Platycodon grandiflorum, as a medicinal and food homologous plant: a comprehensive review of anti-tumor components, mechanisms, modern applications, and preventive healthcare.

Introduction

Malignant tumors are a class of diseases with complex pathogenesis, poor prognosis, and high morbidity and mortality rates. According to World Health Organization (WHO) reports, 17.5 million cancer patients deaths and 27 million new cancer patients will happen annually by 2050 ( 1 ). Nowadays, traditional treatment methods still form the backbone of clinical tumor treatment, including surgery, radiotherapy, and chemotherapy. However, these methods often cannot avoid affecting normal tissues-thus having the characteristic of “non-specificity” ( 2 ). In addition, targeted therapy for tumors is a precise treatment method that selectively targets specific receptors on tumor cells. However, targeted therapy also encounters challenges, including tumor cell resistance, high costs, a diversity of therapeutic targets, and potential side effects ( 3 ). Therefore, continued research and development of new treatment methods are crucial to improve treatment effectiveness and safety.

Traditional Chinese medicine (TCM), as one of the effective means of prevention and treatment of malignant tumors, has achieved significant efficacy in tumor treatment. Active natural compounds derived from traditional Chinese herbs play a crucial role in cancer treatment by producing anti-cancer effects, effectively improving clinical effects, and reducing the toxic side effects associated with chemotherapy and radiation therapy. According to the literature, natural products have a more diverse structure and can effectively exert specific biological functions. For example, they mainly regulate the body’s internal environment to inhibit tumor growth, reduce tumor metastasis, and modulate immune responses ( 4 ). Statistics show that a significant proportion of FDA-approved anti-cancer drugs are derived from natural plants. This makes natural compounds promising and practical alternatives for cost-effective, highly effective, and safer cancer treatments and prevention. However, currently only 2.5–5 million plant species have been thoroughly studied, which means there is still enormous potential to be explored in the development of anti-cancer therapies based on natural plants.

Platycodon grandiflorum (Jacq.) A. D C. ( P. grandiflorum ), known as “Jiegeng” or “Lingdanghua” (in China), “Doraji” (in Korea) and “Kikyo” (in Japan), is a dried root of the Platycodon genus, which attributes to the Campanulaceae family ( 5 ). The Campanulaceae family has about 60–70 genera, and P. grandiflorum is the only genus in this family ( 6 ). P. grandiflorum is primarily found in the northeastern, northern, and central regions of China, along with Korea, Japan, the Russian Far East, and southeastern Siberia ( 7 ). According to a record of TCM dated 2000 years ago, P. grandiflorum was first mentioned in “ Shennong Bencao Jing ” (a famous monograph of TCM). The ancient book stated that P. grandiflorum had a slightly warm and pungent taste, and it was used to treat chest and hypochondriac pain, fullness in the abdomen, faint intestinal sounds, and palpitations caused by fear. Subsequently, throughout different historical periods, medical scholars have consistently described the taste and efficacy of P. grandiflorum . “Mingyi Bie Lu,” “Xinxiu Bencao,” “Kaibao Bencao,” “Tangye Bencao,” “Jingyue Quanshu,” and “Bencao Gangmu” all described P. grandiflorum having a bitter and slightly warm taste, which can relieve sore throat and help to evacuate pus. Since the Qing Dynasty, people have commonly used P. grandiflorum to make pickled vegetables in northeastern of China. Therefore, P. grandiflorum is a medicinal and edible species, which has great potential in the development and application of medicine, health care products, dietary supplements and food ( 8 ).

Currently, the rhizome of P. grandiflorum has been widely used in TCM with remarkable ability to promote lung function, ease sore throat, eliminate phlegm and pus, as determined by the Committee for the Pharmacopoeia of PR China (2020). Modern pharmacological studies have shown that the medicinal component of P. grandiflorum is its root, which has various pharmacological effects such as cough suppression ( 9 ), immune stimulation ( 10 ), anti-inflammatory activity ( 11 ), anti-oxidant activity, and anti-tumor activity ( 12 ). According to the literature, an increasing number of research evidence has demonstrated the anticancer potential of P. grandiflorum . However, there is a notable absence of comprehensive reports detailing the anti-tumor effects of P. grandiflorum . It has been shown that the active ingredients of P. grandiflorum , such as saponins, flavonoids and polysaccharides play important roles in inhibiting tumor cell proliferation, inducing cell apoptosis and cell autophagy, inhibiting the invasion and migration of tumor cells, regulating immune function, inhibiting tumor angiogenesis ( 13 ).

Before writing this review, we reviewed the literature search in PubMed, 1 Google Scholar, 2 ScienceDirect, 3 Web of Science, 4 and other databases using the keywords of “ Platycodon grandiflorum ” AND (“anti-tumor” OR “anti-cancer”) and “Platycodin D ” AND (“anti-tumor” OR “anti-cancer”) from the past 5 years. Fortunately, two reviews attracted our attention, primarily focusing on summarizing the botanical description, distribution, traditional uses, chemical composition, and pharmacological effects of P. grandiflorum ( 5 , 14 ). However, due to the over-comprehensive describe the P. grandiflorum efficacy, only a brief summary on the anti-tumor potential of P. grandiflorum provided without a comprehensive discussion on the antitumor mechanism. Consequently, to address this research gap, we conducted a comprehensive and systematic review in the present study. The purpose of this review is to systematically clarify the anti-tumor potential of P. grandiflorum , including its anti-tumor components (platycodin D, P. grandiflorum polysaccharides, luteolin, apigenin, and lobetyolin), mechanisms, application prospects, and preventive healthcare, with the following research objectives and implementation processes, shown as in graphical abstract.

Network pharmacological analysis of P. grandiflorum

The active ingredients of P. grandiflorum were analyzed by TCMSP database 5 (accessed May 10, 2025) using the screening criteria of Drug-Like (DL) ≥ 0.18 and Oral Bioavailability (OB) ≥ 0.3. The active components were obtained and their corresponding ID, Molecule Name, OB and DL values were displayed in Supplementary Table 1 . The targets of P. grandiflorum ’s active ingredients were predicted by TCMSP database, and the targets were corrected by UniProt database 6 (accessed May 12, 2025) and converted to gene targets. Additionally, SwissTargetPrediction database 7 (accessed May 12, 2025) was incorporated to further supplement the active ingredients of P. grandiflorum and their corresponding gene targets. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis through the Metascape database 8 (accessed May 12, 2025), the pathway information was obtained and their corresponding Description, Gene Ratio, gene ID, and Count were displayed in Supplementary Table 2 . Next, we visualized the result through the Wei Shengxin platform. 9 Based on the screening criteria, a total of five active ingredients and 95 targets of P. grandiflorum were obtained in the TCMSP database. After importing into Cytoscape3.8 (The Cytoscape Consortium, United States), the “target-ingredient” network was constructed in Figure 1A . Then, these drug targets were imported into the Metascape database. The results indicated that among the top 20 signaling pathways enriched in P. grandiflorum drug targets, six pathways were primarily associated with cancer, including hepatocellular cancer, pancreatic cancer, bladder cancer, small cell lung cancer, prostate cancer, pathways in cancer, etc. ( Figure 1B ). Therefore, based on the network pharmacology results, we have reason to believe that P. grandiflorum has widely anti-tumor effects.

Main active ingredients of P. grandiflorum

The roots of P. grandiflorum contain high levels of carbohydrates (90%), protein (2.4%), fat (0.1%), ash (1.5%), and approximately 2% triterpene saponins ( 15 ). Over the past several decades, at least 100 compounds have been isolated from P. grandiflorum , including steroidal saponins, flavonoids, polysaccharide, phenolic acids, polyacetylenes, sterols, fatty oils, fatty acids, various amino acids, and vitamins, etc. ( 16 , 17 ). The variety of natural chemical components makes the pharmacological applications of P. grandiflorum very broad. The P. grandiflorum main active components ( Table 1 ) and chemical structures with potential medicinal functions ( Figure 2 ).

First of all, triterpene saponins are a class of compounds found in many plants. Platycodin refers to a variety of purified cholane-type triterpene saponins with diverse pharmacological activities present in the roots of P. grandiflorum ( 18 ). There are numerous types of Platycodin, including platycodin A, platycodin B, platycodin D, Polygala D, Polygala D2, etc. ( 19 ). Among all the saponin components, platycodin D is the first saponin isolated from P. grandiflorum , and is recognized as one of the most potent pharmacological components ( 15 ). It has been reported to have antitussive, anti-inflammatory, anti-tumor, regulating metabolism effects ( 20 ). Subsequently, Flavonoids are primarily found in the aboveground parts of P. grandiflorum and can be classified into flavonoids, dihydroflavonoids, and flavonoid glycosides. To date, more than 10 flavonoid components have been isolated from the aboveground parts ( 21 ), including apigenin, luteolin, acacetin, tangerine, quercetin-7-O-glucoside, quercetin-7-O-rutin, delphinidin-3-rutin-7-glucoside and others. Among these components, apigenin and luteolin are the main constituents ( 22 ). According to relevant studies, luteolin glycosidic acid and luteolin 7-glucoside exhibit antioxidant, anti-tumor, antimicrobial, anti-inflammatory, anti-apoptotic, anti-allergic, and neuroprotective properties ( 23 ). P. grandiflorum polysaccharide is an important active ingredient in P. grandiflorum ( 24 ). Polysaccharide is composed of fructose, mannose, xylose, and arabinose; mannose is the main sugar component ( 25 ). Currently, polysaccharides with known structures have been identified, such as the eustoma polysaccharides GF2 ~ GF9. They have significant pharmacological effects in enhancing immune function, anti-tumor, hypoglycemic, anti-aging and anti-viral effects, which are well documented in the China Pharmacopoeia ( 26 ). Park et al. ( 27 ) found that P. grandiflorum polysaccharide can effectively inhibit the autophagic damage induced by chromium (VI) [Cr(VI)] to the mitochondria of DF-1 cells. In addition to saponins, flavonoids, and polysaccharides, P. grandiflorum also contains active ingredients such as phenolic acids, lobetyolin, polyacetylene, sterols, and amino acids. Lee et al. ( 28 ) isolated two phenolic compounds from the roots of P. grandiflorum , namely coniferyl palmitate and coniferyl oleate.

Extraction process and detection method of antitumor components from P. grandiflorum

In recent years, the extraction of active components from natural plants using safe, eco-friendly, and efficient methods has gained significant popularity. The extraction methods of natural compounds mainly include water extraction, alcohol extraction, cold immersion extraction, ultrasonic extraction and supercritical extraction, among which organic solvent extraction method is the most widely used method. In addition, many determination techniques have been developed for plant extracts ( 29 ). Among these determination methods, high-performance liquid chromatography (HPLC) is the most widely employed, and it is characterized by high sensitivity, excellent repeatability, and straightforward standardization ( 30 ).

In this review, we focused primarily on the anti-tumor active components and extraction methods of P. grandifloram. P. grandiflorum , as a plant with both medicinal and edible properties, contains various anti-tumor active components-including platycodin D ( 31 ), luteolin, apigenin ( 32 , 33 ), polysaccharides ( 34 ) and lobetyolin ( 35 ). Currently, the extraction methods and processes for these components have been extensively studied ( 36 , 37 ). Jingyin et al. ( 38 ) determined that the content of platycodin D has been recognized as the major active compound in P. grandiflorum roots than that of leaves. Kwon et al. ( 39 , 40 ) used HPLC-ELSD to determine that the content of platycodin D in P. grandiflorum root varies depending on three processing methods: alcohol extraction, water extraction, and ultrasonic-assisted extraction. In addition, luteolin and apigenin, as flavonoids, are mainly found in the above-ground parts of the P. grandiflorum. Zhou et al. ( 41 ) used ultrasonic extraction and HPLC simultaneous determined the contents of luteolin and apigenin in P. grandiflorum.

Currently, the extraction of polysaccharides has attracted significant attention. Zhang et al. ( 42 ) used water reflux extraction and ultrasonic extraction method to extract polysaccharides of P. grandiflorum, among them, the water reflux extraction efficiency is as high as 44%. In addition, there are other methods for polysaccharides. Zhang et al. ( 43 ) determined the content of polysaccharides in the roots of P. grandiflorum from China’s three major production areas via the phenol-concentrated sulfuric acid method, and reported that the content ranged from 18.1 to 23.1% ( 44 ). Meanwhile, Yin et al. ( 45 ) used ultrasonic extraction and HPLC determined the contents of platycodin D and lobetyolin from P. grandiflorum (The content of platycodin D was 5.12 ± 0.13 mg/g, and the yield of lobetyolin was 0.14 ± 0.01 mg/g). Since lobetyolin is mainly found in the root of the P. grandiflorum , its extraction usually uses the root as the raw material. Chen et al. ( 46 ) employed accelerated solvent extraction methods and used HPLC to detect content level of lobetyolin. In conclusion, we summarized the extraction sites, extraction processes and detection methods of these anti-tumor components in P. grandiflorum , as shown in Table 2 .

Anti-cancer effects and underlying mechanisms

In the anti-cancer research, Platycodin D is the main active component of P. grandiflorum , which has been the most extensively studied ( 47 ); followed by flavonoids and polysaccharides, which have also received significant research attention in anti-cancer studies. In addition, the network pharmacological analysis and literature retrieval of P. grandiflorum extracts and active components have been demonstrated which can inhibit multiple types of cancer (Colon cancer, gallbladder cancer, stomach cancer, hepatoma carcinoma cell lung cancer, etc.) and have anti-tumor activity by inhibiting several signaling pathways, including PI3K/AKT/mTOR, MAPK, JNK/STAT3, Wnt, Notch-1, and NF-κB signaling pathways, etc. Further research findings have indicated that P. grandiflorum has promising therapeutical potential for cancer treatment. It inhibits cancer cell proliferation, induces cancer cell apoptosis, suppresses cancer cell migration and invasion, inhibits angiogenesis, and regulates autophagy, etc. ( Table 3 ).

Inhibiting cell proliferation and blocking cell cycle

Excessive cell proliferation is one of the key indicators of cancer development, and cancer cells possess the capability to evade apoptosis through the activation of survival support signals, which stands as a significant characteristic. The PI3K/AKT signaling pathway is commonly overexpressed in a variety of human cancers ( 48 ). The c-Myc transcription factors play an essential role in normal, untransformed cells, regulating proliferation, differentiation, cell growth, and apoptosis ( 49 ). Cancer cells often escape terminal differentiation by increasing the c-Myc expression, which is an effective inhibitor of differentiation in numerous cell lines ( 50 ). In gastric cancer, platycodin D exerts its anti-cancer effect by promoting c-Myc protein ubiquitination and degradation ( 51 ). Liu et al. ( 52 ) found that platycodin D can suppresses tumor cell growth in vitro and vivo by down-regulating the p-PI3K and p-AKT expression in HCT116 cells. Zhou et al. ( 53 ) found that the water extract of P. grandiflorum inhibits the PI3K/Akt signaling pathway, thereby reducing the apoptosis of lung cells and the infiltration of inflammatory cells in mice induced by lipopolysaccharide.

In addition, abnormal cell cycle progression is also one of the basic mechanisms of tumor proliferation ( 54 ). Cyclin B1 is a crucial constituent of the cyclin family, which can activate specific cyclin dependent kinases (CDKs) required for cell cycle progression ( 55 ). Activated Cyclin B1 can promote cells from the G2 phase to the M phase, and initiate mitotic progression ( 56 ). In the study, Lee et al. ( 57 ) found that apigenin can trigger G2/M cell cycle arrest, inhibit the expression of Cyclin B1, Cdc2, and Cdc25c, thereby inhibiting the proliferation of HCT116 colon cancer cells. In their study, Ujiki et al. ( 58 ) discovered that the growth of pancreatic cancer cells is hindered by apigenin due to its ability to suppress the G2/M cell cycle and decreased the activity of CyclinB1-Cdc2. In ovarian cancer, luteolin induced cell apoptosis and arrested cell cycle in G2/M by reducing the expression of VRK1 and activating the p53 signaling pathway, and inhibited HGSOC cell proliferation ( 59 ). P53 is a transcription factor responsible for inhibiting tumor growth. Its main anti-tumor mechanisms include inhibiting cell proliferation by blocking the cell cycle and promoting cell apoptosis ( 60 ). In the study of esophageal cancer, luteolin can inhibit the proliferation and growth of EC1, EC9706, KYSE30, and KYSE450 cells; Up-regulation of the expression of cell cycle inhibitory proteins p21 and p53 inhibits ESCC cells proliferation ( 61 ). He et al. ( 62 ) evaluated the tumor growth inhibitory effects of two P. grandiflorum polysaccharides (PRP1 and PRP2) isolated and purified from hot water extraction on liver cancer. PRP1 inhibited the proliferation of HepG2 cells by down-regulating miR-21 and activating PTEN. Cai et al. ( 63 ) extracted and purified polysaccharides from P. grandiflorum and conducted in vitro cell experiments. The results confirmed that P. grandiflorum polysaccharides promote apoptosis in liver cancer cells by enhancing the expression of LINC01554 (a long non-coding RNA), thereby inhibiting the progression of liver cancer.

Inducing tumor cell apoptosis

Apoptosis is a cell suicide plan executed by caspases, which is crucial for maintaining tissue homeostasis. Impaired apoptosis is now known to be a key step in cancer development. Whether a cell is alive or dead is largely determined by the anti-apoptotic modulators of the Bcl-2 family, and the release of cytochrome C into the cytoplasm is a crucial event in mitochondrial apoptosis, and it is regulated by the Bcl-2 protein family. Therefore, Bcl-2 plays a crucial role in intrinsic apoptosis by regulating mitochondrial membranes ( 64 ). In bladder cancer, platycodin D can increase the expression of Caspase-9, Caspase-8, Caspase-3 and p53 in tumor tissue, and promote cancer cell apoptosis by reducing the expression of Bcl-2 ( 64 ). Zeng et al. ( 65 ) demonstrated that platycodin D upregulated the expression of cytochrome C by regulating Bcl-2 in gallbladder cancer, further validating the endogenous cell apoptosis mechanism induced by platycodin D. In addition, the anti-apoptosis mechanism of platycodin D has been confirmed in many cancers, such as breast cancer ( 50 ), colon cancer ( 52 ), gallbladder cancer ( 66 ), prostate cancer ( 67 ) and non-small cell lung cancer ( 68 ). In gastric cancer, a research has shown that luteolin can suppress the proliferation of MKN45 cells, induce apoptosis, lower the mitochondrial membrane potential, and increase the expression of BAX, Caspase3, and cytochrome C, and reduce the expression of Bcl-2 and p-AKT ( 69 ). As is well known, triggering tumor cell apoptosis is related to various signaling pathways (PI3K/AKT/mTOR, MAPK, JAK/STAT3, and NF-κB, etc.). In liver cancer research, apigenin can induce the expression of PTEN protein in human liver cancer cells, though inhibiting PI3K/AKT signaling and reducing the level of phosphorylated Bad protein, thereby achieving the effect of inducing liver cancer cell apoptosis ( 70 ); apigenin has also been proven to have therapeutic effects on cancer cells. Apigenin induces autophagy by inhibiting the activity of key molecules p-AKT and p-mTOR in gastric cancer cells, thereby enhancing the apoptotic ability of gastric cancer cells ( 71 ).

Lu et al. ( 72 ) used the polysaccharides extracted from dried P. grandiflorum root to conduct in vitro studies. They found that the P. grandiflorum polysaccharides could significantly inhibit the growth of HeLa cancer cells. Moreover, they could also suppress the growth of U-14 transplanted tumors by up-regulating the p19ARF and Bcl-2 and down-regulating the expression of mutant p53, thereby inducing apoptosis in cancer cells. Wang et al. ( 73 ) administered S180 tumor-bearing mice with P. grandiflorum polysaccharides by gavage. They found that the lymphocyte proliferation index significantly increased, while the protein expression levels of TLR4, MyD88, and NF- κ B significantly decreased. This might be related to the inhibition of tumor growth and the improvement of the body’s immune function.

Inhibiting tumor cell migration and invasion

Tumor invasion and migration is a complex, multi-step biochemical process that is considered to be one of the hallmarks of cancer biology. The degradation of the basement membrane and remodeling of the ECM are hallmarks of tumor invasion and metastasis ( 74 ). Abnormal expression of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, has been observed in tumors, and their involvement in tumor invasion and metastasis is widely recognized. Lee et al. ( 75 ) found that the aqueous extract of P. grandiflorum root inhibits tumor invasion and metastasis. Zhang et al. ( 76 ) found that platycodin D hindered NF-κ B regulates the activity of downstream genes of MMP-2 and MMP-9, thereby hindering the migration and invasion of oral squamous cell carcinoma cells. This phenomenon has also been confirmed in gallbladder cancer ( 66 ) and prostate cancer ( 77 ). In the study of liver cancer, platycodin D effectively hindered the growth of HePG2 and Hep3B cells by significantly suppressing the development of HepG2 cell colonies, and triggering cellular apoptosis, and inhibited TPA induced cell migration and invasion ( 78 ). Huang et al. ( 79 ) found that luteolin can inhibit the expression of EMT and MMP2, MMP7 and MMP9 in a dose-dependent manner, and inhibit the invasive ability of PANC-1 and SW1990 pancreatic cancer cells. In gastric cancer research, Zhang et al. ( 80 ) found that luteolin can significantly suppress the migration and invasion of NCI-N87 and MKN28 cell through the Notch1 pathway, induce cell apoptosis, and reverse the occurrence of EMT. In colorectal cancer, luteolin hindered migration and invasion of SW620 and SW480 cancer cells through inhibiting the STAT3 pathway ( 81 ). In non-small cell lung cancer, luteolin inhibited the growth of H460 cells by EGFR/PI3K/AKT pathway and inhibited cell migration by reducing the expression levels of MMP-2 and ICAM-1 ( 82 ). Zhang et al. ( 83 ) modified the P. grandiflorum polysaccharide (PGP40-1) using the HNO3/Na2SeO3 method to obtain seleniumated P. grandiflorum polysaccharide (Se-PGP40-1). Se-PGP40-1 could inhibit tumor proliferation and migration by inducing cell apoptosis and blocking angiogenesis.

Inhibition of new vascular growth

The metastasis and recurrence of tumors are closely related to neovascularization, which is a complex physiological process and is considered a marker of cancer progression ( 74 ). The VEGF is a highly characteristic factor that promotes endothelial cell growth and has the effect of promoting angiogenesis. The VEGF and IL-8 play crucial roles in promoting tumor angiogenesis by directly enhancing processes like endothelial cell proliferation, adhesion, migration, and angiogenesis. Therefore, developing drugs with high selectivity for VEGF could improve the prognosis of patients with metastatic cancer. The anti-angiogenic effects of platycodin D have recently been studied. Heydarzadeh et al. ( 84 ) have shown that platycodin D inhibited HUVEC proliferation, migration, and angiogenesis in a dose-dependent manner. The anti-angiogenic activity can be achieved by inhibiting VEGF induced p-VEGFR-2 and downstream targets. In studies of non-small cell lung cancer, platycodin D has been shown to hinder A549 cell proliferation and trigger apoptosis by modulating the p53/VEGF/MMP2 pathway ( 85 ). Meanwhile, in the study of esophageal cancer, apigenin was known as a tumor cell IL-6 transcription inhibitor, which inhibited the transcription and expression of IL-6, thereby inhibiting Eca-109 and Kyse-30 cell proliferation, inducing angiogenesis, and promoting apoptosis of esophageal cancer cell ( 86 ).

Regulating cell autophagy

Autophagy, known as type II programmed cell death, plays a dual role in the development of cancer. First, autophagy can maintain genomic stability and prevent the occurrence, proliferation, invasion, and metastasis of tumors. In addition, autophagy can also serve as a cellular defense mechanism, maintaining functional mitochondria, reducing DNA damage, and thus maintaining tumor development, and even promoting tumor tissue metastasis and drug resistance ( 87 ). Research has shown that platycodin D can trigger autophagy in different cancer cells (A549, H358, MCF7, HT29, and HepG2) ( 88 , 89 ). In non-small cell lung cancer, Zhao et al. ( 90 ) found that P. grandiflorum induced autophagy in NCI-H460 and A549 cells by inhibiting the PI3K/AKT/mTOR signaling pathway and activating the JNK/MAPK signaling pathway. In liver cancer, platycodin D has anti-tumor effects of inhibiting BEL-7402 cell proliferation and inducing cell apoptosis. At the same time, it can trigger autophagy by activating the ERK and JNK pathways ( 91 ). In liver cancer research, luteolin can reduce the activity of SMMC-7721 cells, induce apoptosis, upregulate Caspase-8, downregulate the expression level of Bcl-2, and promote the transformation of LC-I to LC3-II, increase the expression of Beclin-1, and activate autophagy ( 92 ). In gastric cancer research, apigenin inhibited APG induced autophagy through endoplasmic reticulum stress and inhibited HIF-1α inducing endoplasmic reticulum stress and autophagy with Ezh2 to activate AGS tumor cell death ( 93 ).

In summary, this study found that P. grandiflorum can inhibit tumor progression through multiple components, multiple targets, and multiple pathways. Based on literature review, among its active components, platycodin D has been the most extensively studied for its anti-tumor effects, with flavonoids (such as apigenin and luteolin) and polysaccharides also playing important roles. Its inhibitory effects have been demonstrated in various tumor cells (e.g., lung cancer cells, hepatoma cells), primarily through the PI3K/AKT signaling pathways. In addition, P. grandiflorum exerts its anti-tumor effects by inhibiting tumor cell proliferation, promoting apoptosis, and preventing metastasis, etc. The anticancer signaling pathways of P. grandiflorum extract are illustrated in Figure 3 . Furthermore, given the diverse molecular mechanisms underlying cancer, the mechanisms involved in the tumor-inhibiting process of P. grandiflorum extracts and their active components are shown in Figure 4 .

The effect-enhancing and toxicity-reducing of the active ingredient derived from P. grandiflorum

The protective effects on the liver and kidneys

Some active ingredients in P. grandiflorum not only have anti-cancer effects, but also have functions such as protecting the liver and reducing nephrotoxicity. Kim et al. ( 94 ) found that the fermentation extract of P. grandiflorum can alleviate acute liver injury induced by endotoxin in mice through reducing liver cell apoptosis and oxidative stress. Platycodin D protected against liver damage from acetaminophen by inhibiting oxidative stress and cell apoptosis. In addition, platycodin D can inhibit cisplatin-induced cell damage through various pathways, reverse cell apoptosis induced by Bax, Bad, Caspase-3, Caspase-9, and modulate PI3K/Akt and ERK/JNK/p38 signaling pathways, providing evidence for reduced cisplatin-induced nephrotoxicity. Apigenin has antioxidant, liver protective, anti-viral, and anti-inflammatory effects. In the treatment of a rat model of liver injury induced by chemotherapy drug cyclophosphamide, it can reduce liver function indicators, prevent liver cell damage, and inhibit ROS, LPO, NF- κ B. Pro-inflammatory mediators and indicators of apoptosis by activating Nrf2 signaling and reducing oxidative damage and inflammatory responses ( 95 ). Similarly, luteolin can also have a protective effect on liver cell damage caused by acetaminophen ( 96 ). P. grandiflorum polysaccharides also have certain liver-protective activity. Hou et al. ( 97 ) prepared nano-selenium saikosaponin complexes using the vitamin C reduction method. They administered the drugs by gavage and compared the protective effects of the nano-selenium saikosaponin complex and saikosaponin on liver-damaged mice. In addition, Liu et al. ( 98 ) found that the P. grandiflorum polysaccharides also have anti-inflammatory and antioxidant effects, and can regulate the immune function of the colon. They can alleviate ulcerative colitis caused by DSS through the mesenteric lymph circulation. Hou et al. ( 99 ) found that Lobetyolin , a Q-marker isolated from radix of P. grandiflorum , exerted protective effects on cisplatin-induced cytotoxicity in HEK293 cells ( Figure 5 ; Table 4 ).

In summary, the primary active components of P. grandiflorum listed in the table—including platycodin D, flavonoids, polysaccharides, and lobetyolin—have demonstrated significant liver and kidney protective effects in both in vitro cell experiments and animal models. Their key mechanism involves regulating key signaling pathways such as PI3K/AKT, ERK/JNK, and NF-κB, thereby inhibiting oxidative stress responses and inflammatory cascades, which contributes to their organ-protective effects. The emphasis of these components is different: platycodin D exhibits liver and kidney protective effects in vitro and in vivo , and also protects against acute lung injury; flavonoids show notable protective effects against acute liver injury in animal experiments; polysaccharides have confirmed liver protective effects in animal studies; and lobetyolin demonstrates liver and kidney protective potential in both in vitro and in vivo models. However, current research is limited to in vitro and animal studies, with no published clinical data available. Due to the absence of human pharmacokinetic information (such as drug concentration distribution in blood and target tissues), clinical efficacy indicators (such as symptom improvement and pathological changes), and safety evaluations (including adverse event incidence and dose tolerance), it is currently impossible to accurately assess the actual efficacy and potential risks of these components in humans. Therefore, their clinical translational value requires further validation through well-designed, standardized clinical trials.

Combined use of chemotherapeutic drugs

Chinese medicines can significantly enhance sensitivity to chemotherapeutic drugs, enhance tumor suppression and inhibit adverse reactions to chemotherapeutic drugs ( 100 ). Currently, there are more studies on Chinese medicine monomers and their active ingredients, and the combination of Chinese medicine with anti-tumor chemotherapeutic drug treatment can achieve significant tumor inhibition, reduce drug resistance, and improve adverse reactions and patients’ quality of life ( 101 ). Natural compounds frequently exhibit more diverse “Drug like” and “Biological friendliness” characteristics than pure synthetic compounds, and have enormous potential in future drug research and development. The literature consistently demonstrates that the most valuable aspect of the main active ingredients of P. grandiflorum lies in its ability to exert anti-tumor activity and synergistic effects with various anticancer chemotherapy drugs, while virtually having no cytotoxic effects on normal cells, and also having excellent auxiliary properties. P. grandiflorum has low toxicity and side effects, which is a traditional Chinese herbal medicine with similar medicinal and nutritional uses and has great potential for development. For example, platycodin D is widely used in combination therapy and adjuvant therapy to enhance anticancer and adjuvant activity. Huang et al. ( 102 ) found that the synergistic effect of platycodin D and sorafenib inhibited p-AKT, thereby promoting sorafenib induced cell apoptosis and G0/G1 phase cell cycle arrest in the PC3 cell line. In multiple myeloma cell lines, Wu et al. ( 103 ) demonstrated that platycodin D and bortezomib (BTZ) also exhibited this synergistic effect, significantly increasing the apoptosis of NCI-H929 and U266B1 cells. In addition, Tan et al. ( 104 ) found platycodin D and doxorubicin (DOX) worked synergistically to increase cellular uptake of doxorubicin, enhance its inhibitory effect on cell proliferation, and inhibit DOX anti-inflammatory effect in MCF-7 and MDA-MB-231 cells. Lei et al. ( 105 ) discovered that platycodin D, without damaging the membranes of organelles, can promote the escape within the body, thereby reversing the drug resistance of HepG2 cells to chemotherapy drugs. Zhang et al. ( 106 ) observed that the aqueous extract of P. grandifloras and platycodin D can affect the Cyclophosphamide (CTX) pharmacokinetic parameters (delays the absorption process of CTX in the body, reduces the peak concentration, and makes the absorption process more gradual). The combination of P. grandiflorum extract or platycodin D has a reducing-toxicity and enhancing-effect significance on CTX. To sum up, these results indicates that platycodin D may enhance efficacy and reduce toxicity by reversing drug resistance and influencing the pharmacokinetics of chemotherapeutic drugs.

In addition to platycodin D, the combination of some flavonoids in P. grandiflorum with doxorubicin can also alter the pharmacokinetics of doxorubicin in vivo . For instance, the combination of apigenin and doxorubicin can hinder the growth of HepG2 cells, increase the G0/G1 phase arrest of liver cancer cells, and increase the apoptosis of hepatocellular carcinoma ( 107 ). Similarly, Ahmed et al. ( 108 ) found that the combined of luteolin and doxorubicin can enhance the cytotoxicity of breast cancer, inhibit its proliferation and promote apoptosis. Chen et al. ( 109 ) found that luteolin increased the sensitivity of cisplatin induced apoptosis in HepG2 cells by upregulating p-JNK protein expression. Overall, studies have shown that the combination of the active ingredients of P. grandiflorum and anti-tumor chemotherapy drugs (bortezomib, doxorubicin, cisplatin, cyclic adenosine phosphate) performed adequately in promoting the uptake of therapeutic drugs, promoting therapeutic efficacy, and reducing the damage of chemotherapy drugs to normal cells. Therefore, the active ingredients of P. grandiflorum can be used as a synergistic herbal medicine for treating tumors and has broad clinical application potential.

New drug delivery systems anti-tumor-nanotechnology

The natural extracts of P. grandiflorum (such as platycodin D, flavonoids, and polysaccharides) exhibit significant antitumor activity. However, these active components generally suffer from low water solubility, and the amount that enters the bloodstream via traditional administration routes is insufficient—this not only impairs their oral bioavailability but also restricts their clinical application ( 110 ). Therefore, improving the bioavailability of the active components from P. grandiflorum is crucial for the prevention and treatment of cancer. Studies have shown that nanodelivery systems can significantly enhance therapeutic efficacy by prolonging drug circulation time, reducing side effects, improving bioavailability, and achieving tissue targeting ( 111 ). In recently years, the widely studied nanoparticulate drug delivery systems mainly include solid lipid nanoparticles, liposomes, chitosan nanoparticles, polymeric micelles, hydrogels, etc. ( 112 ). The differences in their key properties are determined by carrier materials, structural design, and functional positioning.

Liposomes research is the most extensive, which exhibit advantages such as low toxicity, high targeting ability, high biodegradability, and ease of functionalization. These properties enable them to facilitate the targeted delivery of the drugs they carry, thereby exerting unique advantages in tumor therapy ( 113 ). Among them, Solid lipid nanoparticles (SLNs) have a wide range of applications in drug delivery systems, which can be used to encapsulate drugs and achieve targeted delivery to improve drug efficacy and reduce adverse reactions ( 114 ). Polymer nanoparticles are mainly used for the surface modification of small molecules like RNA and proteins, with the aim of enhancing the targeting ability of antitumor drugs ( 115 ). Hydrogels are composed of hydrophilic polymers and are similar to the extracellular matrix, possessing good biocompatibility. They can be modified through processes that prevent the degradation of biomolecules during delivery while maintaining the sustained release of drugs ( 116 ). Chitosan nanoparticles have good biocompatibility and safety. They are suitable for oral administration, capable of overcoming the intestinal barrier, and exhibit sustained and controlled release properties. Furthermore, they have no restrictions on gene size and are simple to prepare ( 117 ). Currently, Conjugated nanodelivery systems, such as polymer-lipid hybrid nanoparticles (PLHNPs), not only have strong stability and high drug-loading capacity but also possess long circulation time and excellent biodegradability ( 118 ). In addition to the aforementioned organic nanoparticles, inorganic nanoparticles (such as silica, iron oxide, gold nanoparticles, and selenium nanoparticles, etc.) have attracted considerable attention in cancer treatment. They can be used both as carriers for drug delivery and as active pharmaceutical ingredients themselves, exhibiting great potential and safety in the field of medical applications ( 119 ).

Notably, the new drug delivery system has significantly improved the anti-tumor activity of P. grandiflorum extract. Consequently, the integration of P. grandiflorum extract with nanotechnology held considerable promise for the future development of clinical anti-tumor drugs (as shown in Figure 6 ). Firstly, the combination of platycodin D and liposomes nanoparticles becomes an effective drug delivery method and effectively improves drug stability, bioavailability, targeting of platycodin D and prolong its circulating time in vivo . Kim et al. ( 120 ) demonstrated that the combination of platycodin D and liposome nanotechnology enables the delivery of therapeutic cargoes to cells, offers enhanced protection for drugs during the delivery process, and exhibits no hepatotoxicity. In colorectal cancer, we developed platycodin D2 and liposomes as a tumor-targeting therapy. The platycodin D2-liposomes treatment demonstrated a successful tumor-targeting ability in the colorectal cancer xenografts, in which PCD2 not only exerted a potent antitumor effect by inducing apoptotic cell death and but also functioned as a liposome membrane stabilizer ( 121 ). Luteolin, as one of the flavonoids in P. grandiflorum . Cao et al. ( 122 ) developed luteolin-loaded nanoliposomes that target the PG-1 receptor on the surface of liver cancer cells, enhancing drug accumulation at the tumor site. Meanwhile, these nanoliposomes increase the expression of lactate dehydrogenase (LDH), disrupting tumor growth pathways and thereby addressing the compound’s low oral bioavailability. Adel et al. ( 123 ) found that apigenin bound liposomes enhanced the bioavailability and chemical stability of apigenin in breast cancer, thereby enhancing the anti-breast cancer effect. In the xenograft tumor models of human colorectal cancer HCT-15 and HT-2 cells ( 124 ), Apigenin liposomes not only enhance the apoptosis-inducing effect on tumor cells, but also improve the hemocompatibility and cytocompatibility with normal fibroblasts, thereby reducing drug toxicity. In addition to liposome nanoparticles, chitosan nanoparticles (ChNPs) can also introduce chemotherapy drugs into cells, increase their activity, and release encapsulated compounds over time ( 125 ). In liver cancer, Mabrouk et al. ( 126 ) first added apigenin to chitosan to increase its hydrophobicity, and then coated the chitosan surface with folate albumin to increase its stability and bioavailability. Shi et al. ( 127 ) found an oral herbal system-nanoparticle mixture (HNS), which is formed through self-association of P. grandiflorum - Curcuma zedoaria , and combined with lipid-polymer nanoparticles (LPNs). HNS induced cell apoptosis and regulated the expression of MMP-9 and TGF-β1, thereby reducing lung metastasis in 4 T1 tumor-bearing mice and altering the tumor microenvironment. In addition, more and more evidence indicated ( 128 ) that P. grandiflorum polysaccharides can be used as a stabilizer to modify nano-selenium particles, thereby enhancing their stability in solution. The polysaccharide PGP-AE can inhibit gastric cancer cells in vitro , but its anti-tumor effect in vivo is not significant; while PGP90 needs to be combined with nano-selenium to significantly enhance its activity, indicating that nano-modification is crucial for the efficacy of the drug.

P. grandiflorum extract combined with nanoparticles have been widely studied in cancer treatment. In conclusion, platycodin D mainly exerts its effects by combining with liposomes, while flavonoid components mostly enhance antitumor efficacy with the help of solid nanoparticles, liposomes, and chitosan nanocarriers. In addition, polymer-based nano-delivery systems are often combined with polysaccharide components, which can significantly improve anti-cancer activity. It can be seen that nanopharmaceutical delivery systems address issues such as low solubility and poor bioavailability of the active components from P. grandiflorum , significantly optimizing them in vivo pharmacokinetic and pharmacodynamic properties, and providing a feasible technical pathway for the clinical translation of these active components.

Homology of medicine and food: preventive healthcare

Clinical trials

In the past decade, researchers have discovered the new pharmacological potential of platycodin in the treatment of chronic conditions, including hyperlipidemia, hypertension, diabetes and obesity ( 129 ). P. grandiflorum , as a homologous plant of medicine and food, not only exhibits anti-tumor potential, which also plays many important roles in prevention and healthcare ( 15 ). We performed a search using the keywords “ Platycodon grandiflorum ” and “preventive healthcare” to identify relevant clinical trials on the International Clinical Trials Registry Platform 10 (accessed June 12, 2025). The search results indicated ( 130 ) that P. grandiflorum extract (GCWB107) can reduce blood lipids in patients with obesity (trial registration number: NCT04023864 ). Another study discovered ( 131 ) that P. grandiflorum extract can enhance human immune function (trial registration number: KCT0005945). In addition, P. grandiflorum extract mixture also can effectively improve oxidative stress (trial registration number: KCT0007161).

These preliminary trials indicate safety, but efficacy data are limited. In addition, P. grandiflorum oral medicine may have certain potential adverse reactions, with common ones including gastrointestinal discomfort and allergic reactions; high-dose use or long-term administration may also cause liver damage. In terms of drug-nutrient interactions, concurrent use of these preparations with anticoagulant drugs may increase the risk of bleeding, while co-administration with gastrointestinal drugs can affect the absorption of their own active ingredients, resulting in absorption disorders ( 132 ). Therefore, further clinical verification of the efficacy of P. grandiflorum is required. Only through clinical trials can the optimal dosage (suitable for specific populations) and administration method be determined, and its side effects and potential risks be comprehensively evaluated. This process ensures that the drug data are thoroughly validated and comply with research and regulatory standards.

Preventive healthcare product

P. grandiflorum is integrated into daily therapeutic or preventive medicine on the basis of its properties as both a drug and a food. This practice not only improves the edible va lue of P. grandiflorum, but also maximizes the medicinal value of P. grandiflorum . Currently, there are numerous health products containing P. grandiflorum as a primary ingredient in treatments and preventive medications available on the market. A search of the Special Food Information Query Platform 11 (accessed June 22, 2025) of China’s State Administration for Market Regulation reveals that there are currently 11 health products with a “National Food Health Note” on the market. The P. grandiflorum -based health products are recognized not only for their ability to alleviate throat discomfort and enhance laryngeal health but also for their role in boosting immunity, as shown in Table 5 . However, P. grandiflorum preparations still face challenges in regulation and dose standardization. Specifically, natural medicine complex composition—containing saponins, polysaccharides, flavonoids, and other active substances—further exacerbates difficulties in standardization; meanwhile, variations in raw materials (e.g., variety, origin) and dosage forms can cause fluctuations in the content and absorption efficiency of active ingredients, rendering precise dose control difficult ( 133 ). Therefore, to ensure the quality of health products, it is essential to emphasize clinical validation and strengthen regulatory oversight of products classified under “food-medicine homology.

Summary and future prospects

Cancer is a complex malignancy, not only because of its diverse proliferation and metastasis, but also because cancer cells are highly adaptable. Chinese herbal medicines, as natural compounds, often have diverse chemical structures and biological activities, and are widely studied and applied in the prevention and treatment of multiple tumors. Through an analysis of relevant literature and network pharmacological results, this paper showed that the anti-tumor active ingredients of P. grandiflorum include platycodin D, P. grandiflorum polysaccharides, Lobetyolin, luteolin, and apigenin. In this paper, we investigated the mechanism of P. grandiflorum on cell proliferation, cell cycle, and cell migration based on its active components. It has been found that platycodin D mainly hindered cancer cell proliferation and induced cancer cell apoptosis, which is the main mechanism for producing anti-cancer activity. Apigenin mainly inhibited tumor growth, induced endogenous apoptosis and autophagy, and inhibited angiogenesis as the main mechanism for producing anti-cancer activity. Luteolin and Lobetyolin mainly inhibited the growth, migration and invasion of tumor cells, which were the main mechanisms of tumor activity. P. grandiflorum polysaccharides can stimulate the activity of immune cells and macrophages, enhance the functions of T cells and NK cells, thereby improving the body’s immune surveillance and clearance ability against tumors. Additionally, we explored the application of extracts from P. grandiflorum in modern drug development. These extracts can be combined with certain chemotherapy drugs to target tumor tissues based on their anti-tumor effects, ultimately enhancing efficacy while reducing toxicity. With the emergence of new drug delivery systems, the challenges of low utilization and poor solubility of active ingredients in traditional oral Chinese medicine have been extensively studied. Among them, Nano-delivery systems have the advantages of high bioavailability, strong targeting ability, and good sustained release effect, gradually improving the limitations of P. grandiflorum extract anti-tumor applications. Furthermore, as an herbal medicine, P. grandiflorum has a long history of medicinal and edible use. In recently years, P. grandiflorum also plays many important roles in prevention and health care of cancer. However, there is a lack of large-scale, rigorously designed, and well-implemented clinical trials to confirm the anti-cancer properties of P. grandiflorum. With the continued development of research methods and the deepening of the level of research, it is worth looking forward to the application of the active ingredients of P. grandiflorum in the development of clinical drug formulations with anti-tumor effects. Therefore, in the future, we need to strengthen a series of clinical application research based on sufficient basic research, expanding the scope of clinical application from conventional applications to various fields such as cancer, antiviral agents, vaccine adjuvants, etc.

The authors acknowledge any support given which is not covered by the authors’ contribution or funding sections.

1 https://pubmed.ncbi.nlm.nih.gov

2 https://scholar.google.com

3 https://www.sciencedirect.com

4 https://www.webofscience.com

5 https://tcmsp-e.com/

6 https://www.uniprot.org/uniprot/

7 http://swisstargetprediction.ch/

8 https://metascape.org/

9 www.bioinformatics.com.cn

10 https://trialsearch.who.int/

11 http://ypzsx.gsxt.gov.cn/specialfood/#/food

Author contributions

WL: Writing – original draft. SJ: Visualization, Writing – review & editing. XM: Software, Writing – review & editing. DL: Visualization, Writing – review & editing. YD: Writing – review & editing. ZZ: Software, Writing – review & editing. LY: Writing – review & editing. RY: Conceptualization, Writing – review & editing. YN: Conceptualization, Writing – review & editing, Funding acquisition, Supervision.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The authors declare that no Gen AI was used in the creation of this manuscript.

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Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2025.1674705/full#supplementary-material

References

1. Beaumont JEJ Beelen NA Wieten L Rouschop KMA . The immunomodulatory role of hypoxic tumor-derived extracellular vesicles . Cancer . ( 2022 ) 14 : 4001 . doi: 10.3390/cancers14164001 , PMID: 36010994 PMC9406714

2. Lu W Chen T Xiao D Qin X Chen Y Shi S . Application and prospects of nucleic acid nanomaterials in tumor therapy . RSC Adv . ( 2023 ) 13 : 26288 – 301 . doi: 10.1039/D3RA04081J , PMID: 37670995 PMC10476027

3. Zhou Y Farooqi AA Xu B . Comprehensive review on signaling pathways of dietary saponins in cancer cells suppression . Crit Rev Food Sci Nutr . ( 2023 ) 63 : 4325 – 50 . doi: 10.1080/10408398.2021.2000933 , PMID: 34751072

4. Yan Z Lai Z Lin J . Anticancer properties of traditional Chinese medicine . Comb Chem High Throughput Screen . ( 2017 ) 20 : 423 – 9 . doi: 10.2174/1386207320666170116141818 , PMID: 28093974

5. Zhang L Wang Y Yang D Zhang C Zhang N Li M . Platycodon grandiflorus - an ethnopharmacological, phytochemical and pharmacological review . J Ethnopharmacol . ( 2015 ) 164 : 147 – 61 . doi: 10.1016/j.jep.2015.01.052 , PMID: 25666431

6. Ma C-H Gao Z-J Zhang J-J Zhang W Shao J-H Hai M-R . Candidate genes involved in the biosynthesis of triterpenoid Saponins in Platycodon grandiflorum identified by transcriptome analysis . Front Plant Sci . ( 2016 ) 7 : 673 . doi: 10.3389/fpls.2016.00673 , PMID: 27242873 PMC4871891

7. Kim Y-A Oh S-H Lee G-H Hoa PT Jin SW Chung YC . Platycodon grandiflorum -derived saponin attenuates the eccentric exercise-induced muscle damage . Food Chem Toxicol . ( 2018 ) 112 : 150 – 6 . doi: 10.1016/j.fct.2017.12.045 , PMID: 29287792

8. Jiang Tao Z Juxiong LL . Research progress in targeted breeding of medicinal and edible Platycodon grandiflorum . Modern Distance Educ Tradit Chin Med China . ( 2018 ) 16 : 158 – 60 .

9. Lee S Han EH Lim M-K Lee S-H Yu HJ Lim YH . Fermented Platycodon grandiflorum extracts relieve airway inflammation and cough reflex sensitivity in vivo . J Med Food . ( 2020 ) 23 : 1060 – 9 . doi: 10.1089/jmf.2019.4595 , PMID: 32758004

10. Noh E-M Kim J-M Lee HY Song H-K Joung SO Yang HJ . Immuno-enhancement effects of Platycodon grandiflorum extracts in splenocytes and a cyclophosphamide-induced immunosuppressed rat model . BMC Complement Altern Med . ( 2019 ) 19 : 322 . doi: 10.1186/s12906-019-2724-0 , PMID: 31752816 PMC6868875

11. Wang Y Zhang X Wei Z Wang J Zhang Y Shi M . Platycodin D suppressed LPS-induced inflammatory response by activating LXRα in LPS-stimulated primary bovine mammary epithelial cells . Eur J Pharmacol . ( 2017 ) 814 : 138 – 43 . doi: 10.1016/j.ejphar.2017.07.037 , PMID: 28736281

12. Wang B Tu Y Zhao SP Hao YH Liu JX Liu FH . Effect of tea saponins on milk performance, milk fatty acids, and immune function in dairy cow . J Dairy Sci . ( 2017 ) 100 : 8043 – 52 . doi: 10.3168/jds.2016-12425 , PMID: 28755948

13. Kiran A Altaf A Sarwar M Malik A Maqbool T Ali Q . Phytochemical profiling and cytotoxic potential of Arnebia nobilis root extracts against hepatocellular carcinoma using in-vitro and in-silico approaches . Sci Rep . ( 2023 ) 13 : 11376 . doi: 10.1038/s41598-023-38517-8 , PMID: 37452082 PMC10349071

14. Zhang S Chai X Hou G Zhao F Meng Q . Platycodon grandiflorum (Jacq.) a. DC.: a review of phytochemistry, pharmacology, toxicology and traditional use . Phytomedicine . ( 2022 ) 106 : 154422 . doi: 10.1016/j.phymed.2022.154422 , PMID: 36087526

15. Nyakudya E Jeong JH Lee NK Jeong Y-S . Platycosides from the roots of Platycodon grandiflorum and their health benefits . JFN . ( 2014 ) 19 : 59 – 68 . doi: 10.3746/pnf.2014.19.2.059 , PMID: 25054103 PMC4103729

16. Su X Liu Y Han L Wang Z Cao M Wu L . A candidate gene identified in converting platycoside E to platycodin D from Platycodon grandiflorus by transcriptome and main metabolites analysis . Sci Rep . ( 2021 ) 11 : 9810 . doi: 10.1038/s41598-021-89294-1 , PMID: 33963244 PMC8105318

17. Wang Z Wang P Cao H Liu M Kong L Wang H . Genome-wide identification of bZIP transcription factors and their expression analysis in Platycodon grandiflorus under abiotic stress . Front Plant Sci . ( 2024 ) 15 : 1403220 . doi: 10.3389/fpls.2024.1403220 , PMID: 38863542 PMC11165138

18. Wang C Zhang N Wang Z Qi Z Zhu H Zheng B . Nontargeted Metabolomic analysis of four different parts of Platycodon grandiflorum grown in Northeast China . Molecules . ( 2017 ) 22 : 1280 . doi: 10.3390/molecules22081280 , PMID: 28769024 PMC6152411

19. Luo Q Wei G Wu X Tang K Xu M Wu Y . Platycodin D inhibits platelet function and thrombus formation through inducing internalization of platelet glycoprotein receptors . J Transl Med . ( 2018 ) 16 : 311 . doi: 10.1186/s12967-018-1688-z , PMID: 30442147 PMC6238268

20. Guo R Meng Q Wang B Li F . Anti-inflammatory effects of Platycodin D on dextran sulfate sodium (DSS) induced colitis and E. coli lipopolysaccharide (LPS) induced inflammation . Int Immunopharmacol . ( 2021 ) 94 : 107474 . doi: 10.1016/j.intimp.2021.107474 , PMID: 33611056

21. Shuting Z Miaomiao T Zheng X Wei H . The historical evolution, product development, and modern research Progress of Platycodon grandiflorum processing . Specialty Res ( 2023 ): 1 – 7 . doi: 10.16720/j.cnki.tcyj.2023.018

22. Mazol I Gleńsk M Cisowski W . Polyphenolic compounds from Platycodon grandiflorum a . DC Acta Pol Pharm . ( 2004 ) 61 : 203 – 8 . 15481246

23. Huang L Kim M-Y Cho JY . Immunopharmacological activities of Luteolin in chronic diseases . Int J Mol Sci . ( 2023 ) 24 : 2136 . doi: 10.3390/ijms24032136 , PMID: 36768462 PMC9917216

24. Pang D-J Huang C Chen M-L Chen Y-L Fu Y-P Paulsen BS . Characterization of inulin-type Fructan from Platycodon grandiflorus and study on its prebiotic and Immunomodulating activity . Molecules . ( 2019 ) 24 : 1199 . doi: 10.3390/molecules24071199 , PMID: 30934739 PMC6479354

25. Liu Z-J Wang Y-L Li Q-L Yang L . Improved antimelanogenesis and antioxidant effects of polysaccharide from Cuscuta chinensis lam seeds after enzymatic hydrolysis . Braz J Med Biol Res . ( 2018 ) 51 : e7256 . doi: 10.1590/1414-431x20187256 , PMID: 29846408 PMC5995039

26. Jun Z BoBai Y Yang HX . Research progress on chemical components and modern pharmacology of Platycodon grandiflorum . J Liaoning Univ Tradit Chin Med . ( 2019 ) 21 : 113 – 6 . doi: 10.13194/j.issn.1673-842x.2019.01.031

27. Park MJ Ryu HS Kim JS Lee HK Kang JS Yun J . Platycodon grandiflorum polysaccharide induces dendritic cell maturation via TLR4 signaling . Food Chem Toxicol . ( 2014 ) 72 : 212 – 20 . doi: 10.1016/j.fct.2014.07.011 , PMID: 25019244

28. Lee J-Y Yoon J-W Kim C-T Lim S-T . Antioxidant activity of phenylpropanoid esters isolated and identified from Platycodon grandiflorum a. DC . Phytochemistry . ( 2004 ) 65 : 3033 – 9 . doi: 10.1016/j.phytochem.2004.08.030 , PMID: 15504438

29. Xue X Zhao A Wang Y Ren H Su W Li Y . Metabolomics and transcriptomics analyses for characterizing the alkaloid metabolism of Chinese jujube and sour jujube fruits . Front Plant Sci . ( 2023 ) 14 : 1267758 . doi: 10.3389/fpls.2023.1267758 , PMID: 37790781 PMC10544937

30. Shi X Li X Li X He Z Chen X Song J . Antibacterial properties of TMA against Escherichia coli and effect of temperature and storage duration on TMA content, lysozyme activity and content in eggs . Foods . ( 2022 ) 11 : 527 . doi: 10.3390/foods11040527 , PMID: 35206004 PMC8870930

31. Choi YH Yoo DS Cha M-R Choi CW Kim YS Choi S-U . Antiproliferative effects of saponins from the roots of Platycodon grandiflorum on cultured human tumor cells . J Nat Prod . ( 2010 ) 73 : 1863 – 7 . doi: 10.1021/np100496p , PMID: 20939516

32. Singh Tuli H Rath P Chauhan A Sak K Aggarwal D Choudhary R . Luteolin, a potent anticancer compound: from chemistry to cellular interactions and synergetic perspectives . Cancers . ( 2022 ) 14 : 5373 . doi: 10.3390/cancers14215373 , PMID: 36358791 PMC9658186

33. Moslehi M Rezaei S Talebzadeh P Ansari MJ Jawad MA Jalil AT . Apigenin in cancer therapy: prevention of genomic instability and anticancer mechanisms . Clin Exp Pharmacol Physiol . ( 2023 ) 50 : 3 – 18 . doi: 10.1111/1440-1681.13725 , PMID: 36111951

34. Guifeng Z Chuang L Guangdong L Rentang Z . Research Progress on antitumor mechanism and structure-activity relationship of plant polysaccharides . Sci Technol Food Ind . ( 2023 ) 44 : 428 – 37 . doi: 10.13386/j.issn1002-0306.2022050063

35. He W Tao W Zhang F Jie Q He Y Zhu W . Lobetyolin induces apoptosis of colon cancer cells by inhibiting glutamine metabolism . J Cellular Molecular Medi . ( 2020 ) 24 : 3359 – 69 . doi: 10.1111/jcmm.15009 , PMID: 31990147 PMC7131919

36. Juan L . Extract process and quality standard of platycodongrandiflorum extract . [Master’s Thesis]. Heifei: Hefei University ( 2009 ).

37. Ping S Hui X Yanhong H Zerun L Yupeng N Shanshan W . Review of extraction methods and pharmacological effect of chemical components from Platycodon grandiflorum . China Brewing . ( 2022 ) 41 : 18 – 23 .

38. Jingyin G Zibing L Peng Z Yuqing Z Tao Z Tingting B . General situation of research on quality standard of Jiegeng ( Platycodon grandiflorum ) and its processed products . Chin Arch Tradit Chin Med . ( 2024 ) 42 : 151 – 155+287 . doi: 10.13193/j.issn.1673-7717.2024.05.030

39. Wei H Juanmin L Lei G Haiyan F Weiguo S Weidong H . Determination of the content of platycodin D in Platycodon root by HPLC method. Jiangxi . J Tradit Chin Med . ( 2014 ) 45 : 59 – 61 .

40. Kwon J Lee H Kim N Lee J-H Woo MH Kim J . Effect of processing method on platycodin D content in Platycodon grandiflorum roots . Arch Pharm Res . ( 2017 ) 40 : 1087 – 93 . doi: 10.1007/s12272-017-0946-6 , PMID: 28852980

41. Xiujuan Z Xiaoqin C Shaungyin G Jutao W Daiyin P Chuanshan J . Content determination of Luteolin and Apigenin in Platycodon Grandiflorus by high-performance liquid chromatography . J Anhui Univ Chin Med . ( 2013 ) 32 : 73 – 5 .

42. Lizhen Z Zhuang M Xinyue Y Niu S Xing SS Rong W . Optimization of extraction process of Platycodon grandifloras polysaccharide and its Solubilization effect on Platycodin . JShandong Univ Tradit Chin Med . ( 2024 ) 48 : 708 – 16 . doi: 10.16294/j.cnki.1007-659x.2024.06.011

43. Yan Z Jianhe W Juan L Yue J Hongliang J Kun S . Analysis and evaluation of nutritional component of Platycodon grandiflorus in three Main producing areas . Modern Chin Med . ( 2019 ) 21 : 194 – 8 . doi: 10.13313/j.issn.1673-4890.20181017002

44. Xinyue W Weimin W Nan W Ling S Rina W . Research Progress of Platycodon grandiflorum functionality and food development . Food Res Dev . ( 2022 ) 43 : 199 – 206 .

45. Xing Y . Extraction of platycodn D and lobetyolin fromPlatycodon grandifloras and catalytic conversion . [Master’s Thesis]. Northeast Forestry University ( 2023 ).

46. Bao C Xinpei L Xiaohui H Zhiman L Wei L Yinshi S . HPLC method for simultaneous determination of three polyacetylenes in Platycodonis Radix from different habitats. Chinese . J Pharm Anal . ( 2018 ) 38 : 1484 – 9 . doi: 10.16155/j.0254-1793.2018.09.03

47. Yu JS Kim AK . Platycodin D induces apoptosis in MCF-7 human breast Cancer cells . J Med Food . ( 2010 ) 13 : 298 – 305 . doi: 10.1089/jmf.2009.1226 , PMID: 20412017

48. Luo J Manning BD Cantley LC . Targeting the PI3K-Akt pathway in human cancer . Cancer Cell . ( 2003 ) 4 : 257 – 62 . doi: 10.1016/S1535-6108(03)00248-4 , PMID: 14585353

49. Dang CV Lewis BC . Role of oncogenic transcription factor c-Myc in cell cycle regulation, apoptosis and metabolism . J Biomed Sci . ( 1997 ) 4 : 269 – 78 . doi: 10.1007/BF02258350 , PMID: 12386373

50. Khan M Maryam A Zhang H Mehmood T Ma T . Killing cancer with platycodin D through multiple mechanisms . J Cell Mol Med . ( 2016 ) 20 : 389 – 402 . doi: 10.1111/jcmm.12749 , PMID: 26648178 PMC4759477

51. Xu Q Pan G Wang Z Wang L Tang Y Dong J . Platycodin-D exerts its anti-cancer effect by promoting c-Myc protein ubiquitination and degradation in gastric cancer . Front Pharmacol . ( 2023 ) 14 : 1138658 . doi: 10.3389/fphar.2023.1138658 , PMID: 36950011 PMC10025306

52. Liu Y Tian S Yi B Feng Z Chu T Liu J . Platycodin D sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway . Front Oncol . ( 2022 ) 12 : 1046143 . doi: 10.3389/fonc.2022.1046143 , PMID: 36387129 PMC9646952

53. Zhou Y Jin T Gao M Luo Z Mutahir S Shi C . Aqueous extract of Platycodon grandiflorus attenuates lipopolysaccharide-induced apoptosis and inflammatory cell infiltration in mouse lungs by inhibiting PI3K/Akt signaling . Chin Med . ( 2023 ) 18 : 36 . doi: 10.1186/s13020-023-00721-z , PMID: 37016413 PMC10071731

54. Liu J Peng Y Wei W . Cell cycle on the crossroad of tumorigenesis and cancer therapy . Trends Cell Biol . ( 2022 ) 32 : 30 – 44 . doi: 10.1016/j.tcb.2021.07.001 , PMID: 34304958 PMC8688170

55. Zhang H Zhang X Li X Meng W-B Bai Z-T Rui S-Z . Effect of CCNB1 silencing on cell cycle, senescence, and apoptosis through the p53 signaling pathway in pancreatic cancer . J Cell Physiol . ( 2018 ) 234 : 619 – 31 . doi: 10.1002/jcp.26816 , PMID: 30069972

56. Dai P Xiong L Wei Y Wei X Zhou X Zhao J . A pancancer analysis of the oncogenic role of cyclin B1 (CCNB1) in human tumors . Sci Rep . ( 2023 ) 13 : 16226 . doi: 10.1038/s41598-023-42801-y , PMID: 37758792 PMC10533567

57. Lee Y Sung B Kang YJ Kim DH Jang J-Y Hwang SY . Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells . Int J Oncol . ( 2014 ) 44 : 1599 – 606 . doi: 10.3892/ijo.2014.2339 , PMID: 24626522

58. Ujiki MB Ding X-Z Salabat MR Bentrem DJ Golkar L Milam B . Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest . Mol Cancer . ( 2006 ) 5 : 76 . doi: 10.1186/1476-4598-5-76 , PMID: 17196098 PMC1779363

59. Chang X Tamauchi S Yoshida K Yoshihara M Yokoi A Shimizu Y . Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway . Gynecol Oncol . ( 2023 ) 173 : 31 – 40 . doi: 10.1016/j.ygyno.2023.04.003 , PMID: 37075494

60. Kanapathipillai M . Treating p53 mutant aggregation-associated Cancer . Cancers . ( 2018 ) 10 : 154 . doi: 10.3390/cancers10060154 , PMID: 29789497 PMC6025594

61. Chen P Zhang J-Y Sha B-B Ma Y-E Hu T Ma Y-C . Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450 . Oncotarget . ( 2017 ) 8 : 27471 – 80 . doi: 10.18632/oncotarget.15832 , PMID: 28460467 PMC5432349

62. He J-Q Zheng M-X Ying H-Z Zhong Y-S Zhang H-H Xu M . PRP1, a heteropolysaccharide from Platycodonis Radix, induced apoptosis of HepG2 cells via regulating miR-21-mediated PI3K/AKT pathway . Int J Biol Macromol . ( 2020 ) 158 : 542 – 51 . doi: 10.1016/j.ijbiomac.2020.04.193 , PMID: 32380108

63. Yanwei C Yijiong Y . Mechanisms of polysaccharides of radix platycodonis in the proliferation and apoptosis of liver cancer cells via LINC01554 . Chin J Cell Stem Cell . ( 2022 ) 12 : 14 – 8 .

64. Li XG Gao S Yang WS Sun S . Investigation of the inhibitory effect of Platycodin D in human transitional cell carcinoma cell line 5637 . Folia Biol . ( 2021 ) 67 : 37 – 47 . doi: 10.14712/fb2021067010037 , PMID: 34273265

65. Zeng C-C Zhang C Yao J-H Lai S-H Han B-J Li W . Platycodin D induced apoptosis and autophagy in PC-12 cells through mitochondrial dysfunction pathway . Spectrochim Acta A Mol Biomol Spectrosc . ( 2016 ) 168 : 199 – 205 . doi: 10.1016/j.saa.2016.06.005 , PMID: 27294548

66. Zhang X Zhai T Hei Z Zhou D Jin L Han C . Effects of Platycodin D on apoptosis, migration, invasion and cell cycle arrest of gallbladder cancer cells . Oncol Lett . ( 2020 ) 20 : 1 . doi: 10.3892/ol.2020.12174 , PMID: 33093920 PMC7573877

67. Zhou R Lu Z Liu K Guo J Liu J Zhou Y . Platycodin D induces tumor growth arrest by activating FOXO3a expression in prostate cancer in vitro and in vivo . Curr Cancer Drug Targets . ( 2015 ) 14 : 860 – 71 . doi: 10.2174/1568009614666141128104642 , PMID: 25431082 PMC4997962

68. Seo Y-S Kang O-H Kong R Zhou T Kim S-A Ryu S . Polygalacin D induces apoptosis and cell cycle arrest via the PI3K/Akt pathway in non-small cell lung cancer . Oncol Rep . ( 2018 ) 39 : 1702 – 10 . doi: 10.3892/or.2018.6230 , PMID: 29393481

69. Yajie D Feng L Zhaoyan LI Yan X Nida C Guangao Z . Efficacy of luteolin on the human gastric cancer cell line MKN45 and underlying mechanism . J Tradit Chin Med . ( 2023 ) 43 : 34 – 41 . doi: 10.19852/j.cnki.jtcm.2023.01.005 36639993 PMC9924784

70. Youhua W Xiaohong A Dai Wenxiang W Xiaoping TS Hao J . Apigenin induces apoptosis in human liver cancer cells by upregulating PTEN protein expression . China J Modern Med . ( 2009 ) 19 : 1793 – 6 .

71. Sun Yue Y Kun YW . Apigenin induces autophagy in gastric cancer SGC-7901 cells and its effect on apoptosis . CarcinogenesisDistortionMutation . ( 2017 ) 29 : 289-294+299 .

72. Wenzong L Yali Y Guangfeng J Chen Z . Anti-tumor activity of polysaccharides isolated from Radix platycodonis . Northwest Pharm J . ( 2013 ) 28 : 43 – 5 .

73. Wang J Lei L . The effects of Radix platycodonis polysaccharide on tumor growth and immune function in S180 tumor-bearing mice . Current Immunol . ( 2021 ) 41 : 462 – 7 .

74. Hanahan D Weinberg RA . Hallmarks of cancer: the next generation . Cell . ( 2011 ) 144 : 646 – 74 . doi: 10.1016/j.cell.2011.02.013 , PMID: 21376230

75. Lee KJ Kim JY Choi JH Kim HG Chung YC Roh SH . Inhibition of tumor invasion and metastasis by aqueous extract of the radix of Platycodon grandiflorum . Food Chem Toxicol . ( 2006 ) 44 : 1890 – 6 . doi: 10.1016/j.fct.2006.06.009 , PMID: 16890340

76. Zhang Z Zhao M Zheng W Liu Y . Platycodin D, a triterpenoid saponin from Platycodon grandiflorum , suppresses the growth and invasion of human oral squamous cell carcinoma cells via the NF-κB pathway . J Biochem Mol Toxicol . ( 2017 ) 31 :9. doi: 10.1002/jbt.21934 28548219

77. Lu Z Song W Zhang Y Wu C Zhu M Wang H . Combined anti-Cancer effects of Platycodin D and Sorafenib on androgen-independent and PTEN-deficient prostate Cancer . Front Oncol . ( 2021 ) 11 : 648985 . doi: 10.3389/fonc.2021.648985 , PMID: 34026624 PMC8138035

78. Li T Xu W-S Wu G-S Chen X-P Wang Y-T Lu J-J . Platycodin D induces apoptosis, and inhibits adhesion, migration and invasion in HepG2 hepatocellular carcinoma cells . Asian Pac J Cancer Prev . ( 2014 ) 15 : 1745 – 9 . doi: 10.7314/apjcp.2014.15.4.1745 , PMID: 24641402

79. Huang X Dai S Dai J Xiao Y Bai Y Chen B . Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial-mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells . Onco Targets Ther . ( 2015 ) 8 : 2989 – 3001 . doi: 10.2147/OTT.S91511 26527884 PMC4621199

80. Zang M Hu L Fan Z Wang H Zhu Z Cao S . Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the notch signaling pathway . J Transl Med . ( 2017 ) 15 : 52 . doi: 10.1186/s12967-017-1151-6 , PMID: 28241766 PMC5327575

81. Jiang J Zhu F Zhang H Sun T Fu F Chen X . Luteolin suppresses the growth of colon cancer cells by inhibiting the IL-6/STAT3 signaling pathway . J Gastrointest Oncol . ( 2022 ) 13 : 1722 – 32 . doi: 10.21037/jgo-22-507 , PMID: 36092354 PMC9459197

82. Lin H-W Shen T-J Yang N-C Wang M Hsieh W-C Chuang C-J . Luteolin reduces aqueous extract PM2.5-induced metastatic activity in H460 lung Cancer cells . Int J Med Sci . ( 2022 ) 19 : 1502 – 9 . doi: 10.7150/ijms.73947 , PMID: 36185331 PMC9515691

83. Zhang J Li Y Li Y Li Y Gong X Zhou L . Structure, selenization modification, and antitumor activity of a glucomannan from Platycodon grandiflorum . Int J Biol Macromol . ( 2022 ) 220 : 1345 – 55 . doi: 10.1016/j.ijbiomac.2022.09.029 , PMID: 36087750

84. Heydarzadeh S Moshtaghie AA Daneshpour M Hedayati M . The effect of Apigenin on Glycometabolism and cell death in an anaplastic thyroid cancer cell line . Toxicol Appl Pharmacol . ( 2023 ) 475 : 116626 . doi: 10.1016/j.taap.2023.116626 , PMID: 37437745

85. Li J Ma A Lan W Liu Q . Platycodon D-induced A549 cell apoptosis through RRM1-regulated p53/VEGF/MMP2 pathway . ACAMC . ( 2022 ) 22 : 2458 – 67 . doi: 10.2174/1871520622666220128095355 , PMID: 35088678

86. Ma J Pan Z Du H Chen X Zhu X Hao W . Luteolin induces apoptosis by impairing mitochondrial function and targeting the intrinsic apoptosis pathway in gastric cancer cells . Oncol Lett . ( 2023 ) 26 : 327 . doi: 10.3892/ol.2023.13913 , PMID: 37415631 PMC10320424

87. Liu Z Qin G Yang J Wang W Zhang W Lu B . Targeting mitochondrial degradation by chimeric autophagy-tethering compounds . Chem Sci . ( 2023 ) 14 : 11192 – 202 . doi: 10.1039/d3sc03600f , PMID: 37860639 PMC10583747

88. Lee SJ Choi Y-J Kim HI Moon HE Paek SH Kim TY . Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation . Mol Oncol . ( 2022 ) 16 : 250 – 68 . doi: 10.1002/1878-0261.12966 , PMID: 33931944 PMC8732342

89. El-Baba C Baassiri A Kiriako G Dia B Fadlallah S Moodad S . Terpenoids’ anti-cancer effects: focus on autophagy . Apoptosis . ( 2021 ) 26 : 491 – 511 . doi: 10.1007/s10495-021-01684-y , PMID: 34269920

90. Zhao R Chen M Jiang Z Zhao F Xi B Zhang X . Platycodin-D induced autophagy in non-small cell lung Cancer cells via PI3K/Akt/mTOR and MAPK signaling pathways . J Cancer . ( 2015 ) 6 : 623 – 31 . doi: 10.7150/jca.11291 , PMID: 26078792 PMC4466411

91. Li T Xu X Tang Z Wang Y Leung C Ma D . Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells . Acta Pharmacol Sin . ( 2015 ) 36 : 1503 – 13 . doi: 10.1038/aps.2015.99 , PMID: 26592509 PMC4816242

92. Cao Z Zhang H Cai X Fang W Chai D Wen Y . Luteolin promotes cell apoptosis by inducing autophagy in hepatocellular carcinoma . Cell Physiol Biochem . ( 2017 ) 43 : 1803 – 12 . doi: 10.1159/000484066 , PMID: 29049999

93. 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 : 13455 . doi: 10.3390/ijms222413455 , PMID: 34948250 PMC8706813

94. Kim SR Park EJ Dusabimana T Je J Jeong K Yun SP . Platycodon grandiflorus fermented extracts attenuate endotoxin-induced acute liver injury in mice . Nutrients . ( 2020 ) 12 : 2802 . doi: 10.3390/nu12092802 , PMID: 32933130 PMC7551015

95. Al-Amarat W Abukhalil MH Alruhaimi RS Alqhtani HA Aldawood N Alfwuaires MA . Upregulation of Nrf2/HO-1 signaling and attenuation of oxidative stress, inflammation, and cell death mediate the protective effect of Apigenin against cyclophosphamide hepatotoxicity . Meta . ( 2022 ) 12 : 648 . doi: 10.3390/metabo12070648 , PMID: 35888772 PMC9322057

96. Lanzhi H Yakun M HanYanzhonbg ZZ Pin Y Xiuxiu S Xiaohai X . The protective effect of luteolin on acetaminophen induced L02 liver cell injury . Chin J Chin Mater Med . ( 2016 ) 41 : 4234 – 9 . 10.4268/cjcmm20162224 28933094

97. Wei H Guoqing L Ji Z Xiaofeng Z . Hypoglycemic effect of nano-selenium/ Platycodon polysaccharides complex . Stud Trace Elements Health . ( 2019 ) 36 : 1 – 4 .

98. Liu Y Dong Y Shen W Du J Sun Q Yang Y . Platycodon grandiflorus polysaccharide regulates colonic immunity through mesenteric lymphatic circulation to attenuate ulcerative colitis . Chin J Nat Med . ( 2023 ) 21 : 263 – 78 . doi: 10.1016/S1875-5364(23)60435-2 , PMID: 37120245

99. Hou Y Qi S Leng J Shen Q Tang S Zhang J . Lobetyolin, a Q-marker isolated from Radix Platycodi, exerts protective effects on cisplatin-induced cytotoxicity in HEK293 cells . J Nat Med . ( 2023 ) 77 : 721 – 34 . doi: 10.1007/s11418-023-01714-w , PMID: 37353674

100. Ren N Yu L Qian L Ye G Zhu Z Yu J . Exploring the pharmacological mechanism of the effective Chinese medicines against gynecological Cancer based on Meta-analysis combined with network pharmacology analysis . Front Oncol . ( 2022 ) 12 : 817772 . doi: 10.3389/fonc.2022.817772 , PMID: 35875080 PMC9298573

101. Yang Y Yuan L Liu W Lu D Meng F Yang Y . Banxia-Shengjiang drug pair inhibits gastric cancer development and progression by improving body immunity . Medicine . ( 2024 ) 103 : e36303 . doi: 10.1097/MD.0000000000036303 , PMID: 38457601 PMC10919495

102. Huang M-Y Jiang X-M Xu Y-L Yuan L-W Chen Y-C Cui G . Platycodin d triggers the extracellular release of programed death Ligand-1 in lung cancer cells . Food Chem Toxicol . ( 2019 ) 131 : 110537 . doi: 10.1016/j.fct.2019.05.045 , PMID: 31150782

103. Wu D Zhang W Chen Y Ma H Wang M . Platycodin D inhibits proliferation, migration and induces chemosensitization through inactivation of the NF-κB and JAK2/STAT3 pathways in multiple myeloma cells . Clin Exp Pharmacol Physiol . ( 2019 ) 46 : 1194 – 200 . doi: 10.1111/1440-1681.13145 , PMID: 31347196

104. Tang Z-H Li T Gao H-W Sun W Chen X-P Wang Y-T . Platycodin D from Platycodonis Radix enhances the anti-proliferative effects of doxorubicin on breast cancer MCF-7 and MDA-MB-231 cells . Chin Med . ( 2014 ) 9 : 16 . doi: 10.1186/1749-8546-9-16 , PMID: 24982689 PMC4075934

105. Zhe Z Jiarao L Xiaoyong C Libing R Ling L Genyun T . Research progress on the mechanism of Saponin compounds in anti-liver cancer . Central Southern Pharm . ( 2023 ) 21 : 1307 – 14 .

106. Weibin Z Dancai F Zhang Min Y Wanlin DX Shuhui X Shigu D . The effect of the aqueous extract of Platycodon grandiflorum and its main component Platycodin D on the pharmacokinetics of cyclophosphamide . J Chin Med Mater . ( 2016 ) 39 : 2633 – 5 . doi: 10.13863/j.issn1001-4454.2016.11.049

107. Jinlin D Wanting D Zhao Jiao J Aixia LQ . The effect of apigenin combined with doxorubicin on the proliferation, apoptosis, and cell cycle of HepG2 liver cancer cells . Acta Chin Med Pharmacol . ( 2021 ) 49 : 31 – 4 . doi: 10.19664/j.cnki.1002-2392.210107

108. Ahmed S Khan H Fratantonio D Hasan MM Sharifi S Fathi N . Apoptosis induced by luteolin in breast cancer: mechanistic and therapeutic perspectives . Phytomedicine . ( 2019 ) 59 : 152883 . doi: 10.1016/j.phymed.2019.152883 , PMID: 30986716

109. Sihan C Dedong Z Liyun F . Sensitization effect and mechanism of luteolin on cisplatin induced apoptosis of HepG2 cells in liver cancer . Chin J Clin Pharmacol . ( 2018 ) 34 : 1637 – 40 . doi: 10.13699/j.cnki.1001-6821.2018.14.015

110. Thilakarathna SH Rupasinghe HPV . Flavonoid bioavailability and attempts for bioavailability enhancement . Nutrients . ( 2013 ) 5 : 3367 – 87 . doi: 10.3390/nu5093367 , PMID: 23989753 PMC3798909

111. Yu B Tai HC Xue W Lee LJ Lee RJ . Receptor-targeted nanocarriers for therapeutic delivery to cancer . Mol Membr Biol . ( 2010 ) 27 : 286 – 98 . doi: 10.3109/09687688.2010.521200 , PMID: 21028937 PMC3789246

112. Olajubutu O Ogundipe OD Adebayo A Adesina SK . Drug delivery strategies for the treatment of pancreatic Cancer . Pharmaceutics . ( 2023 ) 15 : 1318 . doi: 10.3390/pharmaceutics15051318 , PMID: 37242560 PMC10222836

113. Nsairat H Khater D Sayed U Odeh F Al Bawab A Alshaer W . Liposomes: structure, composition, types, and clinical applications . Heliyon . ( 2022 ) 8 : e09394 . doi: 10.1016/j.heliyon.2022.e09394 , PMID: 35600452 PMC9118483

114. Kang C Wang J Li R Gong J Wang K Wang Y . Smart targeted delivery Systems for Enhancing Antitumor Therapy of active ingredients in traditional Chinese medicine . Molecules . ( 2023 ) 28 : 5955 . doi: 10.3390/molecules28165955 , PMID: 37630208 PMC10459615

115. Sun Y Li B Cao Q Liu T Li J . Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment . Stem Cell Res Ther . ( 2022 ) 13 : 489 . doi: 10.1186/s13287-022-03180-9 , PMID: 36182897 PMC9526954

116. Skopinska-Wisniewska J De La Flor S Kozlowska J . From supramolecular hydrogels to multifunctional carriers for biologically active substances . IJMS . ( 2021 ) 22 : 7402 . doi: 10.3390/ijms22147402 , PMID: 34299020 PMC8307912

117. Wang Z Wu G Yang Z Li X Feng Z Zhao Y . Chitosan/hyaluronic acid/MicroRNA-21 nanoparticle-coated smooth titanium surfaces promote the functionality of human gingival fibroblasts . IJN . ( 2022 ) 17 : 3793 – 807 . doi: 10.2147/IJN.S375180 , PMID: 36072958 PMC9444039

118. Mohanty A Uthaman S Park I-K . Utilization of polymer-lipid hybrid nanoparticles for targeted anti-Cancer therapy . Molecules . ( 2020 ) 25 : 4377 . doi: 10.3390/molecules25194377 , PMID: 32977707 PMC7582728

119. Xiang J Zhao R Wang B Sun X Guo X Tan S . Advanced Nano-carriers for anti-tumor drug loading . Front Oncol . ( 2021 ) 11 : 758143 . doi: 10.3389/fonc.2021.758143 , PMID: 34604097 PMC8481913

120. Kim J Gao C Guo P Sheng J Wang J . A novel approach to alleviate acetaminophen-induced hepatotoxicity with hybrid balloon flower root-derived exosome-like nanoparticles (BDEs) with silymarin via inhibition of hepatocyte MAPK pathway and apoptosis . Cell Commun Signal . ( 2024 ) 22 : 334 . doi: 10.1186/s12964-024-01700-z , PMID: 38890646 PMC11184736

121. Cho E Mun S-J Jeon M Kim HK Baek H Ham YS . Tumor-targeted liposomes with platycodin D2 promote apoptosis in colorectal cancer . Mater Today Bio . ( 2023 ) 22 : 100745 . doi: 10.1016/j.mtbio.2023.100745 , PMID: 37576871 PMC10415802

122. Cao X Wang B . Targeted PD-L1 PLGA/liposomes-mediated luteolin therapy for effective liver cancer cell treatment . J Biomater Appl . ( 2021 ) 36 : 843 – 50 . doi: 10.1177/08853282211017701 , PMID: 34000859

123. Adel M Zahmatkeshan M Akbarzadeh A Rabiee N Ahmadi S Keyhanvar P . Chemotherapeutic effects of Apigenin in breast cancer: preclinical evidence and molecular mechanisms; enhanced bioavailability by nanoparticles . Biotechnol Rep (Amst) . ( 2022 ) 34 : e00730 . doi: 10.1016/j.btre.2022.e00730 , PMID: 35686000 PMC9171451

124. 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 . doi: 10.1016/j.jcis.2016.12.025 , PMID: 28012918

125. Elsayed AM Sherif NM Hassan NS Althobaiti F Hanafy NAN Sahyon HA . Novel quercetin encapsulated chitosan functionalized copper oxide nanoparticles as anti-breast cancer agent via regulating p53 in rat model . Int J Biol Macromol . ( 2021 ) 185 : 134 – 52 . doi: 10.1016/j.ijbiomac.2021.06.085 , PMID: 34147524

126. Mabrouk Zayed MM Sahyon HA Hanafy NAN El-Kemary MA . The effect of encapsulated Apigenin nanoparticles on HePG-2 cells through regulation of P53 . Pharmaceutics . ( 2022 ) 14 : 1160 . doi: 10.3390/pharmaceutics14061160 , PMID: 35745733 PMC9228521

127. Shi J Zhang R Wang Y Sun Y Gu X An Y . Herb–nanoparticle hybrid system for improved Oral delivery efficiency to alleviate breast Cancer lung metastasis . IJN . ( 2024 ) 19 : 7927 – 44 . doi: 10.2147/IJN.S463657 39114181 PMC11304439

128. Xiaodan D . The structural characteristics、SeleniumNanoparticles modification and antitumor activity of Platycodon Grandiflorus polysaccharides . [PhD Thesis]. Tianjin: Tianjin University of Science and Technology ( 2022 ).

129. Han L-K Kimura Y Okuda H Xu B-J Zheng Y . Platycodi Radix affects lipid metabolism in mice with high fat diet–induced obesity . J Nutr . ( 2000 ) 130 : 2760 – 4 . doi: 10.1093/jn/130.11.2760 11053518

130. Kim YJ Kwon E-Y Kim J-W Lee Y Ryu R Yun J . Intervention study on the efficacy and safety of Platycodon grandiflorus ethanol extract in overweight or moderately obese adults: a single-center, randomized, double-blind, placebo-controlled trial . Nutrients . ( 2019 ) 11 : 2445 . doi: 10.3390/nu11102445 , PMID: 31615016 PMC6836286

131. Park E-J Jung AJ Lee S-H Kang S-K Lee H-J . An 8-week randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of red Platycodon grandiflorus root extract on enhancement of immune function . Phytomedicine . ( 2021 ) 93 : 153811 . doi: 10.1016/j.phymed.2021.153811 , PMID: 34735908

132. Joint committee for guideline revision. 2016 Chinese guidelines for the management of dyslipidemia in adults . J Geriatr Cardiol . ( 2018 ) 15 : 1 – 29 . doi: 10.11909/j.issn.1671-5411.2018.01.011 29434622 PMC5803534

133. Zhang H Wang Y Mehmood K Chang Y-F Tang Z Li Y . Treatment of tibial dyschondroplasia with traditional Chinese medicines: “lesson and future directions” . Poult Sci . ( 2020 ) 99 : 6422 – 33 . doi: 10.1016/j.psj.2020.08.055 , PMID: 33248557 PMC7704743

134. Lee K . Protective effect of saponins derived from roots of Platycodon grandiflorum on tert-butyl hydroperoxide-induced oxidative hepatotoxicity . Toxicol Lett . ( 2004 ) 147 : 271 – 82 . doi: 10.1016/j.toxlet.2003.12.002 , PMID: 15104119

135. Zhang L Wang X Zhang J Liu D Bai G . Ethnopharmacology, phytochemistry, pharmacology and product application of Platycodon grandiflorum : a review . Chin Herbal Med . ( 2024 ) 16 : 327 – 43 . doi: 10.1016/j.chmed.2024.01.005 , PMID: 39072195 PMC11283231

136. Yin H Chunlei S Moxaing L Hongyan Y . Determination of 8 platycodins in platycodon cut crude drug by HPLC-ELSD method . J Yangzhou Univ . ( 2008 ) 11 : 41 – 4 . doi: 10.19411/j.1007-824x.2008.04.011

137. Xing Y . Study on the extraction and catalytic conversion process of Isabelline Saponin D and Codonanolide from Platycodon grandiflorum . Northeast For Univ . ( 2023 ). doi: 10.27009/d.cnki.gdblu.2023.001038

138. Xiulin Z . Research progress in chemical constituents, biological activities and exploration utilization of Platycodon grandiflorum . China Condiment . ( 2012 ) 37 : 5-8+24

139. Sun Xiaowen D Xianjun XF Che X Kejian L . Research Progress on the preparation and biological activity of Platycodon grandiflorum polysaccharides . Modern Food Sci Technol . ( 2024 ) 40 : 338 – 45 . doi: 10.13982/j.mfst.1673-9078.2024.2.0021

140. Qingfen Z Zhanjun L Xiaoxue L Siquan S Jiao L Fengjian Y . Research on the process of extracting PD from Platycodon by homogenization combined with ultrasound-microwave synergistic extraction . For Eng . ( 2022 ) 38 : 110 – 20 .

141. Hsu W-C Ramesh S Shibu MA Chen M-C Wang T-F Day CH . Platycodin D reverses histone deacetylase inhibitor resistance in hepatocellular carcinoma cells by repressing ERK1/2-mediated cofilin-1 phosphorylation . Phytomedicine . ( 2021 ) 82 : 153442 . doi: 10.1016/j.phymed.2020.153442 , PMID: 33412494

142. Hnit SST Yao M Xie C Bi L Wong M Liu T . Apigenin impedes cell cycle progression at G2 phase in prostate cancer cells . Discov Oncol . ( 2022 ) 13 : 44 . doi: 10.1007/s12672-022-00505-1 , PMID: 35670862 PMC9174405

143. Liu X Zhao T Shi Z Hu C Li Q Sun C . Synergism Antiproliferative effects of Apigenin and Naringenin in NSCLC cells . Molecules . ( 2023 ) 28 : 4947 . doi: 10.3390/molecules28134947 , PMID: 37446609 PMC10343727

144. Zhu J Han M Yang Y Feng R Hu Y Wang Y . Exploring the mechanism of Brucea javanica against ovarian cancer based on network pharmacology and the influence of luteolin on the PI3K/AKT pathway . Comb Chem High Throughput Screen . ( 2023 ). doi: 10.2174/1386207326666230627114111 37366364

145. Zheng H Zhu X Gong E Lv Y Li Y Cai X . Luteolin suppresses lung cancer progression through targeting the circ_0000190/miR-130a-3p/notch-1 signaling pathway . J Chemother . ( 2023 ) 35 : 330 – 42 . doi: 10.1080/1120009X.2022.2102303 , PMID: 35943044

146. Wenzong L Fan G Rui G Chen Z Guangfeng J . Optimization of polysaccharide extracting Technology of Platycodon Grandiflorus with response surface method and its anti-Cancer capacity . J Xi’an Technol Univ . ( 2015 ) 35 : 534 – 9 . doi: 10.16185/j.jxatu.edu.cn.2015.07.004

147. Cheng L Zhai H Du J Zhang G Shi G . Lobetyolin inhibits cell proliferation and induces cell apoptosis by downregulating ASCT2 in gastric cancer . Cytotechnology . ( 2023 ) 75 : 435 – 48 . doi: 10.1007/s10616-023-00588-w , PMID: 37655270 PMC10465467

148. Liu L Liu Z Yang L Wu X Zhu J Liu L . Lobetyolin suppressed lung cancer in a mouse model by inhibiting epithelial-mesenchymal transition . Eur J Histochem . ( 2022 ) 66 : 66 . doi: 10.4081/ejh.2022.3423 , PMID: 35785916 PMC9294612

149. Li W Liu Y Wang Z Han Y Tian Y-H Zhang G-S . Platycodin D isolated from the aerial parts of Platycodon grandiflorum protects alcohol-induced liver injury in mice . Food Funct . ( 2015 ) 6 : 1418 – 27 . doi: 10.1039/c5fo00094g , PMID: 25927324

150. Hu J-N Leng J Shen Q Liu Y Li X-D Wang S-H . Platycodin D suppresses cisplatin-induced cytotoxicity by suppressing ROS-mediated oxidative damage, apoptosis, and inflammation in HEK-293 cells . J Biochem Mol Toxicol . ( 2021 ) 35 : e22624 . doi: 10.1002/jbt.22624 , PMID: 32881195

151. Tao W Su Q Wang H Guo S Chen Y Duan J . Platycodin d attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro . Int Immunopharmacol . ( 2015 ) 27 : 138 – 47 . doi: 10.1016/j.intimp.2015.05.005 , PMID: 25981110

152. Wei H Liyan H Yunjie Z Xiaofeng Z Guiseng L Xiang P . Protective effects of nano-selenium/platycodon polysaccharides complex on CCl4-induced liver damage in mice . Sci Technol Food Ind . ( 2018 ) 39 : 308-311+317 . doi: 10.13386/j.issn1002-0306.2018.01.056

153. Chen Z Su Y Ding J He J Lai L Song Y . Lobetyolin protects mice against LPS-induced sepsis by downregulating the production of inflammatory cytokines in macrophage . Front Pharmacol . ( 2024 ) 15 : 15 . doi: 10.3389/fphar.2024.1405163 , PMID: 38799158 PMC11116692