensitivity, modulating the tumor microenvironment, and effectively inducing apoptosis [ 931 , 934 , 935 ]. Moreover, co-treatment with silibinin and IPI-549 improves anti-cancer efficacy in breast cancer by inhibiting cell migration in vitro and in vivo, while significantly reducing Tregs and MDSCs [ 936 ]. Additionally, combining silibinin with other natural compounds further inhibits tumor cell migration. For example, silibinin combined with curcumin significantly downregulates Ob-R protein expression in breast cancer (MCF-7) cells [ 937 ]. Likewise, silibinin and epigallocatechin-3-gallate synergistically suppress lung cancer (A549) cell migration by down-regulating pro-angiogenic factors associated with the miR-17–92 cluster and up-regulating anti-angiogenic factors linked to miR-19b [ 938 ].

Silibinin also demonstrates protective effects against chemotherapy-induced toxicity. It reduces hepatotoxicity and neurotoxicity caused by drugs such as cisplatin and paclitaxel by mitigating DNA damage and restoring cellular proliferative potential in ovarian cancer (A2780/DDP) cells and cisplatin-treated mice [ 883 , 900 ]. In addition, silibinin-loaded PLGA nanoparticles alleviate dacarbazine (DTIC)-induced hepatotoxicity in a melanoma mouse model by lowering liver enzyme and bilirubin levels and upregulating detoxification enzymes like NQO1 and GSTP1 [ 884 ]. Clinical studies further underscore the potential of silibinin in reducing side effects associated with cancer therapies, improving chemotherapy and radiotherapy responses, and enhancing overall clinical outcomes [ 902 , 939 , 940 ].

Silibinin derivatives inhibit cancer progression

Based on the promising anti-cancer properties of silibinin, various silibinin derivatives have been extensively studied in recent years, including oxidized derivatives such as 2,3-dehydrosilybin, carbamate-modified silibinin, 2,3-dehydrosilybin derivatives with carbamate groups, and glycosylated silibinin derivatives. These derivatives improved solubility and enhanced biological activity compared to silibinin, demonstrating stronger anti-cancer and sensitization effects. Mechanistically, they enhance anti-proliferative and anti-inflammatory activities, induce cell cycle arrest (G2/M phase), promote cell apoptosis, and modulate the activity of proteins such as P-gp and acetylcholinesterase [ 941 – 943 ]. Notably, several 7-O-tyrosyl silibinin derivatives have shown significant anti-prostate cancer efficacy by inducing pronounced G0/G1 phase arrest and apoptosis [ 944 ]. Compared to silibinin, these derivatives provide superior solubility, enhanced biological activity, and exert their anti-cancer effects through diverse mechanisms, including targeted cell cycle arrest and induction of apoptosis. This highlights the potential of silibinin derivatives as improved therapeutic agents in cancer treatment.

Investigating silibinin anti-cancer effects through drug delivery system

The low water solubility and poor bioavailability of silibinin limit its therapeutic efficacy at tumor sites. To address these challenges, various nano-based delivery systems, including nanoparticles, cationic liposomes, smart nano-caged carriers, and other nano-formulations, have been developed to replace traditional formulations and effectively inhibit the progression of cancers such as breast, ovarian, and prostate cancers [ 945 ].

Silibinin encapsulated in nano-carriers can enhance the effects of drugs on apoptosis and immunogenic cell death in melanoma (B16-F10) cells [ 946 ]. For instance, PEG 400-OA as a nano-carrier significantly enhances the bioavailability and stability of silibinin [ 947 ]. Silibinin-gold nanoparticles (Sb-GNPs) prepared through physical adsorption and inhalable silymarin-loaded solid lipid nanoparticles exhibit narrow size distributions, increased bioavailability, and enhanced cytotoxic effects, increasing the cell-killing efficacy by 4–5 times in human lung adenocarcinoma (A549) cells [ 948 , 949 ]. Chitosan nanoparticles loaded with silibinin significantly upregulate the gene expression of Bax and Caspase-3 in glioma (C6) cells, effectively inducing apoptosis [ 950 ]. Similarly, silibinin-loaded magnetic niosome nanoparticles minimize systemic drug distribution side effects while maximizing therapeutic effects by improving targeting and cytotoxicity in colon cancer (HT-29) cells [ 951 ]. Therefore, nano-based formulations of silibinin demonstrate significant improvements in drug bioavailability, stability, and apoptotic efficacy across various cancer models, highlighting their potential as cutting-edge therapeutic alternatives.

Silibinin intervenes in cancer through epigenetic modifications

Silibinin exerts its anti-cancer effects via epigenetic mechanisms, notably through the modulation of miRNA expression and the consequent dysregulation of their target genes, alongside alterations in DNA methylation patterns [ 947 , 952 , 953 ]. MicroRNAs (miRNAs) are a highly conserved class of RNAs, whose improper regulation has been associated with human diseases, including cancer. Research indicates that silibinin can reduce the levels of miRNAs ( miR-125b , miR-182 , and miR-20b ), and up-regulate the levels of pro-apoptotic genes ( p53 , Bax , Caspase-9 , PTEN , and Bcl2L11 ), decrease the level of anti-apoptotic gene ( Bcl-2 ), thereby inducing apoptosis in breast cancer cells (T-47D, MCF-7, and MDA-MB-231) [ 947 , 954 ]. In pancreatic cancer cells (MIA PaCa-2 and PANC-1), slibinin induces apoptosis and suppresses migration by downregulating certain onco-miRNAs ( miR-155 , miR-222 , and miR-21 ) and their associated targets ( Bcl-2 , CD34 , AKT3 , MASPINE , EGF , and BMP7 ). Additionally, it promotes the expression of tumor-suppressor miRNAs ( miR-34a , miR-126 , and miR-let7b ) and enhances the gene levels of Caspase-9 , p53 , APAF1 , and Bax [ 952 , 955 ]. Moreover, silibinin induces programmed cell death in human hepatocarcinoma (Hep G2) cells by promoting the secretion of specific miRNAs ( miR223-3p and miR16-5p ) that potentially target the PTEN/AKT signaling pathway, and enhances the cytotoxic effect of sorafenib through the downregulation of miR-92a [ 956 ]. Thus, silibinin’s ability to modulate epigenetic mechanisms, particularly through the regulation of miRNA expression and DNA methylation, enhances its anti-cancer potential. By down-regulating oncogenic miRNAs and up-regulating tumor suppressor miRNAs, silibinin induces apoptosis and inhibits cell migration in various cancers, including breast, pancreatic, and liver cancers. Furthermore, its ability to modulate the PTEN/AKT pathway and enhance the efficacy of chemotherapy drugs such as sorafenib underscores its potential in combination therapies.

Application of multi-omics techniques to investigate the anti-cancer properties of silibinin

Recent advancements in omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have significantly enhanced the capability to elucidate the anti-cancer mechanisms of silibinin [ 957 , 958 ]. For instance, transcriptomic analysis have provided a more precise understanding of silibinin's influence on gene expression within various lung cancer (H1650, H1975, A549, H838, and H2030) cells, identifying a connection between silibinin and the modulation of key STAT3 target genes ( BIRC5 , BRCA1 , and FOXM1 ) that contribute to its anti-cancer effects [ 958 ]. Proteomics identified proteins that were highly expressed when silibinin intervened in basal cell carcinoma, and further analyzed their pathways, discovering a new target of RAC2 [ 959 ]. Metabolomics analysis based on nuclear magnetic resonance (NMR) and mass spectrometry showed that silibinin restrains glucose metabolism to impede the biosynthetic requirements of breast cancer cells and increases levels of BCAAs isoleucine, leucine, and valine, thereby inducing apoptosis in breast cancer (MDA-MB-468, MDA-MB-231, and BT-549) and prostate cancer (PC-3) cells [ 960 , 961 ]. Therefore, the application of multi-omics techniques has provided a deeper understanding of silibinin’s anti-cancer properties, revealing its complex interactions with cancer cell molecular, protein, and metabolic networks. By modulating key signaling pathways like STAT3, targeting novel proteins such as RAC2, and interfering with cancer cell metabolism, silibinin demonstrates its potential as a multifaceted therapeutic agent.

In sum, silibinin stands out for its ability to orchestrate multiple anti-cancer pathways, spanning immunity, autophagy, and epigenetic control, while also optimizing standard therapies and alleviating their toxicities. By reshaping key signaling axes (e.g., PI3K/AKT and Wnt/β-catenin) and rewiring metabolic and microRNA networks, it imposes broad restraint on tumor progression. These insights from multi-omics profiling underscore silibinin’s translational promise across various malignancies.

Triptolide

Triptolide, a diterpenoid triepoxide, is extracted from Tripterygium wilfordii (Leigongteng in Chinese) [ 962 ]. Triptolide demonstrates a wide range of activities, such as anti-inflammatory, immunosuppressive, neuroprotective, prevention of bone loss and anti-tumor effects [ 963 , 964 ]. Triptolide has been shown to possess a broad spectrum of anti-cancer characteristics and to be efficacious against several cancer types, including lung, breast, colon, bladder, liver, gastric, head and neck, thyroid, pancreatic cancers, as well as glioblastoma, melanoma, and leukemia [ 965 ]. In silico analysis identifies key targets such as CDKN1A, c-JUN, RELA, and TP53, suggesting that triptolide may treat thyroid cancer by inhibiting cell proliferation, inducing apoptosis, and modulating inflammatory pathways like NF- κ B and MAPK [ 966 ]. Furthermore, ex vivo study demonstrates that triptolide effectively inhibits the growth of colorectal cancer organoids, indicating its potential to disrupt cancer cell proliferation and tumor formation at the organoid level [ 964 ]. Additionally, triptolide impedes muscle development and cell proliferation in zebrafish larvae by interfering with several signaling pathways, including Notch1 and STAT3, which are also involved in cancer cell regulation [ 967 ]. Meanwhile, the prodrug of triptolide, has been developed in clinical trials for patients with advanced solid tumors ( NCT03129139 ) and refractory pancreatic malignancy ( NCT03117920 and NCT04896073 ). The subsequent section presents a succinct synthesis elucidating the intricate modalities and precise molecular targets by which triptolide manifests its therapeutic actions across a spectrum of malignancies.

Triptolide improves tumor immunity

Triptolide exerts notable immunomodulatory effects by engaging with various immune cell populations, such as macrophages, NK cells and T cells, across different cancer types including glioma, oral, breast, and colon cancers [ 963 , 968 ]. Recent study demonstrated that triptolide directly affects the tumor microenvironment by selectively depleting TAMs, inhibiting the function of M2 macrophage differentiation and viability, and suppressing M2 marker expression and anti-inflammatory cytokine secretion, leading to reduced tumor burden in experimental models of cancer [ 969 , 970 ]. Specifically, triptolide reduces TAM infiltration in colon cancer (HT-29 and CT26) cells by down-regulating CXCL12 gene and protein expression via the NF- κ B-ERK1/2 signaling axis, while delaying M2 polarization. In combination with aspirin, triptolide further blocks NF- κ B activation in cancer cells through distinct mechanisms involving p53 and ERK1/2, contributing to a reduction in cancer incidence [ 971 , 972 ]. Furthermore, triptolide suppresses M2 polarization of TAMs in vitro functioning as an integrin β 3 inhibitor [ 973 ]. For T cells, triptolide is reported to overturn T cell suppression, particularly CD4 + T cells subset in glioma (T98G) cells under IFN- γ treatment, while significantly decreases the proportion of Tregs in the spleen and axillary lymph nodes of melanoma (B16-F10) bearing mice, thereby impairing their suppressive function through the down-regulation of Foxp3, IL-10, and transforming growth factor in both protein and mRNA levels [ 974 , 975 ]. While triptolide presents challenges due to its water-insolubility and high cytotoxicity, innovative delivery systems and derivatives have enabled diverse anti-cancer mechanisms, suggesting promising avenues for future research and therapeutic development.

Dextran-conjugated triptolide and triptolide nano-MOFs enhance TNF- α levels, promoting an immune response that ultimately inhibits tumor progression in pancreatic cancer with KRAS mutation, while also reducing toxicity compared to free triptolide [ 976 , 977 ]. Triptolide attenuates IL-6-induced activation of STAT3 target genes, such as Mcl-1 and Bcl-2 , by decreasing STAT3 phosphorylation and inhibiting its nuclear translocation in NSCLC (PC9 and A549) cells, while also reversing IL-4 or LPS-induced up-regulation of IL-6 at the gene level, thereby reducing cell survival, apoptosis, and the polarization of myeloid cells into immunosuppressive macrophages and MDSCs within the tumor microenvironment [ 978 , 979 ]. In a colitis-induced colon cancer model, triptolide further suppresses IL-6 secretion and reduces the expression of IL-6 receptor (IL-6R), JAK1, and phosphorylated STAT3 proteins. By inhibiting the IL-6R-JAK/STAT signaling pathway, triptolide impedes tumor cell proliferation, survival, and the inflammatory response, which are critical for cancer progression [ 980 ]. Moreover, triptolide inhibits CXCL12 gene expression within the tumor microenvironment, leading to the suppression of the CXCL12 / CXCR4 axis and a reduction in TAM infiltration. This is achieved through downregulation of tumor-derived CXCL12 via the NF- κ B/ERK1/2 signaling pathway, which delays macrophage polarization towards the M2 phenotype. As a result, there is a decrease in the gene expression of immunosuppressive markers such as Arg-1 , CD206 , and IL-10 in both human and mouse colon tumors [ 971 , 981 ]. Therefore, triptolide demonstrates multifaceted anti-tumor effects across various cancer models by inhibiting cytokine production, tumor progression, and angiogenesis, while also modulating the tumor microenvironment to enhance anti-cancer immunity and minimize toxicity.

Triptolide treatment significantly suppresses PD-L1 expression in oral squamous cell carcinoma and NSCLC, modulating the immune checkpoint response and effectively inhibiting tumor growth in PDTX models and an IFN- γ -modulated environment, while its combination with IFN- γ in locoregional treatment enhances antitumor immunity in triple negative breast cancer by reversing IFN- γ -induced PD-L1 expression and activating cytotoxic CD8 + T lymphocytes, resulting in synergistic tumor growth inhibition [ 982 – 984 ]. Interestingly, in glioma (U251-MG, T98G, U-87 MG, A172, LN-229, and LN-18) cells, triptolide downregulates PD-L1 protein expression induced by IFN- γ on the cell surface, helping to reverse T cell inhibition, particularly affecting CD4 + T cells, and counteracting immunosuppression within the tumor microenvironment [ 974 ]. Moreover, treated with triptolide resulted in a significant reduction in the protein expression of CD47 and CD126 in the THP-1 macrophage cell line and the KG-1 erythroleukemia cell line, with the fold changes for CD47 were 0.3 (THP-1) and 0.55 (KG-1) in vitro [ 985 ]. Thus, triptolide exhibits multifaceted anti-cancer effects by modulating the tumor immune microenvironment, depleting immunosuppressive macrophages, promoting T cell activity, and inhibiting immune checkpoint proteins like PD-L1. It also impacts critical signaling pathways, such as NF- κ B, ERK1/2, and IL-6/STAT3, to reduce tumor progression and promote anti-cancer immunity. Although challenges exist due to its solubility and cytotoxicity, advancements in DDS have shown promise in improving its therapeutic application.

Triptolide reverses tumor drug resistance

Triptolide holds promise for reversing drug resistance across cancers, including NSCLC, prostate, and liver cancers, by enhancing chemosensitivity through mechanisms such as down-regulation of P-gp at both mRNA and protein levels, inhibition of the HNF1A/SHH and Keap1/NRF2 pathways [ 986 ]. Triptolide influences the EGFR primarily through modulation of protein expression and signaling pathways; it down-regulates ADAM12 in pituitary adenoma (TtT/GF and AtT-20) cells, thereby inhibiting ADAM12/EGFR signaling, and directly targets EGFR in bladder cancer (5637) cells, disrupting the PI3K/AKT pathway, while also enhancing the efficacy of EGFR tyrosine kinase inhibitors in NSCLC (H1975) cells by up-regulating E-cadherin and down-regulating proteins associated with EMT, highlighting its potential as a therapeutic agent in overcoming drug resistance and improving treatment outcomes [ 983 , 987 – 990 ]. Therefore, triptolide’s ability to down-regulate drug efflux pumps, inhibit survival pathways (e.g., HNF1A/SHH and Keap1/NRF2), and target the EGFR/PI3K/AKT axis establishes its potential for overcoming chemo-resistance and targeted therapies resistance. Notably, its synergy with EGFR tyrosine kinase inhibitors in NSCLC highlights its value in combination therapies.

Triptolide attenuates cancer cells by regulating the process of autophagy and ferroptosis

Triptolide has been shown to exhibit antitumor effects in ovarian cancer (SK-OV-3 and SK-OV-3/DDP) cells by inducing autophagy through ROS generation and JAK2/STAT3 pathway inhibition, enhancing chemotherapy sensitivity and inhibiting tumor growth, as well as by inducing apoptosis and reducing the protein expression of MMP-2, Sorcin, and VEGF, thereby disrupting the Mcl-1/Beclin1 interaction and highlighting its multifaceted therapeutic potential [ 991 , 992 ]. It also alters the autophagic protein expression, notably reducing mTOR and AKT levels [ 993 ]. Furthermore, triptolide induces glioma cell growth via autophagy through ROS/JNK activation and inhibition of the AKT/mTOR signaling pathway. Besides, it can also induce autophagy in glioma (U87 and U251) cells, as evidenced by increased LC3-II/LC3-I ratio, upregulating protein expression of Beclin-1 and ATG7, and a notable increase of autophagosomes number observed via immunofluorescence [ 994 ]. Interestingly, triptolide is found to enhance the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in pancreatic cancer cells by autophagy activation through Pumilio RNA-binding family member 1 (PUM1) downregulation, suggesting a potential strategy to increase tumor sensitivity to TRAIL [ 995 ]. Therefore, triptolide demonstrates versatile anti-cancer effects across various cancer types, highlighting its potential as a promising therapeutic agent with broad-spectrum activity against tumors.

Triptolide induces ferroptosis in various cancers by modulating key pathways at both gene and protein levels; it downregulates NRF2 in leukemia (K-562 and HL-60) cells, increasing ROS and lipid oxidation to sensitize cells to doxorubicin (DOX), inhibits GPX4 in glioblastoma (U-87 MG and U251-MG) cells through the NRF2/SLC7A11/GPX4 axis to promote lipid peroxide accumulation, and enhances ferroptosis in NSCLC (A549) cells by increasing ROS via the NF- κ B pathway while simultaneously reducing drug resistance proteins such as P-gp and GPX4 [ 977 , 996 – 998 ]. Triptolide nano-MOFs induce cancer cells ferroptosis, which releases a lot of DAMPs, allowing DCs to present antigens and to multiply into CTLs, thereby preventing lung metastasis of melanoma [ 977 ]. An acid and GSH dual-controlled nanoplatform enhances cancer treatment by using triptolide to regulate NRF2 and inhibit GSH protein expression, reducing GPX4 activity and promoting ferroptosis, while minimizing toxicity [ 999 ]. However, one of its adverse effects is triptolide-induced cardiotoxicity, which involves ferroptosis [ 1000 ]. Although triptolide holds promise as a potential therapeutic agent, its cardiotoxicity associated with ferroptosis underscores the importance of targeted tumor approaches to mitigate adverse effects.

Triptolide suppresses cancer progression via classical modalities

Triptolide can regulate the cell cycle in various cancer types, including breast, lung, prostate, and liver cancers. Triptolide exerts its effects by inducing cell cycle arrest at the G0/G1 phase, preventing the transition to the S phase, which inhibits cancer cell proliferation. Additionally, it can induce G2/M phase arrest, disrupting mitosis and promoting apoptosis. Triptolide exerts significant effects on the cell cycle across various cancer types, predominantly inducing G0/G1 phase arrest by enhancing the expression of cell cycle inhibitors in multiple myeloma (RPMI 8266) cells and suppressing proliferating cell nuclear antigen and Cyclin D1 in airway smooth muscle (ASMCs) cells in response to PDGF stimulation, thereby decreasing cell proliferation [ 1001 , 1002 ]. In bladder cancer cells, the combination of triptolide and hydroxycamptothecin significantly enhances G0/G1 phase arrest by inhibiting CDK4, CDK6, and Cyclin D1. It also suppresses laryngocarcinoma HEp-2 cell proliferation by inducing G0/G1 phase arrest and apoptosis via Caspase activation and increased p53 stability. In NSCLC, triptolide further strengthens this arrest by reducing ribosomal protein L4, which disrupts the MDM2-p53 signaling pathway, thereby boosting its effects on inhibiting proliferation and promoting apoptosis [ 1003 , 1004 ]. Additionally, triptolide induces G1 phase arrest in esophageal squamous cell cancer (KYSE150 and KYSE180) cells by regulating Cyclin D1 and CDKs [ 1005 ]. In triple negative breast cancer (BT-549 and MDA-MB-231) cells, human nasopharyngeal carcinoma (NPC-TW 039 and NPC-TW 076) cells and paclitaxel-resistant A549 cells, triptolide induces S phase arrest by causing DNA strand breaks, suppressing cyclin A-CDK2 complex formation and enhancing chemosensitivity to cisplatin and paclitaxel [ 1006 – 1008 ]. Furthermore, in glioma (U251) cells, triptolide triggers G2/M phase arrest while promoting apoptosis and autophagy, associated with the activation of ROS/c-JNK signaling pathways and inhibition of AKT/mTOR signaling [ 1009 ]. Collectively, these findings illustrate that triptolide modulates cell cycle progression primarily by inducing G0/G1 phase arrest through mechanisms such as enhancing cell cycle inhibitors and suppressing cyclins and CDKs, while also affecting S and G2/M phases, highlighting its potential as a multifaceted anti-cancer agent targeting diverse cell cycle regulatory pathways.

Triptolide's potent cytotoxicity indicates the influence in cancer therapy, and its principal mechanism is the induction of cell apoptosis. Triptolide demonstrates its effectiveness against gastric cancer (AGS and IM95) cells by increasing ROS levels, which trigger endoplasmic reticulum stress and induce cytoprotective autophagy, leading to the promotion of apoptosis. Additionally, in TNF- α -stimulated gastric cancer (AGS and MKN45) cells, triptolide enhances apoptosis via modulation of the H19/ miR-204-5p /NF- κ B/FLIP axis, suggesting that its ability to induce apoptosis is multifaceted and includes both the promotion of ROS generation and the regulation of specific signaling pathways [ 1010 , 1011 ]. The AS1411-triptolide conjugate shows promising potential as a targeted therapy for triple negative breast cancer, demonstrating high specificity and cytotoxicity against MDA-MB-231 cells, leading to significant tumor reduction and enhanced apoptosis in mouse models, with minimal toxicity to major organs [ 1012 ]. Additionally, triptolide promotes apoptosis and inhibits metastasis in glioblastoma cells in a dose-dependent manner by upregulating p21 and Bax protein expression while suppressing MMP-2 and MMP-9 protein levels, with PROX1 transcriptional inhibition elucidated as a mechanistic pathway, while in NSCLC, triptolide induces apoptosis and mitigates metastasis by targeting the IL-6/STAT3 signaling axis, characterized by reduced STAT3 phosphorylation and downregulation of STAT3 target genes, including c-Myc, Bcl-2, Mcl-1, and MMP-9, which are implicated in cell survival and migratory processes [ 978 , 1013 ]. Thus, triptolide exhibits multifaceted anti-cancer effects by effectively inducing apoptosis and modulating critical signaling pathways across various cancer types.

Triptolide combined with other medications for cancer treatment

Triptolide has demonstrated as a synergistic agent in combination therapies across various cancers, including lung and breast cancers, as well as renal cell carcinoma and nasopharyngeal carcinoma. Triptolide combined with first-line treatment for recurrent nasopharyngeal carcinoma significantly enhances therapeutic efficacy and improves patients’ life quality compared to single chemotherapy [ 1014 ]. In lung cancer, triptolide enhances the efficacy of EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, and icotinib, which are standard targeted therapies for NSCLC with EGFR mutation cell carcinoma [ 988 ]. These combinations highlight the versatility of triptolide in cancer therapy, effectively targeting key pathways and improving therapeutic outcomes. Given the disappointing outcomes of Bcl-2 inhibitor ABT-199 monotherapy in chronic lymphocytic leukemia, the combination of triptolide with ABT-199 has emerged as a promising strategy for acute myeloid leukemia treatment, as it enhances cytotoxicity by effectively targeting antiapoptotic proteins (Bcl-2 and Mcl-1), which may help improve therapeutic efficacy [ 1015 ]. Therefore, the combination of triptolide with chemotherapy, targeted therapies, and apoptosis-inducing agents has demonstrated significant potential in enhancing treatment outcomes, overcoming drug resistance, and improving patients' quality of life across various cancer types. The synergistic effects of triptolide when used alongside other medications, such as EGFR inhibitors in lung cancer, TRAIL receptor agonists in renal cell carcinoma, and Bcl-2 inhibitors in leukemia, further highlight its therapeutic promise.

Triptolide derivatives inhibit cancer progression

Due to its water-insolubility and high cytotoxicity, triptolide derivatives have been developed to enhance the therapeutic efficacy and safety profile of the parent compound by addressing issues such as high toxicity and poor solubility. These modifications include mitochondrial-targeting strategies, such as conjugation with lipophilic cations (e.g., TPP + or F16) for selective accumulation in tumor mitochondria, and biomimetic delivery systems like adipocyte-encapsulated triptolide derivatives combined with photosensitizers for melanoma treatment [ 1016 ]. Derivatives like LA67, triptolide-succinic acid ester, and compound 33 demonstrate increased bioavailability, targeted cytotoxicity, and innovative therapeutic options, including photodynamic therapy and NO-releasing capabilities, thus broadening triptolide's clinical application potential in cancer treatment [ 1017 , 1018 ]. Additionally, biomimetic delivery systems like pTP-Ce6-Apo, where adipocytes encapsulate a palmitic acid-conjugated triptolide derivative (pTP) and a photosensitizer (Ce6), enable cytotoxic and photodynamic effects specifically in melanoma cells [ 1019 ]. Thus, triptolide derivatives can overcome the solubility and cytotoxicity limitations of the parent compound, enhancing bioavailability, targeting specificity, and reducing toxicity, while also providing innovative therapeutic modalities such as photodynamic therapy and optical imaging capabilities for improved cancer treatment outcomes.

Application of multi-omics techniques to investigate the anti-cancer properties of triptolide

Triptolide exhibits significant anti-cancer effects as revealed through various omics studies. RNA sequencing and RNAPII-ChIP-Seq analyses demonstrate triptolide's biphasic impact on gene expression in pancreatic cancer (MIA PaCa-2) cells and cancer-associated fibroblasts, highlighting transcriptional down-regulation and specific alterations in histone acetylation [ 1020 , 1021 ]. In an oncogenesis model (MCF10A-ErSrc), triptolide induces both down-regulation and up-regulation of tumorigenesis-associated genes, illustrating its complex regulatory influence [ 1022 ]. Metabolomics in CT26 tumor-bearing mice identifies alterations in amino acid and ketone body metabolism, with potential biomarkers indicating triptolide's multifaceted impact on tumor metabolism. Additionally, proteomics reveals 54 triptolide-interacting proteins, including Annexin A1 and Peroxiredoxin I/II, suggesting novel therapeutic strategies for colon cancer [ 1023 ]. Collectively, by employing a multi-dimensional omics strategy, the intricate effects of triptolide on cancer cells have been meticulously characterized. The synthesis of this comprehensive analysis positions triptolide as a potent candidate for oncotherapy, harnessing its mechanisms that span across transcriptional modulation, metabolic reengineering, and the precise engagement of oncogenic proteins. By taking these three steps, precision oncology can advance in novel ways.

Investigating triptolide anti-cancer effects through drug delivery system

Recent developments in nanocarrier systems for triptolide have significantly advanced the treatment of tumor, such as liver cancer and malignant mesothelioma and leukemia. One approach involves a biomimetic nano-system that combines cancer cell-platelet hybrid membranes to co-deliver sorafenib and triptolide, achieving targeted delivery and prolonged circulation, which enhances tumor cell apoptosis and synergistic effects [ 1024 ]. Another innovation is the platinum/gold bimetallic nanoshell-coated triptolide liposomes (Pt@Au-TP-Lips), which utilize near-infrared light for chemophotothermal therapy, demonstrating higher photothermal conversion efficiency and substantial tumor growth inhibition [ 1025 ]. Additionally, a pH/ROS dual-responsive nanoparticle system for co-delivery of TP and the photosensitizer Chlorin e6 (Ce6) amplifies the effects of chemo-photodynamic therapy by enhancing oxidative stress and facilitating drug release in the tumor microenvironment [ 1026 ]. Moreover, an antibody–drug conjugate combining the anti-CD26 monoclonal antibody YS110 with triptolide (Y-TR1) selectively targets CD26-positive cancer cells (malignant mesothelioma and leukemia), effectively inhibiting RNA polymerase II activity [ 1027 ]. Together, these innovative nanocarrier strategies highlight the potential for improving liver cancer treatment through enhanced therapeutic efficacy and reduced toxicity. To address the limitations of triptolide's pharmacokinetics and toxicity, a novel antibody–drug conjugate, Cet-triptolide, is developed for targeted delivery to EGFR-overexpressing cancers, showing enhanced tumor-specific cytotoxicity and reduced toxicity compared to triptolide or cetuximab alone [ 987 ]. The triptolide nanoparticle with a CRPPR peptide-modified micelle to target the tumor microenvironment, following the priming action of a-mangostin-loaded nanoparticles that target CAFs and disrupt TGF- β signaling, leading to robust tumor growth suppression through a sequential targeting approach [ 1028 ]. The development of galactosylated-chitosan-triptolide-nanoparticles (GC-TP-NPs) for liver cancer enhanced antitumor efficacy by inducing apoptosis through the TNF/NF- κ B/Bcl-2 pathway, while minimizing systemic side effects [ 1029 ]. Overall, nanocarrier systems for triptolide, including antibody–drug conjugates and targeted nanoparticles, show great promise in enhancing therapeutic efficacy and minimizing toxicity. Future research should focus on optimizing these delivery methods to maximize triptolide's potential in clinical oncology.

Overall, triptolide orchestrates multi-front tumor suppression by reshaping the immune microenvironment, subverting drug resistance, and provoking autophagy-or ferroptosis-related cell death. It tampers with key signals, including IL-6/STAT3, NF-κB, and ERK1/2, to limit immunosuppressive macrophages and disable cancer-cell survival pathways. Although its inherent toxicity constrains clinical use, novel derivatives and smart delivery vehicles (e.g., nano-formulations and antibody–drug conjugates) have expanded triptolide’s therapeutic window. Multi-omics analyses further reveal extensive transcriptional, metabolic, and protein-network remodeling, suggesting deeper translational opportunities across diverse malignancies.

Ursolic acid (UA)

UA, a hydroxy pentacyclic triterpene acid, is prevalent in various plants such as Crataegi fructus or Crataegus pinnatifida (Shanzha in Chinese) [ 1030 , 1031 ]. This compound showcases a wide array of pharmacological effects, including anti-cancer, anti-bacterial, antioxidant, and anti-diabetic properties [ 1032 ]. It is particularly noted for its extensive anti-cancer capabilities, proving effective against a diverse range of cancers, including lung, breast, colon, prostate, stomach, and liver cancers, as well as melanoma [ 899 , 1033 ]. The robust anti-cancer properties of UA are ascribed to its capacity to suppress tumor cell proliferation, facilitate apoptosis, induce cellular autophagy, and specifically target drug-resistant cancer cells [ 1034 , 1035 ]. In silico analysis of UA binding to key EMT markers, including Snail, Slug, and Fibronectin, using quantum-polarized-ligand (QM/MM) docking, shows strong binding affinities and interactions, supporting its potential as an anticancer agent by regulating these markers in breast cancer [ 1036 ]. Moreover, in zebrafish models, UA significantly inhibits the growth and metastasis of breast cancer without causing detectable toxicity, supporting its potential as a therapeutic agent for breast cancer [ 1037 ]. Currently, UA nanoliposomes are undergoing clinical trials for various applications, including treatments for liver cancer (CTR20230593), gastric cancer (CTR20140180), and colon cancer (CTR20140395). The following discussion will concentrate on UA's anti-cancer properties and mechanisms.

UA improves tumor immunity

UA has shown promising immunomodulatory effects in breast and colon, liver cancers by interacting with a variety of immune cell types and in modulating the tumor microenvironment [ 1038 , 1039 ]. In breast cancer, UA inhibits cancer progression by augmenting the population of immune cells, promoting apoptosis, and restraining tumor-promoting immune cells, thereby regulating the tumor microenvironment [ 1040 – 1042 ]. It also inhibits breast cancer (4T1) tumor growth by reducing the number of Treg and MDSCs in tumor tissue through inhibiting STAT5 phosphorylation and IL-10 secretion [ 1043 ]. In addition, UA improves the tumor microenvironment by regulating tumor-associated fibroblasts (CAFs) in the tumor microenvironment, and it inhibits proliferation, migration and invasion of cancer cells by down-regulating the secretion of CXCL12 and decreasing the protein expression of CXCR4 and CXCR7 on the surface of colon cancer (HCT 116 and SW480) cells [ 1044 ]. Therefore, by targeting immune cell populations such as Tregs and MDSCs and modulating signaling pathways that regulate tumor cell migration and immune suppression, UA offers a promising strategy for enhancing anti-tumor immunity.

UA reverses tumor drug resistance

UA exhibits the ability to reverse multidrug resistance in cancer cells through various mechanisms. It can enhance the anti-tumor effects of drugs like first-line molecular drugs (adriamycin, cisplatin, and paclitaxel) and targeted drugs (sorafenib) in breast cancer (MCF-7 and MDA-MB-231), ovarian cancer (SK-OV-3 and A2780), osteosarcoma (HOS and 143B), lung cancer (A549), and liver cancer (Hep G2) cells [ 1045 ].

Adriamycin remains a prevalent therapeutic agent for breast cancer (MCF-7/ADR); however, MDR poses significant challenges in its efficacy, with UA emerging as a potential modulator of this resistance [ 1046 ]. Furthermore, UA has demonstrated the capacity to potentiate adriamycin’s anti-tumor effects by inhibiting proliferation and migration of breast cancer (MDA-MB-231/DOX and MCF-7/ADR) cells, as well as by inducing mitochondrial dysfunction via the AMPK/mTOR/PGC-1 α signaling pathway [ 1047 ]. Besides, in studies on adriamycin resistance in ovarian cancer, UA has been linked to the HuR/MDR1 axis, where it not only mitigates resistance but also enhances the sensitivity of ovarian cancer (SK-OV-3 and A2780) cells to adriamycin [ 1048 ]. UA enhances the anti-tumor effects of cisplatin through multiple mechanisms. In osteosarcoma (HOS and 143B) cells, UA promotes autophagic degradation of ferritin, leading to iron overload, lipid peroxidation, and ferroptosis, thereby increasing cisplatin's effectiveness [ 1049 ]. Additionally, in lung cancer (A549) cells, UA inhibits the JAK2/STAT3 pathway, reducing cancer stem cell marker expression and tumor stem cell populations, which sensitizes these cells to cisplatin [ 1050 ]. Paclitaxel is also a common drug used in the treatment of breast cancer. UA enhances paclitaxel sensitivity in breast cancer (MDA-MB-231/PTX) cells by up-regulating miR-149-5p , which down-regulates MyD88 protein expression and reverses drug resistance [ 1051 ]. Additionally, by down-regulating ING5 protein expression and inhibiting the PI3K/AKT signaling pathway, UA reverses liver cancer (Hep G2) cells resistance to sorafenib [ 1052 ]. Overall, UA demonstrates a broad capacity to reverse multidrug resistance in various cancer types, thereby enhancing the efficacy of common chemotherapy and targeted drugs. Through mechanisms such as inhibition of drug efflux pumps, modulation of metabolic pathways, regulation of miRNAs, and manipulation of key signaling pathways, UA sensitizes cancer cells to drugs like adriamycin, cisplatin, paclitaxel, and sorafenib.

UA suppresses cancer growth by regulating the processes of autophagy and ferroptosis

UA exhibits a unique mechanism of action inhibiting cancer growth, which is particularly critical through the regulation of autophagy and ferroptosis processes. Growing evidence shows that UA induces autophagy and ferroptosis in esophageal squamous cell carcinoma (TE-8 and TE-12), colon cancer (HCT-8/5-FU), breast cancer (MDA-MB-231 and BT-549) and osteosarcoma (HOS and 143B) cells [ 899 , 1053 ]. One of the key mechanisms of UA involves regulating autophagy, a cellular process that can either promote or inhibit cancer progression, depending on the cellular environment and the type of cancer [ 1054 , 1055 ]. UA regulates live ROS-mediated autophagy through the AKT/mTOR signaling pathway, and acts on esophageal squamous cell carcinoma (TE-8 and TE-12) cells to inhibit proliferation, migration, invasion, and induce apoptosis [ 1056 ]. Furthermore, UA regulates autophagy by inhibiting mTOR phosphorylation, and acts on 5-FU-resistant human colon cancer (HCT-8/5-FU) cells to induce apoptosis and autophagy, inhibit proliferation, and reverse multidrug resistance in cancer cells, which provides a rationale for colon cancer treatment [ 1057 ]. It also inhibited autophagosome maturation in breast cancer (MCF-7) cells, impaired cellular lipid homeostasis and lysosomal membrane integrity, and combined with cationic amphiphilic drugs could enhance the killing effect on breast cancer [ 1058 ].

UA inhibits the proliferation of triple-negative breast cancer (MDA-MB-231 and BT-549) and progression of osteosarcoma (HOS and 143B) cells by inducing ferroptosis [ 1049 , 1059 ]. UA induces iron death by inhibiting the NRF2 pathway and acts on MDA-B-231 and BT-549 cell-derived triple-negative breast cancer stem-like cells (BCSCs), effectively reducing their stemness characteristics and proliferative capacity, and inhibiting the cell proliferation of BCSCs in vitro and in vivo [ 1059 ]. In osteosarcoma (HOS and 143B), UA acts synergistically with cisplatin to activate autophagic degradation of ferritin, leading to intracellular accumulation of iron ions, generating lipid peroxidation and triggering iron death [ 1049 ]. Thus, UA promotes autophagic cell death and triggers ferroptosis, establishing it as a promising therapeutic agent in cancer treatment. By modulating critical pathways like AKT/mTOR in autophagy and NRF2 in ferroptosis, UA exhibits substantial anti-cancer effects across various types of cancer.

UA suppresses cancer progression via classical modalities

UA regulates cancer cell proliferation through inducing cell cycle at G0/G1, S, and G2/M phases in various cancer types, including breast, prostate, colon, and liver cancers. UA inhibits cancer progression through the regulation of classical ways like inducing cell cycle arrest and cell apoptosis [ 1060 , 1061 ]. UA inhibits breast cancer (MCF-7) cell proliferation by up-regulating protein expression of p53 and p21, and down-regulating that of CDK4, Cyclin D, CDK2, and cyclin E in the G0/G1 phase [ 1062 ]. In NSCLC (A549 and H460) cells, UA inhibits the EGFR/JAK2/STAT3 pathway to reduce tumor angiogenesis, migration and invasion, promote apoptosis and induce cell cycle arrest at G0/G1 phase [ 1063 ]. In colon cancer (SW480 and HCT 116), UA induces cell cycle arrest at the G0/G1 phase and promotes cell apoptosis. It enhances apoptosis by activating ROS and up-regulating the protein expression of Bax and down-regulating Bcl-2 protein level [ 1064 ]. In breast cancer (MCF-7), it induces cell cycle arrest at the G2/M cell phase, increases ROS levels and inhibits the PI3K/AKT signaling pathway, thereby promoting apoptosis, and also accelerates apoptotic processes by down-regulating Bcl-2 and up-regulating Bax protein expression [ 1034 ]. UA inhibits papillary thyroid carcinoma (IHH-4 and TPC-1) cells by classical mechanisms, which inhibits EMT by down-regulating fibronectin-1 (FN1), blocks invasive behaviors of cancer cells, reduces the protein expression of Bcl-2, and activates Caspase-3, which further promotes apoptosis [ 1065 ]. Therefore, UA demonstrates potent anti-cancer effects through classical mechanisms, primarily by inducing cell cycle arrest and promoting apoptosis. By modulating key signaling pathways such as p53, PI3K/AKT, EGFR/JAK2/STAT3, and Bax/Bcl-2, UA effectively inhibits cancer cell proliferation, migration, and invasion, while enhancing apoptosis.

UA combined with other medications for cancer treatment

UA can play a role in colon, stomach, prostate, liver, and lung cancer cells by combining first-line chemotherapeutic agents and natural products [ 1066 ]. UA is combined with other drugs in the treatment of cancer, it mainly works by inhibiting cancer cell migration, inducing apoptosis and mitochondrial autophagy, inhibiting the expression of tumor stem cell markers, increasing the anti-tumor efficacy of the drugs, and decreasing drug resistance in cancer cells [ 1067 – 1069 ]. UA is combined with the first-line chemotherapeutic drug Adriamycin, it can target and inhibit the AKT signaling pathway and activate the Hippo signaling pathway, reducing drug resistance, increasing apoptosis, inhibiting colon cancer (HCT 116) cell migration, and decreasing tumorigenesis [ 1069 , 1070 ]. UA can act in combination with sorafenib on a variety of human cancer (e.g., AGS, HCT 116, PC-3, Hep G2, and SMMC-7721) cells. It has potential anti-tumor effects in vivo by influencing the expression of the anti-apoptotic protein Mcl-1, reducing the potential of the mitochondrial membrane, triggering autophagy, and other mechanisms [ 1071 , 1072 ]. Additionally, combining UA with oleanolic acid can down-regulate the MMPs pathway to inhibit colon cancer (HT-29 and SW620) cell migration and enhance cancer cell death by inducing mitochondrial autophagy [ 1067 ]. This combination also potentially inhibits cancer cells by down-regulating the AKT/mTOR signaling pathway, activating the antioxidant response of NRF2 and affecting the intracellular autophagy mechanism in lung cancer (A549) cells [ 1068 ]. Thus, by enhancing the effects of chemotherapeutic agents such as adriamycin and sorafenib, and natural compounds like oleanolic acid, UA contributes to the inhibition of cancer cell migration, induction of apoptosis, and mitochondrial autophagy. Additionally, UA's ability to target key signaling pathways, including AKT, mTOR, and NRF2, enhances the anti-tumor efficacy of the combination therapies, while also reducing drug resistance.

UA derivatives inhibit cancer progression

Notable derivatives such as UA232 and UA derivatives substituted at the C-3 position are fascinating advancements that expand UA's potential in fighting breast and cervical cancers. Such structural modifications increase the selectivity and potency of these compounds, presenting new potential directions and applications for cancer therapy [ 1073 – 1077 ]. UA232 is chemically modified and synthesized to inhibit lung cancer (H460 and A549) cell proliferation by activating the PERK-eIF2a-CHOP pathway and inducing endoplasmic reticulum stress [ 1078 ]. In addition, UA232 activates the PERK/ATF4/CHOP pathway, triggers endoplasmic reticulum stress-associated apoptosis, and promotes lysosome-dependent cell death by increasing lysosomal membrane permeability, thereby effectively inhibiting the proliferation of breast cancer (MCF-7) and cervical cancer (HeLa) cells [ 1075 ]. Besides, a series of UA derivatives with different amino acid and dipeptide substitutions at the C-3 position, MDA-MB-231, are synthesized, and some of these derivatives (e.g., 4c, 7a, 10a) shows high cytotoxicity against triple-negative breast cancer (MDA-MB-231) cells, and inhibits cancer cell proliferation and migration, induces apoptosis and autophagy through various pathways [ 1079 ]. Therefore, UA derivatives, including UA232 and C-3 substituted derivatives, significantly expand the therapeutic potential of UA in cancer treatment. These derivatives exhibit enhanced potency and selectivity, enabling them to effectively inhibit cancer cell proliferation, migration, and metastasis through mechanisms such as the activation of the PERK/eIF2 α /CHOP pathway, induction of ER stress, and lysosome-dependent cell death.

Application of multi-omics techniques to investigate the anti-cancer properties of UA

The application of multi-omics techniques has brought new research opportunities for UA research. UA inhibits breast cancer (MCF-7) cell proliferation through multilevel regulation. Metabolomic and epigenetic analyses showed that UA modulates metabolite levels, alters gene methylation patterns, and affects key signaling pathways such as RAF/ERK and IKK/NF- κ B in cancer cells [ 1080 ]. In prostate cancer (VCaP) cells, UA regulates critical metabolites and signaling pathways, such as S-adenosylmethionine (SAM), glycolysis, and phospholipid metabolism, while RNA sequencing indicates UA’s impact on pathways related to cancer metastasis and oxidative stress [ 1081 ]. As a result, by regulating key metabolites, gene methylation patterns, and signaling pathways involved in cancer cell growth, metabolism, and metastasis, UA shows promise as a multifaceted therapeutic agent.

Investigating UA anti-cancer effects through drug delivery system

UA has potential for clinical application as an antitumor agent; however, effective targeting of tumors remains challenging due to limitations such as poor water solubility, rapid plasma clearance and low targeting efficiency. To overcome these challenges, recent studies have focused on improving the therapeutic efficacy of UA in colon, breast and lung cancers using DDS via nanoparticle encapsulation, polymeric micelles and hydrogels [ 1082 ]. Nanoparticle-based UA drug delivery system UA/(AS-IV)@PDA-HA synergistically inhibits the proliferation and metastasis of NSCLC (CTC-TJH-01 and A549) cells by chemotherapy, PTT and immunotherapy, demonstrating good biocompatibility and tumor targeting [ 1083 ]. UA can be synthesized into polyursolic acid (PUA) by polycondensation reaction, and the self-assembly of this PUA with paclitaxel can form PUA-NPs@PTX nanoparticles, and this PUA-NPs@PTX can be retained for a longer period of time in CT26 hormone mice, which has strong anti-tumor effects on colon cancer (CT26) cells [ 1084 ]. Furthermore, UA and the pharmaceutical agent 5-fluorouracil (5-FU) can be utilized in a nano-delivery system, which is prepared through a pore space allocation strategy to regulate the release of both substances. This approach consequently results in a more pronounced inhibitory effect on breast cancer (4T1) cells [ 1085 ]. Besides, in breast cancer cell (MCF-7/ADR), the inhibitory effect of adriamycin hydrochloride on drug-resistant tumors is enhanced by constructing micelles with mitochondria-targeting and ROS-sensitive functionality (TDTD@ UA/HA) and inhibits the proliferation of drug-resistant breast cancer cells [ 1086 ]. In the hydrogel delivery system, UA can be constructed with cisplatin (DDP) as a co-loaded pectin/cellulose hydrogel, which acts on mouse lung cancer (LA795) cells to inhibit the proliferation, migration and promote apoptosis of lung cancer cells by inhibiting the TMEM16A, regulating the MAPK and EMT signaling pathways and other mechanisms [ 1087 ]. Therefore, nanoparticle encapsulation, polymeric micelles, hydrogels, and other formulations have addressed the challenges of poor solubility, rapid clearance, and low targeting efficiency, making UA a more viable option for clinical use. These innovative delivery systems improve the bioavailability and targeted delivery of UA to tumor sites, enhancing its anti-cancer effects in various cancer types.

In sum, UA orchestrates diverse anti-cancer mechanisms from reconfiguring the tumor immune landscape and reversing multidrug resistance to provoking autophagy, and ferroptosis-driven cell death. By modulating critical pathways (e.g., AKT/mTOR, JAK/STAT, and NRF2) in tandem with Tregs, MDSCs, and fibroblasts, it dampens tumor progression while enhancing chemotherapy responsiveness. Recent innovations in nano-formulations and hydrogels circumvent its solubility barriers, enabling potent synergy with conventional therapies. Multi-omics evidence underscores UA’s broad regulatory impact, emphasizing its potential for robust tumor suppression across multiple cancers.

Conclusion

This review highlights the potential of natural anti-cancer products derived from herbal medicine, underscoring their diverse pharmacological properties and mechanisms of action. Compounds such as apigenin, artemisinin, berberine, and curcumin, among others, have demonstrated significant immunomodulatory, anti-proliferative, pro-apoptotic, and anti-metastatic effects, both in vitro and in vivo. These natural products hold promise for the development of novel anti-cancer therapies, potentially as standalone treatments or in synergy with existing therapies to enhance efficacy and reduce side effects. They exhibit multi-target and multi-mechanism anti-cancer actions, including direct cytotoxicity against tumor cells, suppression of tumor growth and metastasis, immunomodulation, and enhancement of chemotherapy effectiveness, along with reduced treatment-related side effects.

However, several challenges remain, including variability in the quality of herbal extracts, limited clinical data supporting their effectiveness, and the need for more rigorous pharmacokinetic and pharmacodynamic studies. Addressing the bioavailability and pharmacokinetic limitations of these natural compounds is also crucial for improving their targeted therapeutic effects on tumor tissues. Emerging DDS, such as nanoparticles, micelles, and affinity hydrogels, have successfully enhanced the targeting and efficacy of certain natural products like UA.

In addition, integrating multi-omics technologies has allowed deeper insights into the molecular networks underlying the actions of natural compounds. For instance, metabolomics and methylation analyses have revealed the metabolic reprogramming and epigenetic regulatory effects of UA on cancer cells. The research methodologies typically employed in oncology pharmacology—including efficacy assays, omics predictions, target verification, and drug modification—culminate in integrating the unique characteristics of these compounds with advanced DDS to optimize clinical application. Figure 3 presented in this paper provides a standardized research strategy to guide future investigators.

Until now, small molecules in herbal medicines have been relatively well-studied, but they are very low proportion of the components in herbal medicines. Even though polysaccharides have captured significant research interests, numerous components within herbal medicines, including proteins, lipids, and nucleic acids, await comprehensive exploration. Emerging evidence indicates that the plant-derived exosomes have promising avenues and offer unique opportunities for the innovation and development of herbal medicines. Future studies should prioritize standardized extraction protocols, rigorous clinical trials, mechanistic studies, and the application of machine learning to fully harness the therapeutic potential of natural products from herbal medicines. Ultimately, these efforts aim to integrate natural substances into standard cancer treatment regimens, providing a holistic approach that complements and enhances contemporary oncological practices. The fusion of traditional herbal wisdom with advanced scientific technologies promises a new chapter in cancer therapy, potentially improving patient survival rates and quality of life.

Acknowledgements

We would like to thank Prof. WANG Yitao, Prof. CHEN Xiuping, Prof. LU Jinjian, and all our colleagues for their sincere and generous help.

Abbreviations

ATP-binding cassette subfamily B member 1

Acyl-CoA synthetase long chain family member 4

Actin filament associated protein 1-like 2

AMP-activated protein kinase

Autophagy-related genes

Bcl-2-associated death promoter

Bcl-2 homologous antagonist/killer

Bcl-2-associated x protein

B-cell lymphoma 2

B-cell lymphoma-extra large

Breast cancer resistance protein

Biopharmaceutical classification system

Bisdemethoxycurcumin

Bcl-2-interacting mediator of cell death

Colitis-associated colon cancer

C–C motif chemokine ligand 2

Curcumin difluorinated

Cyclin-dependent kinase

Chronic myelogenous leukaemia

Cyclooxygenase-2

Cytotoxic T lymphocyte

Cytotoxic T-lymphocyte-associated protein 4

C-X-C motif chemokine ligand

C-X-C chemokine receptor type

Dendritic cells

Drug delivery systems

Demethoxycurcumin

Dual specificity phosphatase 1

Epidermal growth factor

Epidermal growth factor receptor

Epithelial-mesenchymal transformation

Fatty acid synthase

Glucose transporter 1

Glycerol-3-phosphate acyltransferase 1

Glutathione peroxidase 4

Glutathione, HAS2: Hyaluronan synthase 2

Human epidermal growth factor receptor

Hypoxia-inducible factor 1-alpha

Head and neck squamous cell carcinoma

Heat shock protein 90

Interleukin

Inducible nitric oxide synthase

C-Jun n-terminal kinase

Kirsten rat sarcoma viral oncogene homolog

Laminin subunit beta 3

Leukotriene C4

Mitogen-activated protein kinase

Myeloid cell leukemia-1

Myeloid-derived suppressor cells

Matrix metalloproteinases

Multidrug resistance protein 1

Mammalian target of rapamycin

Mammalian target of rapamycin complex 1

Nuclear receptor corepressor 2

Neutrophil extracellular traps

Nuclear factor kappa-B

Natural killer

Nuclear magnetic resonance

Nuclear factor erythroid 2-related factor 2

Poly (ADP-ribose) polymerase

Peripheral blood mononuclear cells

Programmed death-1

Platelet-derived growth factor

Programmed death-ligand 1

Plasmodium falciparum multidrug resistance protein 1

P-glycoprotein

Phosphoinositide 3-kinase

Phosphatase and tensin homolog

Parathyroid hormone-like hormone

Quantitative structure–activity relationship

Reactive oxygen species

Receptor tyrosine kinases

Senescence-associated secretory phenotype

Stearoyl-coA desaturase

Stromal cell-derived factor 1

Src homology 2 domain-containing inositol phosphatase 1

Salt-inducible kinase 3

Solute carrier family 7 member 11

Self-microemulsifying drug delivery system

SRY-related HMG-box 11

Signal transducer and activator of transcription 3

Tumor-associated macrophages

Transcription factor 4

Transforming growth factor-beta

Tetrahydrocurcumin

Toll-like receptor

Tumor necrosis factor-alpha

Tocopheryl polyethylene glycol 1000 succinate

Regulatory T cells

Twist family BHLH transcription factor 1

Unc-51 like autophagy activating kinase 1

Vascular endothelial growth factor receptor

WEE1 G2 checkpoint kinases

Author contributions

ZZ, WT, and YF designed, organized, and supervised this word. DC, CZ, LZ, JZ, JW, LH, HJ, QK, YZ, NL, ZS, WZ, JW, SZ drafted the manuscript. DC, CZ, WT, and ZZ revised the manuscript. All authors read and approved of the final manuscript.

Funding

The work was supported by grants from the Science and Technology Development Fund, Macau SAR, China (No. 0123/2022/A, 0008/2023/RIC, 001/2023/ALC, 0006/2020/AKP, and 005/2023/SKL), the Outstanding Youth of the Fundamental Research Funds for the Central Universities (lzujbky-2021-ey21), the Shenzhen-Hong Kong-Macau S&T Program (Category C) (SGDX2020110309420200), the Research Fund of University of Macau (MYRG-GRG2023-00198-ICMS and SRG2022-00052-ICMS), the Research Grants Committee Fund, Hong Kong (Project Codes: 17152116 and 17121419), the Health and Medical Research Fund, Hong Kong (Project code: 18192141 and 21222101), and the Innovation and Technology Fund, Hong Kong (PRP/069/22FX).

Availability of data and materials

Not applicable.

Declarations

Consent for publication

The manuscript is approved by all authors for publication.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dianxin Cui, Cheng Zhang and Lili Zhang have contributed equally to this work.

Contributor Information

Yibin Feng, Email: yfeng@hku.hk.

Wen Tan, Email: tanwen@lzu.edu.cn.

Zhangfeng Zhong, Email: zfzhong@um.edu.mo.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2024;74(3):229–63.

2. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics. Cancer J Clin. 2025;75(1):10–45.

3. Liao P, Yan B, Wang C, et al. Telomeres: dysfunction, maintenance, aging and cancer. Aging Dis. 2024;15(6):2595–631.

4. Kordowitzki P, Graczyk S, Mechsner S, et al. Shedding Light on the Interaction Between Rif1 and telomeres in ovarian cancer. Aging Dis. 2024;15(2):535–45.

5. Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25.

6. Megerian MF, Kim JS, Badreddine J, et al. Melatonin and prostate cancer: anti-tumor roles and therapeutic application. Aging Dis. 2023;14(3):840–57.

7. Holder AM, Dedeilia A, Sierra-Davidson K, et al. Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours. Nat Rev Cancer. 2024;24(7):498–512.

8. Rani L, Thapa K, Kanojia N, et al. An extensive review on the consequences of chemical pesticides on human health and environment. J Clean Prod. 2021;283: 124657.

9. Tang X, Yang T, Yu D, et al. Current insights and future perspectives of ultraviolet radiation (UV) exposure: Friends and foes to the skin and beyond the skin. Environ Int. 2024;185: 108535.

10. Pfefferkorn RM, Mortzfeld BM, Fink C, et al. Recurrent phases of strict protein limitation inhibit tumor growth and restore lifespan in a drosophila intestinal cancer model. Aging Dis. 2024;15(1):226–44.

11. Ruiz E, Kandil E, Alhassan S, et al. An integrative multi-omics analysis of the molecular links between aging and aggressiveness in thyroid cancers. Aging Dis. 2023;14(3):992–1012.

12. Zhong ZF, Vong CT, Chen FY, et al. Immunomodulatory potential of natural products from herbal medicines as immune checkpoints inhibitors: Helping to fight against cancer via multiple targets. Med Res Rev. 2022;42(3):1246–79.

13. Huang J, Shi R, Chen F, et al. Exploring the anti-hepatocellular carcinoma effects of Xianglian pill: Integrating network pharmacology and RNA sequencing via in silico and in vitro studies. Phytomedicine. 2024;133: 155905.

14. Luo H, Vong CT, Chen H, et al. Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine. Chin Med. 2019. 10.1186/s13020-019-0270-9.

15. Tan W, Lu J, Huang M, et al. Anti-cancer natural products isolated from Chinese medicinal herbs. Chin Med. 2011;6:27.

16. Zhou FF, Aipire A, Xia LJ, et al. Marchantia polymorpha L. ethanol extract induces apoptosis in hepatocellular carcinoma cells via intrinsic- and endoplasmic reticulum stress-associated pathways. Chin Med. 2021. 10.1186/1749-8546-6-27.

17. Yuan RYK, Fan QM, Liang XW, et al. Cucurbitacin B inhibits TGF-β1-induced epithelial-mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways. Chin Med. 2022;17(1):1.

18. Dou XJ, Zhou ZQ, Ren RM, et al. Apigenin, flavonoid component isolated from Gentiana veitchiorum flower suppresses the oxidative stress through LDLR-LCAT signaling pathway. Biomed Pharmacother. 2020;128:40.

19. Alghamdi A, Almuqbil M, Alrofaidi MA, et al. Potential antioxidant activity of apigenin in the obviating stress-mediated depressive symptoms of experimental mice. Molecules. 2022;27(24):5.

20. Sherif SG, Tarek M, Sabry YG, et al. Effect of apigenin on dynamin-related protein 1 in type 1 diabetic rats with cardiovascular complications. Gene. 2024;898:14.

21. Hong S, Dia VP, Zhong QX. Synergistic anti-inflammatory activity of apigenin and curcumin co-encapsulated in caseins assessed with lipopolysaccharide-stimulated RAW 264.7 macrophages. Int J Biol Macromol. 2021;193:702–12.

22. Jiang Z-B, Wang W-J, Xu C, et al. Luteolin and its derivative apigenin suppress the inducible PD-L1 expression to improve anti-tumor immunity in KRAS-mutant lung cancer. Cancer Lett. 2021;515:36–48.

23. Adel M, Zahmatkeshan M, Akbarzadeh A, et al. Chemotherapeutic effects of Apigenin in breast cancer: Preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles. Biotechnol Rep. 2022;34: e00730.

24. Tong J, Shen Y, Zhang Z, et al. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through NF-κB/Snail signaling pathway. Biosci Rep. 2019;39(5):16.

25. Woo J-S, Choo G-S, Yoo E-S, et al. Apigenin induces apoptosis by regulating Akt and MAPK pathways in human melanoma cell A375SM. Mol Med Rep. 2020;22(6):4877–89.

26. Chien M-H, Lin Y-W, Wen Y-C, et al. Targeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis. J Exp Clin Cancer Res. 2019;38:1–17.

27. Bao Y, Wu X, Jin X, et al. Apigenin inhibits renal cell carcinoma cell proliferation through G2/M phase cell cycle arrest. Oncol Res. 2022;47(3):1–7.

28. Chen Y-H, Wu J-X, Yang S-F, et al. Anticancer effects and molecular mechanisms of apigenin in cervical cancer cells. Cancers. 2022;14(7):1824.

29. Heydarzadeh S, Moshtaghie AA, Daneshpour M, et al. The effect of Apigenin on glycometabolism and cell death in an anaplastic thyroid cancer cell line. Toxicol Appl Pharmacol. 2023;475: 116626.

30. Ruela-de-Sousa R, Fuhler GM, Blom N, et al. Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death Dis. 2010;1(1):e19–e19.

31. Huang J, Chen X, Chang Z, et al. Boosting anti-tumour immunity using adjuvant Apigenin. Anticancer Agents Med Chem. 2023;23(3):266–77.

32. Li Q, Li L, Zhao X, et al. Apigenin induces apoptosis and reverses the drug resistance of ovarian cancer cells. Int J Clin Exp Med. 2020;13(3):1987–94.

33. Liang Y, Zhong Q, Ma R, et al. Apigenin, a natural flavonoid, promotes autophagy and ferroptosis in human endometrial carcinoma Ishikawa cells in vitro and in vivo. Food Sci Hum Wellness. 2023;12(6):2242–51.

34. Wang W, Liu X, Zhang Z, et al. Apigenin induced apoptosis by downregulating Sulfiredoxin expression in cutaneous squamous cell carcinoma. Oxid Med Cell Longev. 2022;2022(1):8172866.

35. Akash S, Bayil I, Hossain MS, et al. Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by Apigenin derivatives. Sci Rep. 2023. 10.1038/s41598-023-43175-x.

36. Zhang J, Liu D, Huang Y, et al. Biopharmaceutics classification and intestinal absorption study of apigenin. Int J Pharm. 2012;436(1):311–7.

37. Altamimi MA, Elzayat EM, Alshehri SM, et al. Utilizing spray drying technique to improve oral bioavailability of apigenin. Adv Powder Technol. 2018;29(7):1676–84.

38. Perez-Moral N, Saha S, Philo M, et al. Comparative bio-accessibility, bioavailability and bioequivalence of quercetin, apigenin, glucoraphanin and carotenoids from freeze-dried vegetables incorporated into a baked snack versus minimally processed vegetables: Evidence from in vitro models and a human bioavailability study. J Funct Foods. 2018;48:410–9.

39. Zhao L, Zhang L, Meng L, et al. Design and evaluation of a self-microemulsifying drug delivery system for apigenin. Drug Dev Ind Pharm. 2013;39(5):662–9.

40. Alshehri SM, Shakeel F, Ibrahim MA, et al. Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques. Saudi Pharm J. 2019;27(2):264–73.

41. Huang S, Yu M, Shi N, et al. Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro. J Cancer. 2020;11(8):2123.

42. Şirin N, Elmas L, Seçme M, et al. Investigation of possible effects of apigenin, sorafenib and combined applications on apoptosis and cell cycle in hepatocellular cancer cells. Gene. 2020;737: 144428.

43. Zhang X, Zhang W, Chen F, et al. Combined effect of chrysin and apigenin on inhibiting the development and progression of colorectal cancer by suppressing the activity of P38-MAPK/AKT pathway. IUBMB Life. 2021;73(5):774–83.

44. Zhou X, Wang F, Zhou R, et al. Apigenin: A current review on its beneficial biological activities. J Food Biochem. 2017;41(4): e12376.

45. Villalobos-Ayala K, Ortiz Rivera I, Alvarez C, et al. Apigenin increases SHIP-1 expression, promotes tumoricidal macrophages and anti-tumor immune responses in murine pancreatic cancer. Cancers. 2020. 10.1177/03946320231161174.

46. Feng Y-B, Chen L, Chen F-X, et al. Immunopotentiation effects of apigenin on NK cell proliferation and killing pancreatic cancer cells. Int J Immunopathol Pharmacol. 2023;37:03946320231161174.

47. Coombs MRP, Harrison ME, Hoskin DW. Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells. Cancer Lett. 2016;380(2):424–33.

48. Ghițu A, Schwiebs A, Radeke HH, et al. A comprehensive assessment of apigenin as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. Nutrients. 2019;11(4):858.

49. Xu L, Zhang Y, Tian K, et al. Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects. J Exp Clin Cancer Res. 2018;37:1–15.

50. Myo A, Hasym M, Nor N, et al. Effects of apigenin, Luteolin, and Quercetin on the Natural Killer (NK-92) cells proliferation: a potential role as immunomodulator. SAINS MALAYS. 2021;50(3):821–8.

51. Hu W-J, Liu J, Zhong L-K, et al. Apigenin enhances the antitumor effects of cetuximab in nasopharyngeal carcinoma by inhibiting EGFR signaling. Biomed Pharmacother. 2018;102:681–8.

52. Boeckx C, Op de Beeck K, Wouters A, et al. Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins. Cancer Lett. 2014;354(2):365–77.

53. Bhattacharya B, Low S, Soh C, et al. Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. Br J Pharmacol. 2014;171(13):3255–67.

54. Jiang T, Zhou M-L, Fan J. Inhibition of GLUT-1 expression and the PI3K/Akt pathway to enhance the chemosensitivity of laryngeal carcinoma cells in vitro. Onco Targets Ther. 2018;11:7865–72.

55. Xu YY, Wu TT, Zhou SH, et al. Apigenin suppresses GLUT-1 and p-AKT expression to enhance the chemosensitivity to cisplatin of laryngeal carcinoma Hep-2 cells: an in vitro study. Int J Clin Exp Pathol. 2014;7(7):3938–47.

56. Kelly GL, Strasser A. Toward targeting antiapoptotic MCL-1 for cancer therapy. Annu Rev Cell Dev Biol. 2020;4(1):299–313.

57. Qi Y, Ding Z, Yao Y, et al. Apigenin induces apoptosis and counteracts cisplatin-induced chemoresistance via Mcl-1 in ovarian cancer cells. Exp Ther Med. 2020;20(2):1329–36.

58. Gao AM, Ke ZP, Wang JN, et al. Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis. 2013;34(8):1806–14.

59. Gao AM, Zhang XY, Hu JN, et al. Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis. Chem Biol Interact. 2018;280:45–50.

60. Angelini A, Di Ilio C, Castellani ML, et al. Modulation of multidrug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin-resistant sarcoma cells (MES-SA/DX-5): implications for natural sedatives as chemosensitizing agents in cancer therapy. J Biol Regul Homeost Agents. 2010;24(2):197–205.

61. Zhu Y, Liu C, Nadiminty N, et al. Inhibition of ABCB1 expression overcomes acquired docetaxel resistance in prostate cancer. Mol Cancer Ther. 2013;12(9):1829–36.

62. Seo HS, Ku JM, Choi HS, et al. Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells. Oncol Rep. 2017;38(2):715–24.

63. Li K, Li M, Luo Z, et al. Overcoming the hypoxia-induced drug resistance in liver tumor by the concurrent use of apigenin and paclitaxel. Biochem Biophys Res Commun. 2020;526(2):321–7.

64. Hazari Y, Bravo-San Pedro JM, Hetz C, et al. Autophagy in hepatic adaptation to stress. J Hepatol. 2020;72(1):183–96.

65. Yang Y, Klionsky DJ. Autophagy and disease: unanswered questions. Cell Death Differ. 2020;27(3):858–71.

66. Ashrafizadeh M, Mohammadinejad R, Tavakol S, et al. Autophagy, anoikis, ferroptosis, necroptosis, and endoplasmic reticulum stress: potential applications in melanoma therapy. J Cell Physiol. 2019;234(11):19471–9.

67. Lee Y, Sung B, Kang YJ, et al. Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Int J Oncol. 2014;44(5):1599–606.

68. Yang J, Pi C, Wang G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed Pharmacother. 2018;103:699–707.

69. Chen X, Xu H, Yu X, et al. Apigenin inhibits in vitro and in vivo tumorigenesis in cisplatin-resistant colon cancer cells by inducing autophagy, programmed cell death and targeting m-TOR/PI3K/Akt signalling pathway. J buon. 2019;24(2):488–93.

70. Landis-Piwowar KR, Milacic V, Dou QP. Relationship between the methylation status of dietary flavonoids and their growth-inhibitory and apoptosis-inducing activities in human cancer cells. J Cell Biochem. 2008;105(2):514–23.

71. Kim TW, Lee HG. Apigenin induces autophagy and cell death by targeting EZH2 under hypoxia conditions in gastric cancer cells. Int J Mol Sci. 2021;22(24):13455.

72. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.

73. Adham AN, Abdelfatah S, Naqishbandi AM, et al. Cytotoxicity of apigenin toward multiple myeloma cell lines and suppression of iNOS and COX-2 expression in STAT1-transfected HEK293 cells. Phytomedicine. 2021;80: 153371.

74. Shao C, Yuan J, Liu Y, et al. Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis. Proc Natl Acad Sci U S A. 2020;117(19):10155–64.

75. Liu R, Rong G, Liu Y, et al. Delivery of apigenin-loaded magnetic Fe2O3/Fe3O4@ mSiO2 nanocomposites to A549 cells and their antitumor mechanism. Mater Sci Eng C Mater Biol Appl. 2021;120: 111719.

76. Imran M, Aslam Gondal T, Atif M, et al. Apigenin as an anticancer agent. Phytother Res. 2020;34(8):1812–28.

77. Cheng Y, Han X, Mo F, et al. Apigenin inhibits the growth of colorectal cancer through down-regulation of E2F1/3 by miRNA-215-5p. Phytomedicine. 2021;89: 153603.

78. Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther. 2006;5(4):843–52.

79. Sharma A, Sinha S, Keswani H, et al. Kaempferol and Apigenin suppresses the stemness properties of TNBC cells by modulating Sirtuins. Mol Divers. 2022;26(6):3225–40.

80. Zheng P-W, Chiang L-C, Lin C-C. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci. 2005;76(12):1367–79.

81. Lu H-F, Chie Y-J, Yang M-S, et al. Apigenin induces caspase-dependent apoptosis in human lung cancer A549 cells through Bax-and Bcl-2-triggered mitochondrial pathway. Int J Oncol. 2010;36(6):1477–84.

82. Qin Y, Zhao D, Zhou HG, et al. Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma. Oncotarget. 2016;7(27):41421–31.

83. Cao H-H, Chu J-H, Kwan H-Y, et al. Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma. Sci Rep. 2016;6(1):21731.

84. Abcha I, Souilem S, Neves MA, et al. Ethyl oleate food-grade O/W emulsions loaded with apigenin: Insights to their formulation characteristics and physico-chemical stability. Food Rev Int. 2019;116:953–62.

85. Kim BK, Cho AR, Park DJ. Enhancing oral bioavailability using preparations of apigenin-loaded W/O/W emulsions: In vitro and in vivo evaluations. Food Chem. 2016;206:85–91.

86. Banerjee K, Banerjee S, Mandal M. Enhanced chemotherapeutic efficacy of apigenin liposomes in colorectal cancer based on flavone-membrane interactions. J Colloid Interface Sci. 2017;491:98–110.

87. Jin X, Yang Q, Zhang Y. Synergistic apoptotic effects of apigenin TPGS liposomes and tyroservatide: implications for effective treatment of lung cancer. Int J Nanomedicine. 2017;12:5109–18.

88. Ding B, Chen H, Wang C, et al. Preparation and in vitro evaluation of apigenin loaded lipid nanocapsules. J Nanosci Nanotechnol. 2013;13(10):6546–52.

89. Das S, Das J, Samadder A, et al. Strategic formulation of apigenin-loaded PLGA nanoparticles for intracellular trafficking, DNA targeting and improved therapeutic effects in skin melanoma in vitro. Toxicol Lett. 2013;223(2):124–38.

90. Yu L, Zheng S, Chen Y, et al. Assessing the interactions between p53 gene and three types of flavonoid therapeutic compound in ovarian cancer cell line. Int J Chin Exp Med. 2017;10(3):4764–71.

91. Bhattacharya S, Mondal L, Mukherjee B, et al. Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats. Nanomedicine. 2018;14(6):1905–17.

92. Meng Y, Ma N, Lyu H, et al. Recent pharmacological advances in the repurposing of artemisinin drugs. Med Res Rev. 2021;41(6):3156–81.

93. Cheong DHJ, Tan DWS, Wong FWS, et al. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol Res. 2020;158: 104901.

94. Chen S, Liao B, Guo S, et al. Genetic analysis reveals the inconsistency of amorpha-4,11-diene synthase, a key enzyme in the artemisinin synthesis pathway, in asteraceae. Chin Med. 2023. 10.1186/s13020-023-00708-w.

95. Shi HA, Wang ZQ, Xu FJ, et al. A discovery-based metabolomic approach using UPLC-Q-TOF-MS/MS reveals potential antimalarial compounds present in artemisia annua L. Int J Mol Sci. 2022;23(23):14903.

96. Wang XG, Zheng BH, Ashraf U, et al. Artemisinin inhibits the replication of flaviviruses by promoting the type I interferon production. Antiviral Res. 2020;179:104810.

97. Chung IY, Jang HJ, Yoo YJ, et al. Artemisinin displays bactericidal activity via copper-mediated DNA damage. Virulence. 2022;13(1):149–59.

98. Favero FD, Basting RT, de Freitas AS, et al. Artemisinin and deoxyartemisinin isolated from Artemisia annua L. promote distinct antinociceptive and anti-inflammatory effects in an animal model. Biomed Pharmacother. 2024;178:117299.

99. Kadioglu O, Klauck SM, Fleischer E, et al. Selection of safe artemisinin derivatives using a machine learning-based cardiotoxicity platform and in vitro and in vivo validation. Arch Toxicol. 2021;95(7):2485–95.

100. Ye Y, Yang Y, Yan L, et al. Integrating network pharmacology and experimental validation to explore the effects and mechanisms of qinghao biejia decoction and its active compound artemisinin b against non-small-cell lung cancer. Drug Des Devel Ther. 2023;17:2461–79.

101. Zhou X, Zijlstra SN, Soto-Gamez A, et al. Artemisinin derivatives stimulate DR5-specific TRAIL-induced apoptosis by regulating wildtype P53. Cancers. 2020;12(9):2514.

102. Zhang Q, Yi H, Yao H, et al. Artemisinin derivatives inhibit non-small cell lung cancer cells through induction of ROS-dependent apoptosis/ferroptosis. J Cancer. 2021;12(13):4075–85.

103. Zhou X, Chen Y, Wang F, et al. Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact. 2020;331:109273.

104. Zhou Y, Li X, Chen K, et al. Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers. Eur J Med Chem. 2021;211:113000.

105. Guan X, Guan Y. Artemisinin induces selective and potent anticancer effects in drug-resistant breast cancer cells by inducing cellular apoptosis and autophagy and G2/M cell cycle arrest. J BUON. 2020;25(3):1330–6.

106. Posadino AM, Giordo R, Pintus G, et al. Medicinal and mechanistic overview of artemisinin in the treatment of human diseases. Biomed Pharmacother. 2023;163: 114866.

107. Sun X, Yan P, Zou C, et al. Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives. Med Res Rev. 2019;39(6):2172–93.

108. Dai X, Zhang X, Chen W, et al. Dihydroartemisinin: a potential natural anticancer drug. Int J Biol Sci. 2021;17(2):603–22.

109. Ma Z, Woon CY, Liu CG, et al. Repurposing artemisinin and its derivatives as anticancer drugs: a chance or challenge? Front Pharmacol. 2021;12: 828856.

110. Gao F, Sun Z, Kong F, et al. Artemisinin-derived hybrids and their anticancer activity. Eur J Med Chem. 2020;188: 112044.

111. Zeng ZW, Chen D, Chen L, et al. A comprehensive overview of Artemisinin and its derivatives as anticancer agents. Eur J Med Chem. 2023;247: 115000.

112. Zhang M, Wang L, Liu W, et al. Targeting inhibition of accumulation and function of myeloid-derived suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK pathways enhances anti-PD-L1 immunotherapy in melanoma and liver tumors. J Immunol Res. 2022;2022:1.

113. Lu Z, Bi J, Wan X. Artemisinin sensitizes tumor cells to NK cell-mediated cytolysis. Biochem Biophys Res Commun. 2020;524(2):418–23.

114. Wang C-Z, Wan C, Li C-H, et al. Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation. Cancer Chemother Pharmacol. 2024;93(5):411–25.

115. Xiong G, Huang D, Lu L, et al. Near-infrared-II light induced mild hyperthermia activate cisplatin-artemisinin nanoparticle for enhanced chemo/chemodynamic therapy and immunotherapy. Small Methods. 2022;6(9): e2200379.

116. Wang Y, Li Y, Shang D, et al. Interactions between artemisinin derivatives and P-glycoprotein. Phytomedicine. 2019;60:152998.

117. Zhang X, Li N, Zhang G, et al. Nano strategies for artemisinin derivatives to enhance reverse efficiency of multidrug resistance in breast cancer. Curr Pharm Des. 2023;29(43):3458–66.

118. Ma Z, Chen W, Liu Y, et al. Artesunate sensitizes human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy. Autophagy. 2024;20(3):541–56.

119. Li Z, Zhu YT, Xiang M, et al. Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate. Acta Pharmacol Sin. 2021;42(4):624–32.

120. Zhuo Z, Zhang D, Lu W, et al. Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation. Oncol Res. 2024;32(6):1093–107.

121. Chen Y, Li R, Zhu Y, et al. Dihydroartemisinin induces growth arrest and overcomes dexamethasone resistance in multiple myeloma. Front Oncol. 2020;10:767.

122. Wang Y, Yang Z, Zhu W, et al. Dihydroartemisinin inhibited stem cell-like properties and enhanced oxaliplatin sensitivity of colorectal cancer via AKT/mTOR signaling. Drug Dev Res. 2023;84(5):988–98.

123. Cai X, Miao J, Sun R, et al. Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer. Pharmacol Res. 2021;170: 105701.

124. Zhao FG, Vakhrusheva O, Markowitsch SD, et al. Artesunate impairs growth in cisplatin-resistant bladder cancer cells by cell cycle arrest, apoptosis and autophagy induction. Cells. 2020;9(12):2643.

125. Elbadawi M, Boulos JC, Dawood M, et al. The novel artemisinin dimer isoniazide ELI-XXIII-98–2 induces c-MYC inhibition, DNA damage, and autophagy in leukemia cells. Pharmaceutics. 2023;15(4):1107.

126. Zhang J, Zhou L, Xiang JD, et al. Artesunate-induced ATG5-related autophagy enhances the cytotoxicity of NK92 cells on endometrial cancer cells via interactions between CD155 and CD226/TIGIT. Int Immunopharmacol. 2021;97: 107705.

127. Chen Y, Wang F, Wu P, et al. Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling. Cell Signal. 2021;88: 110167.

128. Shi X, Wang L, Ren L, et al. Dihydroartemisinin, an antimalarial drug, induces absent in melanoma 2 inflammasome activation and autophagy in human hepatocellular carcinoma HepG2215 cells. Phytother Res. 2019;33(5):1413–25.

129. Chen F, Lu J, Zheng B, et al. artesunate inhibits the growth of insulinoma cells via SLC7A11/GPX4-mediated ferroptosis. Curr Pharm Des. 2024;30(3):230–9.

130. Liu X, Cai Y, Zhang Y, et al. Artesunate: a potential drug for the prevention and treatment from hepatitis to hepatocellular carcinoma. Pharmacol Res. 2024;210:107526.

131. Liang L, Liu Y, Wu X, et al. Artesunate induces ferroptosis by inhibiting the nuclear localization of SREBP2 in myeloma cells. Int J Med Sci. 2023;20(12):1535–50.

132. Chen Y, Tao H, Wang F, et al. Artesunate synergistically promotes sorafenib-induced apoptosis and ferroptosis in non-Hodgkin lymphoma cells through inhibition of the STAT3 pathway. Oncol Rep. 2023. 10.3892/or.2023.8584.

133. Wang Z, Li M, Liu Y, et al. Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response-induced upregulation of CHAC1 expression. Oncol Rep. 2021. 10.3892/or.2021.8191.

134. Chen GQ, Benthani FA, Wu J, et al. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ. 2020;27(1):242–54.

135. Grignano E, Cantero-Aguilar L, Tuerdi Z, et al. Dihydroartemisinin-induced ferroptosis in acute myeloid leukemia: links to iron metabolism and metallothionein. Cell Death Discov. 2023;9(1):97.

136. Du J, Wang T, Li Y, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;131:356–69.

137. Zhong Y, Li ZN, Jiang XY, et al. Identification of novel artemisinin hybrids induce apoptosis and ferroptosis in MCF-7 cells. Int J Mol Sci. 2022;23(24):1568.

138. Huang Z, Gan S, Zhuang X, et al. artesunate inhibits the cell growth in colorectal cancer by promoting ROS-dependent cell senescence and autophagy. Cells. 2022;11(16):2472.

139. Yu C, Sun P, Zhou Y, et al. Inhibition of AKT enhances the anti-cancer effects of Artemisinin in clear cell renal cell carcinoma. Biomed Pharmacother. 2019;118: 109383.

140. Fan HN, Zhu MY, Peng SQ, et al. Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling. Pathol Res Pract. 2020;216(2): 152795.

141. Liang R, Chen W, Chen XY, et al. Dihydroartemisinin inhibits the tumorigenesis and invasion of gastric cancer by regulating STAT1/KDR/MMP9 and P53/BCL2L1/CASP3/7 pathways. Pathol Res Pract. 2021;218: 153318.

142. Luo Q, Zhang S, Zhang D, et al. Effects and mechanisms of anlotinib and dihydroartemisinin combination therapy in ameliorating malignant biological behavior of gastric cancer cells. Curr Pharm Biotechnol. 2021;22(4):523–33.

143. Xiao P, Liang Q, Chen Q, et al. Artemisinin potentiates apoptosis and triggers cell cycle arrest to attenuate malignant growth of salivary gland tumor cells. Acta Biochim Pol. 2022;69(1):177–87.

144. Tao J, Diao L, Chen F, et al. pH-sensitive nanoparticles codelivering docetaxel and dihydroartemisinin effectively treat breast cancer by enhancing reactive oxidative species-mediated mitochondrial apoptosis. Mol Pharm. 2021;18(1):74–86.

145. Zhao Y, Liu J, Liu L. Artesunate inhibits lung cancer cells via regulation of mitochondrial membrane potential and induction of apoptosis. Mol Med Rep. 2020;22(4):3017–22.

146. Hu P, Ni C, Teng P. Effects of artesunate on the malignant biological behaviors of non-small cell lung cancer in human and its mechanism. Bioengineered. 2022;13(3):6590–9.

147. Zheng J, Li X, Yang W, et al. Dihydroartemisinin regulates apoptosis, migration, and invasion of ovarian cancer cells via mediating RECK. J Pharmacol Sci. 2021;146(2):71–81.

148. McCorkle JR, Ahn R, Cao CD, et al. Antineoplastic drug synergy of artesunate with navitoclax in models of high-grade serous ovarian cancer. Cancers. 2024;16(7):1321.

149. Wang T, Wang J, Ren W, et al. Combination treatment with artemisinin and oxaliplatin inhibits tumorigenesis in esophageal cancer EC109 cell through Wnt/β-catenin signaling pathway. Thorac Cancer. 2020;11(8):2316–24.

150. Wang Z, Wang Q, He T, et al. The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer. Clin Exp Pharmacol Physiol. 2020;47(6):1083–91.

151. Caddeo C, Gabriele M, Nácher A, et al. Resveratrol and artemisinin eudragit-coated liposomes: a strategy to tackle intestinal tumors. Int J Pharm. 2021;592: 120083.

152. D’Amico S, Krasnowska EK, Manni I, et al. DHA affects microtubule dynamics through reduction of phospho-TCTP levels and enhances the antiproliferative effect of T-DM1 in trastuzumab-resistant HER2-positive breast cancer cell lines. Cells. 2020;9(5):1260.

153. Ni L, Zhu X, Zhao Q, et al. Dihydroartemisinin, a potential PTGS1 inhibitor, potentiated cisplatin-induced cell death in non-small cell lung cancer through activating ROS-mediated multiple signaling pathways. Neoplasia. 2024;51: 100991.

154. Dai X, Chen W, Qiao Y, et al. Dihydroartemisinin inhibits the development of colorectal cancer by GSK-3β/TCF7/MMP9 pathway and synergies with capecitabine. Cancer Lett. 2024;582: 216596.

155. Li Y, Zhou X, Liu J, et al. Dihydroartemisinin inhibits the tumorigenesis and metastasis of breast cancer via downregulating CIZ1 expression associated with TGF-β1 signaling. Life Sci. 2020;248: 117454.

156. Gao J, Ma F, Wang X, et al. Combination of dihydroartemisinin and resveratrol effectively inhibits cancer cell migration via regulation of the DLC1/TCTP/Cdc42 pathway. Food Funct. 2020;11(11):9573–84.

157. Ackermann A, Çapcı A, Buchfelder M, et al. Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell death. Sci Rep. 2021;11(1):20766.

158. Moses BS, McCullough S, Fox JM, et al. Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax. Blood Adv. 2021;5(3):711–24.

159. Du J, Wang X, Li Y, et al. DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism. Cell Death Dis. 2021;12(7):705.

160. Wang Z, Duan X, Lv Y, et al. Low density lipoprotein receptor (LDLR)-targeted lipid nanoparticles for the delivery of sorafenib and dihydroartemisinin in liver cancers. Life Sci. 2019;239: 117013.

161. Cui Z, Wang H, Li S, et al. Dihydroartemisinin enhances the inhibitory effect of sorafenib on HepG2 cells by inducing ferroptosis and inhibiting energy metabolism. J Pharmacol Sci. 2022;148(1):73–85.

162. Yao X, Zhao CR, Yin H, et al. Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells. Acta Pharmacol Sin. 2020;41(12):1609–20.

163. Abdulkareem SJ, Jafari-Gharabaghlou D, Farhoudi-Sefidan-Jadid M, et al. Co-delivery of artemisinin and metformin via PEGylated niosomal nanoparticles: potential anti-cancer effect in treatment of lung cancer cells. Daru. 2024;32(1):133–44.

164. Amandi AF, Jokar E, Eslami M, et al. Enhanced anti-cancer effect of artemisinin- and curcumin-loaded niosomal nanoparticles against human colon cancer cells. Med Oncol. 2023;40(6):14.

165. Nosrati F, Barzegari P, Danafar H, et al. Biotin-functionalized copolymeric PEG-PCL micelles for in vivo tumour-targeted delivery of artemisinin. Artif Cells Nanomed Biotechnol. 2019;47(1):104–14.

166. Hassani N, Jafari-Gharabaghlou D, Dadashpour M, et al. The effect of dual bioactive compounds artemisinin and metformin co-loaded in PLGA-PEG nano-particles on breast cancer cell lines: potential apoptotic and anti-proliferative action. Appl Biochem Biotechnol. 2022;194(10):4930–45.

167. Zhang H, Li M, Zhu X, et al. Artemisinin co-delivery system based on manganese oxide for precise diagnosis and treatment of breast cancer. Nanotechnology. 2021;32:32.

168. Wang Q, Wei N, Guo J, et al. Hemin-lipid assembly as an artemisinin oral delivery system for enhanced cancer chemotherapy and immunotherapy. Nanoscale. 2021;13(31):13231–40.

169. Zhu X, Bi C, Cao W, et al. A self-assembled copper-artemisinin nanoprodrug as an efficient reactive oxygen species amplified cascade system for cancer treatment. J Mater Chem B. 2024;12(36):8902–10.

170. Cui J, Cai X, Qian R, et al. Tween 80 micelles loaded with Fe(3)O(4) nanoparticles and artemisinin for combined oxygen-independent ferroptosis therapy of cancer. Pharmaceutics. 2024;16(5):42.

171. Lu Y, Wen Q, Luo J, et al. Self-assembled dihydroartemisinin nanoparticles as a platform for cervical cancer chemotherapy. Drug Deliv. 2020;27(1):876–87.

172. Yu R, Jin L, Li F, et al. Dihydroartemisinin inhibits melanoma by regulating CTL/Treg anti-tumor immunity and STAT3-mediated apoptosis via IL-10 dependent manner. J Dermatol Sci. 2020;99(3):193–202.

173. Zhang Q, Jin L, Jin Q, et al. Inhibitory effect of dihydroartemisinin on the proliferation and migration of melanoma cells and experimental lung metastasis from melanoma in mice. Front Pharmacol. 2021;12: 727275.

174. Cao D, Chen D, Xia JN, et al. Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation. Biomed Pharmacother. 2022;155: 113705.

175. Yu Y, Chen D, Wu T, et al. Dihydroartemisinin enhances the anti-tumor activity of oxaliplatin in colorectal cancer cells by altering PRDX2-reactive oxygen species-mediated multiple signaling pathways. Phytomedicine. 2022;98: 153932.

176. Peng J, Zhou J, Sun R, et al. Dual-targeting of artesunate and chloroquine to tumor cells and tumor-associated macrophages by a biomimetic PLGA nanoparticle for colorectal cancer treatment. Int J Biol Macromol. 2023;244: 125163.

177. Han W, Duan X, Ni K, et al. Co-delivery of dihydroartemisinin and pyropheophorbide-iron elicits ferroptosis to potentiate cancer immunotherapy. Biomaterials. 2022;280: 121315.

178. Hao L, Guo Y, Peng Q, et al. Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma. Phytomedicine. 2022;96: 153913.

179. Duan X, Chan C, Han W, et al. Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors. Nat Commun. 2019;10(1):1899.

180. Ding W, Liao L, Liu J, et al. Lower dose of metformin combined with artesunate induced autophagy-dependent apoptosis of glioblastoma by activating ROS-AMPK-mTOR axis. Exp Cell Res. 2023;430(1): 113691.

181. Lin L, Lu W, Dai T, et al. Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway. Bioorg Chem. 2021;106: 104496.

182. Lu X, Elbadawi M, Blatt S, et al. Artemisinin derivative FO-ARS-123 as a novel VEGFR2 inhibitor suppresses angiogenesis, cell migration, and invasion. Chem Biol Interact. 2022;365: 110062.

183. Dong J, Chen Y, Yang W, et al. Antitumor and anti-angiogenic effects of artemisinin on breast tumor xenografts in nude mice. Res Vet Sci. 2020;129:66–9.

184. Rao Q, Yu H, Li R, et al. Dihydroartemisinin inhibits angiogenesis in breast cancer via regulating VEGF and MMP-2/-9. Fundam Clin Pharmacol. 2024;38(1):113–25.

185. Lu X, Blatt S, Dawood M, et al. Novel artemisinin derivative FO8643 with anti-angiogenic activity inhibits growth and migration of cancer cells via VEGFR2 signaling. Eur J Pharmacol. 2022;930: 175158.

186. Li ZJ, Dai HQ, Huang XW, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2021;42(2):301–10.

187. Chen Y, Mi Y, Zhang X, et al. Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells. J Exp Clin Cancer Res. 2019;38(1):402.

188. Yang XX, Xu X, Wang MF, et al. A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin. J Nanobiotechnology. 2022;20(1):230.

189. Tian CX, Li MY, Shuai XX, et al. Berberine plays a cardioprotective role by inhibiting macrophage Wnt5a/beta-catenin pathway in the myocardium of mice after myocardial infarction. Phytother Res. 2023;37(1):50–61.

190. Jiang X, Wang H, Nie K, et al. Targeting lipid droplets and lipid droplet-associated proteins: a new perspective on natural compounds against metabolic diseases. Chin Med. 2024. 10.1186/s13020-024-00988-w.

191. Zhang Y, Gu Y, Ren H, et al. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun. 2020;11(1):5015.

192. Zhao M-M, Lu J, Li S, et al. Berberine is an insulin secretagogue targeting the KCNH6 potassium channel. Nat Commun. 2021;12(1):5616.

193. Ma S-R, Tong Q, Lin Y, et al. Berberine treats atherosclerosis via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway in gut microbiota. Signal Transduct Target Ther. 2022;7(1):207.

194. Hu J, Shi Q, Xue C, et al. Berberine protects against hepatocellular carcinoma progression by regulating intrahepatic T cell heterogeneity. Adv Sci. 2024;11(39): e2405182.

195. Coppinger C, Pomales B, Movahed MR, et al. Berberine: a multi-target natural PCSK9 inhibitor with the potential to treat diabetes, Alzheimer’s, cancer and cardiovascular disease. Curr Rev Clin Exp Pharmacol. 2024;19(4):312–26.

196. Samal S, Meher RK, Dubey D, et al. In-silico and in-vitro evaluation of docetaxel and berberine as potential p53 modulating apoptotic inducers in oral squamous cell carcinoma. Asian Pac J Trop Biomed. 2022;12(12):530–40.

197. Kaboli PJ, Leong MP-Y, Ismail P, et al. Antitumor effects of berberine against EGFR, ERK1/2, P38 and AKT in MDA-MB231 and MCF-7 breast cancer cells using molecular modelling and in vitro study. Pharmacological Rep. 2019;71(1):13–23.

198. Sammarco A, Beffagna G, Sacchetto R, et al. Antitumor effect of berberine analogs in a canine mammary tumor cell line and in Zebrafish reporters via wnt/β-catenin and hippo pathways. Biomedicines. 2023;11(12):9.

199. Xie J, Du X, Li Y, et al. Berberine shaping the tumor immune landscape via pyroptosis. Cell Immunol. 2025;408:39.

200. Le LT, Nguyen HT, Bui HTT, et al. Drug release system based on a composite polycaprolactone nanofiber membrane with dual functionality of shape memory effect and antibacterial ability. RSC Adv. 2024;14(37):26884–95.

201. Costa F, Giorgini G, Minnelli C, et al. Membrane composition allows the optimization of berberine encapsulation in liposomes. Mol Pharm. 2024;21(11):5818–26.

202. Heidarzadeh M, Amininasab M, Rezayat SM, et al. Investigation of antioxidant and anti-inflammatory properties of berberine nanomicelles: in vitro and in vivo studies. Curr Drug Deliv. 2024;21(9):1273–83.

203. Qiao W, Niu L, Jiang W, et al. Berberine ameliorates endothelial progenitor cell function and wound healing in vitro and in vivo via the miR-21-3p/RRAGB axis for venous leg ulcers. Regen Ther. 2024;26:458–68.

204. Pu Z, Wen H, Jiang H, et al. Berberine improves negative symptoms and cognitive function in patients with chronic schizophrenia via anti-inflammatory effect: a randomized clinical trial. Chin Med. 2023. 10.1186/s13020-023-00746-4.

205. Sun Y, Zhou Q, Chen F, et al. Berberine inhibits breast carcinoma proliferation and metastasis under hypoxic microenvironment involving gut microbiota and endogenous metabolites. Pharmacol Res. 2023;193: 106817.

206. Wang Y, Zeng Y, Yang W, et al. Targeting CD8(+) T cells with natural products for tumor therapy: revealing insights into the mechanisms. Phytomedicine. 2024;129: 155608.

207. Shi X, Wang X, Yao W, et al. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives. Signal Transduct Target Ther. 2024;9(1):192.

208. Almatroodi SA, Alsahli MA, Rahmani AH. Berberine: an important emphasis on its anticancer effects through modulation of various cell signaling pathways. Molecules. 2022;27(18):58.

209. Shou JW, Shaw PC. Berberine activates PPARdelta and promotes gut microbiota-derived butyric acid to suppress hepatocellular carcinoma. Phytomedicine. 2023;115: 154842.

210. Liu Y, Liu X, Zhang N, et al. Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5. Acta Pharm Sin B. 2020;10(12):2299–312.

211. Ma W, Zhang Y, Yu M, et al. In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. Int Immunopharmacol. 2020;87: 106787.

212. Tong Y, Zhang J, Sun N, et al. Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p. Sci Bull (Beijing). 2021;66(18):1895–905.

213. Qian K, Tang CY, Chen LY, et al. Berberine reverses breast cancer multidrug resistance based on fluorescence pharmacokinetics in vitro and in vivo. ACS Omega. 2021;6(16):10645–54.

214. Mortazavi H, Nikfar B, Esmaeili SA, et al. Potential cytotoxic and anti-metastatic effects of berberine on gynaecological cancers with drug-associated resistance. Eur J Med Chem. 2020;187: 111951.

215. Cheng Y, Ji Y. Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity. J Control Release. 2020;318:38–49.

216. Wang Y, Liu Y, Du X, et al. Berberine reverses doxorubicin resistance by inhibiting autophagy through the PTEN/Akt/mTOR signaling pathway in breast cancer. Onco Targets Ther. 2020;13:1909–19.

217. Mohammadinejad R, Ahmadi Z, Tavakol S, et al. Berberine as a potential autophagy modulator. J Cell Physiol. 2019;234(9):14914–26.

218. Li S, Cai X, Chen L, et al. Inhibition of hepatocellular carcinoma growth via modulation of the miR-221/SOX11 axis by curcumin and berberine. PeerJ. 2023;11: e16593.

219. Zhao Y, Lin X, Zeng W, et al. Berberine inhibits the progression of renal cell carcinoma cells by regulating reactive oxygen species generation and inducing DNA damage. Mol Biol Rep. 2023;50(7):5697–707.

220. Jin Y, Zhang J, Pan Y, et al. Berberine suppressed the progression of human glioma cells by inhibiting the TGF-β1/SMAD2/3 signaling pathway. Integr Cancer Ther. 2022;21:15347354221130304.

221. Mohammadlou M, Abdollahi M, Hemati M, et al. Apoptotic effect of berberine via Bcl-2, ROR1, and mir-21 in patients with B-chronic lymphocytic leukemia. Phytother Res. 2021;35(4):2025–33.

222. Huang C, Wang XL, Qi FF, et al. Berberine inhibits epithelial-mesenchymal transition and promotes apoptosis of tumour-associated fibroblast-induced colonic epithelial cells through regulation of TGF-β signalling. J Cell Commun Signal. 2020;14(1):53–66.

223. Song J, Lin C, Yang X, et al. Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways. J Control Release. 2019;294:27–42.

224. Park GS, Park B, Lee MY. Berberine Induces Autophagic Cell Death by Inactivating the Akt/mTOR Signaling Pathway. Planta Med. 2022;88(13):1116–22.

225. Liu J, Liu P, Xu T, et al. Berberine induces autophagic cell death in acute lymphoblastic leukemia by inactivating AKT/mTORC1 signaling. Drug Des Devel Ther. 2020;14:1813–23.

226. Zhang Q, Wang X, Cao S, et al. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed Pharmacother. 2020;128: 110245.

227. Wang Q, Yang S, Wang K, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer. J Hematol Oncol. 2019;12(1):63.

228. Chen Z, Vallega KA, Chen H, et al. The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition. Pharmacol Res. 2022;175:105998–105998.

229. He J, Wei Q, Jiang R, et al. The core-targeted RRM2 gene of berberine hydrochloride promotes breast cancer cell migration and invasion via the epithelial-mesenchymal transition. Pharmaceuticals. 2022;16(1):74.

230. Gao X, Wang J, Li M, et al. Berberine attenuates XRCC1-mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs. J Cell Mol Med. 2019;23(10):6797–804.

231. Goel A. Current understanding and future prospects on Berberine for anticancer therapy. Chem Biol Drug Des. 2023;102(1):177–200.

232. Ramesh-Kumar D, Guil S. The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer. Semin Cancer Biol. 2022;86(Pt 3):18–31.

233. Alomari M. TRIM21—a potential novel therapeutic target in cancer. Pharmacol Res. 2021;165: 105443.

234. Gui Z, Li J, Li J, et al. Berberine promotes IGF2BP3 ubiquitination by TRIM21 to induce G1/S phase arrest in colorectal cancer cells. Chem Biol Interact. 2023;374: 110408.

235. Hu S, Chen CW, Chen ST, et al. Inhibitory effect of berberine on interleukin-2 secretion from PHA-treated lymphocytic Jurkat cells. Int Immunopharmacol. 2019;66:267–73.

236. Li Q, Zhao H, Chen W, et al. Berberine induces apoptosis and arrests the cell cycle in multiple cancer cell lines. Arch Med Sci. 2023;19(5):1530–7.

237. Cheng Y, Ji YH. Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity. J Controlled Release. 2020;318:38–49.

238. Li Q, Qing L, Xu W, et al. Berberine affects the proliferation, migration, invasion, cell cycle, and apoptosis of bladder cancer cells T24 and 5637 by down-regulating the HER2/PI3K/AKT signaling pathway. Arch Esp Urol. 2023;76(2):152–60.

239. Cao F, Xia W, Dai S, et al. Berberine: an inspiring resource for the treatment of colorectal diseases. Biomed Pharmacother. 2023;167: 115571.

240. Samadi P, Sarvarian P, Gholipour E, et al. Berberine: a novel therapeutic strategy for cancer. IUBMB Life. 2020;72(10):2065–79.

241. Xu X, Liu M, Wu H. Berberine inhibits the growth of osteosarcoma through modulating MMP/NM-23 and MAPK/JNK signal pathways. Am J Transl Res. 2023;15(2):729–44.

242. Lin C, Yang X, Li H, et al. Self-assembled nanomedicine combining a berberine derivative and doxorubicin for enhanced antitumor and antimetastatic efficacy via mitochondrial pathways. Nanoscale. 2021;13(13):6605–23.

243. Sun Y, Huang H, Zhan Z, et al. Berberine inhibits glioma cell migration and invasion by suppressing TGF-β1/COL11A1 pathway. Biochem Biophys Res Commun. 2022;625:38–45.

244. Yang LJ, He JB, Jiang Y, et al. Berberine hydrochloride inhibits migration ability via increasing inducible NO synthase and peroxynitrite in HTR-8/SVneo cells. J Ethnopharmacol. 2023;305: 116087.

245. Xu M, Ren L, Fan J, et al. Berberine inhibits gastric cancer development and progression by regulating the JAK2/STAT3 pathway and downregulating IL-6. Life Sci. 2022;290: 120266.

246. Devarajan N, Jayaraman S, Mahendra J, et al. Berberine-A potent chemosensitizer and chemoprotector to conventional cancer therapies. Phytother Res. 2021;35(6):3059–77.

247. Babaeenezhad E, Rashidipour M, Jangravi Z, et al. Cytotoxic and epigenetic effects of berberine-loaded chitosan/pectin nanoparticles on AGS gastric cancer cells: Role of the miR-185-5p/KLF7 axis, DNMTs, and global DNA methylation. Int J Biol Macromol. 2024;260: 129618.

248. Gao X, Zhang C, Wang Y, et al. Berberine and cisplatin exhibit synergistic anticancer effects on osteosarcoma MG-63 cells by inhibiting the MAPK pathway. Molecules. 2021;26(6):35.

249. Zheng X, Zhao Y, Jia Y, et al. Biomimetic co-assembled nanodrug of doxorubicin and berberine suppresses chemotherapy-exacerbated breast cancer metastasis. Biomaterials. 2021;271: 120716.

250. Zhang F, Jia Y, Zheng X, et al. Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence. Acta Biomater. 2019;100:352–64.

251. Aleissa MS, Al-Zharani M, Alneghery LM, et al. Berberine enhances the sensitivity of radiotherapy in ovarian cancer cell line (SKOV-3). Saudi Pharm J. 2023;31(1):110–8.

252. He L, Chen M, Liang Q et al. Current Advances in Coptidis Rhizoma for Gastrointestinal and Other Cancers. Frontiers in Pharmacology. 2022, 12:

253. Chen Y, Li K, Zhao H, et al. Integrated lipidomics and network pharmacology analysis to reveal the mechanisms of berberine in the treatment of hyperlipidemia. J Transl Med. 2022;20(1):412.

254. Xing L, Zhou X, Li AH, et al. Atheroprotective effects and molecular mechanism of berberine. Front Mol Biosci. 2021;8: 762673.

255. Guo SF, Wang ZB, Xie DD, et al. Berberine mediates exosomes regulating the lipid metabolism pathways to promote apoptosis of RA-FLS cells. Pharmaceuticals. 2024;17(11):4.

256. Fang X, Wu H, Wang X, et al. Modulation of gut microbiota and metabolites by berberine in treating mice with disturbances in glucose and lipid metabolism. Front Pharmacol. 2022;13: 870407.

257. Ghanem HB, Emam MN, Mohammed DA, A, et al. Impact of berberine on some epigenetic, transcription regulation and inflammatory biomarkers in a mice model of epilepsy. Rep Biochem Mol Biol. 2021;10(3):362–72.

258. Wang Y, Zhang Z, Du M, et al. Berberine alleviates ETEC-induced intestinal inflammation and oxidative stress damage by optimizing intestinal microbial composition in a weaned piglet model. Front Immunol. 2024;15:1460127.

259. Askari VR, Khosravi K, Baradaran Rahimi V, et al. A mechanistic review on how berberine use combats diabetes and related complications: molecular, cellular, and metabolic effects. Pharmaceuticals. 2023;17(1):9.

260. Sun A, Yang H, Li T, et al. Molecular mechanisms, targets and clinical potential of berberine in regulating metabolism: a review focussing on databases and molecular docking studies. Front Pharmacol. 2024;15:1368950.

261. Zeng LT, Yu GP, Hao WS, et al. The efficacy and safety of Curcuma longa extract and curcumin supplements on osteoarthritis: a systematic review and meta-analysis. Biosci Rep. 2021;41(6):7.

262. Li Z, Hao E, Cao R, et al. Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups. Chin Herb Med. 2022;14(4):479–93.

263. Zhao CZ, Zhou XE, Ye L, et al. Curcumin and analogues against head and neck cancer: from drug delivery to molecular mechanisms. Phytomedicine. 2023;119:75.

264. Sharma MR, Arya P, Kaur R, et al. Differential binding of piperine & curcumin with modified cellulose, alginate and pectin supports: in-vitro & in-silico studies. Int J Biol Macromol. 2023;233:7.

265. Kura Y, De Velasco MA, Sakai K, et al. Immunomodulatory effects of curcumin monoglucuronide on PD1 immune checkpoint blockade in mouse Pten-null prostate cancer. Cancer Res. 2023;83(7):189.

266. Abadi AJ, Mirzaei S, Mahabady MK, et al. Curcumin and its derivatives in cancer therapy: potentiating antitumor activity of cisplatin and reducing side effects. Phytother Res. 2022;36(1):189–213.

267. Yuvashri R, Thendral ED, Jonathan DR, et al. Evaluating a series of new curcumin derivatives as potential anti-breast cancer agents: a collective analysis of in-vitro and in-silico characterization. Chemical Phys Impact. 2024;9:100663.

268. Akyuz A, Sirin DYASAR. In silico and in vitro verification of the effects of chemotherapeutic doxorubicin and 5-fluorouracil in combination with curcumin and vitamin C on MCF-7 Cells. J Cell Biochem. 2025. 10.1002/jcb.30688.

269. Zoi V, Galani V, Lianos GD, et al. The role of curcumin in cancer treatment. Biomedicines. 2021;9(9):1086.

270. Jiang T, Charcosset C. Encapsulation of curcumin within oil-in-water emulsions prepared by premix membrane emulsification: Impact of droplet size and carrier oil on the chemical stability of curcumin. Food Rev Int. 2022, 157.

271. Ma Y, Chen S, Liao W, et al. Formation, physicochemical stability, and redispersibility of curcumin-loaded rhamnolipid nanoparticles using the pH-driven method. J Agric Food Chem. 2020;68(27):7103–11.

272. Lu ZH, Gao ZW, Song HY et al. Synthesis, Biological Evaluation and Action Mechanism Study of New Mitochondria-Targeted Curcumin Derivative as Potential Antitumor Drugs. Chem Biodivers. 2023.

273. Deshpande SS, Veeragoni D, Rachamalla HK et al. Anticancer properties of ZnO-Curcumin nanocomposite against melanoma cancer and its genotoxicity profiling. J Drug Delivery Sci Technol. 2022, 75.

274. Jin M, Kong L, Han Y, et al. Gut microbiota enhances the chemosensitivity of hepatocellular carcinoma to 5-fluorouracil in vivo by increasing curcumin bioavailability. Phytother Res. 2021;35(10):5823–37.

275. Victorelli FD, Manni LS, Biffi S, et al. Potential of curcumin-loaded cubosomes for topical treatment of cervical cancer. J Colloid Interface Sci. 2022;620:419–30.

276. Gholami L, Momtazi-Borojeni AA, Malaekeh-Nikouei B, et al. Selective cellular uptake and cytotoxicity of curcumin-encapsulated SPC and HSPC liposome nanoparticles on human bladder cancer cells. Curr Pharm Des. 2023;29(13):1046–58.

277. Gunther JR, Chadha AS, Guha S et al. A phase II randomized double blinded trial evaluating the efficacy of curcumin with pre-operative chemoradiation for rectal cancer. J Gastrointest Oncol. 2022.

278. Khan S, Miles GJ, Demetriou C, et al. Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies. Mutagenesis. 2022;37(5–6):227–37.

279. Sanlier N, Kocabas S, Erdogan K et al. Effects of curcumin, its analogues, and metabolites on various cancers: focusing on potential mechanisms. Food Rev Int. 2022.

280. Weng W, Goel A. Curcumin and colorectal cancer: an update and current perspective on this natural medicine. Semin Cancer Biol. 2022;80:73–86.

281. Hasanzadeh S, Read MI, Bland AR, et al. Curcumin: an inflammasome silencer. Pharmacol Res. 2020;159:104921.

282. Mollazadeh H, Cicero AFG, Blesso CN, et al. Immune modulation by curcumin: The role of interleukin-10. Crit Rev Food Sci Nutr. 2019;59(1):89–101.

283. Liu L, Lim MA, Jung S-N, et al. The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer. Phytomedicine. 2021;92:153758.

284. Tong Q, Wu Z. Curcumin inhibits colon cancer malignant progression and promotes T cell killing by regulating miR-206 expression. Clin Anat. 2023. 10.1002/ca.24057.

285. Tian S, Liao L, Zhou Q, et al. Curcumin inhibits the growth of liver cancer by impairing myeloid-derived suppressor cells in murine tumor tissues. Oncol Lett. 2021. 10.3892/ol.2021.12547.

286. Wang TT, Wang J, Jiang H et al. Targeted regulation of tumor microenvironment through the inhibition of MDSCs by curcumin loaded self-assembled nano-filaments. Materials Today Bio. 2022, 15.

287. Jiang M, Qi Y, Huang W et al. Curcumin Reprograms TAMs from a Protumor Phenotype towards an Antitumor Phenotype via Inhibiting MAO-A/STAT6 Pathway. Cells. 2022, 11(21).

288. Ge SK, Sun X, Sang LM, et al. Curcumin inhibits malignant behavior of colorectal cancer cells by regulating M2 polarization of tumor-associated macrophages and metastasis associated in colon cancer 1 (MACC1) expression. Chem Biol Drug Des. 2023;102(5):1202–12.

289. Fan Y, He S. The characteristics of tumor microenvironment in triple negative breast cancer. Cancer Manag Res. 2022;14:1–17.

290. Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022;19(4):237–53.

291. Abdel-Hakeem MA, Mongy S, Hassan B, et al. Curcumin loaded chitosan-protamine nanoparticles revealed antitumor activity via suppression of NF-kB, proinflammatory cytokines and Bcl-2 gene expression in the breast cancer cells. J Pharm Sci. 2021;110(9):3298–305.

292. Qian XW, Jiang C, Zhu ZT, et al. Curcumin mediates the proliferation and apoptosis of colorectal cancer cells by downregulating the expression of interleukin-1β through the nuclear factor-κB signaling pathway. Pharmacogn Mag. 2021;17(75):539–44.

293. Afshari H, Noori S, Nourbakhsh M et al. A novel imidazo[1,2-a]pyridine derivative and its co-administration with curcumin exert anti-inflammatory effects by modulating the STAT3/NF-κB/iNOS/COX-2 signaling pathway in breast and ovarian cancer cell lines. Bioimpacts. 2023.

294. Coker-Gurkan A, Ozakaltun B, Akdeniz B-S, et al. Proinflammatory cytokine profile is critical in autocrine GH-triggered curcumin resistance engulf by atiprimod cotreatment in MCF-7 and MDA-MB-231 breast cancer cells. Mol Biol Rep. 2020;47(11):8797–808.

295. Ba PF, Xu MC, Yu M, et al. Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer-associated fibroblasts of TSCC. Oral Dis. 2020;26(7):1375–83.

296. Liu L, Lim MA, Jung SN et al. The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer. Phytomedicine. 2021, 92.

297. Tong Q, Wu ZQ. Curcumin inhibits colon cancer malignant progression and promotes T cell killing by regulating miR-206 expression. Clin Anat. 2023.

298. Zhao G-j, Lu Z-q, Tang L-m, et al. Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. Int Immunopharmacol. 2012;14(1):99–106.

299. Yamauchi Y, Izumi Y, Yamamoto J, et al. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res. 2014;28(5):728–35.

300. Xiao Z, Su Z, Han S, et al. Dual pH-sensitive nanodrug blocks PD-1 immune checkpoint and uses T cells to deliver NF-κB inhibitor for antitumor immunotherapy. Sci Adv. 2020;6(6):9.

301. Ge Y-X, Zhang T-W, Zhou L, et al. Enhancement of anti-PD-1/PD-L1 immunotherapy for osteosarcoma using an intelligent autophagy-controlling metal organic framework. Biomaterials. 2022;282:8.

302. Khatoon E, Banik K, Harsha C, et al. Phytochemicals in cancer cell chemosensitization: current knowledge and future perspectives. Semin Cancer Biol. 2022;80:306–39.

303. Yang L, Li D, Tang PY, et al. Curcumin increases the sensitivity of K562/DOX cells to doxorubicin by targeting S100 calcium-binding protein A8 and P-glycoprotein. Oncol Lett. 2020;19(1):83–92.

304. Zhang N, Gao M, Wang ZH, et al. Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level. J Pharm Biomed Anal. 2021;201:7.

305. Ye MX, Zhao YL, Li Y, et al. Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1α and caspase-3 mechanisms. Phytomedicine. 2012;19(8–9):779–87.

306. Guo Y, Ashrafizadeh M, Tambuwala MM, et al. P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators. Drug Discov Today. 2024;29:11.

307. Diao L, Shen A, Yang YX, et al. CD44-targeted hyaluronic acid-curcumin reverses chemotherapeutics resistance by inhibiting P-gp and anti-apoptotic pathways. RSC Adv. 2019;9(70):40873–82.

308. Zhao MD, Li JQ, Chen FY, et al. Co-delivery of curcumin and paclitaxel by “core-shell” targeting amphiphilic copolymer to reverse resistance in the treatment of ovarian cancer. Int J Nanomedicine. 2019;14:9453–67.

309. Punfa W, Suzuki S, Pitchakarn P, et al. Curcumin-loaded PLGA nanoparticles conjugated with anti-P-glycoprotein antibody to overcome multidrug resistance. Asian Pac J Cancer Prev. 2014;15(21):9249–58.

310. Han W, Yin HL, Ma H, et al. Curcumin regulates ERCC1 expression and enhances oxaliplatin sensitivity in resistant colorectal cancer cells through its effects on miR-409–3p. Evid Based Complement Alternat Med. 2020;2020:88.

311. Kaur M, Badhan RKS. Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier: an in-vitro study. Brain Res. 2017;1654:9–23.

312. Kusuhara H, Furuie H, Inano A, et al. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol. 2012;166(6):1793–803.

313. Iyer R, Bharthuar A. A review of erlotinib - an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. Expert Opin Pharmacother. 2010;11(2):311–20.

314. Wada K, Lee J-Y, Hung H-Y, et al. Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects. Bioorg Med Chem. 2015;23(7):1507–14.

315. Lee T-B, Seo E-J, Lee J-Y, et al. Synergistic anticancer effects of curcumin and hinokitiol on gefitinib resistant non-small cell lung cancer cells. Nat Prod Commun. 2018;13(12):1667–71.

316. Li S, Liu Z, Zhu F, et al. Curcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptor. Oncol Res. 2013;21(3):137–44.

317. Miyazaki K, Morine Y, Xu CM, et al. Curcumin-mediated resistance to lenvatinib via EGFR signaling pathway in hepatocellular carcinoma. Cells. 2023;12(4):40.

318. Yi M, Zheng XL, Niu MK, et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21(1):44.

319. Gong F, Ma J-C, Jia J, et al. Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer. Drug Deliv. 2021;28(1):930–42.

320. Zhang J, Li Y, Li S, et al. Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism. Phytomedicine. 2024;129:1.

321. Ming T, Lei J, Peng Y, et al. Curcumin suppresses colorectal cancer by induction of ferroptosis via regulation of p53 and solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 signaling axis. Phytother Res. 2024;38(8):3954–72.

322. Shakeri A, Cicero AFG, Panahi Y, et al. Curcumin: a naturally occurring autophagy modulator. J Cell Physiol. 2019;234(5):5643–54.

323. Wang T, Wu X, Ma AR, et al. Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells. J Cancer. 2020;11(22):6704–15.

324. Gong XL, Jiang L, Li W, et al. Curcumin induces apoptosis and autophagy inhuman renal cell carcinoma cells via Akt/mTOR suppression. Bioengineered. 2021;12(1):5017–27.

325. Park JW, Kim Y, Lee SB, et al. Autophagy inhibits cancer stemness in triple-negative breast cancer via miR-181a-mediated regulation of ATG5 and/or ATG2B. Mol Oncol. 2022;16(9):1857–75.

326. Zhang L, Qiu L, Xu SC, et al. Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment. Toxicol In Vitro. 2023;93: 105669.

327. Ravindran F, Mhatre A, Koroth J, et al. Curcumin modulates cell type-specific miRNA networks to induce cytotoxicity in ovarian cancer cells. Life Sci. 2023;334: 122224.

328. Jong-Eun L, Sik YS, Jae-Wook L, et al. Curcumin-induced cell death depends on the level of autophagic flux in A172 and U87MG human gliabiastoma cells. Chin J Nat Med. 2020;18(2):114–22.

329. Li J, Wang SH, Liu YT, et al. Inhibition of autophagic flux by the curcumin analog EF-24 and its antiproliferative effect on MCF-7 cancer cells. J Biochem Mol Toxicol. 2023;37(4):9.

330. Firouzjaei AA, Aghaee-Bakhtiari SH, Tafti A et al. Impact of curcumin on ferroptosis-related genes in colorectal cancer: Insights from in-silico and in-vitro studies. Cell Biochem Funct. 2023.

331. Chan KI, Zhang S, Li G, et al. MYC oncogene: a druggable target for treating cancers with natural products. Aging Dis. 2024;15(2):640–97.

332. Chen H, Li Z, Xu J, et al. Curcumin induces ferroptosis in follicular thyroid cancer by upregulating HO-1 expression. Oxid Med Cell Longev. 2023;2023:5.

333. Chen M, Tan AH, Li J. Curcumin represses colorectal cancer cell proliferation by triggering ferroptosis via PI3K/Akt/mTOR signaling. Nutr Cancer. 2023;75(2):726–33.

334. Lin HYJ, Chen XT, Zhang CY, et al. EF24 induces ferroptosis in osteosarcoma cells through HMOX1. Biomed Pharmacother. 2021;136:1.

335. Xu B, Zhu W-J, Peng Y-J, et al. Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene. Transl Cancer Res. 2021;10(7):3158–67.

336. Liczbinski P, Michalowicz J, Bukowska B. Molecular mechanism of curcumin action in signaling pathways: review of the latest research. Phytother Res. 2020;34(8):1992–2005.

337. Sarighieh MA, Montazeri V, Shadboorestan A, et al. The inhibitory effect of curcumin on hypoxia inducer factors (Hifs) as a regulatory factor in the growth of tumor cells in breast cancer stem-like cells. Drug Res. 2020;70(11):512–8.

338. Bai CH, Zhao JQ, Su JL, et al. Curcumin induces mitochondrial apoptosis in human hepatoma cells through BCLAF1-mediated modulation of PI3K/AKT/GSK-3β signaling. Life Sci. 2022;306:5.

339. Chou YT, Koh YC, Nagabhushanam K, et al. A natural degradant of curcumin, feruloylacetone inhibits cell proliferation via inducing cell cycle arrest and a mitochondrial apoptotic pathway in HCT116 colon cancer cells. Molecules. 2021;26(16):1.

340. Li PH, Pu SM, Lin C, et al. Curcumin selectively induces colon cancer cell apoptosis and S cell cycle arrest by regulates Rb/E2F/p53 pathway. J Mol Struct. 2022;1263:6.

341. Ye Z, Chen D, Zheng R, et al. Curcumin induced G2/M cycle arrest in SK-N-SH neuroblastoma cells through the ROS-mediated p53 signaling pathway. J Food Biochem. 2021;45(9):8.

342. Teong B, Lin C-Y, Chang S-J, et al. Enhanced anti-cancer activity by curcumin-loaded hydrogel nanoparticle derived aggregates on A549 lung adenocarcinoma cells. J Mater Sci Mater Med. 2015;26(1):1.

343. Moideen MMJ, Karuppaiyan K, Kandhasamy R, et al. Skimmed milk powder and pectin decorated solid lipid nanoparticle containing soluble curcumin used for the treatment of colorectal cancer. J Food Process Eng. 2020;43(3):7.

344. Zhou H, Ning YC, Zeng GR, et al. Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT. Oncol Res. 2021;45(4):7.

345. Ting G, Jin W, Ting D, et al. Curcumin suppresses leukemia cell proliferation by down-regulation of P13K/AKT/mTOR signalling pathway. Trop J Pharm Res. 2019;18(11):2293–8.

346. Shishodia S, Amin HM, Lai R, et al. Curcumin (diferuloylmethane) inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol. 2005;70(5):700–13.

347. Somers-Edgar TJ, Taurin S, Larsen L, et al. Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. Invest New Drugs. 2011;29(1):87–97.

348. Al-Hujaily EM, Mohamed AG, Al-Sharif I, et al. PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells. Breast Cancer Res Treat. 2011;128(1):97–107.

349. Zhong Z-F, Li Y-B, Wang S-P, et al. Furanodiene enhances tamoxifen-induced growth inhibitory activity of ERa-positive breast cancer cells in a PPARγ independent manner. J Cell Biochem. 2012;113(8):2643–51.

350. Yeap SK, Mohd Ali N, Akhtar MN, et al. Induction of apoptosis and regulation of microRNA expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) treatment on MCF-7 breast cancer cells. Molecules. 2021;26(5):1.

351. Yan G, Graham K, Lanza-Jacoby S. Curcumin enhances the anticancer effects of trichostatin a in breast cancer cells. Mol Carcinog. 2013;52(5):404–11.

352. Kunwar A, Jayakumar S, Srivastava AK, et al. Dimethoxycurcumin-induced cell death in human breast carcinoma MCF7 cells: evidence for pro-oxidant activity, mitochondrial dysfunction, and apoptosis. Arch Toxicol. 2012;86(4):603–14.

353. Pandolfi L, Bellini M, Vanna R, et al. H-ferritin enriches the curcumin uptake and improves the therapeutic efficacy in triple negative breast cancer cells. Biomacromol. 2017;18(10):3318–30.

354. Mittal L, Raman V, Camarillo IG, et al. Viability and cell cycle studies of metastatic triple negative breast cancer cells using low voltage electrical pulses and herbal curcumin. Biomed Phys Eng Express. 2019;5(2): 025040.

355. Cheng TC, Sayseng JO, Tu SH, et al. Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein. J Food Drug Anal. 2021;29(4):622–37.

356. Malhotra L, Sharma S, Hariprasad G, et al. Mechanism of apoptosis activation by curcumin rescued mutant p53Y220C in human pancreatic cancer. Biochim Biophys Acta Mol Cell Res. 2022;1869(12): 119343.

357. Wu MF, Huang YH, Chiu LY, et al. Curcumin induces apoptosis of chemoresistant lung cancer cells via ROS-regulated p38 MAPK phosphorylation. Int J Mol Sci. 2022;23(15):4.

358. Harakeh S, Saber SH, Al-Raddadi R, et al. Novel curcumin nanoformulation induces apoptosis, and reduces migration and angiogenesis in liver cancer cells. Artif Cells Nanomed Biotechnol. 2023;51(1):361–70.

359. Zhao XY, Zhang RW, Song ZT et al. Curcumin suppressed the proliferation and apoptosis of HPV-positive cervical cancer cells by directly targeting the E6 protein. Phytother Res. 2023.

360. Xiang L, He B, Liu Q, et al. Antitumor effects of curcumin on the proliferation, migration and apoptosis of human colorectal carcinoma HCT-116 cells. Oncol Res. 2020;44(5):1997–2008.

361. Wang P, Wu Q, Peng Q et al. Comparative analysis of the molecular mechanism of inhibiting proliferation and migration in cervical cancer HeLa cell by curcumin and resveratrol. Nat Prod Res. 2022.

362. Dong ZQ, Feng QQ, Zhang H, et al. Curcumin enhances drug sensitivity of gemcitabine-resistant lung cancer cells and inhibits metastasis. Pharmazie. 2021;76(11):538–43.

363. Li MJ, Guo TT, Lin JY, et al. Curcumin inhibits the invasion and metastasis of triple negative breast cancer via Hedgehog/Gli1 signaling pathway. J Ethnopharmacol. 2022;283:1.

364. Liu CF, Rokavec M, Huang ZK, et al. Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis. Cell Death Differ. 2023;30(7):1771–85.

365. de la Parte BH, Rodeño-Casado M, Correcher SI, et al. curcumin reduces colorectal cancer cell proliferation and migration and slows in vivo growth of liver metastases in rats. Biomedicines. 2021;9(9):9.

366. Kim MJ, Park KS, Kim KT, et al. The inhibitory effect of curcumin via fascin suppression through JAK/STAT3 pathway on metastasis and recurrence of ovary cancer cells. BMC Womens Health. 2020;20(1):1.

367. Luo HM, Lu LS, Liu N, et al. Curcumin loaded sub-30 nm targeting therapeutic lipid nanoparticles for synergistically blocking nasopharyngeal cancer growth and metastasis. J Nanobiotechnol. 2021;19(1):1.

368. Liu C, Rokavec M, Huang Z, et al. Curcumin activates a ROS/KEAP1/NRF2/<i>miR-34a/b/c</i> cascade to suppress colorectal cancer metastasis. Cell Death Differ. 2023;30(7):1771–85.

369. Luo LJ, Lin CJ, Wang PF, et al. Combined use of immune checkpoint inhibitors and phytochemicals as a novel therapeutic strategy against cancer. J Cancer. 2023;14(12):2315–28.

370. Hayakawa T, Yaguchi T, Kawakami Y. Enhanced anti-tumor effects of the PD-1 blockade combined with a highly absorptive form of curcumin targeting STAT3. Cancer Sci. 2020;111(12):4326–35.

371. Guo L, Li H, Fan T, et al. Synergistic efficacy of curcumin and anti-programmed cell death-1 in hepatocellular carcinoma. Life Sci. 2021;279:2.

372. Bolat ZB, Islek Z, Demir BN, et al. Curcumin- and piperine-loaded emulsomes as combinational treatment approach enhance the anticancer activity of curcumin on HCT116 colorectal cancer model. Front Bioeng Biotechnol. 2020;8:8.

373. Jiang X, Huang YL. Curcumin derivative c086 combined with cisplatin inhibits proliferation of osteosarcoma cells. Med Sci Monit. 2020;26:1.

374. Semlali A, Beji S, Ajala I, et al. Synergistic effects of new curcumin analog (pac) and cisplatin on oral cancer therapy. Curr Issues Mol Biol. 2023;45(6):5018–35.

375. Sheng SP, Wei C, Ma T, et al. Multiplex fluorescence imaging-guided programmed delivery of doxorubicin and curcumin from a nanoparticles/hydrogel system for synergistic chemotherapy. J Polym Sci. 2022;60(10):1557–70.

376. Yin YL, Jiang H, Wang Y, et al. Self-assembled nanodelivery system with rapamycin and curcumin for combined photo-chemotherapy of breast cancer. Pharmaceutics. 2023;15(3):9.

377. Zuo ST, Wang ZY, An XQ, et al. Self-assembly engineering nanodrugs composed of paclitaxel and curcumin for the combined treatment of triple negative breast cancer. Front Bioeng Biotechnol. 2021;9:7.

378. Jalaladdiny S-S, Badoei-dalfard A, Karami Z, et al. Co-delivery of doxorubicin and curcumin to breast cancer cells by a targeted delivery system based on Ni/Ta core-shell metal-organic framework coated with folic acid-activated chitosan nanoparticles. J Iran Chem Soc. 2022;19(10):4287–98.

379. Karavasili C, Andreadis DA, Katsamenis OL, et al. Synergistic antitumor potency of a self-assembling peptide hydrogel for the local co-delivery of doxorubicin and curcumin in the treatment of head and neck cancer. Mol Pharm. 2019;16(6):2326–41.

380. Sesarman A, Tefas L, Sylvester B, et al. Co-delivery of curcumin and doxorubicin in PEGylated liposomes favored the antineoplastic C26 murine colon carcinoma microenvironment. Drug Deliv Transl Res. 2019;9(1):260–72.

381. Yang Z, Liu J, Lu Y. Doxorubicin and CD-CUR inclusion complex co-loaded in thermosensitive hydrogel PLGA-PEG-PLGA localized administration for osteosarcoma. Int J Oncol. 2020;57(2):433–44.

382. Howells LM, Iwuji COO, Irving GRB, et al. Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase IIA trial. J Nutr. 2019;149(7):1133–9.

383. Guorgui J, Wang R, Mattheolabakis G, et al. Curcumin formulated in solid lipid nanoparticles has enhanced efficacy in Hodgkin’s lymphoma in mice. Arch Biochem Biophys. 2018;648:12–9.

384. Ma W, Wang J, Gun Q, et al. Simultaneous determination of doxorubicin and curcumin in rat plasma by LC-MS/MS and its application to pharmacokinetic study. J Pharm Biomed Anal. 2015;111:215–21.

385. Park BH, Lim JE, Jeon HG, et al. Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2. Oncotarget. 2016;7(39):63870–86.

386. Lev-Ari S, Strier L, Kazanov D, et al. Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clin Cancer Res. 2005;11(18):6738–44.

387. Wu R, Mei X, Ye Y, et al. Zn(II)-curcumin solid dispersion impairs hepatocellular carcinoma growth and enhances chemotherapy by modulating gut microbiota-mediated zinc homeostasis. Pharmacol Res. 2019;150:1.

388. Cheng WY, Wu C-Y, Yu J. The role of gut microbiota in cancer treatment: friend or foe? Gut. 2020;69(10):1867–76.

389. Gu JF, Sun RL, Wang QH, et al. Standardized astragalus mongholicus bunge- curcuma aromatica salisb extract efficiently suppresses colon cancer progression through gut microbiota modification in CT26-bearing mice. Front Pharmacol. 2021;12:8.

390. Gholipour F, Amini M, Baradaran B, et al. Anticancer properties of curcumin-treated Lactobacillus plantarum against the HT-29 colorectal adenocarcinoma cells. Sci Rep. 2023;13(1):1.

391. Schmidt DR, Patel R, Kirsch DG, et al. Metabolomics in cancer research and emerging applications in clinical oncology. CA Cancer J Clin. 2021;71(4):333–58.

392. Heitzer E, Haque IS, Roberts CES, et al. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20(2):71–88.

393. Jiang Y, Sun AH, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567(7747):257–61.

394. Zilionis R, Engblom C, Pfirschke C, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity. 2019;50(5):1317–34.

395. Guo Y, Su J, Jiang S, et al. Transcriptomics and metabonomics study on the effect of exercise combined with curcumin supplementation on breast cancer in mice. Heliyon. 2024;10(7):e28807–e28807.

396. Zhou J-L, Zheng J-Y, Cheng X-Q, et al. Chemical markers’ knockout coupled with UHPLC-HRMS-based metabolomics reveals anti-cancer integration effects of the curcuminoids of turmeric (Curcuma longa L.) on lung cancer cell line. J Pharm Biomed Anal. 2019;175:112738.

397. Nirgude S, Desai S, Choudhary B. Curcumin alters distinct molecular pathways in breast cancer subtypes revealed by integrated miRNA/mRNA expression analysis. Cancer Rep. 2022;5(10): e1596.

398. Ravindran F, Mhatre A, Koroth J et al. Curcumin modulates cell type-specific miRNA networks to induce cytotoxicity in ovarian cancer cells. Life Sci. 2023, 334.

399. Mittal L, Aryal UK, Camarillo IG, et al. Effective electrochemotherapy with curcumin in MDA-MB-231-human, triple negative breast cancer cells: a global proteomics study. Bioelectrochemistry. 2020;131: 107350.

400. Yoon D, Choi B-R, Shin WC, et al. Metabolomics reveals that Curcuma longa and demethoxycurcumin inhibit HCT116 human colon cancer cell growth. Appl Biol Chem. 2023;66(1):84.

401. Chueh F-S, Lien J-C, Chou Y-C, et al. Demethoxycurcumin inhibits in vivo growth of xenograft tumors of human cervical cancer cells. In Vivo. 2020;34(5):2469–74.

402. Chen Y, Wu M. Demethoxycurcumin inhibits the growth of human lung cancer cells by targeting of PI3K/AKT/m-TOR signalling pathway, induction of apoptosis and inhibition of cell migration and invasion. Trop J Pharm Res. 2021;20(4):687–93.

403. Kao C-C, Cheng Y-C, Yang M-H, et al. Demethoxycurcumin induces apoptosis in HER2 overexpressing bladder cancer cells through degradation of HER2 and inhibiting the PI3K/Akt pathway. Environ Toxicol. 2021;36(11):2186–95.

404. Li YB, Gao JL, Zhong ZF, et al. Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways. Pharmacol Rep. 2013;65(3):700–9.

405. Chou CH, Wang HK, Lin YC, et al. Bisdemethoxycurcumin promotes apoptosis and inhibits the epithelial-mesenchymal transition through the inhibition of the G-protein-coupled receptor 161/mammalian target of rapamycin signaling pathway in triple negative breast cancer cells. J Agric Food Chem. 2021;69(48):14557–67.

406. Wang X, Zhou Q, Li X, et al. Insights into aptamer-drug delivery systems against prostate cancer. Molecules. 2022;27(11):3446.

407. Wang A, Jain S, Dia V, et al. Shellac micelles loaded with curcumin using a ph cycle to improve dispersibility, bioaccessibility, and potential for colon delivery. J Agric Food Chem. 2022;70(48):15166–77.

408. Soleymani M, Velashjerdi M, Asgari M. Preparation of hyaluronic acid-decorated mixed nanomicelles for targeted delivery of hydrophobic drugs to CD44-overexpressing cancer cells. Int J Pharm. 2021;592: 120052.

409. Pakian S, Radmanesh F, Sadeghi-Abandansari H et al. Gelatin-Based Injectable Hydrogel/Microgel Composite as a Combinational Dual Drug Delivery System for Local Co-delivery of Curcumin and 5-Fluorouracil in Synergistic Therapy of Colorectal Cancer br. ACS Appl Polym Mater. 2022.

410. Kundu M, Sadhukhan P, Ghosh N, et al. pH-responsive and targeted delivery of curcumin via phenylboronic acid-functionalized ZnO nanoparticles for breast cancer therapy. J Adv Res. 2019;18:161–72.

411. Kaewruethai T, Lin Y, Wang Q, et al. The dual modification of PNIPAM and β-cyclodextrin grafted on hyaluronic acid as self-assembled nanogel for curcumin delivery. Polymers-Basel. 2023;15(1):116.

412. He Y, Wu C, Duan J, et al. Anti-glioma effect with targeting therapy using folate modified nano-micelles delivery curcumin. J Biomed Nanotechnol. 2020;16(1):1–13.

413. Chae J, Choi Y, Hong J, et al. Anticancer and antibacterial properties of curcumin-loaded mannosylated solid lipid nanoparticles for the treatment of lung diseases. ACS Appl Bio Mater. 2024;7(4):2175–85.

414. Ghosh S, Dutta S, Sarkar A, et al. Targeted delivery of curcumin in breast cancer cells via hyaluronic acid modified mesoporous silica nanoparticle to enhance anticancer efficiency. Colloids Surf B Biointerfaces. 2021;197: 111404.

415. Lin X, Wang L, Zhao L, et al. Curcumin micelles suppress gastric tumor cell growth by upregulating ROS generation, disrupting redox equilibrium and affecting mitochondrial bioenergetics. Food Funct. 2020;11(5):4146–59.

416. Vaidya FU, Sharma R, Shaikh S, et al. Pluronic micelles encapsulated curcumin manifests apoptotic cell death and inhibits pro-inflammatory cytokines in human breast adenocarcinoma cells. Cancer Rep. 2019;2(1): e1133.

417. Shen J, Zhang J, Wu W, et al. Biocompatible anisole-nonlinear PEG core-shell nanogels for high loading capacity, excellent stability, and controlled release of curcumin. Gels. 2023;9(9):762.

418. Luckanagul JA, Ratnatilaka NBP, Muangnoi C, et al. Self-assembled thermoresponsive nanogel from grafted hyaluronic acid as a biocompatible delivery platform for curcumin with enhanced drug loading and biological activities. Polymers-Basel. 2021;13(2):194.

419. Howaili F, Ozliseli E, Kucukturkmen B, et al. Stimuli-responsive, plasmonic nanogel for dual delivery of curcumin and photothermal therapy for cancer treatment. Front Chem. 2021;8: 602941.

420. Wang Y, Ding R, Zhang Z, et al. Curcumin-loaded liposomes with the hepatic and lysosomal dual-targeted effects for therapy of hepatocellular carcinoma. Int J Pharm. 2021;602: 120628.

421. Moballegh-Nasery M, Mandegary A, Eslaminejad T, et al. Cytotoxicity evaluation of curcumin-loaded affibody-decorated liposomes against breast cancerous cell lines. J Liposome Res. 2021;31(2):189–94.

422. Milane L, Singh A, Mattheolabakis G, et al. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015;219:278–94.

423. Sun D, Zhuang X, Xiang X, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606–14.

424. Aqil F, Munagala R, Jeyabalan J, et al. Exosomes for the enhanced tissue bioavailability and efficacy of curcumin. Aaps J. 2017;19(6):1691–702.

425. Wu H, Zhou J, Zeng C, et al. Curcumin increases exosomal TCF21 thus suppressing exosome-induced lung cancer. Oncotarget. 2016;7(52):87081–90.

426. Taverna S, Giallombardo M, Pucci M, et al. Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth: a possible role for exosomal disposal of miR-21. Oncotarget. 2015;6(26):21918–33.

427. Wang Q, Ren Y, Mu J, et al. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites. Cancer Res. 2015;75(12):2520–9.

428. Sato M, Maulik G, Bagchi D, et al. Myocardial protection by protykin, a novel extract of trans-resveratrol and emodin. Free Radical Res. 2000;32(2):135–44.

429. Kuo YC, Tsai WJ, Meng HC, et al. Immune reponses in human mesangial cells regulated by emodin from polygonum hypoleucum ohwi. Life Sci. 2001;68(11):1271–86.

430. Lee H, Tsai SJ. Effect of emodin on cooked-food mutagen activation. Food Chem Toxicol. 1991;29(11):765–70.

431. Wells JM, Cole RJ, Kirksey JW. Emodin, a toxic metabolite of Aspergillus wentii isolated from weevil-damaged chestnuts. Appl Microbiol. 1975;30(1):26–8.

432. Peigen X, Liyi H, Liwei W. Ethnopharmacologic study of Chinese rhubarb. J Ethnopharmacol. 1984;10(3):275–93.

433. Wang X, Yang S, Li Y, et al. Role of emodin in atherosclerosis and other cardiovascular diseases: pharmacological effects, mechanisms, and potential therapeutic target as a phytochemical. Biomed Pharmacother. 2023;161: 114539.

434. Qu L, Jiao M, Zhang Z, et al. A strategy for selective screening of dual-target bioactive compounds against hypertrophic scar through inhibiting angiotensin II type 1 receptor while stimulating type 2 receptor from Chinese herbs. Chin Med. 2025. 10.1186/s13020-025-01065-6.

435. Xu Y-Y, Zhu M, Wu J, et al. A mannitol-modified emodin nano-drug restores the intestinal barrier function and alleviates inflammation in a mouse model of DSS-induced ulcerative colitis. Chin Med. 2023;18(1):1.

436. Zhang Q, Chen WW, Sun X, et al. The versatile emodin: a natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers. Int J Biol Sci. 2022;18(8):3498–527.

437. Srinivas G, Babykutty S, Sathiadevan PP, et al. Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent. Med Res Rev. 2007;27(5):591–608.

438. Mohammed AE, Ameen F, Aabed K, et al. In-silico predicting as a tool to develop plant-based biomedicines and nanoparticles: Lycium shawii metabolites. Biomed Pharmacother. 2022;150:2.

439. Ahmad W, Ansari MA, Alsayari A, et al. In vitro, molecular docking and in silico adme/tox studies of emodin and chrysophanol against human colorectal and cervical carcinoma. Pharmaceuticals. 2022;15(11):1.

440. Zou G, Zhang X, Wang L, et al. Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription. Theranostics. 2020;10(15):6839–53.

441. Song Y, Sheng Z, Xu Y, et al. Magnetic liposomal emodin composite with enhanced killing efficiency against breast cancer. Biomater Sci. 2019;7(3):867–75.

442. Fu M, Tang W, Liu J-J, et al. Combination of targeted daunorubicin liposomes and targeted emodin liposomes for treatment of invasive breast cancer. J Drug Target. 2020;28(3):245–58.

443. Siri M, Ruocco MJF, Achilli E, et al. Effect of structure in ionised albumin based nanoparticle: characterisation, emodin interaction, and in vitro cytotoxicity. Mater Sci Eng C Mater Biol Appl. 2019;103: 109813.

444. Ren S, Song L, Tian Y, et al. Emodin-conjugated PEGylation of Fe3O4 nanoparticles for FI/MRI dual-modal imaging and therapy in pancreatic cancer. Int J Nanomedicine. 2021;16:7463–78.

445. Li Z, Lin Y, Zhang S, et al. Emodin regulates neutrophil phenotypes to prevent hypercoagulation and lung carcinogenesis. J Transl Med. 2019;17(1):90.

446. Olsson A-K, Cedervall J. NETosis in cancer—platelet-neutrophil crosstalk promotes tumor-associated pathology. Front Immunol. 2016;7:373.

447. Fan Q-M, Jing Y-Y, Yu G-F, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352(2):160–8.

448. Liu Q, Hodge J, Wang J, et al. Emodin reduces breast cancer lung metastasis by suppressing macrophage-induced breast cancer cell epithelial-mesenchymal transition and cancer stem cell formation. Theranostics. 2020;10(18):8365–81.

449. Yin J, Zhao X, Chen X, et al. Emodin suppresses hepatocellular carcinoma growth by regulating macrophage polarization via microRNA-26a/transforming growth factor beta 1/protein kinase B. Bioengineered. 2022;13(4):9548–63.

450. Sougiannis AT, VanderVeen B, Chatzistamou I, et al. Emodin reduces tumor burden by diminishing M2-like macrophages in colorectal cancer. Am J Physiol Gastrointest Liver Physiol. 2022;322(3):G383–95.

451. Wang K-J, Meng X-Y, Chen J-F, et al. Emodin induced necroptosis and inhibited glycolysis in the renal cancer cells by enhancing ROS. Oxid Med Cell Longev. 2021;2021:8840590.

452. Shen Z, Zhao L, Yoo S-A, et al. Emodin induces ferroptosis in colorectal cancer through NCOA4-mediated ferritinophagy and NF-κb pathway inactivation. Apoptosis. 2024;29(9–10):1810–23.

453. Zhou X, Yeasmin Khusbu F, Xie Y, et al. Emodin-induced necroptosis in prostate cancer cells via the mitochondrial fission HSP90/MLKL/PGAM pathway. Chem Biodivers. 2023;20(6): e202201130.

454. Zhou J, Li G, Han G, et al. Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway. Invest New Drugs. 2020;38(1):50–9.

455. Wu W, Lu P, Huang Y, et al. Emodin regulates the autophagy via the miR-371a-5p/PTEN axis to inhibit hepatic malignancy. Biochem Biophys Res Commun. 2022;619:1–8.

456. Qin B, Zeng Z, Xu J, et al. Emodin inhibits invasion and migration of hepatocellular carcinoma cells via regulating autophagy-mediated degradation of snail and β-catenin. BMC Cancer. 2022;22(1):671.

457. Sugiyama Y, Shudo T, Hosokawa S, et al. Emodin, as a mitochondrial uncoupler, induces strong decreases in adenosine triphosphate (ATP) levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve. Genes Cells. 2019;24(8):569–84.

458. Fang X-Q, Kim Y-S, Lee Y-M, et al. Polygonum cuspidatum extract (Pc-Ex) containing emodin suppresses lung cancer-induced cachexia by suppressing TCF4/TWIST1 complex-induced PTHrP expression. Nutrients. 2022;14(7):1508.

459. Wu C-C, Chen M-S, Cheng Y-J, et al. Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis. Cancers (Basel). 2019;11(11):1795.

460. Wang S, Fu J-L, Hao H-F, et al. Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy. Pharmacol Res. 2021;170:1.

461. Li M, Jin S, Cao Y, et al. Emodin regulates cell cycle of non-small lung cancer (NSCLC) cells through hyaluronan synthase 2 (HA2)-HA-CD44/receptor for hyaluronic acid-mediated motility (RHAMM) interaction-dependent signaling pathway. Cancer Cell Int. 2021;21(1):19.

462. Trybus W, Król T, Trybus E, et al. Emodin induces death in human cervical cancer cells through mitotic catastrophe. Anticancer Res. 2019;39(2):679–86.

463. Wahi D, Soni D, Grover A. A double-edged sword: the anti-cancer effects of emodin by inhibiting the redox-protective protein MTH1 and augmenting ROS in NSCLC. J Cancer. 2021;12(3):652–81.

464. Jiang J, Zhou N, Ying P, et al. Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways. Open Life Sci. 2018;13:489–96.

465. Hassan HM, Hamdan AM, Alattar A, et al. Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats. Redox Rep. 2024;29(1):2365590.

466. Liu C, Chen L, Wang W, et al. Emodin suppresses the migration and invasion of melanoma cells. Biol Pharm Bull. 2021;44(6):771–9.

467. Yuan M, Chen L, Wang W, et al. Emodin inhibits the proliferation and migration of B16F10 cells and induces their apoptosis. Transl Cancer Res. 2020;9(10):6198–205.

468. Dai G, Wang D, Ma S, et al. ACSL4 promotes colorectal cancer and is a potential therapeutic target of emodin. Phytomedicine. 2022;102: 154149.

469. Bai J, Wu J, Tang R, et al. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest New Drugs. 2020;38(2):229–45.

470. Long H, Chen H, Yan J, et al. Emodin exerts antitumor effects in ovarian cancer cell lines by preventing the development of cancer stem cells via epithelial mesenchymal transition. Oncol Lett. 2022;23(3):95.

471. Li F, Song X, Zhou X, et al. Emodin attenuates high lipid-induced liver metastasis through the AKT and ERK pathways in vitro in breast cancer cells and in a mouse xenograft model. Heliyon. 2023;9(6): e17052.

472. Zhang N, Wang J, Sheng A, et al. Emodin inhibits the proliferation of MCF-7 human breast cancer cells through activation of aryl hydrocarbon receptor (AhR). Front Pharmacol. 2020;11: 622046.

473. Zhang F-Y, Li R-Z, Xu C, et al. Emodin induces apoptosis and suppresses non-small-cell lung cancer growth via downregulation of sPLA2-IIa. Phytomedicine. 2022;95: 153786.

474. Gao Y, Li Y, Zhu Y, et al. Emodin is a potential drug targeting CD44-positive hepatocellular cancer. Curr Cancer Drug Targets. 2024;24(5):510–8.

475. Liu X, Wei W, Wu Y-Z, et al. Emodin treatment of papillary thyroid cancer cell lines in vitro inhibits proliferation and enhances apoptosis via downregulation of NF-κB and its upstream TLR4 signaling. Oncol Lett. 2023;26(6):514.

476. Nowak-Perlak M, Bromke MA, Ziółkowski P, et al. The comparison of the efficiency of emodin and aloe-emodin in photodynamic therapy. Int J Mol Sci. 2022;23(11):6276.

477. Liu W, Qaed E, Zhu Y, et al. Research progress and new perspectives of anticancer effects of emodin. Am J Chin Med. 2023;51(07):1751–93.

478. Varli M, Ji M, Kim E et al. Emodin disrupts the KITENIN oncogenic complex by binding ErbB4 and suppresses colorectal cancer progression in dual blockade with KSRP-binding compound. Phytomedicine. 2025, 136.

479. Ponnusamy L, Kothandan G, Manoharan R. Berberine and emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway. Biochim Biophys Acta Mol Basis Dis. 2020;1866(11): 165897.

480. Bhattacharjee M, Upadhyay P, Sarker S, et al. Combinatorial therapy of thymoquinone and emodin synergistically enhances apoptosis, attenuates cell migration and reduces stemness efficiently in breast cancer. Biochim Biophys Acta Gen Subj. 2020;1864(11): 129695.

481. Chen S, Zhang Z, Zhang J. Emodin enhances antitumor effect of paclitaxel on human non-small-cell lung cancer cells in vitro and in vivo. Drug Des Devel Ther. 2019;13:1145–53.

482. Peng S, Wang J, Lu C, et al. Emodin enhances cisplatin sensitivity in non-small cell lung cancer through Pgp downregulation. Oncol Lett. 2021;21(3):230.

483. Teng X, Wang SY, Shi YQ, et al. The role of emodin on cisplatin resistance reversal of lung adenocarcinoma A549/DDP cell. Anticancer Drugs. 2021;32(9):939–49.

484. Li T, Si W, Zhu J, et al. Emodin reverses 5-Fu resistance in human colorectal cancer via downregulation of PI3K/Akt signaling pathway. Am J Transl Res. 2020;12(5):1851–61.

485. Zhou G, Xie R-F, Li S-N, et al. Synergic effects and possible mechanism of emodin and stilbene glycosides on colorectal cancer. Phytomedicine. 2024;132: 155821.

486. Trybus W, Trybus E, Król T. Emodin sensitizes cervical cancer cells to vinblastine by inducing apoptosis and mitotic death. Int J Mol Sci. 2022;23(15):8510.

487. Yang M, Xiong Z, Deng H, et al. Effect of emodin combined with cisplatin on the invasion and migration of HepG2 hepatoma cells. J Physiol Pharmacol. 2023;74(4):1.

488. Wang Z, Chen H, Chen J, et al. Emodin sensitizes human pancreatic cancer cells to EGFR inhibitor through suppressing Stat3 signaling pathway. Cancer Manag Res. 2019;11:8463–73.

489. Xu C, Pascual-Sabater S, Fillat C, et al. The LAMB3-EGFR signaling pathway mediates synergistic Anti-Cancer effects of berberine and emodin in Pancreatic cancer. Biochem Pharmacol. 2024;2024:116509.

490. Ma W, Liu F, Yuan L, et al. Emodin and AZT synergistically inhibit the proliferation and induce the apoptosis of leukemia K562 cells through the EGR1 and the Wnt/β-catenin pathway. Oncol Res. 2020;43(1):260–9.

491. Wang X-Y, Sun G-B, Wang Y-J, et al. Emodin inhibits resistance to imatinib by downregulation of Bcr-Abl and STAT5 and allosteric inhibition in chronic myeloid leukemia cells. Biol Pharm Bull. 2020;43(10):1526–33.

492. Wang Y, Zou Z, Jaisi A, et al. Unravelling the protective effects of emodin against cyclophosphamide induced gonadotoxicity in male wistar rats. Drug Des Devel Ther. 2021;15:4403–11.

493. Hsu C-M, Yen C-H, Wang S-C, et al. Emodin ameliorates the efficacy of carfilzomib in multiple myeloma cells via apoptosis and autophagy. Biomedicines. 2022;10(7):1638.

494. Liu R, Liu J, Wang S, et al. Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death. Cell Death Dis. 2019;10(7):527.

495. Karatoprak GS, Akkol EK, Yucel C et al. Advances in Understanding the Role of Aloe Emodin and Targeted Drug Delivery Systems in Cancer. Oxidative Medicine and Cellular Longevity. 2022, 2022.

496. Nowak-Perlak M, Ziolkowski P, Wozniak M. A promising natural anthraquinones mediated by photodynamic therapy for anti-cancer therapy. Phytomedicine. 2023, 119.

497. Okon E, Koval M, Wawruszak A, et al. Emodin-8-O-glucoside-isolation and the screening of the anticancer potential against the nervous system tumors. Molecules. 2023;28(21):7366.

498. Li C, Gao S, Yang W-S, et al. β-dihydroartemisinin-emodin promotes apoptosis by activating extrinsic and intrinsic pathways in human liver cancer cells. Ann Clin Lab Sci. 2019;49(3):281–90.

499. He MT, Nguyen QN, Cho EJ, et al. Aloe-emodin isolated from rheum Undulatum L. regulates cell cycle distribution and cellular senescence in human prostate cancer lncap cells. J Diet Suppl. 2024;21(3):389–407.

500. Hussain T, Alafnan A, Almazni IA, et al. Aloe-emodin exhibits growth-suppressive effects on androgen-independent human prostate cancer DU145 cells via inhibiting the Wnt/β-catenin signaling pathway: an in vitro and in silico study. Front Pharmacol. 2023;14:1325184.

501. Jiang X, Liu Y, Zhang G, et al. Aloe-emodin induces breast tumor cell apoptosis through upregulation of miR-15a/miR-16-1 that suppresses BCL2. Evid Based Complement Alternat Med. 2020;2020:5108298.

502. Wang S, Yan W-W, He M, et al. Aloe emodin inhibits telomerase activity in breast cancer cells: transcriptional and enzymological mechanism. Pharmacol Rep. 2020;72(5):1383–96.

503. Cheng G, Liu Z, Zheng Z, et al. Cell metabolomics reveals the potential mechanism of aloe emodin and emodin inhibiting breast cancer metastasis. Int J Mol Sci. 2022;23(22):13738.

504. Cheng G, Pi Z, Zhuang X, et al. The effects and mechanisms of aloe-emodin on reversing adriamycin-induced resistance of MCF-7/ADR cells. Phytother Res. 2021;35(7):3886–97.

505. Shen F, Ge C, Yuan P. Aloe-emodin induces autophagy and apoptotic cell death in non-small cell lung cancer cells via Akt/mTOR and MAPK signaling. Eur J Pharmacol. 2020;886: 173550.

506. Jiang D, Ding S, Mao Z, et al. Integrated analysis of potential pathways by which aloe-emodin induces the apoptosis of colon cancer cells. Cancer Cell Int. 2021;21(1):238.

507. Du M, Shen P, Tan R, et al. Aloe-emodin inhibits the proliferation, migration, and invasion of melanoma cells via inactivation of the Wnt/beta-catenin signaling pathway. Ann Transl Med. 2021;9(23):1722.

508. Chen S, Guan X, Xie L, et al. Aloe-emodin targets multiple signaling pathways by blocking ubiquitin-mediated degradation of DUSP1 in nasopharyngeal carcinoma cells. Phytother Res. 2023;37(7):2979–94.

509. Du Y, Zhang J, Tao Z, et al. Aloe emodin exerts potent anticancer effects in MIAPaCa-2 and PANC-1 human pancreatic adenocarcinoma cell lines through activation of both apoptotic and autophagic pathways, sub-G1 cell cycle arrest and disruption of mitochondrial membrane potential (ΛΨm). J BUON. 2019;24(2):746–53.

510. Staffieri S, Russo V, Oliva MA, et al. Aloe-emodin overcomes anti-cancer drug resistance to temozolomide and prevents colony formation and migration in primary human glioblastoma cell lines NULU and ZAR. Molecules. 2023;28(16):6024.

511. Maimaiti A, Xingliang L, Shi L. In vitro and in vivo anti-lung cancer activity of emodin: A RNA-seq transcriptome analysis. Curr Med Chem. 2022.

512. Chen C, Gao J, Wang T-S, et al. NMR-based metabolomic techniques identify the toxicity of emodin in HepG2 cells. Sci Rep. 2018;8(1):9379.

513. Jiang X, Ma M, Li M, et al. Preparation and evaluation of novel emodin-loaded stearic acid-g-chitosan oligosaccharide nanomicelles. Nanoscale Res Lett. 2020;15(1):93.

514. Liu H, Zhuang Y, Wang P, et al. Polymeric lipid hybrid nanoparticles as a delivery system enhance the antitumor effect of emodin in vitro and in vivo. J Pharm Sci. 2021;110(8):2986–96.

515. Wei W, Tang J, Hu L, et al. Experimental anti-tumor effect of emodin in suspension - in situ hydrogels formed with self-assembling peptide. Drug Deliv. 2021;28(1):1810–21.

516. Tang L, Liu X-X, Yang X-D, et al. A compound formulation of EGF-modified paclitaxel micelles and EGF-modified emodin micelles enhance the therapeutic effect of ovarian cancer. J Liposome Res. 2023;33(1):89–101.

517. Cao X, Deng T, Zhu Q, et al. Photothermal therapy mediated hybrid membrane derived nano-formulation for enhanced cancer therapy. AAPS PharmSciTech. 2023;24(6):146.

518. Ye Y, Zhong W, Luo R, et al. Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis. J Nanobiotechnology. 2024;22(1):33.

519. Zhang Z, Zhang X, Bi K, et al. Potential protective mechanisms of green tea polyphenol EGCG against COVID-19. Trends Food Sci Technol. 2021;114:11–24.

520. Wu Z, Huang S, Li T et al. Gut microbiota from green tea polyphenol-dosed mice improves intestinal epithelial homeostasis and ameliorates experimental colitis. Microbiome. 2021, 9(1).

521. Aggarwal V, Tuli HS, Tania M, et al. Molecular mechanisms of action of epigallocatechin gallate in cancer: recent trends and advancement. Semin Cancer Biol. 2022;80:256–75.

522. Zhao H, Zhu W, Xie P, et al. A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer. Radiother Oncol. 2014;110(1):132–6.

523. Suhail M, Rehan M, Tarique M et al. Targeting a transcription factor NF-κB by green tea catechins using in silico and in vitro studies in pancreatic cancer. Front Nutr. 2023, 9.

524. Xu X, Li H, Chen J et al. A Universal Strategy to Construct High-Performance Homo- and Heterogeneous Microgel Assembly Bioinks. Small Methods. 2024, 8(12).

525. Zheng X, Chen J, Deng M, et al. G3BP1 and SLU7 jointly promote immune evasion by downregulating MHC-I via PI3K/Akt activation in bladder cancer. Adv Sci. 2024;11(7): e2305922.

526. Mu M, Chen B, Li H, et al. Augmented the sensitivity of photothermal-ferroptosis therapy in triple-negative breast cancer through mitochondria-targeted nanoreactor. J Control Release. 2024;375:733–44.

527. Ravindran Menon D, Li Y, Yamauchi T, et al. EGCG inhibits tumor growth in melanoma by targeting JAK-STAT signaling and its downstream PD-L1/PD-L2-PD1 axis in tumors and enhancing cytotoxic T-cell responses. Pharmaceuticals. 2021;14(11):1081.

528. Lei J, Chen J, Chen J, et al. Epigallocatechin-3-gallate induces immunogenic cell death and enhances cancer immunotherapy in colorectal cancer. Biochem Biophys Res Commun. 2024;736: 150907.

529. Guo Y, Guo Y, Guo Z, et al. Effect of fragment 1 on the binding of epigallocatechin gallate to the PD-L1 dimer explored by molecular dynamics. Molecules. 2023;28(23):7881.

530. Guo Y, Liang J, Liu B, et al. Molecular mechanism of food-derived polyphenols on PD-L1 dimerization: a molecular dynamics simulation study. Int J Mol Sci. 2021;22(20):10924.

531. Xu P, Yan F, Zhao Y, et al. Green tea polyphenol EGCG attenuates MDSCs-mediated immunosuppression through canonical and non-canonical pathways in a 4T1 murine breast cancer model. Nutrients. 2020;12(4):1042.

532. Zhou M, Dong J, Huang J, et al. Chitosan-gelatin-EGCG nanoparticle-meditated LncRNA TMEM44-AS1 silencing to activate the P53 signaling pathway for the synergistic reversal of 5-FU resistance in gastric cancer. Adv Sci (Weinh). 2022;9(22):2105077.

533. Chen J, Zhang F, Ren X, et al. Targeting fatty acid synthase sensitizes human nasopharyngeal carcinoma cells to radiation via downregulating frizzled class receptor 10. Cancer Biol Med. 2020;17(3):740.

534. Zhou Y, Huang S, Guo Y, et al. Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. 2023;37(12):5837–53.

535. Sun W, Wong IL, Law HK-W, et al. In vivo reversal of P-glycoprotein-mediated drug resistance in a breast cancer xenograft and in leukemia models using a novel, potent, and nontoxic epicatechin EC31. Int J Mol Sci. 2023;24(5):4377.

536. Qian F, Wei D, Zhang Q, et al. Modulation of P-glycoprotein function and reversal of multidrug resistance by (–)-epigallocatechin gallate in human cancer cells. Biomed Pharmacother. 2005;59(3):64–9.

537. Wang X, Chen B, Xu D, et al. Molecular mechanism and pharmacokinetics of flavonoids in the treatment of resistant EGF receptor-mutated non-small-cell lung cancer: a narrative review. Br J Pharmacol. 2021;178(6):1388–406.

538. Zhang W, Zhang W, Sun L, et al. The effects and mechanisms of epigallocatechin-3-gallate on reversing multidrug resistance in cancer. Trends Food Sci Technol. 2019;93:221–33.

539. Wen Y, Zhao R, Gupta P, et al. The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by the ABCB1 transporter both in vitro and in vivo. Acta Pharm Sin B. 2019;9(2):316–23.

540. Mayer BF, Stagno MJ, Fuchs J, et al. Epigallocatechin gallate inhibits cell growth and hedgehog signalling in human rhabdomyosarcoma cell lines. Anticancer Res. 2023;43(3):1025–30.

541. Meng J, Chang C, Chen Y, et al. EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC. Onco Targets Ther. 2019;12:6033–43.

542. Yi Z, Chen X, Chen G, et al. General nanomedicine platform by solvent-mediated disassembly/reassembly of scalable natural polyphenol colloidal spheres. ACS Appl Mater Interfaces. 2020;12(34):37914–28.

543. Bae KH, Lai F, Oruc B, et al. Self-assembled daunorubicin/epigallocatechin gallate nanocomplex for synergistic reversal of chemoresistance in leukemia. Int J Mol Sci. 2022;24(1):381.

544. Chen C-Y, Lin Y-J, Wang CC, et al. Epigallocatechin-3-gallate inhibits tumor angiogenesis: involvement of endoglin/Smad1 signaling in human umbilical vein endothelium cells. Biomed Pharmacother. 2019;120: 109491.

545. Dong Z, Wu J, He L et al. EGCG inhibits tobacco smoke-promoted proliferation of lung cancer cells through targeting CCL5. Phytomedicine. 2025, 139.

546. Tang Y, Cao J, Cai Z, et al. Epigallocatechin gallate induces chemopreventive effects on rats with diethylnitrosamine-induced liver cancer via inhibition of cell division cycle 25A. Mol Med Rep. 2020;22(5):3873–85.

547. Kedhari Sundaram M, Haque S, Somvanshi P, et al. Epigallocatechin gallate inhibits HeLa cells by modulation of epigenetics and signaling pathways. Biotech. 2020;10(11):484.

548. Al-Ghamdi MA, Al-Enazy A, Huwait E, et al. Enhancement of Annexin V in response to combination of epigallocatechin gallate and quercetin as a potent arrest the cell cycle of colorectal cancer. Braz J Biol. 2021;83: e248746.

549. Diwan B, Sharma RJB. Green tea EGCG effectively alleviates experimental colitis in middle-aged male mice by attenuating multiple aspects of oxi-inflammatory stress and cell cycle deregulation. Biogerontology. 2022;23(6):789–807.

550. Chen J, Zhang L, Li C, et al. Lipophilized epigallocatechin gallate derivative exerts anti-proliferation efficacy through induction of cell cycle arrest and apoptosis on DU145 human prostate cancer cells. Nutrients. 2019;12(1):92.

551. Zhang S, Jiang S, Deng N, et al. Phytochemical profiles, antioxidant activity and antiproliferative mechanism of Rhodiola rosea L. Phenolic Extract Nutrients. 2022;14(17):3602.

552. Sarkar B, Ullah MA, Islam SS, et al. Analysis of plant-derived phytochemicals as anti-cancer agents targeting cyclin dependent kinase-2, human topoisomerase IIa and vascular endothelial growth factor receptor-2. J Recept Signal Transduct Res. 2021;41(3):217–33.

553. Yoshimura H, Yoshida H, Matsuda S, et al. The therapeutic potential of epigallocatechin-3-gallate against human oral squamous cell carcinoma through inhibition of cell proliferation and induction of apoptosis: In vitro and in vivo murine xenograft study. Mol Med Rep. 2019;20(2):1139–48.

554. Teng C-C, Tung S-Y, Lee K-C, et al. Novel regulator role of CIL-102 in the epigenetic modification of TNFR1/TRAIL to induce cell apoptosis in human gastric cancer. Food Chem Toxicol. 2021;147: 111856.

555. Wang W, Xiong X, Li X, et al. In silico investigation of the anti-tumor mechanisms of epigallocatechin-3-gallate. Molecules. 2019;24(7):1445.

556. Kciuk M, Alam M, Ali N, et al. Epigallocatechin-3-gallate therapeutic potential in cancer: mechanism of action and clinical implications. Molecules. 2023;28(13):5246.

557. Xia Y, Chen R, Lu G, et al. Natural phytochemicals in bladder cancer prevention and therapy. Front Oncol. 2021;11: 652033.

558. Kumar R, Sharma A, Kumari A, et al. Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway. Biogerontology. 2019;20:171–89.

559. Panji M, Behmard V, Zare Z, et al. Synergistic effects of green tea extract and paclitaxel in the induction of mitochondrial apoptosis in ovarian cancer cell lines. Gene. 2021;787: 145638.

560. Chen Z, Wei Y, Zheng Y, et al. SERPINB2, an early responsive gene to epigallocatechin gallate, inhibits migration and promotes apoptosis in esophageal cancer cells. Cells. 2022;11(23):3852.

561. Sharifirad M, Pezzani R, Redaelli M, et al. Preclinical activities of epigallocatechin gallate in signaling pathways in cancer. Molecules. 2020;25(3):467.

562. Qin J, Fu M, Wang J, et al. PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin-3-gallate in ovarian cancer. Oncol Rep. 2020;43(6):1885–96.

563. Bing-Xin D, Pei L, Jun LJCJONM. EGCG and ECG induce apoptosis and decrease autophagy via the AMPK/mTOR and PI3K/AKT/mTOR pathway in human melanoma cells. Chin J Nat Med. 2022, 20(4):290–300.

564. Zhang Z, Zhu Q, Wang S, et al. Epigallocatechin-3-gallate inhibits the formation of neutrophil extracellular traps and suppresses the migration and invasion of colon cancer cells by regulating STAT3/CXCL8 pathway. Mol Cell Biochem. 2023;478(4):887–98.

565. Yang N, Li XJBP. Epigallocatechin gallate relieves asthmatic symptoms in mice by suppressing HIF-1α/VEGFA-mediated M2 skewing of macrophages. Biochem Pharmacol. 2022;202: 115112.

566. Liao Z-H, Zhu H-Q, Chen Y-Y, et al. The epigallocatechin gallate derivative Y6 inhibits human hepatocellular carcinoma by inhibiting angiogenesis in MAPK/ERK1/2 and PI3K/AKT/HIF-1α/VEGF dependent pathways. J Ethnopharmacol. 2020;259: 112852.

567. Fu J, Yao J, Wang H, et al. Effects of EGCG on proliferation and apoptosis of gastric cancer SGC7901 cells via down-regulation of HIF-1α and VEGF under a hypoxic state. Eur Rev Med Pharmacol Sci. 2019;23(1):155–61.

568. Panji M, Behmard V, Zare Z, et al. Suppressing effects of green tea extract and Epigallocatechin-3-gallate (EGCG) on TGF-β-induced epithelial-to-mesenchymal transition via ROS/Smad signaling in human cervical cancer cells. Gene. 2021;794: 145774.

569. Li T, Zhao N, Lu J, et al. Epigallocatechin gallate (EGCG) suppresses epithelial-Mesenchymal transition (EMT) and invasion in anaplastic thyroid carcinoma cells through blocking of TGF-β1/Smad signaling pathways. Bioengineered. 2019;10(1):282–91.

570. Kim B-G, Malek E, Choi SH, et al. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14(1):1–20.

571. Weng C-L, Chen C-C, Tsou H-H, et al. Areca nut procyanidins prevent ultraviolet light B-induced photoaging via suppression of cyclooxygenase-2 and matrix metalloproteinases in mouse skin. Drug Chem Toxicol. 2022;45(1):353–9.

572. Djediai S, Gonzalez Suarez N, El Cheikh-Hussein L, et al. MT1-MMP cooperates with TGF-β receptor-mediated signaling to trigger SNAIL and induce epithelial-to-mesenchymal-like transition in U87 glioblastoma cells. Int J Mol Sci. 2021;22(23):13006.

573. Peng X, McClements DJ, Liu X, et al. EGCG-based nanoparticles: synthesis, properties, and applications. Crit Rev Food Sci Nutr. 2024;22:1–22.

574. Li J, Jiang X, Shang L, et al. L-EGCG-Mn nanoparticles as a pH-sensitive MRI contrast agent. Drug Deliv. 2021;28(1):126–35.

575. Liao T, Chen Z, Kuang Y, et al. Small-size Ti3C2Tx MXene nanosheets coated with metal-polyphenol nanodots for enhanced cancer photothermal therapy and anti-inflammation. Acta Biomater. 2023;159:312–23.

576. Shah SL, Bashir K, Rasheed HM, et al. LC-MS/MS-based metabolomic profiling of constituents from Glochidion velutinum and its activity against cancer cell lines. Molecules. 2022;27(24):9012.

577. Chen X, Liu B, Tong R, et al. Improved stability and targeted cytotoxicity of epigallocatechin-3-gallate palmitate for anticancer therapy. Langmuir. 2021;37(2):969–77.

578. Zhu Q-Q, Yang X-Y, Zhang X-J, et al. EGCG targeting Notch to attenuate renal fibrosis via inhibition of TGFβ/Smad3 signaling pathway activation in streptozotocin-induced diabetic mice. Food Funct. 2020;11(11):9686–95.

579. Wei R, Wirkus J, Yang Z, et al. EGCG sensitizes chemotherapeutic-induced cytotoxicity by targeting the ERK pathway in multiple cancer cell lines. Arch Biochem Biophys. 2020;692: 108546.

580. Liu M, Kuo F, Capistrano KJ, et al. TGF-β suppresses type 2 immunity to cancer. Nature. 2020;587(7832):115–20.

581. Knidel C, Pereira MF, Barcelos DHF, et al. Epigallocatechin gallate has antibacterial and antibiofilm activity in methicillin resistant and susceptible Staphylococcus aureus of different lineages in non-cytotoxic concentrations. Nat Prod Res. 2021;35(22):4643–7.

582. Wu W, Dong J, Gou H, et al. EGCG synergizes the therapeutic effect of irinotecan through enhanced DNA damage in human colorectal cancer cells. J Cell Mol Med. 2021;25(16):7913–21.

583. McDonnell AM, Pyles HM, Diaz-Cruz ES, et al. Enoxacin and epigallocatechin gallate (EGCG) act synergistically to inhibit the growth of cervical cancer cells in culture. Molecules. 2019;24(8):1580.

584. Wei R, Cortez Penso NE, Hackman RM, et al. Epigallocatechin-3-gallate (EGCG) suppresses pancreatic cancer cell growth, invasion, and migration partly through the inhibition of Akt pathway and epithelial–mesenchymal transition: enhanced efficacy when combined with gemcitabine. Nutrients. 2019;11(8):1856.

585. López EP-F, García FG, Jornet PLJAOOB. Combination of 5-florouracil and polyphenol EGCG exerts suppressive effects on oral cancer cells exposed to radiation. Arch Oral Biol. 2019;101:8–12.

586. Sato K, Takigawa N, Kubo T, et al. Effect of a cyclooxygenase-2 inhibitor in combination with (−)-epigallocatechin gallate or polyphenon E on cisplatin-induced lung tumorigenesis in A/J mice. Acta Med Okayama. 2023;77(1):65–70.

587. Yool AJ, Ramesh SJFIP. Molecular targets for combined therapeutic strategies to limit glioblastoma cell migration and invasion. Front Pharmacol. 2020;11:515819.

588. Zhang L, He Y, Wu X, et al. Melatonin and (−)-epigallocatechin-3-gallate: partners in fighting cancer. Cells. 2019;8(7):745.

589. Jin H, Cui D, Fan Y, et al. Recent advances in bioaffinity strategies for preclinical and clinical drug discovery: Screening natural products, small molecules and antibodies. Drug Discov Today. 2024;29(3):3.

590. Chen S, Shen C, Li W, et al. Recent advances in bioactivity-guided drug screening strategies for pre-clinical and clinical drug discovery. Trac-Trends Anal Chem. 2024;181:7.

591. Bai T, Ali M, Somers B, et al. The combination of natural compounds Crila and epigallocatechin gallate showed enhanced antiproliferative effects on human uterine fibroid cells compared with single treatments. F S Sci. 2023;4(4):341–9.

592. Amin A, Wang D, Nannapaneni S, et al. Combination of resveratrol and green tea epigallocatechin gallate induces synergistic apoptosis and inhibits tumor growth in vivo in head and neck cancer models. Oncol Rep. 2021;45(5):87.

593. Porcaro G, Santamaria A, Giordano D, et al. Vitamin D plus epigallocatechin gallate: a novel promising approach for uterine myomas. Eur Rev Med Pharmacol Sci. 2020;24(6):3344–51.

594. Miriello D, Galanti F, Cignini P, et al. Uterine fibroids treatment: do we have new valid alternative? Experiencing the combination of vitamin D plus epigallocatechin gallate in childbearing age affected women. Eur Rev Med Pharmacol Sci. 2021;25(7):2843–51.

595. Zhang Z, Zhang S, Yang J, et al. Integrated transcriptomic and metabolomic analyses to characterize the anti-cancer effects of (−)-epigallocatechin-3-gallate in human colon cancer cells. Toxicol Appl Pharmacol. 2020;401: 115100.

596. Pan T, Han D, Xu Y, et al. LC–MS based metabolomics study of the effects of EGCG on A549 cells. Front Pharmacol. 2021;12: 732716.

597. Sasaki GY, Li J, Cichon MJ, et al. Green tea extract treatment in obese mice with nonalcoholic steatohepatitis restores the hepatic metabolome in association with limiting endotoxemia-TLR4-NFκB-mediated inflammation. Mol Nutr Food Res. 2019;63(24):1900811.

598. Zhou H, Chen JX, Yang CS, et al. Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer. BMC Genomics. 2014;15:1–10.

599. Zan L, Chen Q, Zhang L, et al. Epigallocatechin gallate (EGCG) suppresses growth and tumorigenicity in breast cancer cells by downregulation of miR-25. Bioengineered. 2019;10(1):374–82.

600. Yang L, Zhang W, Chopra S, et al. The epigenetic modification of epigallocatechin gallate (EGCG) on cancer. Curr Drug Targets. 2020;21(11):1099–104.

601. She L, Tang H, Zeng Y, et al. Ginsenoside RK3 promotes neurogenesis in Alzheimer’s disease through activation of the CREB/BDNF pathway. J Ethnopharmacol. 2024;321: 117462.

602. Zhang J, Duan M, Wu S, et al. Comprehensive pharmacological and experimental study of Ginsenoside Re as a potential therapeutic agent for non-alcoholic fatty liver disease. Biomed Pharmacother. 2024;177: 116955.

603. Huang Q, Li J, Chen J, et al. Ginsenoside compound K protects against cerebral ischemia/reperfusion injury via Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy. J Ginseng Res. 2023;47(3):408–19.

604. Jiang R-y, Fang Z-r, Zhang H-p, et al. Ginsenosides: changing the basic hallmarks of cancer cells to achieve the purpose of treating breast cancer. Chin Med. 2023;18(1):1.

605. Nakhjavani M, Smith E, Townsend AR, et al. Anti-angiogenic properties of ginsenoside Rg3. Molecules. 2020;25(21):2.

606. Wang J, Zeng L, Zhang Y, et al. Pharmacological properties, molecular mechanisms and therapeutic potential of ginsenoside Rg3 as an antioxidant and anti-inflammatory agent. Front Pharmacol. 2022;13: 975784.

607. Sun X, Hong Y, Shu Y, et al. The involvement of Parkin-dependent mitophagy in the anti-cancer activity of Ginsenoside. J Ginseng Res. 2022;46(2):266–74.

608. Sun D, Zou Y, Song L, et al. A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer. Acta Pharm Sin B. 2022;12(1):378–93.

609. Zeng Z, Nian Q, Chen N, et al. Ginsenoside Rg3 inhibits angiogenesis in gastric precancerous lesions through downregulation of Glut1 and Glut4. Biomed Pharmacother. 2022;145: 112086.

610. Chen YJ, Wu JY, Deng YY, et al. Ginsenoside Rg3 in combination with artesunate overcomes sorafenib resistance in hepatoma cell and mouse models. J Ginseng Res. 2022;46(3):418–25.

611. Liu X, Mi X, Wang Z, et al. Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway. Cell Death Dis. 2020;11(6):454.

612. Lai Q, Liu FM, Rao WL, et al. Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure. Acta Pharmacol Sin. 2022;43(8):2003–15.

613. Kim H, Ji HW, Kim HW, et al. Ginsenoside Rg3 prevents oncogenic long noncoding RNA ATXN8OS from inhibiting tumor-suppressive microRNA-424–5p in breast cancer cells. Biomolecules. 2021;11(1):1.

614. Nahar J, Boopathi V, Murugesan M, et al. Investigating the anticancer activity of G-Rh1 using in silico and in vitro studies (A549 lung cancer cells). Molecules. 2022;27(23):1.

615. Cui L, Liu X, Yan R, et al. Amino acid modified OCMC-g-Suc-β-CD nanohydrogels carrying lapatinib and ginsenoside Rg1 exhibit high anticancer activity in a zebrafish model. Front Pharmacol. 2023;14:3.

616. Fu YY, Cen JK, Song HL, et al. Ginsenoside Rh2 ameliorates neuropathic pain by inhibition of the miRNA21-TLR8-mitogen-activated protein kinase axis. Mol Pain. 2022;18:17448069221126078.

617. Chen S, He Z, Xie W, et al. Ginsenoside Rh2 attenuates CDAHFD-induced liver fibrosis in mice by improving intestinal microbial composition and regulating LPS-mediated autophagy. Phytomedicine. 2022;101: 154121.

618. Chen X, Xu T, Lv X, et al. Ginsenoside Rh2 alleviates ulcerative colitis by regulating the STAT3/miR-214 signaling pathway. J Ethnopharmacol. 2021;274: 113997.

619. Shi LS, Ji CH, Liu Y, et al. Ginsenoside Rh2 administration produces crucial antidepressant-like effects in a CUMS-induced mice model of depression. Brain Behav. 2022;12(8): e2705.

620. Hou J, Yun Y, Cui C, et al. Ginsenoside Rh2 mitigates doxorubicin-induced cardiotoxicity by inhibiting apoptotic and inflammatory damage and weakening pathological remodelling in breast cancer-bearing mice. Cell Prolif. 2022;55(6): e13246.

621. Huang MY, Chen YC, Lyu WY, et al. Ginsenoside Rh2 augmented anti-PD-L1 immunotherapy by reinvigorating CD8(+) T cells via increasing intratumoral CXCL10. Pharmacol Res. 2023;198: 106988.

622. Zhang F, Xu H, Xia R, et al. Pseudo-ginsenoside Rh2 induces protective autophagy in hepatocellular carcinoma HepG2 cells. Recent Pat Anticancer Drug Discov. 2021;16(4):521–32.

623. Ding L, Gao Z, Wu S, et al. Ginsenoside compound-K attenuates OVX-induced osteoporosis via the suppression of RANKL-induced osteoclastogenesis and oxidative stress. Nat Prod Bioprospect. 2023;13(1):49.

624. Li Y, Wu J, Zhuo N. Ginsenoside compound K alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis. Exp Ther Med. 2023;26(2):406.

625. Huang J, Pan D, Liu F, et al. Ginsenoside compound K inhibits the proliferation, migration and invasion of Eca109 cell via VEGF-A/Pi3k/Akt pathway. J Cardiothorac Surg. 2022;17(1):99.

626. Liu M, Zhang Y, Zhang A, et al. Compound K is a potential clinical anticancer agent in prostate cancer by arresting cell cycle. Phytomedicine. 2023;109: 154584.

627. Chen J, Wang Z, Fu J, et al. Ginsenoside compound K induces ferroptosis via the FOXO pathway in liver cancer cells. BMC Complement Med Ther. 2024;24(1):174.

628. Gao S, Fang C, Wang T, et al. The effect of ginsenoside Rg3 combined with chemotherapy on immune function in non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials. Medicine. 2023;102(14): e33463.

629. Zhu Y, Liang J, Gao C, et al. Multifunctional ginsenoside Rg3-based liposomes for glioma targeting therapy. J Control Release. 2021;330:641–57.

630. Xia J, Ma S, Zhu X, et al. Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches. Sci Adv. 2022;8(6):eabj1262.

631. Xia J, Zhang S, Zhang R, et al. Targeting therapy and tumor microenvironment remodeling of triple-negative breast cancer by ginsenoside Rg3 based liposomes. J Nanobiotechnol. 2022;20(1):414.

632. Yang C, Qian C, Zheng W, et al. Ginsenoside Rh2 enhances immune surveillance of natural killer (NK) cells via inhibition of ERp5 in breast cancer. Phytomedicine. 2024;123: 155180.

633. Li Q, He J, Li S, et al. The combination of gemcitabine and ginsenoside Rh2 enhances the immune function of dendritic cells against pancreatic cancer via the CARD9-BCL10-MALT1 / NF-kappaB pathway. Clin Immunol. 2023;248: 109217.

634. Wang H, Huang M, Zhu M, et al. Paclitaxel combined with compound K inducing pyroptosis of non-small cell lung cancer cells by regulating Treg/Th17 balance. Chin Med. 2024;19(1):26.

635. Lee JH, Lee DY, Lee HJ, et al. Inhibition of STAT3/PD-L1 and activation of miR193a-5p are critically involved in apoptotic effect of compound k in prostate cancer cells. Cells. 2021;10(8):1.

636. Chen Z, Wei X, Shen L, et al. 20(S)-ginsenoside-Rg3 reverses temozolomide resistance and restrains epithelial-mesenchymal transition progression in glioblastoma. Cancer Sci. 2019;110(1):389–400.

637. Tan Q, Lin S, Zeng Y, et al. Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non-small cell lung cancer cells. Environ Toxicol. 2020;35(6):643–51.

638. Ahmmed B, Kampo S, Khan M, et al. Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-κB- and HIF-1α-mediated downregulation of PTX3. J Cell Physiol. 2019;234(7):10680–97.

639. Zhu Y, Wang A, Zhang S, et al. Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells. J Adv Res. 2023;49:159–73.

640. Zhao W, Ma J, Zhang Q, et al. Ginsenoside Rg3 overcomes tamoxifen resistance through inhibiting glycolysis in breast cancer cells. Cell Biol Int. 2024;48(4):496–509.

641. Zou J, Su H, Zou C, et al. Ginsenoside Rg3 suppresses the growth of gemcitabine-resistant pancreatic cancer cells by upregulating lncRNA-CASC2 and activating PTEN signaling. J Biochem Mol Toxicol. 2020;34(6): e22480.

642. Wu Y, Zhang J, Tian Y et al. 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters. J Adv Res. 2024, 11:S2090–1232(2024)00390–00394.

643. Bian S, Zhao Y, Li F, et al. 20(S)-ginsenoside Rg3 promotes HeLa cell apoptosis by regulating autophagy. Molecules. 2019;24(20):3655.

644. Jeong YJ, Yu MH, Cho Y, et al. Rg3-enriched red ginseng extracts enhance apoptosis in CoCl(2)-stimulated breast cancer cells by suppressing autophagy. J Ginseng Res. 2024;48(1):31–9.

645. Lu SL, Wang YH, Liu GF, et al. Graphene oxide nanoparticle-loaded ginsenoside Rg3 improves photodynamic therapy in inhibiting malignant progression and stemness of osteosarcoma. Front Mol Biosci. 2021;8: 663089.

646. Zhao X, Wu J, Guo D, et al. Dynamic ginsenoside-sheltered nanocatalysts for safe ferroptosis-apoptosis combined therapy. Acta Biomater. 2022;151:549–60.

647. Wang J, Bian S, Wang S, et al. Ginsenoside Rh2 represses autophagy to promote cervical cancer cell apoptosis during starvation. Chin Med. 2020;15(1):118.

648. Yin Q, Chen H, Ma RH, et al. Ginsenoside CK induces apoptosis of human cervical cancer HeLa cells by regulating autophagy and endoplasmic reticulum stress. Food Funct. 2021;12(12):5301–16.

649. Wang B, Xu Q, Zhou C, et al. Liposomes co-loaded with ursolic acid and ginsenoside Rg3 in the treatment of hepatocellular carcinoma. Acta Biochim Pol. 2021;68(4):711–5.

650. Hong S, Cai W, Huang Z, et al. Ginsenoside Rg3 enhances the anticancer effect of 5-FU in colon cancer cells via the PI3K/AKT pathway. Oncol Rep. 2020;44(4):1333–42.

651. Peng Y, Zhang R, Yang X, et al. Ginsenoside Rg3 suppresses the proliferation of prostate cancer cell line PC3 through ROS-induced cell cycle arrest. Oncol Lett. 2019;17(1):1139–45.

652. Meng L, Ji R, Dong X, et al. Antitumor activity of ginsenoside Rg3 in melanoma through downregulation of the ERK and Akt pathways. Int J Oncol. 2019;54(6):2069–79.

653. Li J, Yang B. Ginsenoside Rg3 enhances the radiosensitivity of lung cancer A549 and H1299 cells via the PI3K/AKT signaling pathway. In Vitro Cell Dev Biol Anim. 2023;59(1):19–30.

654. Zhang H, Yi JK, Huang H, et al. 20 (S)-ginsenoside Rh2 inhibits colorectal cancer cell growth by suppressing the Axl signaling pathway in vitro and in vivo. J Ginseng Res. 2022;46(3):396–407.

655. Zhang H, Yi J, Kim E, et al. 20(S)-ginsenoside Rh2 suppresses oral cancer cell growth by inhibiting the Src-Raf-ERK signaling pathway. Anticancer Res. 2021;41(1):227–35.

656. Li JK, Jiang XL, Zhang Z, et al. 20(S)-ginsenoside Rh2 induces apoptosis and autophagy in melanoma cells via suppressing Src/STAT3 signaling. J Ginseng Res. 2024;48(6):559–69.

657. Zhang S, Zhang M, Chen J, et al. Ginsenoside compound K regulates HIF-1alpha-mediated glycolysis through bclaf1 to inhibit the proliferation of human liver cancer cells. Front Pharmacol. 2020;11: 583334.

658. Lv S, Chen X, Chen Y, et al. Ginsenoside Rg3 induces apoptosis and inhibits proliferation by down-regulating TIGAR in rats with gastric precancerous lesions. BMC Complement Med Ther. 2022;22(1):188.

659. Dai Y, Wang W, Sun Q, et al. Ginsenoside Rg3 promotes the antitumor activity of gefitinib in lung cancer cell lines. Exp Ther Med. 2019;17(1):953–9.

660. Hu S, Zhu Y, Xia X, et al. Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal Cell Pathol. 2019;2019:3815786.

661. Zhao L, Shou H, Chen L, et al. Effects of ginsenoside Rg3 on epigenetic modification in ovarian cancer cells. Oncol Rep. 2019;41(6):3209–18.

662. Wang X, He R, Geng L, et al. Ginsenoside Rg3 alleviates cisplatin resistance of gastric cancer cells through inhibiting SOX2 and the PI3K/Akt/mTOR signaling axis by up-regulating miR-429. Front Genet. 2022;13: 823182.

663. Kim JH, Bae YC, Lee JW, et al. Effects of ginsenoside Rg3 on apoptosis in A375.S2 melanoma cells. Transl Cancer Res. 2019;8(2):357–66.

664. Ma Z, Zuo Y, Wang W. Ginsenoside Rg3 inhibits renal cell carcinoma cell migration, invasion, colony formation, and tube formation and enhances apoptosis through promoting the DNA demethylation and histone acetylation. J Pharm Pharmacol. 2023;75(1):76–86.

665. Li C, Gao H, Feng X, et al. Ginsenoside Rh2 impedes proliferation and migration and induces apoptosis by regulating NF-kappaB, MAPK, and PI3K/Akt/mTOR signaling pathways in osteosarcoma cells. J Biochem Mol Toxicol. 2020;34(12): e22597.

666. Li H, Han C, Chen C, et al. (20S) ginsenoside Rh2-activated, distinct apoptosis pathways in highly and poorly differentiated human esophageal cancer cells. Molecules. 2022;27(17):5602.

667. Zhang J, Zhou J, Yuan Q, et al. Characterization of ginsenoside compound K loaded ionically cross-linked carboxymethyl chitosan-calcium nanoparticles and its cytotoxic potential against prostate cancer cells. J Ginseng Res. 2021;45(2):228–35.

668. Li X, Liu W, Geng C, et al. Ginsenoside Rg3 suppresses epithelial-mesenchymal transition via downregulating notch-Hes1 signaling in colon cancer cells. Am J Chin Med. 2021;49(1):217–35.

669. Mao X, Jin Y, Feng T, et al. Ginsenoside rg3 inhibits the growth of osteosarcoma and attenuates metastasis through the Wnt/β-catenin and EMT signaling pathway. Evid Based Complement Alternat Med. 2020;2020:6065124.

670. Wang D, Wu C, Liu D, et al. Ginsenoside Rg3 inhibits migration and invasion of nasopharyngeal carcinoma cells and suppresses epithelial mesenchymal transition. Biomed Res Int. 2019;2019:8407683.

671. Sun MY, Song YN, Zhang M, et al. Ginsenoside Rg3 inhibits the migration and invasion of liver cancer cells by increasing the protein expression of ARHGAP9. Oncol Lett. 2019;17(1):965–73.

672. Peng K, Luo T, Li J, et al. Ginsenoside Rh2 inhibits breast cancer cell growth via ERbeta-TNFalpha pathway. Acta Biochim Biophys Sin. 2022;54(5):647–56.

673. Wu H, Wei G, Luo L, et al. Ginsenoside Rg3 nanoparticles with permeation enhancing based chitosan derivatives were encapsulated with doxorubicin by thermosensitive hydrogel and anti-cancer evaluation of peritumoral hydrogel injection combined with PD-L1 antibody. Biomater Res. 2022;26(1):77.

674. Shan K, Deng Y, Du Z, et al. Examination of combined treatment of ginsenoside Rg3 and 5-fluorouracil in lung adenocarcinoma cells. Comput Math Methods Med. 2022;2022:2813142.

675. Shan K, Wang Y, Hua H, et al. Ginsenoside Rg3 combined with oxaliplatin inhibits the proliferation and promotes apoptosis of hepatocellular carcinoma cells via downregulating PCNA and cyclin D1. Biol Pharm Bull. 2019;42(6):900–5.

676. Wei Q, Ren Y, Zheng X, et al. Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway. Bioengineered. 2022;13(5):13919–28.

677. Zeng X, Liu S, Yang H, et al. Synergistic anti-tumour activity of ginsenoside Rg3 and doxorubicin on proliferation, metastasis and angiogenesis in osteosarcoma by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. J Pharm Pharmacol. 2023;75(11):1405–17.

678. Changizi V, Gharekhani V, Motavaseli E. Co-treatment with ginsenoside 20(S)-Rg3 and curcumin increases radiosensitivity of MDA-MB-231 Cancer Cell Line. Iran J Med Sci. 2021;46(4):291–7.

679. Gu H, Shi R, Xu C, et al. EGFR-targeted liposomes combined with ginsenoside Rh2 inhibit triple-negative breast cancer growth and metastasis. Bioconjug Chem. 2023;34(6):1157–65.

680. Ren Z, Chen X, Hong L, et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis. Small. 2020;16(2): e1905233.

681. Zhou Z, Li Y, Wu S, et al. Host-microbiota interactions in collagen-induced arthritis rats treated with human umbilical cord mesenchymal stem cell exosome and ginsenoside Rh2. Biomed Pharmacother. 2024;174: 116515.

682. Xia T, Zhang B, Li Y, et al. New insight into 20(S)-ginsenoside Rh2 against T-cell acute lymphoblastic leukemia associated with the gut microbiota and the immune system. Eur J Med Chem. 2020;203: 112582.

683. Wang L, Shao L, Chen MY, et al. Effect of ginsenoside compound K on alleviating colitis via modulating gut microbiota. Chin Med. 2022;17(1):146.

684. Zhang S, Zheng B, Wei Y, et al. Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity. Biomater Sci. 2024;12(10):2672–88.

685. He S, Tian S, He X, et al. Multiple targeted self-emulsifying compound RGO reveals obvious anti-tumor potential in hepatocellular carcinoma. Mol Ther Oncolytics. 2021;22:604–16.

686. Mathiyalagan R, Wang C, Kim YJ, et al. Preparation of polyethylene glycol-ginsenoside Rh1 and Rh2 conjugates and their efficacy against lung cancer and inflammation. Molecules. 2019;24(23):4367.

687. Xia X, Tao J, Ji Z, et al. Increased antitumor efficacy of ginsenoside Rh(2) via mixed micelles: in vivo and in vitro evaluation. Drug Deliv. 2020;27(1):1369–77.

688. Long J, Hu W, Ren T, et al. Combating multidrug resistance of breast cancer with ginsenoside Rh2-irrigated nano-in-thermogel. Int J Pharm. 2024;650: 123718.

689. You X, Liu H, Chen Y, et al. Multifunctional liposomes co-modified with ginsenoside compound K and hyaluronic acid for tumor-targeted therapy. POLYMERS-BASEL. 2024;16(3):405.

690. Kim YJ, Perumalsamy H, Markus J, et al. Development of Lactobacillus kimchicus DCY51(T)-mediated gold nanoparticles for delivery of ginsenoside compound K: in vitro photothermal effects and apoptosis detection in cancer cells. Artif Cells Nanomed Biotechnol. 2019;47(1):30–44.

691. Zhang J, Jiang Y, Li Y, et al. Micelles modified with a chitosan-derived homing peptide for targeted intracellular delivery of ginsenoside compound K to liver cancer cells. Carbohydr Polym. 2020;230: 115576.

692. Qian Q, Li SL, Sun E, et al. Metabolite profiles of icariin in rat plasma by ultra-fast liquid chromatography coupled to triple-quadrupole/time-of-flight mass spectrometry. J Pharm Biomed Anal. 2012;66:392–8.

693. Chen Y, Xia H, Zhong X. In Vitro evaluation of the anti-pancreatic cancer activity of epimedium herb. Front Pharmacol. 2024;15:1389221.

694. Zhang WD, Li N, Du ZR, et al. IGF-1 receptor is involved in the regulatory effects of icariin and icaritin in astrocytes under basal conditions and after an inflammatory challenge. Eur J Pharmacol. 2021;906: 174269.

695. Zhou X, Wu D, Mi T, et al. Icaritin activates p53 and inhibits aerobic glycolysis in liver cancer cells. Chem Biol Interact. 2024;392: 110926.

696. Luo P, An Y, He J, et al. Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma. Cancer Lett. 2024;587: 216621.

697. Song L, Chen X, Mi L, et al. Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer. Cancer Sci. 2020;111(11):4242–56.

698. Zheng X, Li D, Li J, et al. Optimization of the process for purifying icariin from Herba Epimedii by macroporous resin and the regulatory role of icariin in the tumor immune microenvironment. Biomed Pharmacother. 2019;118: 109275.

699. Hao H, Zhang Q, Zhu H, et al. Icaritin promotes tumor T-cell infiltration and induces antitumor immunity in mice. Eur J Immunol. 2019;49(12):2235–44.

700. Huang JJ, Hu HX, Lu YJ, et al. Computer-aided design of α-L-rhamnosidase to increase the synthesis efficiency of icariside I. Front Bioeng Biotechnol. 2022;10: 926829.

701. Wang Z, Liu C, Yu H, et al. Icaritin preparation from icariin by a special epimedium flavonoid-glycosidase from Aspergillus sp.y848 strain. J Microbiol Biotechnol. 2022;32(4):437–46.

702. Zhang C, Xu H, Sui X, et al. Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime. Mol Ther Oncolytics. 2022;25:288–304.

703. Lu Y, Gao Y, Yang H, et al. Nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma. Mil Med Res. 2022;9(1):69.

704. Chen C, Wang S, Wang N, et al. Icariin inhibits prostate cancer bone metastasis and destruction via suppressing TAM/CCL5-mediated osteoclastogenesis. Phytomedicine. 2023;120: 155076.

705. Bi Z, Zhang W, Yan X. Anti-inflammatory and immunoregulatory effects of icariin and icaritin. Biomed Pharmacother. 2022;151:1.

706. Zhou J, Wu J, Chen X, et al. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int Immunopharmacol. 2011;11(7):890–8.

707. Tao H, Liu M, Wang Y, et al. Icaritin induces anti-tumor immune responses in hepatocellular carcinoma by inhibiting splenic myeloid-derived suppressor cell generation. Front Immunol. 2021;12: 609295.

708. Li C, Yang S, Ma H, et al. Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Cancer Cell Int. 2021;21(1):206.

709. Song B, Wei F, Peng J, et al. Icariin regulates EMT and stem cell-like character in breast cancer through modulating lncRNA NEAT1/TGFβ/SMAD2 signaling pathway. Biol Pharm Bull. 2024;47(2):399–410.

710. Zhao X, Lin Y, Jiang B, et al. Icaritin inhibits lung cancer-induced osteoclastogenesis by suppressing the expression of IL-6 and TNF-a and through AMPK/mTOR signaling pathway. Anticancer Drugs. 2020;31(10):1004–11.

711. Mo D, Zhu H, Wang J, et al. Icaritin inhibits PD-L1 expression by targeting protein IκB kinase α. Eur J Immunol. 2021;51(4):978–88.

712. Qin SK, Li Q, Ming XuJ, et al. Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: immunodynamic biomarkers and overall survival. Cancer Sci. 2020;111(11):4218–31.

713. Huang C, Li Z, Zhu J, et al. Systems pharmacology dissection of Epimedium targeting tumor microenvironment to enhance cytotoxic T lymphocyte responses in lung cancer. Aging (Albany NY). 2021;13(2):2912–40.

714. Cao Y, Fang J, Shi Y, et al. Screening potential P-glycoprotein inhibitors by combination of a detergent-free membrane protein extraction with surface plasmon resonance biosensor. Acta Pharm Sin B. 2022;12(7):3113–23.

715. Seyedi Z, Amiri MS, Mohammadzadeh V, et al. Icariin: a promising natural product in biomedicine and tissue engineering. J Funct Biomater. 2023;14(1):7.

716. Cheng X, Tan S, Duan F, et al. Icariin induces apoptosis by suppressing autophagy in tamoxifen-resistant breast cancer cell line MCF-7/TAM. Breast Cancer. 2019;26(6):766–75.

717. Sun L, Chen W, Qu L, et al. Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and P-glycoprotein expression. Mol Med Rep. 2013;8(6):1883–7.

718. Wang ZD, Wang RZ, Xia YZ, et al. Reversal of multidrug resistance by icaritin in doxorubicin-resistant human osteosarcoma cells. Chin J Nat Med. 2018;16(1):20–8.

719. Bailly C. Molecular and cellular basis of the anticancer activity of the prenylated flavonoid icaritin in hepatocellular carcinoma. Chem-Biol Interact. 2020;325:1.

720. Jiang S, Chang H, Deng S, et al. Icariin enhances the chemosensitivity of cisplatin-resistant ovarian cancer cells by suppressing autophagy via activation of the AKT/mTOR/ATG5 pathway. Int J Oncol. 2019;54(6):1933–42.

721. Zhao M, Xu P, Shi W, et al. Icariin exerts anti-tumor activity by inducing autophagy via AMPK/mTOR/ULK1 pathway in triple-negative breast cancer. Cancer Cell Int. 2024;24(1):74.

722. Huang S, Xie T, Liu W. Icariin inhibits the growth of human cervical cancer cells by inducing apoptosis and autophagy by targeting mTOR/PI3K/AKT signalling pathway. J buon. 2019;24(3):990–6.

723. Tao CC, Wu Y, Gao X, et al. The antitumor effects of icaritin against breast cancer is related to estrogen receptors. Curr Mol Med. 2021;21(1):73–85.

724. Yu Z, Guo J, Hu M, et al. Icaritin exacerbates mitophagy and synergizes with doxorubicin to induce immunogenic cell death in hepatocellular carcinoma. ACS Nano. 2020;14(4):4816–28.

725. Yang JG, Lu R, Ye XJ, et al. Icaritin reduces oral squamous cell carcinoma progression via the inhibition of STAT3 signaling. Int J Mol Sci. 2017;18(1):132.

726. Zhu F, Ren Z. Icariin inhibits the malignant progression of lung cancer by affecting the PI3K/Akt pathway through the miR-205-5p/PTEN axis. Oncol Rep. 2022;47(6):115.

727. Zhang Y, Li M, Han X. Icariin affects cell cycle progression and proliferation of human retinal pigment epithelial cells via enhancing expression of H19. PeerJ. 2020;8: e8830.

728. Wang P, Zhang J, Xiong X, et al. Icariin suppresses cell cycle transition and cell migration in ovarian cancer cells. Oncol Rep. 2019;41(4):2321–8.

729. Zhang DC, Liu JL, Ding YB, et al. Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-κB. Acta Pharmacol Sin. 2013;34(2):301–8.

730. Fu Y, Liu H, Long M, et al. Icariin attenuates the tumor growth by targeting miR-1-3p/TNKS2/Wnt/β-catenin signaling axis in ovarian cancer. Front Oncol. 2022;12: 940926.

731. Wang S, Wang Q, Wang H, et al. Induction of ROS and DNA damage-dependent senescence by icaritin contributes to its antitumor activity in hepatocellular carcinoma cells. Pharm Biol. 2019;57(1):424–31.

732. Wang Y, Wang G, Liu Y, et al. Icaritin inhibits endometrial carcinoma cells by suppressing O-GlcNAcylation of FOXC1. Phytomedicine. 2023;120: 155062.

733. Liu M, Hu T, Gou W, et al. Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation. Front Pharmacol. 2022;13:993022.

734. Zhang C, Wang X, Zhang C. Icaritin inhibits CDK2 expression and activity to interfere with tumor progression. Science. 2022;25(9):104991.

735. Wu T, Wang S, Wu J, et al. Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma. J Exp Clin Cancer Res. 2015;34(1):17.

736. Chen X, Song L, Hou Y, et al. Reactive oxygen species induced by icaritin promote DNA strand breaks and apoptosis in human cervical cancer cells. Oncol Rep. 2019;41(2):765–78.

737. Sun L, Zhang J. Icariin inhibits oral squamous cell carcinoma cell proliferation and induces apoptosis via inhibiting the NF-κB and PI3K/AKT pathways. Exp Ther Med. 2021;22(3):942.

738. Di S, Fan C, Yang Y, et al. Activation of endoplasmic reticulum stress is involved in the activity of icariin against human lung adenocarcinoma cells. Apoptosis. 2015;20(9):1229–41.

739. Wang S, Gao J, Li Q, et al. Study on the regulatory mechanism and experimental verification of icariin for the treatment of ovarian cancer based on network pharmacology. J Ethnopharmacol. 2020;262: 113189.

740. Wang Q, Hao J, Pu J, et al. Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. Int J Oncol. 2011;39(4):973–80.

741. Wu X, Kong W, Qi X, et al. Icariin induces apoptosis of human lung adenocarcinoma cells by activating the mitochondrial apoptotic pathway. Life Sci. 2019;239: 116879.

742. Zhou Y, Huang N, Li Y, et al. Effect of icaritin on autophagy-related protein expression in TDP-43-transfected SH-SY5Y cells. PeerJ. 2022;10: e13703.

743. Cao Z, Cheng Y, Wang J, et al. HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression. J Exp Clin Cancer Res. 2021;40(1):118.

744. Li H, Liu Y, Jiang W, et al. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma. BMC Cancer. 2021;21(1):318.

745. Kim B, Seo JH, Lee KY, et al. Icariin sensitizes human colon cancer cells to TRAIL-induced apoptosis via ERK-mediated upregulation of death receptors. Int J Oncol. 2020;56(3):821–34.

746. Gao S, Zhang X, Liu J, et al. Icariin Induces Triple-Negative Breast Cancer Cell Apoptosis and Suppresses Invasion by Inhibiting the JNK/c-Jun Signaling Pathway. Drug Des Devel Ther. 2023;17:821–36.

747. Zhu YH, Zhang XR, Zhang Q, et al. Icaritin-elevated circ_0000190 suppresses the malignant progression of multiple myeloma by targeting miR-301a. Kaohsiung J Med Sci. 2022;38(5):447–56.

748. Han S, Gou Y, Jin D, et al. Effects of Icaritin on the physiological activities of esophageal cancer stem cells. Biochem Biophys Res Commun. 2018;504(4):792–6.

749. Gao L, Ouyang Y, Li R, et al. icaritin inhibits migration and invasion of human ovarian cancer cells via the Akt/mTOR signaling pathway. Front Oncol. 2022;12: 843489.

750. Xu W, Ding J, Li B, et al. Effects of icariin and curcumol on autophagy, ferroptosis, and lipid metabolism based on miR-7/m-TOR/SREBP1 pathway on prostate cancer. BioFactors. 2023;49(2):438–56.

751. Zeng H, Li X, Liu Y, et al. An icaritin-loaded microemulsion based on coix oil for improved pharmacokinetics and enhanced antitumor efficacy. Drug Deliv. 2022;29(1):3454–66.

752. Hu T, Gou W, Ren Z, et al. Icaritin increases radiosensitivity of nasopharyngeal carcinoma cells by regulating iron death. Nan Fang Yi Ke Da Xue Xue Bao. 2023;43(10):1665–73.

753. Zhang X, Kang Z, Li Q, et al. Antigen-adjuvant effects of icariin in enhancing tumor-specific immunity in mastocytoma-bearing DBA/2J mice. Biomed Pharmacother. 2018;99:810–6.

754. Dongye Z, Wu X, Wen Y, et al. Icaritin and intratumoral injection of CpG treatment synergistically promote T cell infiltration and antitumor immune response in mice. Int Immunopharmacol. 2022;111: 109093.

755. Li Z, Liu P, Chen W, et al. Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis. J Nanobiotechnology. 2023;21(1):221.

756. He K, Wang J, Zhou Y, et al. Network pharmacology analysis of Icariside II against bladder cancer. Eur J Pharmacol. 2023;955: 175914.

757. Kong Q, Ma M, Zhang L, et al. Icariside II potentiates the anti-PD-1 antitumor effect by reducing chemotactic infiltration of myeloid-derived suppressor cells into the tumor microenvironment via ROS-mediated inactivation of the SRC/ERK/STAT3 signaling pathways. Phytomedicine. 2023;110: 154638.

758. Li S, Zhan Y, Xie Y, et al. The impact of icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway. Drug Des Devel Ther. 2020;14:4169–78.

759. Yang C, Jin YY, Mei J, et al. Identification of icaritin derivative IC2 as an SCD-1 inhibitor with anti-breast cancer properties through induction of cell apoptosis. Cancer Cell Int. 2022;22(1):202.

760. Chen G, Cao Z, Shi Z, et al. Microbiome analysis combined with targeted metabolomics reveal immunological anti-tumor activity of icariside I in a melanoma mouse model. Biomed Pharmacother. 2021;140: 111542.

761. Chen G, Huang J, Lei H, et al. Icariside I—a novel inhibitor of the kynurenine-AhR pathway with potential for cancer therapy by blocking tumor immune escape. Biomed Pharmacother. 2022;153: 113387.

762. Sun YS, Thakur K, Hu F, et al. Icariside II suppresses cervical cancer cell migration through JNK modulated matrix metalloproteinase-2/9 inhibition in vitro and in vivo. Biomed Pharmacother. 2020;125: 110013.

763. Sun YS, Thakur K, Hu F, et al. Icariside II inhibits tumorigenesis via inhibiting AKT/Cyclin E/ CDK 2 pathway and activating mitochondria-dependent pathway. Pharmacol Res. 2020;152: 104616.

764. Tang Z, Du W, Xu F, et al. Icariside II enhances cisplatin-induced apoptosis by promoting endoplasmic reticulum stress signalling in non-small cell lung cancer cells. Int J Biol Sci. 2022;18(5):2060–74.

765. Shi CJ, Li SY, Shen CH, et al. Icariside II suppressed tumorigenesis by epigenetically regulating the circβ-catenin-Wnt/β-catenin axis in colorectal cancer. Bioorg Chem. 2022;124: 105800.

766. Liu X, Li Z, Li M, et al. Icariside II overcomes BRAF inhibitor resistance in melanoma by inducing ROS production and inhibiting MITF. Oncol Rep. 2020;44(1):360–70.

767. Yu R, Zhou Y, Shi S, et al. Icariside II induces ferroptosis in renal cell carcinoma cells by regulating the miR-324-3p/GPX4 axis. Phytomedicine. 2022;102: 154182.

768. Yang J, Lan J, Du H, et al. Icariside II induces cell cycle arrest and differentiation via TLR8/MyD88/p38 pathway in acute myeloid leukemia cells. Eur J Pharmacol. 2019;846:12–22.

769. Wang YX, Jin YY, Wang J, et al. Icaritin derivative IC2 induces cytoprotective autophagy of breast cancer cells via SCD1 inhibition. Molecules. 2023;28(3):1109.

770. Li J, Shen S, Liu Z, et al. Synthesis and structure-activity analysis of icaritin derivatives as potential tumor growth inhibitors of hepatocellular carcinoma cells. J Nat Prod. 2023;86(2):290–306.

771. Hou Y, Kuang W, Min W, et al. Design, synthesis, and biological evaluation of icaritin derivatives as novel putative deptor inhibitors for multiple myeloma treatment. J Med Chem. 2021;64(20):14942–54.

772. Liu YM, Li XQ, Zhang XR, et al. Uncovering the key pharmacodynamic material basis and possible molecular mechanism of extract of epimedium against liver cancer through a comprehensive investigation. J Ethnopharmacol. 2023;317: 116765.

773. Jin YB, Liang XC, Cai JH, et al. Mechanism of action of icaritin on uterine corpus endometrial carcinoma based on network pharmacology and experimental evaluation. Front Oncol. 2023;13:1205604.

774. Chen W, Xin J, Wei X, et al. Integrated transcriptomic and metabolomic profiles reveal the protective mechanism of modified Danggui Buxue decoction on radiation-induced leukopenia in mice. Front Pharmacol. 2023;14:1178724.

775. Xue Z, Zhang F, Xu S, et al. Investigating the effect of icaritin on hepatocellular carcinoma based on network pharmacology. Front Pharmacol. 2023;14:1208495.

776. Fahmy UA, Fahmy O, Alhakamy NA. Optimized icariin cubosomes exhibit augmented cytotoxicity against SKOV-3 ovarian cancer cells. Pharmaceutics. 2020;13(1):20.

777. Ji Y, Zhang Z, Hou W, et al. Enhanced antitumor effect of icariin nanoparticles coated with iRGD functionalized erythrocyte membrane. Eur J Pharmacol. 2022;931: 175225.

778. Xiao Y, Yao W, Lin M, et al. Icaritin-loaded PLGA nanoparticles activate immunogenic cell death and facilitate tumor recruitment in mice with gastric cancer. Drug Deliv. 2022;29(1):1712–25.

779. Liu J, Lin S, Dang J, et al. Anticancer and bone-enhanced nano-hydroxyapatite/gelatin/polylactic acid fibrous membrane with dual drug delivery and sequential release for osteosarcoma. Int J Biol Macromol. 2023;240: 124406.

780. Liu M, Wang B, Guo C, et al. Novel multifunctional triple folic acid, biotin and CD44 targeting pH-sensitive nano-actiniaes for breast cancer combinational therapy. Drug Deliv. 2019;26(1):1002–16.

781. Alhakamy NA, Badr-Eldin SM, Alharbi WS, et al. Development of an icariin-loaded bilosome-melittin formulation with improved anticancer activity against cancerous pancreatic cells. Pharmaceuticals. 2021;14(12):1309.

782. Song X, Gan K, Qin S, et al. Preparation and characterization of general-purpose gelatin-based co-loading flavonoids nano-core structure. Sci Rep. 2019;9(1):6365.

783. Yang JG, Zhang J, Chen XJ, et al. Stable loading and delivery of icaritin using PEG-PCL micelles for effective treatment of oral squamous cell carcinoma. Curr Drug Deliv. 2021;18(7):975–83.

784. Xiang L, Li Y, Gu X, et al. Nucleolin recognizing silica nanoparticles inhibit cell proliferation by activating the Bax/Bcl-2/caspase-3 signalling pathway to induce apoptosis in liver cancer. Front Pharmacol. 2023;14:1117052.

785. Guo J, Zeng H, Liu Y, et al. Multicomponent thermosensitive lipid complexes enhance desmoplastic tumor therapy through boosting anti-angiogenesis and synergistic strategy. Int J Pharm. 2021;601: 120533.

786. Wei Y, Yu Z, Lin K, et al. Fabrication and characterization of resveratrol loaded zein-propylene glycol alginate-rhamnolipid composite nanoparticles: physicochemical stability, formation mechanism and in vitro digestion. Food Hydrocolloids. 2019;95:336–48.

787. Zheng J, Zhao R, Uliana AA, et al. Separation of textile wastewater using a highly permeable resveratrol-based loose nanofiltration membrane with excellent anti-fouling performance. Chem Eng J. 2022;434: 134705.

788. Yuan SF, Yi X, Johnston TG, et al. De novo resveratrol production through modular engineering of an Escherichia coli-Saccharomyces cerevisiae co-culture. Microb Cell Fact. 2020;19(1):143.

789. Li J, Qiu ZT, Zhao GR. Modular engineering of E. coli coculture for efficient production of resveratrol from glucose and arabinose mixture. Synth Syst Biotechnol. 2022;7(2):718–29.

790. Jayan H, Leena MM, Sundari SKS, et al. Improvement of bioavailability for resveratrol through encapsulation in zein using electrospraying technique. J Funct Foods. 2019;57:417–24.

791. Chen Z, Wang X, Du S, et al. A review on traditional Chinese medicine natural products and acupuncture intervention for Alzheimer’s disease based on the neuroinflammatory. Chin Med. 2024;19(1):1.

792. Zhang Z, Xu Z, Wang S, et al. Optimized new shengmai powder modulation of cAMP/Rap1A signaling pathway attenuates myocardial fibrosis in heart failure. Chin Med. 2024;19(1):1.

793. Ren B, Kwah MX-Y, Liu C, et al. Resveratrol for cancer therapy: challenges and future perspectives. Cancer Lett. 2021;515:63–72.

794. Zhang YM, Zhang Z, Mousavi M, et al. Resveratrol inhibits glioblastoma cells and chemoresistance progression through blockade P-glycoprotein and targeting AKT/PTEN signaling pathway. Chem Biol Interact. 2023;376: 110409.

795. Cho CJ, Yang CW, Wu CL, et al. The modulation study of multiple drug resistance in bladder cancer by curcumin and resveratrol. Oncol Lett. 2019;18(6):6869–76.

796. Ferraresi A, Esposito A, Girone C, et al. Resveratrol contrasts LPA-induced ovarian cancer cell migration and platinum resistance by rescuing hedgehog-mediated autophagy. Cells. 2021;10(11):3213.

797. Alexandru DM, Coman AM, Gruia MI, et al. Study on the antioxidant properties of resveratrol in oncology prophylaxis. Rev Romana Med Vet. 2021;31(3):7–11.

798. Yuan L, Zhou MM, Huang DW, et al. Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial-mesenchymal transition via the AKT/GSK-3β/Snail signaling pathway. Mol Med Rep. 2019;20(3):2783–95.

799. Alam MK, Alqhtani NR, Alnufaiy B, et al. A systematic review and meta-analysis of the impact of resveratrol on oral cancer: potential therapeutic implications. BMC Oral Health. 2024;24(1):412.

800. Arena A, Romeo MA, Benedetti R, et al. New insights into curcumin- and resveratrol-mediated anti-cancer effects. Pharmaceuticals. 2021;14(11):1068.

801. Bian P, Hu W, Liu C, et al. Resveratrol potentiates the anti-tumor effects of rapamycin in papillary thyroid cancer: PI3K/AKT/mTOR pathway involved. Arch Biochem Biophys. 2020;689: 108461.

802. Srivani G, Behera SK, Dariya B, et al. Resveratrol binds and inhibits transcription factor HIF-1α in pancreatic cancer. Exp Cell Res. 2020;394(1):1.

803. Moar K, Brahma M, Kakde GS et al. Protective Effect of Resveratrol Against Non-Small Cell Lung Cancer: In-Vitro and In-Silico Studies. Polycyclic Aromat Compd. 2024.

804. Liu G-Y, Xiao K-H, Li H, et al. Efficacy and safety of resveratrol in the treatment of bladder cancer derived organoids. Adv Ther. 2024;7(6):5.

805. Zhang Q, Huang H, Zheng F, et al. Resveratrol exerts antitumor effects by downregulating CD8+CD122+ Tregs in murine hepatocellular carcinoma. Oncoimmunology. 2020;9(1):8.

806. Wu S-X, Xiong R-G, Huang S-Y, et al. Effects and mechanisms of resveratrol for prevention and management of cancers: an updated review. Crit Rev Food Sci Nutr. 2023;63(33):12422–40.

807. Neamah WH, Rutkovsky A, Abdullah O, et al. Resveratrol attenuates 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated induction of myeloid-derived suppressor cells (MDSC) and their functions. Nutrients. 2023;15(21):4667.

808. Pradhan R, Paul S, Acharya SS, et al. Nano formulated resveratrol inhibits PD-L1 in oral cancer cells by deregulating the association between tumor associated macrophages and cancer associated fibroblasts through IL-6/JAK2/STAT3 signaling axis. J Nutr Biochem. 2024;125: 109568.

809. Li CC, Xu YJ, Zhang JF, et al. The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice. Sci Rep. 2023;13(1):13278.

810. Zhang W, Zhang RH, Chang ZG, et al. Resveratrol activates CD8+ T cells through IL-18 bystander activation in lung adenocarcinoma. Front Pharmacol. 2022;13:1031438.

811. Kim JS, Jeong SK, Oh SJ, et al. The resveratrol analogue, HS-1793, enhances the effects of radiation therapy through the induction of anti-tumor immunity in mammary tumor growth. Int J Oncol. 2020;56(6):1405–16.

812. Ivanova D, Zhelev Z, Semkova S, et al. Resveratrol modulates the redox-status and cytotoxicity of anticancer drugs by sensitizing leukemic lymphocytes and protecting normal lymphocytes. Anticancer Res. 2019;39(7):3745–55.

813. Sui XX, Zhang CJ, Jiang YD, et al. Resveratrol activates DNA damage response through inhibition of polo-like kinase 1 (PLK1) in natural killer/T cell lymphoma. Ann Transl Med. 2020;8(11):688.

814. Zhang QF, Huang HD, Zheng F, et al. Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma. Oncoimmunology. 2020;9(1):1829346.

815. Lee Y, Shin H, Kim J. In vivo anti-cancer effects of resveratrol mediated by NK cell activation. J Innate Immun. 2021;13(2):94–106.

816. Lee YJ, Kim J. Resveratrol activates natural killer cells through Akt- and mTORC2-mediated c-Myb upregulation. Int J Mol Sci. 2020;21(24):9575.

817. Yao DB, Dong M, Dai CL, et al. Inflammation and inflammatory cytokine contribute to the initiation and development of ulcerative colitis and its associated cancer. Inflamm Bowel Dis. 2019;25(10):1595–602.

818. Buhrmann C, Shayan P, Brockmueller A, et al. Resveratrol suppresses cross-talk between colorectal cancer cells and stromal cells in multicellular tumor microenvironment: a bridge between in vitro and in vivo tumor microenvironment study. Molecules. 2020;25(18):4292.

819. Buhrmann C, Yazdi M, Popper B, et al. Evidence that TNF-β induces proliferation in colorectal cancer cells and resveratrol can down-modulate it. Exp Biol Med. 2019;244(1):1–12.

820. Jiang H, Wang GT, Wang Z, et al. Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts. World J Gastrointest Oncol. 2024;16(9):3980–93.

821. Lin CC, Chin YT, Shih YJ, et al. Resveratrol antagonizes thyroid hormone-induced expression of checkpoint and proliferative genes in oral cancer cells. J Dent Sci. 2019;14(3):255–62.

822. Pilankar A, Singhavi H, Raghuram GV, et al. A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: results of an exploratory study (RESCU 004). Front Oncol. 2022;12:1000957.

823. Chen J, Huang ST, Chen JG, et al. Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment. Neoplasma. 2022;69(5):1129–37.

824. Uzawa K, Amelio AL, Kasamatsu A, et al. Resveratrol targets urokinase-type plasminogen activator receptor expression to overcome cetuximab-resistance in oral squamous cell carcinoma. Sci Rep. 2019;9:12179.

825. Singh CK, Chhabra G, Ndiaye MA, et al. Quercetin-resveratrol combination for prostate cancer management in TRAMP mice. Cancers. 2020;12(8):2141.

826. Moreira H, Szyjka A, Grzesik J, et al. Celastrol and resveratrol modulate SIRT genes expression and exert anticancer activity in colon cancer cells and cancer stem-like cells. Cancers. 2022;14(6):1372.

827. Jin XX, Wei YZ, Liu YS, et al. Resveratrol promotes sensitization to doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/β-catenin signaling pathway in breast cancer. Cancer Med. 2019;8(3):1246–57.

828. Komorowska D, Gajewska A, Hikisz P, et al. Comparison of the effects of resveratrol and its derivatives on the radiation response of MCF-7 breast cancer cells. Int J Mol Sci. 2021;22(17):9511.

829. Patra S, Pradhan B, Nayak R, et al. Apoptosis and autophagy modulating dietary phytochemicals in cancer therapeutics: current evidences and future perspectives. Phytother Res. 2021;35(8):4194–214.

830. Peng L, Hu X-Z, Liu Z-Q et al. Therapeutic potential of resveratrol through ferroptosis modulation: insights and future directions in disease therapeutics. Frontiers in Pharmacology. 2024, 15.

831. Yao HW, Fan M, He XZ. Autophagy suppresses resveratrol-induced apoptosis in renal cell carcinoma 786-O cells. Oncol Lett. 2020;19(4):3269–77.

832. Ma RY, Yu DD, Peng Y, et al. Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells. Acta Biochim Biophys Sin (Shanghai). 2021;53(6):775–83.

833. Wang HY, Peng Y, Wang J, et al. Effect of autophagy on the resveratrol-induced apoptosis of ovarian cancer SKOV3 cells. J Cell Biochem. 2019;120(5):7788–93.

834. Sun DP, Chen JT, Yang ST, et al. Resveratrol triggers the ER stress-mediated intrinsic apoptosis of neuroblastoma cells coupled with suppression of Rho-dependent migration and consequently prolongs mouse survival. Chem Biol Interact. 2023;382: 110645.

835. Wang J, Huang P, Pan XF, et al. Resveratrol reverses TGF-β1-mediated invasion and metastasis of breast cancer cells via the SIRT3/AMPK/autophagy signal axis. Phytother Res. 2023;37(1):211–30.

836. Xu Z, Sun XA, Ding B, et al. Resveratrol attenuated high intensity exercise training-induced inflammation and ferroptosis via Nrf2/FTH1/GPX4 pathway in intestine of mice. Turk J Med Sci. 2023;53(2):446–54.

837. Zhu TT, Jin SZ, Tong DN, et al. Enhancing the anti-tumor efficacy of NK cells on canine mammary tumors through resveratrol activation. Animals. 2024;14(11):1636.

838. Zhang ZT, Ji Y, Hu N, et al. Ferroptosis-induced anticancer effect of resveratrol with a biomimetic nano-delivery system in colorectal cancer treatment. Asian J Pharm Sci. 2022;17(5):751–66.

839. Diab RF, Abdelghany TM, Gad S, et al. Novel resveratrol smart lipids; design, formulation, and biological evaluation of anticancer activity. J Pharm Pharmacol. 2024;76(6):631–45.

840. Sinha S, Chatterjee S, Paul S, et al. Olaparib enhances the resveratrol-mediated apoptosis in breast cancer cells by inhibiting the homologous recombination repair pathway. Exp Cell Res. 2022;420(1): 113338.

841. D’Arcy MS, Pike CVS, Coussons PJ. A novel combined resveratrol/berberine phytochemotheraputic using the HePG2 cell line as a model for the treatment of hepatocarcinoma. Cell Biol Int. 2021;45(12):2499–509.

842. Cesmeli S, Bagca BG, Caglar HO, et al. Combination of resveratrol and BIBR1532 inhibits proliferation of colon cancer cells by repressing expression of LncRNAs. Med Oncol. 2022;39(1):12.

843. Amini P, Nodooshan SJ, Ashrafizadeh M, et al. Resveratrol induces apoptosis and attenuates proliferation of MCF-7 cells in combination with radiation and hyperthermia. Curr Mol Med. 2021;21(2):142–50.

844. Wang Y, Su LX, Hu ZS, et al. Resveratrol suppresses liver cancer progression by downregulating AKR1C3: targeting HCC with HSA nanomaterial as a carrier to enhance therapeutic efficacy. Apoptosis. 2024;29(9–10):1429–53.

845. Li D, Wang GC, Jin GG, et al. Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway. Int J Mol Med. 2019;43(1):630–40.

846. Yu XK, Sun ZY, Nie SY, et al. Effects of resveratrol on mouse B16 melanoma cell proliferation through the SHCBP1-ERK1/2 signaling pathway. Molecules. 2023;28(22):7614.

847. Sun XD, Fu P, Xie LX, et al. Resveratrol inhibits the progression of cervical cancer by suppressing the transcription and expression of HPV E6 and E7 genes. Int J Mol Med. 2021;47(1):335–45.

848. Sawata Y, Matsukawa T, Doi S, et al. A novel compound, ferulic acid-bound resveratrol, induces the tumor suppressor gene p15 and inhibits the three-dimensional proliferation of colorectal cancer cells. Mol Cell Biochem. 2019;462(1–2):25–31.

849. Ali D, Chen L, Kowal JM, et al. Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells. Bone. 2020;133: 115252.

850. Gao Y, Zhang D, Wang P, et al. Acrylamide-induced meiotic arrest of spermatocytes in adolescent mice by triggering excessive DNA strand breaks: potential therapeutic effects of resveratrol. Hum Exp Toxicol. 2023;42:9603271231188292.

851. Chatterjee K, Mukherjee S, Vanmanen J, et al. Dietary polyphenols, resveratrol and pterostilbene exhibit antitumor activity on an HPV E6-positive cervical cancer model: an in vitro and in vivo analysis. Front Oncol. 2019;9:352.

852. Bostan M, Mihaila M, Petrica-Matei GG, et al. Resveratrol modulation of apoptosis and cell cycle response to cisplatin in head and neck cancer cell lines. Int J Mol Sci. 2021;22(12):6322.

853. Synowiec A, Brodaczewska K, Wcislo G, et al. Hypoxia, but not normoxia, reduces effects of resveratrol on cisplatin treatment in A2780 ovarian cancer cells: a challenge for resveratrol use in anticancer adjuvant cisplatin therapy. Int J Mol Sci. 2023;24(6):5715.

854. Madencioglu S, Becer E, Kabadayi H, et al. Resveratrol triggers apoptosis in colon cancer cells rather than senescence. PROG NUTR. 2021;23(1): e2021018.

855. Chen L, Xia JS, Wu JH, et al. Resveratrol inhibits oral squamous cell carcinoma cells proliferation while promoting apoptosis through inhibition ofCBX7protein. Environ Toxicol. 2020;35(11):1234–40.

856. Kim TH, Park JH, Woo JS. Resveratrol induces cell death through ROS-dependent downregulation of Notch1/PTEN/Akt signaling in ovarian cancer cells. Mol Med Rep. 2019;19(4):3353–60.

857. Chen HY, Lin PH, Shih YH, et al. Natural antioxidant resveratrol suppresses uterine fibroid cell growth and extracellular matrix formation in vitro and in vivo. Antioxidants. 2019;8(4):99.

858. Zhao YN, Cao YN, Sun J, et al. Anti-breast cancer activity of resveratrol encapsulated in liposomes. J Mater Chem B. 2020;8(1):27–37.

859. Sun Y, Zhou QM, Lu YY, et al. Resveratrol Inhibits the migration and metastasis of MDA-MB-231 human breast cancer by reversing TGF-β1-induced epithelial-mesenchymal transition. Molecules. 2019;24(6):1131.

860. Patra S, Pradhan B, Nayak R, et al. Chemotherapeutic efficacy of curcumin and resveratrol against cancer: chemoprevention, chemoprotection, drug synergism and clinical pharmacokinetics. Semin Cancer Biol. 2021;73:310–20.

861. Gavrilas LI, Cruceriu D, Ionescu C, et al. Pro-apoptotic genes as new targets for single and combinatorial treatments with resveratrol and curcumin in colorectal cancer. Food Funct. 2019;10(6):3717–26.

862. Huang L, Zhang S, Zhou J, et al. Effect of resveratrol on drug resistance in colon cancer chemotherapy. RSC Adv. 2019;9(5):2572–80.

863. Wang K, Hou DZ, Ouyang YM, et al. Resveratrol enhances paclitaxel-induced apoptosis through oxidative DNA damage in Caco-2 human colon cancer cells. S Afr J Bot. 2023;157:579–86.

864. Zhang YT, Li Y, Sun CC, et al. Effect of pterostilbene, a natural derivative of resveratrol, in the treatment of colorectal cancer through Top1/Tdp1-mediated DNA repair pathway. Cancers. 2021;13(16):4002.

865. Shin HJ, Han JM, Choi YS, et al. Pterostilbene suppresses both cancer cells and cancer stem-like cells in cervical cancer with superior bioavailability to resveratrol. Molecules. 2020;25(1):228.

866. Iacopetta D, Lappano R, Mariconda A, et al. Newly synthesized imino-derivatives analogues of resveratrol exert inhibitory effects in breast tumor cells. Int J Mol Sci. 2020;21(20):7797.

867. Awan Z, Kutbi HI, Ahmad A, et al. Molecular design, synthesis and biological characterization of novel Resveratrol derivative as potential anticancer agent targeting NF-κB. J Appl Biomed. 2020;18(1):8–17.

868. Grau L, Soucek R, Pujol MD. Resveratrol derivatives: synthesis and their biological activities. Eur J Med Chem. 2023;246: 114962.

869. Chen X, Wang YT, Tian J, et al. Quantitative chemical proteomics reveals resveratrol inhibition of A549 cell migration through binding multiple targets to regulate cytoskeletal remodeling and suppress EMT. Front Pharmacol. 2021;12: 636213.

870. Ancic D, Orsolic N, Odeh D, et al. Resveratrol and its nanocrystals: a promising approach for cancer therapy? Toxicol Appl Pharmacol. 2022;435: 115851.

871. Liu XJ, Liu JH, Xu SS, et al. Gold nanoparticles functionalized with au-se-bonded peptides used as gatekeepers for the off-target release of resveratrol in the treatment of triple-negative breast cancer. ACS Appl Mater Interfaces. 2023;15(2):2529–37.

872. Thipe VC, Amiri KP, Bloebaum P, et al. Development of resveratrol-conjugated gold nanoparticles: interrelationship of increased resveratrol corona on anti-tumor efficacy against breast, pancreatic and prostate cancers. Int J Nanomedicine. 2019;14:4413–28.

873. Lian BL, Wu MF, Feng ZQ, et al. Folate-conjugated human serum albumin-encapsulated resveratrol nanoparticles: preparation, characterization, bioavailability and targeting of liver tumors. Artif Cells Nanomed Biotechnol. 2019;47(1):154–65.

874. Melo BL, Lima-Sousa R, Alves CG, et al. Chitosan-based injectable in situ forming hydrogels containing dopamine-reduced graphene oxide and resveratrol for breast cancer chemo-photothermal therapy. Biochem Eng J. 2022;185: 108529.

875. Jagwani S, Jalalpure S, Dhamecha D, et al. Pharmacokinetic and pharmacodynamic evaluation of resveratrol loaded cationic liposomes for targeting hepatocellular carcinoma. ACS Biomater Sci Eng. 2020;6(9):4969–84.

876. Liu Y, Xu W, Zhai T, et al. Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway. Acta Pharm Sin B. 2019;9(4):745–57.

877. Sun M, Zhao H, Jin Z, et al. Silibinin protects against sepsis and septic myocardial injury in an NR1H3-dependent pathway. Free Radic Biol Med. 2022;187:141–57.

878. Sameri S, Mohammadi C, Mehrabani M, et al. Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer. BMC Complement Med Ther. 2021;21(1):160.

879. Tuli HS, Mittal S, Aggarwal D, et al. Path of Silibinin from diet to medicine: a dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance. Semin Cancer Biol. 2021;73:196–218.

880. Firouzi J, Sotoodehnejadnematalahi F, Shokouhifar A, et al. Silibinin exhibits anti-tumor effects in a breast cancer stem cell model by targeting stemness and induction of differentiation and apoptosis. Bioimpacts. 2022;12(5):415–29.

881. Li W, Zhao X, Lv X, et al. Silibinin retards colitis-associated carcinogenesis by repression of Cdc25C in mouse model. Inflamm Bowel Dis. 2019;25(7):1187–95.

882. Dan W, Fan Y, Hou T, et al. Silibinin inhibits the migration, invasion and epithelial-mesenchymal transition of prostate cancer by activating the autophagic degradation of YAP. J Cancer. 2022;13(13):3415–26.

883. Wang XL, Lin FL, Xu W, et al. Silybin B exerts protective effect on cisplatin-induced neurotoxicity by alleviating DNA damage and apoptosis. J Ethnopharmacol. 2022;288: 114938.

884. Durymanov M, Permyakova A, Reineke J. Pre-treatment With PLGA/Silibinin nanoparticles mitigates dacarbazine-induced hepatotoxicity. Front Bioeng Biotechnol. 2020;8:495.

885. Venkatesh D, Sarkar S, Kandasamy T, et al. In-silico identification and validation of Silibinin as a dual inhibitor for ENO1 and GLUT4 to curtail EMT signaling and TNBC progression. Comput Biol Chem. 2025. 10.3389/fbioe.2020.00495.

886. Verdura S, Encinar JA, Gratchev A, et al. Silibinin is a suppressor of the metastasis-promoting transcription factor ID3. Phytomedicine. 2024;128:5.

887. Bosch-Barrera J, Roque A, Teixidor E, et al. Clinical management of COVID-19 in cancer patients with the STAT3 inhibitor silibinin. Pharmaceuticals. 2021;15(1):19.

888. Elyasi S, Hosseini S, Niazi Moghadam MR, et al. Effect of oral silymarin administration on prevention of radiotherapy induced mucositis: a randomized, double-blinded. Placebo-Controlled Clinical Trial Phytother Res. 2016;30(11):1879–85.

889. Rugamba A, Kang DY, Sp N, et al. Silibinin regulates tumor progression and tumorsphere formation by suppressing PD-L1 expression in non-small cell lung cancer (NSCLC) cells. Cells. 2021;10(7):1632.

890. Wu S, Liu D, Li W, et al. Enhancing TNBC chemo-immunotherapy via combination reprogramming tumor immune microenvironment with immunogenic cell death. Int J Pharm. 2021;598: 120333.

891. Bittencourt MLF, Rodrigues RP, Kitagawa RR, et al. The gastroprotective potential of silibinin against Helicobacter pylori infection and gastric tumor cells. Life Sci. 2020;256: 117977.

892. Xie W, Li H, Lin Q, et al. Network pharmacological analysis and experimental validation of the effects of silybin on proliferation, migration, and immunotherapy of papillary thyroid cancer. Endocr Metab Immune Disord Drug Targets. 2024;24(6):672–90.

893. Zhao Z, Li C, Zhang Y, et al. Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases. Bioact Mater. 2023;27:474–87.

894. Banafshe Abadi JA, Farnaz Sedghy, Merat Mahmoodi, Hossein Fallah. Silibinin improved the function of T cells in peripheral blood mononuclear cells (PBMCs) co-cultured with U-87 MG cell line. Avicenna J Phytomed. 2023 14(2):166–176.

895. Jafari S, Heydarian S, Lai R, et al. Silibinin induces immunogenic cell death in cancer cells and enhances the induced immunogenicity by chemotherapy. Bioimpacts. 2023;13(1):51–61.

896. Tang S, Zhang X, Duan Z, et al. The novel hepatoprotective mechanisms of silibinin-phospholipid complex against d-GalN/LPS-induced acute liver injury. Int Immunopharmacol. 2023;116: 109808.

897. Sellam LS, Zappasodi R, Chettibi F, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690: 108479.

898. Miyazawa M, Yasuda M, Miyazawa M, et al. Hypoxia-inducible factor-1alpha suppression in ovarian clear-cell carcinoma cells by silibinin administration. Anticancer Res. 2020;40(12):6791–8.

899. Ashrafizadeh M, Zhang W, Zou R et al. A bioinformatics analysis, pre-clinical and clinical conception of autophagy in pancreatic cancer: Complexity and simplicity in crosstalk. Pharmacological Research. 2023, 194.

900. Yang Z, Pan Q, Zhang D, et al. Silibinin restores the sensitivity of cisplatin and taxol in A2780-resistant cell and reduces drug-induced hepatotoxicity. Cancer Manag Res. 2019;11:7111–22.

901. Sharifi-Azad M, Kaveh Zenjanab M, Shahpouri M et al. Codelivery of methotrexate and silibinin by niosome nanoparticles for enhanced chemotherapy of CT26 colon cancer cells. Biomed Mater. 2024, 19(5).

902. Bosch-Barrera J, Verdura S, Ruffinelli JC, et al. Silibinin suppresses tumor cell-intrinsic resistance to nintedanib and enhances its clinical activity in lung cancer. Cancers. 2021;13(16):4168.

903. Verdura S, Encinar JA, Teixidor E, et al. Silibinin overcomes EMT-driven lung cancer resistance to new-generation ALK inhibitors. Cancers. 2022;14(24):6101.

904. Rajput M, Mishra D, Kumar K, et al. Silibinin radiosensitizes EGF receptor-knockdown prostate cancer cells by attenuating DNA repair pathways. J Cancer Prev. 2022;27(3):170–81.

905. Hossein-Tehrani M, Abbasalipourkabir R, Ziamajidi N. The role of miR-133a in silibinin-mediated inhibition of the PI3K/AKT/mTOR pathway in MCF-7 breast carcinoma cells. Mol Biol Res Commun. 2024;13(2):79–83.

906. Hua C, Wang X, Liang S, et al. BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR. Biochem Biophys Res Commun. 2022;589:1–8.

907. Li Y, Ren L, Song G, et al. Silibinin ameliorates fructose-induced lipid accumulation and activates autophagy in HepG2 cells. Endocr Metab Immune Disord Drug Targets. 2019;19(5):632–42.

908. Fu J, Liu W, Liu S, et al. Inhibition of YAP/TAZ pathway contributes to the cytotoxicity of silibinin in MCF-7 and MDA-MB-231 human breast cancer cells. Cell Signal. 2024;119: 111186.

909. Fan YZ, Hou T, Dan WC, et al. Silibinin inhibits epithelial-mesenchymal transition of renal cell carcinoma through autophagy-dependent Wnt/β-catenin signaling. Int J Mol Med. 2020;45(5):1341–50.

910. Yassin NYS, AbouZid SF, El-Kalaawy AM, et al. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/beta-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother. 2022;145: 112409.

911. Liu W, Ji Y, Sun Y, et al. Estrogen receptors participate in silibinin-caused nuclear translocation of apoptosis-inducing factor in human breast cancer MCF-7 cells. Arch Biochem Biophys. 2020;689: 108458.

912. Song XY, Liu PC, Liu WW, et al. Silibinin inhibits ethanol- or acetaldehyde-induced ferroptosis in liver cell lines. Toxicol In Vitro. 2022;82: 105388.

913. Si LL, Fu JN, Liu WW, et al. Silibinin-induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells. Arch Biochem Biophys. 2020;685: 108284.

914. Du Q, Wu X, Ma K, et al. Silibinin alleviates ferroptosis of rat islet beta cell INS-1 induced by the treatment with palmitic acid and high glucose through enhancing PINK1/parkin-mediated mitophagy. Arch Biochem Biophys. 2023;743: 109644.

915. Duan W, Ou Z, Huang Y, et al. Silibinin Inhibits Cell Ferroptosis and Ferroptosis-Related Tissue Injuries. Antioxidants (Basel). 2023;12(12):2119.

916. Zhou L, Liu J, Meng W, et al. Evaluation of silibinin-loaded microbubbles combined with ultrasound in ovarian cancer cells: cytotoxicity and mechanisms. Anticancer Agents Med Chem. 2022;22(7):1320–7.

917. Lotia S, Patel S, Patel A, et al. Unravelling the role of Silibinin in targeting CD44+cancer stem cells: therapeutic implications, effective strategies and approaches. Phytother Res. 2024;38(4):1830–7.

918. Faixová D, Ratvaj M, Maruscáková IC, et al. Silybin showed higher cytotoxic, antiproliferative, and anti-inflammatory activities in the CaCo cancer cell line while retaining viability and proliferation in normal intestinal IPEC-1 cells. Life. 2023;13(2):492.

919. Bai Y, Chen J, Hu W, et al. Silibinin therapy improves cholangiocarcinoma outcomes by regulating ERK/mitochondrial pathway. Front Pharmacol. 2022;13: 847905.

920. Shi Z, Zhou Q, Gao S, et al. Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation. Life Sci. 2019;217:70–80.

921. Sameri S, Saidijam M, Bahreini F, et al. Cancer chemopreventive activities of silibinin on colorectal cancer through regulation of E-cadherin/β-catenin pathway. Nutr Cancer. 2021;73(8):1389–99.

922. Zhang H, Kim H, Kim SY, et al. Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway. J Cancer. 2023;14(10):1875–87.

923. Zhang X, Jiang J, Chen Z, et al. Silibinin inhibited autophagy and mitochondrial apoptosis in pancreatic carcinoma by activating JNK/SAPK signaling. Pathol Res Pract. 2019;215(9): 152530.

924. Murali Iyangar R, Devaraj E. Silibinin triggers the mitochondrial pathway of apoptosis in human oral squamous carcinoma cells. Asian Pac J Cancer Prev. 2020;21(7):1877–82.

925. Yassin NYS, AbouZid SF, El-Kalaawy AM, et al. Tackling of renal carcinogenesis in wistar rats by silybum marianum total extract, silymarin, and silibinin via modulation of oxidative stress, apoptosis, Nrf2, PPARgamma, NF-kappaB, and PI3K/Akt signaling pathways. Oxid Med Cell Longev. 2021;2021:7665169.

926. Yu Y, Li LF, Tao J, et al. Silibinin induced apoptosis of human epidermal cancer A431 cells by promoting mitochondrial NOS. Free Radic Res. 2019;53(7):714–26.

927. Si L, Fu J, Liu W, et al. Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Mol Cell Biochem. 2020;463(1–2):189–201.

928. Liao W, Zhang L, Chen X, et al. Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer. Phytomedicine. 2023;108:2.

929. Lashgarian HE, Adamii V, Ghorbanzadeh V, et al. Silibinin inhibit cell migration through downregulation of RAC1 gene expression in highly metastatic breast cancer cell line. Drug Res. 2020;70(10):478–83.

930. Xu S, Zhang H, Wang A, et al. Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1. Cell Mol Biol Lett. 2020;25:36.

931. Huo MR, Wang HL, Zhang Y, et al. Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation. J Control Release. 2020;321:198–210.

932. Koushki M, Khedri A, Aberomand M, et al. Synergistic anti-cancer effects of silibinin-etoposide combination against human breast carcinoma MCF-7 and MDA-MB-231 cell lines. Iran J Basic Med Sci. 2021;24(9):1211–9.

933. Ghadi R, Pandey PK, Gabhale A, et al. Genipin-crosslinked albumin nanoparticles containing neratinib and silibinin: a dual-death therapy for triple negative breast cancer. Int J Pharm. 2023;648: 123570.

934. Jafari-Gharabaghlou D, Jabbari A, Soltani A. Development of a magnetic nanostructure for co-delivery of metformin and silibinin on growth of lung cancer cells: Possible action through leptin gene and its receptor regulation. ANN ONCOL. 2022;33:S116–S116.

935. Salmani-Javan E, Jafari-Gharabaghlou D, Bonabi E, et al. Fabricating niosomal-PEG nanoparticles co-loaded with metformin and silibinin for effective treatment of human lung cancer cells. Front Oncol. 2023;13:1193708.

936. Jiang M, He K, Qiu T, et al. Tumor-targeted delivery of silibinin and IPI-549 synergistically inhibit breast cancer by remodeling the microenvironment. Int J Pharm. 2020;581: 119239.

937. Dalimi-Asl S, Babaahmadi-Rezaei H, Mohammadzadeh G. Combination of silibinin and curcumin reduced leptin receptor expression in MCF-7 human breast cancer cell line. Iran J Med Sci. 2020;45(6):477–84.

938. Mirzaaghaei S, Foroughmand AM, Saki G, et al. Combination of epigallocatechin-3-gallate and silibinin: a novel approach for targeting both tumor and endothelial cells. ACS Omega. 2019;4(5):8421–30.

939. Cerretti G, Cecchin D, Denaro L, et al. Impressive response to dabrafenib and trametinib plus silybin in a heavily pretreated IDH wild-type glioblastoma patient with BRAFV600E -mutant and SOX2 amplification. Anticancer Drugs. 2023;34(1):190–3.

940. Karbasforooshan H, Hosseini S, Elyasi S, et al. Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: a randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2019;33(2):379–86.

941. Xi JJ, Cao Y, He RY, et al. Design, synthesis and biological evaluation of glycosylated derivatives of silibinin as potential anti-tumor agents. Drug Des Devel Ther. 2023;17:2063–76.

942. Wu Q, Zeng J, Dong J. Synthesis and antitumor activity of novel silibinin and 2,3-dehydrosilybin derivatives with carbamate groups. Med Chem Res. 2022;31(4):533–44.

943. Dobiasova S, Rehorova K, Kucerova D, et al. Multidrug resistance modulation activity of silybin derivatives and their anti-inflammatory potential. Antioxidants. 2020;9(5):455.

944. Romanucci V, Pagano R, Kandhari K, et al. 7-O-tyrosyl silybin derivatives as a novel set of anti-prostate cancer compounds. Antioxidants. 2024;13(4):418.

945. Chen R, Huang L, Hu K. Natural products remodel cancer-associated fibroblasts in desmoplastic tumors. Acta Pharmaceutica Sinica B. 2020;10(11):2140–55.

946. Amiri M, Jafari S, Lavasanifar A et al. Nano-delivery of Silibinin Potentiate the Induction of Immunogenic Cell Death (ICD) in Melanoma Cells. Curr Pharm Biotechnol. 2024.

947. Hossainzadeh S, Ranji N, Naderi Sohi A, et al. Silibinin encapsulation in polymersome: a promising anticancer nanoparticle for inducing apoptosis and decreasing the expression level of miR-125b/miR-182 in human breast cancer cells. J Cell Physiol. 2019;234(12):22285–98.

948. Ravi R, Zeyaullah M, Ghosh S, et al. Use of gold nanoparticle-silibinin conjugates: a novel approach against lung cancer cells. Front Chem. 2022;10:1018759.

949. Lim DY, Pang M, Lee J, et al. Enhanced bioavailability and hepatoprotective effect of silymarin by preparing silymarin-loaded solid dispersion formulation using freeze-drying method. Arch Pharm Res. 2022;45(10):743–60.

950. Alipour M, Reza Bigdeli M, Aligholi H, et al. Sustained release of silibinin-loaded chitosan nanoparticle induced apoptosis in glioma cells. J Biomed Mater Res A. 2020;108(3):458–69.

951. Patel P, Raval M, Airao V, et al. Silibinin loaded inhalable solid lipid nanoparticles for lung targeting. J Microencapsul. 2022;39(1):1–24.

952. Khakinezhad Tehrani F, Ranji N, Kouhkan F, et al. PANC-1 cancer stem-like cell death with silybin encapsulated in polymersomes and deregulation of stemness-related miRNAs and their potential targets. Iran J Basic Med Sci. 2021;24(4):514–23.

953. Barros TMB, Lima APB, Almeida TC, et al. Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ Mol Mutagen. 2020;61(4):445–55.

954. Ranapour S, Motamed N. Effect of silibinin on the expression of Mir-20b, Bcl2L11, and Erbb2 in breast cancer cell lines. Mol Biotechnol. 2023;65(12):1979–90.

955. Tehrani FK, Ranji N, Kouhkan F, et al. Apoptosis induction and proliferation inhibition by silibinin encapsulated in nanoparticles in MIA PaCa-2 cancer cells and deregulation of some miRNAs. Iran J Basic Med Sci. 2020;23(4):469–82.

956. Zappavigna S, Vanacore D, Lama S, et al. Silybin-induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in human hepatocarcinoma cells. Int J Mol Sci. 2019;20(9):2190.

957. Zhang SN, Liu Q, Li XZ. Combination of omics, bioinformatics, molecular docking, and experimental validation to elucidate the hepatoprotective effects, mechanisms, and active compounds of Shandougen. Biomed Chromatogr. 2024;38(7): e5887.

958. Kaipa JM, Starkuviene V, Erfle H, et al. Transcriptome profiling reveals Silibinin dose-dependent response network in non-small lung cancer cells. PeerJ. 2020;8: e10373.

959. Mishra N, Paudel S, Agarwal C, et al. Silibinin modulates migration and survival pathways in bone marrow mast cells via RAC2: Implications in its anti-cancer activity in basal cell carcinoma growth and progression. Cancer Res. 2023;83(7):21.

960. Iqbal MA, Chattopadhyay S, Siddiqui FA, et al. Silibinin induces metabolic crisis in triple-negative breast cancer cells by modulating EGFR-MYC-TXNIP axis: potential therapeutic implications. FEBS J. 2021;288(2):471–85.

961. Gioti K, Papachristodoulou A, Benaki D, et al. Silymarin enriched extract (silybum marianum) additive effect on doxorubicin-mediated cytotoxicity in PC-3 prostate cancer cells. Planta Med. 2019;85(11–12):997–1007.

962. Fang W-Y, Tseng Y-T, Lee T-Y, et al. Triptolide prevents LPS-induced skeletal muscle atrophy via inhibiting NF-κB/TNF-α and regulating protein synthesis/degradation pathway. Br J Pharmacol. 2021;178(15):2998–3016.

963. Song J, He G-N, Dai L. A comprehensive review on celastrol, triptolide and triptonide: Insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes. Biomedicine & Pharmacotherapy. 2023, 162.

964. Liang X, Xie R, Su J et al. Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis. Journal of Experimental & Clinical Cancer Research. 2019, 38.

965. Noel P, Von Hoff DD, Saluja AK, et al. Triptolide and its derivatives as cancer therapies. Trends Pharmacol Sci. 2019;40(5):327–41.

966. Wang F, An S-J, Yin Y, et al. Triptolide is a promising therapeutic approach in treating thyroid cancer based on in silico and in vitro experiment. Drug Des Devel Ther. 2021;15:4275–87.

967. Lee B, Park Y, Lee Y et al. Triptolide, a Cancer Cell Proliferation Inhibitor, Causes Zebrafish Muscle Defects by Regulating Notch and STAT3 Signaling Pathways. Int J Mol Sci. 2024, 25(9).

968. Kuo C-S, Yang C-Y, Lin C-K et al. Triptolide suppresses oral cancer cell PD-L1 expression in the interferon-γ-modulated microenvironment <i>in vitro</i>, <i>in vivo</i>, and in clinical patients. Biomedicine & Pharmacotherapy. 2021, 133.

969. Li H, Li L, Mei H, et al. Antitumor properties of triptolide: phenotype regulation of macrophage differentiation. Cancer Biol Ther. 2020;21(2):178–88.

970. Liaw K, Sharma R, Sharma A, et al. Systemic dendrimer delivery of triptolide to tumor-associated macrophages improves anti-tumor efficacy and reduces systemic toxicity in glioblastoma. J Control Release. 2021;329:434–44.

971. Jiang X, Cao G, Gao G, et al. Triptolide decreases tumor-associated macrophages infiltration and M2 polarization to remodel colon cancer immune microenvironment via inhibiting tumor-derived CXCL12. J Cell Physiol. 2021;236(1):193–204.

972. Zheng L, Jia J, Dai H, et al. Triptolide-assisted phosphorylation of p53 suppresses inflammation-induced NF-κB survival pathways in cancer cells. Mol Cell Biol. 2017;37(15):e00149-e1117.

973. Shu Y, Qin M, Song Y, et al. M2 polarization of tumor-associated macrophages is dependent on integrin β3 via peroxisome proliferator-activated receptor-γ up-regulation in breast cancer. Immunology. 2020;160(4):345–56.

974. Zhang L, Yu JS. Triptolide reverses helper T cell inhibition and down-regulates IFN-γ induced PD-L1 expression in glioma cell lines. J Neurooncol. 2019;143(3):429–36.

975. Liu B, Zhang HQ, Li J, et al. Triptolide downregulates treg cells and the level of IL-10, TGF-β, and VEGF in melanoma-bearing mice. Planta Med. 2013;79(15):1401–7.

976. Yuan F, Sun M, Liu Z, et al. Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer. Theranostics. 2022;12(3):1061–73.

977. Wang S, Guo Q, Xu R, et al. Combination of ferroptosis and pyroptosis dual induction by triptolide nano-MOFs for immunotherapy of Melanoma. J Nanobiotechnol. 2023;21(1):383.

978. Huang Y, Chen Z, Wang Y, et al. Triptolide exerts an anti-tumor effect on non-small cell lung cancer cells by inhibiting activation of the IL-6/STAT3 axis. Int J Mol Med. 2019;44(1):291–300.

979. Koksalar Alkan F, Caglayan AB, Alkan HK, et al. Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment. Sci Rep. 2024;14(1):22487.

980. Wang Z, Jin H, Xu R, et al. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp Mol Med. 2009;41(10):717–27.

981. Zhang C, Cui GH, Liu F, et al. Inhibitory effect of triptolide on lymph node metastasis in patients with non-Hodgkin lymphoma by regulating SDF-1/CXCR4 axis in vitro. Acta Pharmacol Sin. 2006;27(11):1438–46.

982. Kuo CS, Yang CY, Lin CK, et al. Triptolide suppresses oral cancer cell PD-L1 expression in the interferon-γ-modulated microenvironment in vitro, in vivo, and in clinical patients. Biomed Pharmacother. 2021;133: 111057.

983. Xie Y, Ding J, Gao J, et al. Triptolide reduces PD-L1 through the EGFR and IFN-γ/IRF1 dual signaling pathways. Int Immunopharmacol. 2023;118: 109993.

984. Cai J, Zhong M, Xu J, et al. Codelivery of triptolide and IFN-γ to boost antitumor immunity for triple-negative breast cancer. Int Immunopharmacol. 2023;120: 110346.

985. Roy P, Giri B, Garrido VT, et al. Evaluation of minnelide as a potential therapeutic agent for preventing the relapse of AML. Blood. 2019;134:5159.

986. Li L-b, Yang L-x, Liu L et al. Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer. Acta Pharmacol Sin. 2024, 45(5):1060–1076.

987. Zhang KQ, Ma YL, Guo YM, et al. Cetuximab-triptolide conjugate suppresses the growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II. Mol Ther Oncolytics. 2020;18:304–16.

988. Tong XP, Jiang P, Li Y, et al. Combined treatment with triptolide and tyrosine kinase inhibitors synergistically enhances apoptosis in non-small cell lung cancer H1975 cells but Not H1299 cells through EGFR/Akt pathway. Chem Pharm Bull. 2019;67(8):864–71.

989. Li GY, Song ZW, Ru Y, et al. Small-molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual-inhibiting properties for bladder cancer treatment. Exploration. 2023;3(5):20220141.

990. Wang JW, Zhang Z, Li R, et al. Triptolide inhibits pituitary adenoma cell viability, migration and invasion via ADAM12/EGFR signaling pathway. Life Sci. 2018;194:150–6.

991. Zhong Y, Le F, Cheng J, et al. Triptolide inhibits JAK2/STAT3 signaling and induces lethal autophagy through ROS generation in cisplatin-resistant SKOV3/DDP ovarian cancer cells. Oncol Rep. 2021;45(5):69.

992. Hu H, Zhu SH, Tong Y, et al. Antitumor activity of triptolide in SKOV3 cells and SKOV3/DDP in vivo and in vitro. Anticancer Drugs. 2020;31(5):483–91.

993. Zheng Z, Yan G, Xi N, et al. Triptolide induces apoptosis and autophagy in cutaneous squamous cell carcinoma via Akt/mTOR pathway. Anticancer Agents Med Chem. 2023;23(13):1596–604.

994. Lai M, Liu L, Zhu L, et al. Triptolide reverses epithelial-mesenchymal transition in glioma cells via inducing autophagy. Ann Transl Med. 2021;9(16):1304.

995. Dai H, Jiang Y, Luo Y, et al. Triptolide enhances TRAIL sensitivity of pancreatic cancer cells by activating autophagy via downregulation of PUM1. Phytomedicine. 2019;62: 152953.

996. Wen YY, Li KM, Ni MN, et al. Dendritic polylysine with paclitaxel and triptolide codelivery for enhanced cancer ferroptosis through the accumulation of ROS. ACS Appl Mater Interfaces. 2024;16(16):20143–56.

997. Wu HS, Cao PP, Wang HY, et al. Postoperative injection of a triptolide-preloaded hydrogel prevents the recurrence of glioblastoma by dual-pathway activation of ferroptosis. Small. 2024;20(50): e2406036.

998. Wu X, Chen SQ, Huang KC, et al. Triptolide promotes ferroptosis by suppressing Nrf2 to overcome leukemia cell resistance to doxorubicin. Mol Med Rep. 2023;27(1):17.

999. Fang K, Sun YT, Yang JX, et al. A dual stimuli-responsive nanoplatform loaded ptiv -triptolide prodrug for achieving synergistic therapy toward breast cancer. Adv Healthc Mater. 2023;12(28): e2301328.

1000. Liu X, Chen C, Han D, et al. SLC7A11/GPX4 inactivation-mediated ferroptosis contributes to the pathogenesis of triptolide-induced cardiotoxicity. Oxid Med Cell Longev. 2022;2022:3192607.

1001. Liu YA, Zeng LL, Chen Y, et al. Triptolide inhibits cell growth and induces G0–G1 arrest by regulating P21wap1/cip1 and P27 kip1 in human multiple myeloma RPMI-8226 cells. CHINESE J CANCER RES. 2010;22(2):141–7.

1002. He SY, Chen M, Lin XL, et al. Triptolide inhibits PDGF-induced proliferation of ASMCs through G0/G1 cell cycle arrest and suppression of the AKT/NF-κB/cyclinDl signaling pathway. Eur J Pharmacol. 2020;867: 172811.

1003. Wang TAN, Ding Y, Yang YF, et al. Synergistic antitumour effects of triptolide plus 10-hydroxycamptothecin onbladder cancer. Biomed Pharmacother. 2019;115: 108899.

1004. Tang N, Zhan YJ, Mao JY, et al. Silencing ribosomal protein L4 enhances the inhibitory effects of triptolide on non-small cell lung cancer cells by disrupting the mouse double minute 2 protein-P53 tumor suppressor pathway. Biocell. 2023;47(9):2009–26.

1005. Ma YC, Wang Y, Wang L, et al. Triptolide prevents proliferation and migration of Esophageal Squamous Cell Cancer via MAPK/ERK signaling pathway. Eur J Pharmacol. 2019;851:43–51.

1006. Zhang ZW, Sun CF, Zhang L, et al. Triptolide interferes with XRCC1/PARP1-mediated DNA repair and confers sensitization of triple-negative breast cancer cells to cisplatin. Biomed Pharmacother. 2019;109:1541–6.

1007. Tian Y, Li PW, Xiao ZH, et al. Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/β-catenin signaling pathway in taxol-resistant human lung adenocarcinoma. Transl Cancer Res. 2021;10(2):1007–19.

1008. Wu CW, Wang SG, Lin ML, et al. Downregulation of miR-144 by triptolide enhanced p85α - PTEN complex formation causing S phase arrest of human nasopharyngeal carcinoma cells. Eur J Pharmacol. 2019;855:137–48.

1009. Liu XH, Zhao PY, Wang XJ, et al. Triptolide induces glioma cell autophagy and apoptosis via upregulating the ROS/JNK and downregulating the Akt/mTOR signaling pathways. Front Oncol. 2019;9:387.

1010. Chen P, Zhong X, Song Y, et al. Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells. Cancer Lett. 2024;587: 216622.

1011. Yuan W, Huang J, Hou S, et al. The antigastric cancer effect of triptolide is associated with H19/NF-κB/FLIP Axis. Front Pharmacol. 2022;13: 918588.

1012. He J, Peng T, Peng Y, et al. Molecularly engineering triptolide with aptamers for high specificity and cytotoxicity for triple-negative breast cancer. J Am Chem Soc. 2020;142(6):2699–703.

1013. Yuan C, Liao Y, Liao S, et al. Triptolide inhibits the progression of glioblastoma U251 cells via targeting PROX1. Front Oncol. 2023;13:1077640.

1014. Liu C, Yuan XL, Liu XB, et al. Effect of triptolide and chemotherapy on carcinoembryonic and carbohydrate antigens levels and first-line treatment of recurrent nasopharyngeal carcinoma. Cell Mol Biol. 2021;67(2):109–13.

1015. Shi Y-F, Liu L, He L-L, et al. Combining triptolide with ABT-199 is effective against acute myeloid leukemia through reciprocal regulation of Bcl-2 family proteins and activation of the intrinsic apoptotic pathway. Cell Death Dis. 2020;11(7):555.

1016. Song HN, Xing WL, Shi XJ, et al. Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier. Bioorg Med Chem. 2021;50: 116466.

1017. Cui MH, Jin MJ, Han MF, et al. Improved antitumor outcomes for colon cancer using nanomicelles loaded with the novel antitumor agent LA67. Int J Nanomed. 2020;15:3563–76.

1018. Zang YD, Lai FF, Fu JM, et al. Novel nitric oxide-releasing derivatives of triptolide as antitumor and anti-inflammatory agents: design, synthesis, biological evaluation, and nitric oxide release studies. Eur J Med Chem. 2020;190: 112079.

1019. Zhao Y, Gu Y, Qi F, et al. Engineering adipocytes for targeting delivery of triptolide derivative and Ce6 for malignant melanoma cytotoxic-PDT synergistic strategy. Mater Des. 2023;228: 111860.

1020. Noel P, Hussein S, Ng S, et al. Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts. Oncogenesis. 2020;9(11):100.

1021. Li C, Li Z, Zhang T, et al. 1H NMR-based metabolomics reveals the antitumor mechanisms of triptolide in BALB/c mice bearing CT26 tumors. Front Pharmacol. 2019;10:1175.

1022. Uriostegui-Arcos M, Aguayo-Ortiz R, Valencia-Morales MDP, et al. Disruption of TFIIH activities generates a stress gene expression response and reveals possible new targets against cancer. Open Biol. 2020;10(6): 200050.

1023. 1028.Song F, Li J, Shi Q et al. Quantitative Chemical Proteomics Reveals Triptolide Selectively Inhibi ts HCT116 Human Colon Cancer Cell Viability and Migration Through Bind ing to Peroxiredoxin 1 and Annexin A1. Adv Biol. 8(10):e2300452.

1024. Li Z, Yang G, Han L, et al. Sorafenib and triptolide loaded cancer cell-platelet hybrid membrane-camouflaged liquid crystalline lipid nanoparticles for the treatment of hepatocellular carcinoma. J Nanobiotechnology. 2021;19(1):360.

1025. Luo LY, He HY, Li CH, et al. Near-infrared responsive bimetallic nanovesicles for enhanced synergistic chemophotothermal therapy. ACS Biomater Sci Eng. 2019;5(3):1321–31.

1026. Huang Y, Wu SY, Li JJ, et al. Self-amplified pH/ROS dual-responsive co-delivery nano-system with chemo-photodynamic combination therapy in hepatic carcinoma treatment. Int J Nanomed. 2024;19:3737–51.

1027. Hayashi M, Madokoro H, Yamada K, et al. Novel antibody-drug conjugate with anti-CD26 humanized monoclonal antibody and transcription factor IIH (TFIIH) inhibitor, triptolide, inhibits tumor growth via impairing mRNA synthesis. Cancers. 2019;11(8):1138.

1028. Feng JX, Xu MJ, Wang JH, et al. Sequential delivery of nanoformulated α-mangostin and triptolide overcomes permeation obstacles and improves therapeutic effects in pancreatic cancer. Biomaterials. 2020;241: 119907.

1029. Zhang YQ, Shen Y, Liao MM, et al. Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms. Nanomedicine. 2019;15(1):86–97.

1030. 1036.Paula Sales P, Das Dores Alves de Oliveira M, Figueiredo Watanabe JM et al. Phytochemical characterization, isolation, antioxidant and cytogenotoxic activity of leaves of Heliotropium elongatum (Lehm) I.M. Johnst. J Toxicol Environ Health A. 2023, 86(23):871–897.

1031. Bai X, Zhang Y, Wen X, et al. Structure-based optimization of ursolic acid derivatives as anticancer agents. Chem Nat Compd. 2023;59(2):400–2.

1032. Kashyap D, Tuli HS, Yerer MB, et al. Natural product-based nanoformulations for cancer therapy: opportunities and challenges. Semin Cancer Biol. 2021;69:5–23.

1033. 1039.Li S, Guo X, Liu H et al. Ursolic acid, an inhibitor of TMEM16A, co-loaded with cisplatin in hydrogel drug delivery system for multi-targeted therapy of lung cancer. International Journal of Biological Macromolecules. 2024, 277.

1034. Lin W, Ye H. Anticancer activity of ursolic acid on human ovarian cancer cells via ROS and MMP mediated apoptosis, cell cycle arrest and downregulation of PI3K/AKT pathway. J BUON. 2020;25(2):750–6.

1035. Wang Y, Luo Z, Zhou D, et al. Nano-assembly of ursolic acid with platinum prodrug overcomes multiple deactivation pathways in platinum-resistant ovarian cancer. Biomater Sci. 2021;9(11):4110–9.

1036. Mallepogu V, Sankaran KR, Pasala C, et al. Ursolic acid regulates key EMT transcription factors, induces cell cycle arrest and apoptosis in MDA-MB-231 and MCF-7 breast cancer cells, an in-vitro and in silico studies. J Cell Biochem. 2023;124(12):1900–18.

1037. 1043.Wang S, Chang X, Zhang J et al. Ursolic Acid Inhibits Breast Cancer Metastasis by Suppressing Glycolytic Metabolism via Activating SP1/Caveolin-1 Signaling. Front Oncol. 2021, 11.

1038. Mao Q, Min J, Zeng R, et al. Self-assembled traditional Chinese nanomedicine modulating tumor immunosuppressive microenvironment for colorectal cancer immunotherapy. Theranostics. 2022;12(14):6088–105.

1039. 1045.Kadasah SF, Radwan MO. Overview of Ursolic Acid Potential for the Treatment of Metabolic Disorders, Autoimmune Diseases, and Cancers via Nuclear Receptor Pathways. Biomedicines. 2023, 11(10).

1040. Wang Z, Zhang P, Jiang H, et al. Ursolic acid enhances the sensitivity of MCF-7 and MDA-MB-231 cells to epirubicin by modulating the autophagy pathway. Molecules. 2022;27(11):3399.

1041. Zhang X, Li T, Gong ES, et al. Antiproliferative activity of ursolic acid in MDA-MB-231 human breast cancer cells through Nrf2 pathway regulation. J Agric Food Chem. 2020;68(28):7404–15.

1042. Liu C-H, Wong SH, Tai C-J, et al. Ursolic acid and its nanoparticles are potentiators of oncolytic measles virotherapy against breast cancer cells. Cancers (Basel). 2021;13(1):136.

1043. Zhang N, Liu S, Shi S, et al. Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy. J Control Release. 2020;320:168–78.

1044. Cao X, He Q. Ursolic acid inhibits proliferation, migration and invasion of human papillary thyroid carcinoma cells via CXCL12/CXCR4/CXCR7 axis through cancer-associated fibroblasts. Hum Exp Toxicol. 2022;41:09603271221111333.

1045. Yang K, Chen Y, Zhou J, et al. Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non-small-cell lung carcinoma harbouring EGFR T790M mutations. Br J Pharmacol. 2019;176(24):4609–24.

1046. Zong L, Cheng G, Zhao J, et al. Inhibitory effect of ursolic acid on the migration and invasion of doxorubicin-resistant breast cancer. Molecules. 2022;27(4):1282.

1047. Luo F, Zhao J, Liu S, et al. Ursolic acid augments the chemosensitivity of drug-resistant breast cancer cells to doxorubicin by AMPK-mediated mitochondrial dysfunction. Biochem Pharmacol. 2022;205: 115278.

1048. Li W, Luo L, Shi W, et al. Ursolic acid reduces Adriamycin resistance of human ovarian cancer cells through promoting the HuR translocation from cytoplasm to nucleus. Environ Toxicol. 2021;36(2):267–75.

1049. Tang Z, Dong H, Li T, et al. The synergistic reducing drug resistance effect of cisplatin and ursolic acid on osteosarcoma through a multistep mechanism involving ferritinophagy. Oxid Med Cell Longev. 2021;2021(1):5192271.

1050. Fan L, Wang X, Cheng C, et al. Inhibitory effect and mechanism of ursolic acid on cisplatin-induced resistance and stemness in human lung cancer A549 cells. Evid Based Complement Alternat Med. 2023;2023(1):1307323.

1051. Xiang F, Fan Y, Ni Z, et al. Ursolic acid reverses the chemoresistance of breast cancer cells to paclitaxel by targeting MiRNA-149-5p/MyD88. Front Oncol. 2019;9:501.

1052. Fan Y-J, Pan F-Z, Cui Z-G, et al. The antitumor and sorafenib-resistant reversal effects of ursolic acid on hepatocellular carcinoma via targeting ING5. Int J Biol Sci. 2024;20(11):4190.

1053. Lin J-H, Chen S-Y, Lu C-C, et al. Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine-resistant human pancreatic cancer cells. Phytother Res. 2020;34(8):2053–66.

1054. Deng S, Shanmugam MK, Kumar AP, et al. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer. 2019;125(8):1228–46.

1055. 1061.Limami Y, Pinon A, Wahnou H et al. Ursolic acid’s alluring journey: one triterpenoid vs. cancer hallmarks. Molecules. 2023, 28(23):7897.

1056. Lee N-R, Meng RY, Rah S-Y, et al. Reactive oxygen species-mediated autophagy by ursolic acid inhibits growth and metastasis of esophageal cancer cells. Int J Mol Sci. 2020;21(24):9409.

1057. Jinyan Z, Shilan C, Xuejiao W, et al. Ursolic acid induces apoptosis and autophagy of HCT-8/5-FU cells. JHIP. 2022;3(4):315–23.

1058. Fogde DL, Xavier CP, Balnytė K, et al. Ursolic acid impairs cellular lipid homeostasis and lysosomal membrane integrity in breast carcinoma cells. Cells. 2022;11(24):4079.

1059. Yang X, Liang B, Zhang L, et al. Ursolic acid inhibits the proliferation of triple-negative breast cancer stem-like cells through NRF2-mediated ferroptosis. Oncol Res. 2024;52(1):1–13.

1060. 1066.Zhao H, Tang S, Tao Q et al. Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity. Journal of Agricultural and Food Chemistry. 2023.

1061. 1067.Kim K, Shin EA, Jung JH et al. Ursolic Acid Induces Apoptosis in Colorectal Cancer Cells Partially via Upregulation of MicroRNA-4500 and Inhibition of JAK2/STAT3 Phosphorylation. International Journal of Molecular Sciences. 2019, 20(1).

1062. Kim GD. Ursolic acid decreases the proliferation of MCF-7 cell-derived breast cancer stem-like cells by modulating the ERK and PI3K/AKT signaling pathways. Prev Nutr Food Sci. 2021;26(4):434.

1063. Kang D, Sp N, Lee J, et al. Antitumor effects of ursolic acid through mediating the inhibition of STAT3/PD-L1 signaling in non-small cell lung cancer cells. Biomedicines. 2021;9(3):297.

1064. Yang M, Hu C, Cao Y, et al. Ursolic acid regulates cell cycle and proliferation in colon adenocarcinoma by suppressing cyclin B1. Front Pharmacol. 2021;11: 622212.

1065. Cao M, Xiao D, Ding X. The anti-tumor effect of ursolic acid on papillary thyroid carcinoma via suppressing fibronectin-1. Biosci Biotechnol Biochem. 2020;84(12):2415–24.

1066. 1072.Huang L, Zhao S, Fang F et al. Advances and perspectives in carrier-free nanodrugs for cancer chemo-monotherapy and combination therapy. Biomaterials. 2021, 268.

1067. Piet M, Paduch R. Ursolic and oleanolic acids in combination therapy inhibit migration of colon cancer cells through down-regulation of the uPA/uPAR-dependent MMPs pathway. Chem Biol Interact. 2022;368: 110202.

1068. Castrejón-Jiménez NS, Leyva-Paredes K, Baltierra-Uribe SL, et al. Ursolic and oleanolic acids induce mitophagy in A549 human lung cancer cells. Molecules. 2019;24(19):3444.

1069. Hu D, Meng RY, Nguyen TV, et al. Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway. Mol Med Rep. 2022;27(1):11.

1070. 1076.Fujita M, Chen M-JM, Siwak DR et al. Inhibition of Colorectal Cancer Tumorigenesis by Ursolic Acid and Doxorubicin Is Mediated by Targeting the Akt Signaling Pathway and Activating the Hippo Signaling Pathway. Mol Med Rep. 2022, 27(1):11.

1071. Tong L-W, Le J-Q, Song X-H, et al. Synergistic anti-tumor effect of dual drug co-assembled nanoparticles based on ursolic acid and sorafenib. Colloids Surf B Biointerfaces. 2024;234: 113724.

1072. Li H, Yu Y, Liu Y, et al. Ursolic acid enhances the antitumor effects of sorafenib associated with Mcl-1-related apoptosis and SLC7A11-dependent ferroptosis in human cancer. Pharmacol Res. 2022;182: 106306.

1073. Liu W, Kang S, Chen H, et al. A composition of ursolic acid derivatives from Ludwigia hyssopifolia induces apoptosis in throat cancer cells via the Akt/mTOR and mitochondrial signaling pathways and by modulating endoplasmic reticulum stress. J Ethnopharmacol. 2024;319(Pt 3): 117351.

1074. Khusnutdinova E, Petrova A, Zileeva Z, et al. Novel a-ring chalcone derivatives of oleanolic and ursolic amides with anti-proliferative effect mediated through ROS-triggered apoptosis. Int J Mol Sci. 2021;22(18):9796.

1075. Gou W, Luo N, Yu B, et al. Ursolic acid derivative UA232 promotes tumor cell apoptosis by inducing endoplasmic reticulum stress and lysosomal dysfunction. Int J Biol Sci. 2022;18(6):2639–51.

1076. Mlala S, Oyedeji AO, Gondwe M, et al. Ursolic acid and its derivatives as bioactive agents. Molecules. 2019;24(15):2751.

1077. Panda SS, Thangaraju M, Lokeshwar BL. Ursolic acid analogs as potential therapeutics for cancer. Molecules. 2022;27(24):8981.

1078. Gou W, Luo N, Wei H, et al. Ursolic acid derivative UA232 evokes apoptosis of lung cancer cells induced by endoplasmic reticulum stress. Pharm Biol. 2020;58(1):707–15.

1079. Michalak O, Cybulski M, Szymanowski W, et al. Synthesis, biological activity, ADME and molecular docking studies of novel ursolic acid derivatives as potent anticancer agents. Int J Mol Sci. 2023;24(10):8875.

1080. 1086.Guo W, Xu B, Wang X et al. The analysis of the anti-tumor mechanism of ursolic acid using connectively map approach in breast cancer cells line MCF-7. Cancer Manag Res. 2020:3469–3476.

1081. Li S, Wu R, Wang L, et al. Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer. Mol Carcinog. 2022;61(1):111–21.

1082. Fu S, Li G, Zang W, et al. Pure drug nano-assemblies: a facile carrier-free nanoplatform for efficient cancer therapy. Acta Pharm Sin B. 2022;12(1):92–106.

1083. Xu F, Li M, Que Z, et al. Combined chemo-immuno-photothermal therapy based on ursolic acid/astragaloside IV-loaded hyaluronic acid-modified polydopamine nanomedicine inhibiting the growth and metastasis of non-small cell lung cancer. J Mater Chem B. 2023;11(15):3453–72.

1084. Ou KY, Xu XJ, Guan SY, et al. Nanodrug carrier based on poly(ursolic acid) with self-anticancer activity against colorectal cancer. Adv Funct Mater. 2020;30(9):1907857.

1085. Zhou Z, Ke Q, Wu M, et al. Pore space partition approach of ZIF-8 for pH responsive codelivery of ursolic acid and 5-fluorouracil. ACS Mater Lett. 2023;5(2):466–72.

1086. Guo Y, Yang X, Zhang Y, et al. Hyaluronic acid/dextran-based polymeric micelles co-delivering ursolic acid and doxorubicin to mitochondria for potentiating chemotherapy in MDR cancer. Carbohydr Polym. 2024;332: 121897.

1087. Li S, Guo X, Liu H, et al. Ursolic acid, an inhibitor of TMEM16A, co-loaded with cisplatin in hydrogel drug delivery system for multi-targeted therapy of lung cancer. Int J Biol Macromol. 2024;277(Pt 4): 134587.

1088. Zhu Y, Mao Y, Chen H, et al. Apigenin promotes apoptosis, inhibits invasion and induces cell cycle arrest of T24 human bladder cancer cells. Cancer Cell Int. 2013;13(1):54.

1089. Ketkaew Y, Osathanon T, Pavasant P, et al. Apigenin inhibited hypoxia induced stem cell marker expression in a head and neck squamous cell carcinoma cell line. Arch Oral Biol. 2017;74:69–74.

1090. Maggioni D, Garavello W, Rigolio R, et al. Apigenin impairs oral squamous cell carcinoma growth in vitro inducing cell cycle arrest and apoptosis. Int J Oncol. 2013;43(5):1675–82.

1091. Leslie EM, Mao Q, Oleschuk CJ, et al. Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and ATPase activities by interaction with dietary flavonoids. Mol Pharmacol. 2001;59(5):1171–80.

1092. Vendelbo J, Olesen RH, Lauridsen JK, et al. Increasing BMI is associated with reduced expression of P-glycoprotein (ABCB1 gene) in the human brain with a stronger association in African Americans than Caucasians. Pharmacogenomics J. 2018;18(1):121–6.

1093. Chiang L-C, Ng LT, Lin I-C, et al. Anti-proliferative effect of apigenin and its apoptotic induction in human Hep G2 cells. Cancer Lett. 2006;237(2):207–14.

1094. Choi EJ, Kim G-H. Apigenin causes G2/M arrest associated with the modulation of p21Cip1 and Cdc2 and activates p53-dependent apoptosis pathway in human breast cancer SK-BR-3 cells. J Nutr Biochem. 2009;20(4):285–90.

1095. Khan TH, Sultana S. Apigenin induces apoptosis in Hep G2 cells: possible role of TNF-α and IFN-γ. Toxicology. 2006;217(2):206–12.

1096. Lepley DM, Li B, Birt DF, et al. The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. Carcinogenesis. 1996;17(11):2367–75.

1097. Ujiki MB, Ding X-Z, Salabat MR, et al. Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest. Mol Cancer. 2006;5:1–8.

1098. Wang W, Heideman L, Chung CS, et al. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol Carcinog. 2000;28(2):102–10.

1099. Korsmeyer SJ, Yin X-M, Oltvai ZN, et al. Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochim Biophys Acta. 1995;1271(1):63–6.

1100. Korsmeyer SJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 1999;59(7 Suppl):1693s–700s.

1101. Ji J, Cheng Z, Zhang J, et al. Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway. J Cell Mol Med. 2024;28(8): e18335.

1102. Lu X, Efferth T. Repurposing of artemisinin-type drugs for the treatment of acute leukemia. Semin Cancer Biol. 2021;68:291–312.

1103. Bai B, Wu F, Ying K, et al. Therapeutic effects of dihydroartemisinin in multiple stages of colitis-associated colorectal cancer. Theranostics. 2021;11(13):6225–39.

1104. Lee HH, Cho H. Improved anti-cancer effect of curcumin on breast cancer cells by increasing the activity of natural killer cells. J Microbiol Biotechnol. 2018;28(6):874–82.

1105. Liu D, You M, Xu Y, et al. Inhibition of curcumin on myeloid-derived suppressor cells is requisite for controlling lung cancer. Int Immunopharmacol. 2016;39:265–72.

1106. Yu C-P, Wang Y-R, Hou Y-C, et al. Two curcumin analogs inhibited the function and protein expression of breast cancer resistance protein: in vitro and in vivo studies. Xenobiotica. 2023;53(5):454–64.

1107. 1115.He W-t, Zhu Y-h, Zhang T et al. Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P-Glycoprotein. Chin J Integr Med. 2019, 25(6):416–424.

1108. 1116.Han W, Yin H, Ma H et al. Curcumin Regulates ERCC1 Expression and Enhances Oxaliplatin Sensitivity in Resistant Colorectal Cancer Cells through Its Effects on miR-409–3p. Evid Based Complement Alternat Med. 2020, 2020.

1109. Pajaniradje S, Mohankumar K, Radhakrishnan R, et al. Indole curcumin reverses muttidrug resistance by reducing the expression of ABCB1 and COX2 in induced multidrug resistant human lung cancer cells. Lett Drug Des Discov. 2020;17(9):1146–54.

1110. Gao L, Zhao PR, Li Y, et al. Reversal of P-glycoprotein-mediated multidrug resistance by novel curcumin analogues in paclitaxel-resistant human breast cancer cells. Biochem Cell Biol. 2020;98(4):484–91.

1111. Jin X, Wang J, Shen H, et al. Curcumin co-treatment ameliorates resistance to gefitinib in drug resistant NCI-H1975 lung cancer cells. J Tradit Chin Med. 2017;37(3):355–60.

1112. Tu Y, Wu Z, Tan B, et al. Emodin: Its role in prostate cancer-associated inflammation (review). Oncol Res. 2019;42(4):1259–71.

1113. McDonald SJ, VanderVeen BN, Velazquez KT, et al. Therapeutic potential of emodin for gastrointestinal cancers. Integr Cancer Ther. 2022;21:15347354211067468.

1114. Li W, Wang D, Li M, et al. Emodin inhibits the proliferation of papillary thyroid carcinoma by activating AMPK. Exp Ther Med. 2021;22(4):1075.

1115. Wu C-C, Chen M-S, Chen J-Y. The application of emodin treatment on nasopharyngeal carcinoma therapy. Biomedicines. 2024;12(3):486.

1116. Wei W-T, Lin S-Z, Liu D-L, et al. The distinct mechanisms of the antitumor activity of emodin in different types of cancer (review). Oncol Res. 2013;30(6):2555–62.

1117. Hsu S-C, Chung J-G. Anticancer potential of emodin. Biomedicine-Taiwan. 2012;2(3):108–16.

1118. Tian M, Tian D, Qiao X, et al. Modulation of Myb-induced NF-kB-STAT3 signaling and resulting cisplatin resistance in ovarian cancer by dietary factors. J Cell Physiol. 2019;234(11):21126–34.

1119. Ai Z, Liu S, Qu F, et al. Effect of stereochemical configuration on the transport and metabolism of catechins from green tea across Caco-2 monolayers. Molecules. 2019;24(6):1185.

1120. Lyu C, Wang L, Stadlbauer B, et al. Identification of EZH2 as cancer stem cell marker in clear cell renal cell carcinoma and the anti-tumor effect of epigallocatechin-3-gallate (EGCG). Cancers (Basel). 2022;14(17):4200.

1121. 1130.Zhu F, Xu Y, Pan J et al. Epigallocatechin gallate protects against MNNG-induced precancerous lesions of gastric carcinoma in rats via PI3K/Akt/mTOR pathway. Evid Based Complement Alternat Med. 2021, 2021.

1122. Talib WH, Awajan D, Alqudah A, et al. Targeting cancer hallmarks with epigallocatechin gallate (EGCG): mechanistic basis and therapeutic targets. Molecules. 2024;29(6):1373.

1123. Guo Y, Cui Y, Li Y, et al. Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer. Cancer Commun. 2023;43(5):582–612.

1124. Huang Y-J, Wang K-L, Chen H-Y, et al. Protective effects of epigallocatechin gallate (EGCG) on endometrial, breast, and ovarian cancers. Biomolecules. 2020;10(11):1481.

1125. Koh Y-C, Tsai Y-W, Lee P-S, et al. Amination potentially augments the ameliorative effect of curcumin on inhibition of the IL-6/Stat3/c-Myc pathway and gut microbial modulation in colitis-associated tumorigenesis. J Agric Food Chem. 2022;70(46):14744–54.

1126. Liang Y, Zhang T, Jing S, et al. 20(S)-ginsenoside Rg3 inhibits lung cancer cell proliferation by targeting EGFR-mediated Ras/Raf/MEK/ERK pathway. Am J Chin Med. 2021;49(3):753–65.

1127. Gao J, Fu Y, Song L, et al. Proapoptotic effect of icariin on human ovarian cancer cells via the nf-[formula: see text]B/PI3K-AKT signaling pathway: a network pharmacology-directed experimental investigation. Am J Chin Med. 2022;50(2):589–619.

1128. Fan YM, Li JQ, Yang YX, et al. Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53-dependent pathway: Integrated bioinformatics analysis and experimental validation. Int J Oncol. 2020;57(4):925–38.

1129. Franceschi BT, Bezerra PHA, Torqueti MR. Antitumor effects of co-treatment of resveratrol with antitumor drugs in ER- and HER2-positive breast cancer cells are due to induction of apoptosis and modulation of estrogen receptor expression. Breast Cancer. 2024;31(5):754–68.

1130. Huang WH, Yu LD, Cai WR, et al. Resveratrol protects BEAS-2B cells against erastin-induced ferroptosis through the Nrf2/Keap1 pathway. Planta Med. 2023;89(04):408–15.

1131. Zhu XY, Zhang WQ, Xiang HD, et al. Radiation-enhanced self-cascade catalytic Ti3C2Tx-based platform enables controlled release of trans-resveratrol for synergistic radiosensitization against metastasis of orthotopic breast cancer. Nano Today. 2023;50: 101836.

1132. Zhang XH, Jiang LP, Chen HB, et al. Resveratrol protected acrolein-induced ferroptosis and insulin secretion dysfunction via ER-stress- related PERK pathway in MIN6 cells. Toxicology. 2022;465: 153048.

1133. Qin T, Cheng L, Xiao Y, et al. NAF-1 inhibition by resveratrol suppresses cancer stem cell-like properties and the invasion of pancreatic cancer. Front Oncol. 2020;10:1038.

1134. Li TY, Zhang XY, Cheng LL, et al. Modulation of lncRNA H19 enhances resveratrol-inhibited cancer cell proliferation and migration by regulating endoplasmic reticulum stress. J Cell Mol Med. 2022;26(8):2205–17.

1135. Savio M, Ferraresi A, Corpina C, et al. Resveratrol and its analogue 4,4′-dihydroxy-trans-stilbene inhibit lewis lung carcinoma growth in vivo through apoptosis, autophagy and modulation of the tumour microenvironment in a murine model. Biomedicines. 2022;10(8):1784.

1136. Guo S, Bai X, Liu Y, et al. Inhibition of TMEM16A by natural product silibinin: potential lead compounds for treatment of lung adenocarcinoma. Front Pharmacol. 2021;12: 643489.

1137. Yu D, Liu Y, Zhou Y, et al. Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism. Proc Natl Acad Sci USA. 2020;117(18):9964–72.

1138. Yang C-Y, Lin C-K, Hsieh C-C, et al. Anti-oral cancer effects of triptolide by downregulation of DcR3 in vitro, in vivo, and in preclinical patient-derived tumor xenograft model. Head Neck. 2019;41(5):1260–9.

1139. Guo Q, Nan XX, Yang JR, et al. Triptolide inhibits the multidrug resistance in prostate cancer cells via the downregulation of MDR1 expression. Neoplasma. 2013;60(6):598–604.

1140. Li F, Cui H, Jin X, et al. Triptolide inhibits epithelial-mesenchymal transition and induces apoptosis in gefitinib-resistant lung cancer cells. Oncol Rep. 2020;43(5):1569–79.

1141. 1150.Aarthy M, Panwar U, Singh SKJSr. Structural dynamic studies on identification of EGCG analogues for the inhibition of Human Papillomavirus E7. Sci Rep. 2020, 10(1):8661.

1142. 1151.Hu D, Meng RY, Nguyen TV et al. Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway. Mol Med Rep. 2023, 27(1).

1143. Gupta KB, Gao J, Li X et al. Cytotoxic Autophagy: A Novel Treatment Paradigm against Breast Cancer Using Oleanolic Acid and Ursolic Acid. Cancers. 2024, 16(19).

1144. Wang M, Yu H, Wu R, et al. Autophagy inhibition enhances the inhibitory effects of ursolic acid on lung cancer cells. Int J Mol Med. 2020;46(5):1816–26.

1145. Tian L, Ji H, Wang W, et al. Mitochondria-targeted pentacyclic triterpenoid carbon dots for selective cancer cell destruction via inducing autophagy, apoptosis, as well as ferroptosis. Bioorg Chem. 2023;130: 106259.

1146. Hou W, Zou Y, Li J, et al. Synergistic therapy of melanoma by co-delivery of dacarbazine and ferroptosis-inducing ursolic acid using biomimetic nanoparticles. ACS Omega. 2024;9(40):41532–43.

1147. Shen M, Wang D, Sennari Y, et al. Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth. Med Oncol. 2022;39(8):118.

Associated Data

Data Availability Statement

Not applicable.