Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.

Introduction

Reactive oxygen species (ROS) are an array of byproducts produced in cells through aerobic cellular metabolism that play a stimulatory role in multiple crucial signaling pathways in cells via alterations in intra- and extracellular environmental conditions. 1 The ROS include nitric oxide (NO•), hydrogen peroxide (H 2 O 2 ), superoxide anion (O 2 • − ), hydroxyl radical (OH•), and organic peroxides that act as secondary messengers in many signaling mechanisms and are responsible for cell proliferation and differentiation. 1 An imbalance between ROS production and antioxidant scavenging disrupts redox homeostasis, contributing to cancer onset and progression by causing genetic mutations, DNA damage, genomic instability, and altered cellular metabolism. 2 Elevated ROS levels result in overactivation of key signaling pathways such as extracellular-regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK), and phosphatidyl inositol 3 kinases (PI3Ks), which are crucial for regulating cell survival and propagation. 3

On the other hand, an excessive amount of ROS may promote cellular damage, leading to cell death by regulating certain signaling cascades. 4 This cell death signaling process involves the activation of different signaling cascades such as apoptosis signal-regulating kinase 1 (ASK1), poly (ADP-ribose) polymerase (PARP), and autophagy-related (ATG) 4 (ATG4) by ROS. 5 Thus, the two-edged trait of ROS allows for the exertion of survival or death of cancer cells based on the intracellular levels of ROS. 6

Manipulating ROS levels represents a promising therapeutic strategy involving the use of antioxidants, pro-oxidants, targeted ROS signaling inhibitors, combination therapies, and personalized approaches guided by ROS signatures. 7 However, challenges remain, including achieving selectivity, determining optimal ROS thresholds, distinguishing ROS levels in healthy versus cancer cells, and bridging preclinical and clinical studies. Therefore, as an emerging research frontier, advancing redox-based cancer therapies requires a deep understanding of how aberrant redox states modulate signaling pathways that can both promote and inhibit tumor growth.

While many studies have focused on the mechanisms of ROS in cancer pathogenesis and ROS-modulating therapies, 6 , 7 this review stands out by comprehensively examining the complex roles of ROS in cancer biology, exploring diverse signaling pathways and how ROS modulate them in cell survival and cell death, and offering detailed insights into therapeutic interventions guided by ROS pathogenesis and addressing challenges in cancer treatment.

Insights into ROS

ROS are a collective term for a group of molecules derived from molecular oxygen, which are formed through redox reactions or electronic excitation that play a role in cellular signaling; however, when produced imbalanced, they can cause oxidative stress that damages cellular structures like lipids, proteins, and DNA. 7 They can be classified into nonradical and free-radical species, with the latter having at least one unpaired electron. 8 Among nonradical ROS, H 2 O 2 is produced mainly by NADPH oxidases (NOX) and other enzymes and functions as a two-electron oxidant in redox signaling, with selective reactivity toward certain protein cysteines. 9 Organic hydroperoxides (ROOHs) result from both enzymatic and nonenzymatic lipid peroxidation, contributing to cell signaling and cell death via ferroptosis. 10 Singlet oxygen ( 1 O 2 ) is an electronically excited form of O 2 generated through photoexcitation or enzyme reactions, especially in light-exposed tissues. 11 O 2 • − is a prominent ROS that is dismutated into H 2 O 2 , participating in various redox reactions, notably influencing lipid peroxidation and nitric oxide interactions. 12 OH•, recognized as the most reactive ROS, is generated through Fenton chemistry and plays a critical role in initiating lipid peroxidation. 12 Peroxyl radicals (ROO•) are significant in propagating lipid peroxidation chain reactions, whereas alkoxyl radicals (RO•) act as intermediates in the degradation of lipids. 13 Each of these radicals contributes to cellular damage and oxidative stress through their highly reactive nature and involvement in complex biochemical processes, but in cancer, the O 2 • − , H 2 O 2 , OH•, and ROO• play major roles. 14 O 2 • − is involved in the early stages of oxidative stress and can generate more reactive species, such as H 2 O 2 , which contributes to cancer by inducing genetic mutations and chronic inflammation. 12 OH• causes significant damage to DNA, lipids, and proteins, playing a major role in initiating lipid peroxidation and cancer development. 6 H 2 O 2 diffuses through membranes, disrupting signaling pathways, and promoting oxidative damage, with elevated H 2 O 2 levels linked to increased cancer risk. 6 ROO• propagates lipid peroxidation, leading to cellular damage and contributing to cancer. 13

ROS from a historical perspective

Oxygen is highly reactive and can form several types of ROS through both endogenous and exogenous factors. Among these, H 2 O 2 was first discovered by Louis Jacques Thénard in 1818 in redox chemistry, although its role in biology was not fully understood until 1954. 15

In 1900, catalase was recognized as a key enzyme in breaking down H 2 O 2 , marking an early discovery in antioxidant research. 16 Selenium, identified as a toxic catalyst in 1817, was later found to be an essential component of the glutathione peroxidase (GPX) family, with GPX1 becoming widely accepted as a novel peroxidase in 1957. 17 Thioredoxin reductase (TRXR), discovered in 1964, and peroxiredoxin (PRDX), discovered in 1968, were also noted as key components of antioxidant systems regulating cell responses to stress. 18

That the enzyme NOX was linked to H 2 O 2 production in phagocytes was disclosed in 1964, 17 following earlier discoveries of superoxide radicals by Sbarra and Karnowski in 1959. 19 Studies by Babior in 1973 confirmed O 2 • − as the primary product of respiratory bursts, with H 2 O 2 originating from its metabolism. 17 McCord and Fridovich’s 1969 discovery of superoxide dismutase (SOD) showed that O 2 • − could be converted to H 2 O 2 . 20 The mitochondrial electron transport chain (ETC) was identified as a source of H 2 O 2 in 1967, with Loschen in 1974 confirming that O 2 • − is the precursor in mitochondria. 17

Early studies on ROS highlighted their harmful effects, with key contributions from Gershman and Harman. In 1954, Gershman proposed that excessive oxidants cause tissue injury, linking oxidative stress to cellular damage. 21 In 1956, Harman introduced the “free radical theory of aging,” suggesting that accumulated free radicals damage DNA, proteins, and lipids, driving aging and disease. 22 In 1971, Loschen first demonstrated that ROS are generated during cellular respiration, a finding supported by Nohl and Hegner in 1978, emphasizing the role of ROS in biological processes. 23 In 1977, Mittal and Murad reported that OH• activates guanylate cyclase, which leads to the production of cyclic guanosine monophosphate (GMP), a key signaling molecule. 24 Halliwell and Gutteridge further refined the understanding of ROS in 1989, defining them as both free radicals and nonradical oxygen derivatives. 25

As scientific understanding evolved in the late 20th century, research revealed that ROS, especially H 2 O 2 , are not only destructive agents but also essential regulators of cellular signaling. 17 This shift in understanding demonstrated that ROS, particularly H 2 O 2 , play dual roles: as signaling molecules at low levels (1–100 nM) regulating growth, differentiation, and apoptosis and as damaging agents at higher levels (>100 nM), causing oxidative damage and cell death. 17 The balance between ROS and antioxidant defense relies on adaptive pathways such as the nuclear factor erythroid 2–related factor 2 (Nrf2)/Keap1 and NF-κB pathways. Nrf2, which can induce the expression of phase II detoxifying enzyme-encoding genes through antioxidant response elements (AREs), was defined as a master regulator of antioxidant systems in 1997. 17

Methionine was discovered in 1921 by John Howard Mueller, 26 but its critical role in oxidative modification emerged decades later. In 1999, Van Patten et al. revealed the involvement of methionine in the oxidative modification of antithrombin by H 2 O 2 . 27 Earlier, in 1981, Brot et al. identified methionine sulfoxide reductase A (MsrA) as the first enzyme to repair oxidized methionine. 28 MsrB, which is specific for methionine-R-sulfoxide (Met-RO), was discovered in 1999 by Hans J. Forman’s team. 29 In 2007, free methionine-R-sulfoxide reductase (fMRSR), which is capable of reducing free Met-RO but not protein-bound Met-RO, was identified. 30 Finally, in 2013, Drazic and colleagues highlighted methionine oxidation as a novel mechanism for redox regulation of protein function. 31

The role of ROS in cell death signaling emerged in the late 1990s. In 1998, David G. Green and colleagues identified ROS as key regulators of programmed cell death. 32 In 2007, Scherz-Shouval et al. reported that ROS critically induce autophagy. 33 In 2009, Cho et al. demonstrated that mitochondrial ROS are essential for necroptosis execution. 34 In 2008, Marcus Conrad’s team reported that redox gene modulation could trigger nonapoptotic death, and Yang and Stockwell reported that this form was iron dependent. 35 In 2012, Brent Stockwell’s group formally defined this distinct, iron-regulated, lipid peroxidation-driven cell death as “ferroptosis”. 36

Research on redox detection has progressed significantly since the early 20th century, evolving from basic electrochemical methods to advanced computational and machine learning (ML)-driven approaches. In 2020, Barton and colleagues developed a biocompatible nanoscale tool using quantum sensing with nitrogen-vacancy (NV) centers in nanodiamonds (NDs) coupled to nitroxide radicals, enabling highly sensitive detection of paramagnetic species (~10 spins per ND) and real-time monitoring of redox processes such as ascorbic acid oxidation. 37 In 2023, Oliveira and colleagues developed a method (MD + CB) to calculate redox potential changes by integrating fluctuation relations with molecular dynamics (MD) simulations, efficiently estimating redox potentials using Bayesian inference. 38 Tested on heme proteins, it showed reliable shifts (0.85 correlation) and matched experimental data, aiding in the understating on ROS biology by advancing the prediction and engineering of redox-active proteins and understanding redox signaling in cellular processes and diseases. 38 In 2024, Jinnouchi and colleagues developed a method combining first-principles calculations and machine learning to predict redox potentials with high precision. 39 The method accurately modeled Fe 3+ /Fe 2+ , Cu 2+ /Cu + , and Ag 2+ /Ag + redox potentials, closely aligning with experimental values, advancing ROS biology by enhancing redox reaction modeling and electron transfer studies 39 (Fig. 1a ). Fig. 1 a Key events in the history of the ROS. b The generation of ROS, their regulation through antioxidant defenses, and the role of the Nrf2-Keap1 signaling pathway in oxidative stress. Mitochondria, peroxisomes, the ER, and NOX enzymes are major sources of intracellular ROS. In mitochondria, electron leaks at ETC complexes I and III produce superoxide (O 2 • − ), which SOD converts to hydrogen peroxide (H 2 O 2 ) for redox signaling or detoxification via catalase, glutathione, or thioredoxin systems. Peroxisomes generate ROS through xanthine oxidase (XO) and fatty acid metabolism, with elevated ROS linked to leukemia. ER ROS arise from oxidative protein folding via PDI and Ero1, with disruptions inducing ER stress and the UPR. External factors such as pollutants and radiation also increase ROS. Cells maintain redox homeostasis through antioxidants such as Nrf2-regulated enzymes (SOD, catalase, GPX), which neutralize ROS and prevent oxidative damage. The GSH/GSSG and TRX systems, fueled by NADPH, restore redox balance, emphasizing the interplay between ROS generation and antioxidant defenses in cellular health and disease. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). GPX glutathione peroxidase, NOX NADPH oxidase, TRXR thioredoxin reductase, ETC electron transport chain, PRDX perodoxine, GMP guanosine monophosphate, Msr methionine sulfoxide reductase, AT antithrombin, fMRSR free methionine-R-sulfoxide reductase, MD + CB molecular dynamics and Bayesian inference, CAT catalase, GST glutathione S-transferase, NQO1 NADPH quinone oxidoreductase 1, HO-1 heme oxygenase 1

Source and mechanism of ROS generation

ROS are generated from both endogenous (internal) and exogenous (external) sources. Endogenous sources include cellular processes like mitochondrial respiration and enzyme activity, whereas exogenous sources encompass environmental factors and lifestyle choices. These sources contribute to the overall cellular redox balance, and their dysregulation can lead to oxidative stress and cellular damage.

Endogenous sources of ROS

Endogenous sources of ROS include various cellular organelles and enzymatic reactions within the body:

Mitochondria

Mitochondrial ROS generation primarily occurs at complexes I and III of the ETC due to electron leaks that fail to reach complex IV and instead univalently react with oxygen to form O 2 • − . 40 Superoxide, a membrane-impermeable molecule, is rapidly dismutated into membrane-diffusible H 2 O 2 by SOD. 41 H 2 O 2 is further detoxified into water by catalase, glutathione peroxidase, or thioredoxin peroxidase or participates in redox signal transduction. Alternatively, H 2 O 2 can also undergo further reduction via the Fenton reaction to form OH•, a highly toxic molecule that causes oxidative damage. 41 Additionally, mitochondrial nitric oxide synthase (NOS) produces nitric oxide (NO•), which then reacts with O 2 • − to form peroxynitrite (ONOO − ), a potent oxidant 42 (Fig. 1b ).

Peroxisome activity

Peroxisomes, the major sites of intracellular H 2 O 2 , represent another important source of ROS. In addition, xanthine oxidase (XO) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, generate O 2 •⁻ while catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA). 43 XO also reduces nitrate and nitrite to NO•, which reacts with O 2 •⁻ to form ONOO⁻, a reactive nitrogen species (RNS). Additionally, an electron transport chain in the peroxisomal membrane contributes to O 2 •⁻ production. H 2 O 2 is released during these catalytic activities and can form OH• via Fenton reactions 43 (Fig. 1b ).

Endoplasmic reticulum (ER)

The ER, an organelle critical for protein synthesis, folding, maturation, and assembly, is another significant source of ROS. 44 Oxidative protein folding within the ER is facilitated by oxidoreductases such as protein disulfide isomerases (PDIs), ERp72, and ERp57, with PDI catalyzing thiol-disulfide exchange reactions to form native disulfide bonds in proteins. 45 During this process, PDI is oxidized by endoplasmic reticulum oxidoreductin-1 (Ero1), which transfers electrons from reduced PDI to oxygen, producing H 2 O 2 . Ero1 also promotes the conversion of reduced glutathione (GSH) to glutathione disulfide (GSSG), contributing to ROS accumulation and ER stress. 46 Disruptions in these pathways can lead to protein misfolding and accumulation, triggering ER stress and the unfolded protein response (UPR), thereby inducing cancer. While the UPR initially supports tumor cell survival and propagation, prolonged ER stress can ultimately induce apoptosis in tumor cells 44 (Fig. 1b ).

NOX

The NOX family of enzymes was the first system identified to produce ROS as a primary function rather than as a metabolic byproduct. 47 Evidence strongly correlates NOX-driven ROS generation with leukemogenesis, disease progression, and drug resistance. In 2023, Germon et al. linked FLT3 mutations in AML to increased protein oxidation, phosphorylation, and elevated NOX2 complex activity. 48 NOX2 inhibition synergistically enhances apoptosis in FLT3-mutant AML cells and reduces FLT3 phosphorylation and cysteine oxidation, identifying NOX2 as the primary source of ROS. 48 This finding aligns with previous in vitro studies demonstrating significant reductions in intracellular ROS levels following NOX inhibition or genetic knockout of NOX isoforms or subunits 49 (Fig. 1b ).

Besides, thymidine phosphorylase (TP) enhances ROS production by increasing NADPH levels, which activate NADPH oxidase, and through metal-catalyzed oxidation of excess 2-deoxy-D-ribose-1-phosphate (DR1P). 50 Polyamines (PAs), such as spermine and spermidine, produce H 2 O 2 through catabolic processes involving enzymes like spermine oxidase (SMOX). Additionally, diamine oxidase (DAO) and acetylpolyamine oxidase (APAO) produce H 2 O 2 during polyamine oxidation. 50 The cytochrome P450 (CYP) enzymes in the endoplasmic reticulum and mitochondria, as well as the cyclooxygenases (COXs) and lipoxygenases (LOXs) involved in eicosanoid metabolism, contribute to ROS formation. 51 The PI3K/AKT/phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) signaling pathway influences NOX-derived ROS production. 52 , 53 Enzymes such as protein kinase C (PKC), MAPK, and protein kinase A (PKA) modulate NOX activation, whereas the tumor suppressor p53 regulates both antioxidant and prooxidant responses, promoting ROS production and apoptosis in cancer cells. 52 , 53

Exogenous sources of ROS

Exogenous sources of ROS include external factors outside the body or environmental exposures:

External factors such as pollutants, tobacco smoke, radiation, and certain drugs induce ROS through various mechanisms. 54 For example, tobacco smoke contains more than 4000 chemicals, such as superoxide and hydroxyl radicals. Ionizing radiation can also generate hydroxyl radicals, either directly by oxidizing water or indirectly through the formation of secondary ROS. Transition metals such as iron, copper, zinc, and aluminum catalyze the Fenton and Haber-Weiss reactions, leading to the formation of highly reactive OH• and hydroxyl anion (OH − ) from H 2 O 2 . 55 Carcinogenic metals like antimony, arsenic, and chromium similarly induce ROS through these reactions. Additionally, pathogenic invasion can trigger immune responses, leading to the activation of neutrophils and macrophages, which generate ROS as part of the host defense mechanism. 56 Collectively, various intracellular and extracellular stimuli contribute to ROS formation in cancer cells (Fig. 1b ).

Redox homeostasis

Redox homeostasis refers to the balance between the production of ROS and the antioxidant mechanisms that neutralize these ROS. 4 While basal ROS levels support signaling and defense, mild oxidative stress damages biomolecules, increasing the risk of mutations and diseases like cancer. 57 Conversely, excessive ROS overwhelm the cell’s antioxidant defenses, triggering oxidative damage and, ultimately, programmed cell death. 4 To prevent such damage, cells maintain redox homeostasis through an elaborate antioxidant defense system (Fig. 2a, b ). Fig. 2 a Redox homeostasis, showcasing the balance between oxidative stress and the antioxidant defense system in cells. The diagram highlights key enzymatic pathways managing redox balance. Superoxide dismutase (SOD) converts O 2 • − into H₂O₂, which is further detoxified into water by GPX via GSH. GSH is regenerated from its oxidized form (GSSG) by glutathione reductase (GR) via the use of NADPH as a reducing agent. Similarly, the TRX system, mediated by thioredoxin reductase (TRXR), converts oxidized thioredoxin to its reduced state to maintain protein redox states. Glutaredoxin (GRX) also participates in reducing oxidized proteins, ensuring functional protein repair, and maintaining cellular homeostasis. The figure outlines two outcomes depending on redox imbalance. On the one hand, excessive oxidative stress leads to hyperactivation of prosurvival pathways, increasing cancer risk, and at higher levels, triggers cell death signaling. On the other hand, a sufficient antioxidant response replenishes the antioxidant machinery and enhances the expression of cytoprotective genes. b The dual role of ROS: as mediators of normal signaling at low levels and triggers of both tumor progression and cell death depending on concentration. On the left, normal signaling is shown, where ROS act as second messengers in cellular signaling pathways, maintaining physiological processes. In the middle, at moderate ROS levels, pro-oncogenic signaling is highlighted, promoting carcinogenesis, angiogenesis, metastasis, and resistance to anticancer drugs. At the highest ROS levels, on the right, cell death signaling becomes dominant, leading to programmed cell death. c The mechanism of ROS-mediated regulation of cell growth and carcinogenesis. In the G1 phase, ROS promote G1/S transition via CDK2 oxidation/phosphorylation while inhibiting cyclin D–CDK4/6 through disulfide bond formation, reducing proliferation. During S phase, mitochondrial ROS accelerate replication, and moderate ROS increase CDK2 activity, bypassing senescence and promoting immortalization. In the G2/M phase, sustained ROS inactivate Cdc25 phosphatases, block CDK1 activation, hyperphosphorylate Aurora A (disrupting spindle assembly), and oxidize APC/C components like APC11, prolonging mitotic arrest. ROS also drive carcinogenesis by activating major proliferative and survival pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, ERK, AhR, TGF-β, Ca 2+ signaling, EGFR, HIF1α, JAK/STAT, NF-κB, and Nrf2 pathways. For example, ROS increase β-catenin nuclear translocation to activate c-Myc and cyclin D1, and stimulate PI3K–AKT signaling, promoting survival, metabolism, and mTORC2 feedback activation. ERK-driven CREB phosphorylation increases growth-related gene expression. AhR-ARNT complexes bind XRE/DRE elements to regulate cell cycle genes, whereas TGF-β enhances cyclin D1 via β-catenin. Elevated Ca 2+ activates DREAM and HSFs to trigger proliferation, and HIF1α promotes glycolysis and IGF-2 expression under hypoxia. EGFR activates the Ras-Raf-MAPK and PI3K-AKT pathways; JAK/STAT signaling promotes transcription of survival genes; and NF-κB upregulates cyclin D1 while inhibiting p53. Additionally, ROS-induced oxidative DNA damage activates the ATM/p53/p21 pathway, which may contribute to genomic instability and mutagenesis. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). CDK2 cyclin-dependent kinase, APC/C anaphase-promoting complex/cyclosome, APC11 anaphase-promoting complex subunit 11, ARNT aryl hydrocarbon receptor nuclear translocator, XRE/DRE xenobiotic/dioxin response element, DREAM dimerization partner, RB-like, E2F, and multivulval class B, HSFs heat shock factors, IGF-2 insulin-like growth factor 2, ATM ataxia-telangiectasia mutated

Nrf2 plays a critical role in maintaining redox homeostasis. It is a redox-sensitive transcription factor that regulates the expression of antioxidant and ROS-detoxifying enzymes. Under oxidative stress, ROS modify the Keap1-Nrf2 interaction, allowing Nrf2 to escape degradation, accumulate in the nucleus, and activate AREs. 57 This triggers the transcription of genes encoding antioxidants such as SOD, catalase, GSH, glutathione reductase (GR), GSH S-transferase (GSTP), GPX, TRXR, NADPH quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), which neutralize ROS and protect cells against oxidative stress, especially in conditions such as cancer, where ROS levels are elevated 57 (Fig. 1b ).

When initiated, SOD catalyzes the dismutation of the superoxide anion into H 2 O 2 and oxygen (O 2 ), reducing the risk of oxidative damage from superoxide, a highly reactive ROS. While H 2 O 2 is still a reactive molecule, it is less harmful and is further detoxified by catalase and GPX, thereby protecting cells from oxidative stress. 6 The GSH system, where GSH is the primary intracellular antioxidant, neutralizes ROS and restores oxidized protein thiols, converting GSH into GSSG. 6 The GSH/GSSG ratio reflects the redox state of the cell, with a high ratio indicating a healthy, reducing environment. Glutathione reductase regenerates GSH from GSSG using NADPH. Similarly, the TRX system maintains redox balance by reducing oxidized proteins and scavenging ROS. TRXR, also NADPH-dependent, keeps TRX in its reduced, active state. 58 Both systems, involving enzymes like glutathione peroxidase and peroxiredoxin, are vital for neutralizing peroxides and preventing oxidative stress damage (Fig. 2a ).

While Nrf2 signaling-mediated redox balance is beneficial for healthy cells, it also regulates redox homeostasis in cancer cells, ensuring that ROS do not reach toxic levels that could hinder cell proliferation. 59

ROS and biology of cancer

ROS, particularly H 2 O 2, can induce reversible oxidation of cysteine residues in several signaling proteins. H 2 O 2 can also directly modulate the activities of several antioxidants, protein kinases, and transcriptional regulators for redox regulation. Besides, ROS trigger different phosphatases that dephosphorylate and thus inactivate kinases, thereby promoting signaling pathways. Therefore, ROS are key modulators of a wide array of pathways and transcription factors associated with cell proliferation, differentiation, immune response, epithelial-mesenchymal transition (EMT), and cell death. These pathways vary in subcellular localization: cytoplasmic-localized pathways include epidermal growth factor receptor (EGFR), extracellular-regulated kinase 1/2 (ERK1/2), ASK1, and ATG4, although some (such as ERK1/2 and EGFR) also exert nuclear effects upon activation. 60 In contrast, nuclear-localized factors such as p53 and PARP1, upon ROS-mediated activation, function predominantly in transcription regulation and DNA repair, although neucleocytoplasmic shuttling of p53 is also well documented. 60 , 61 A third redox-sensitive pathway group—including Wnt/β-catenin, PI3K/AKT/mTOR, aryl hydrocarbon receptor (AhR), TGF-β, calcium signaling, Janus kinase (JAK)/signal transducers and activators of transcription (STAT), hypoxia-inducible factor 1 α (HIF1α), NF-κB, Nrf2, c-Jun N-terminal kinase (JNK), p38, and Ataxia-telangiectasia mutated (ATM)—features components that shuttle between the cytoplasm and nucleus, allowing complex regulation of gene expression and cellular fate. 60

In terms of cellular progression or defining cell fate, ROS-modulated prosurvival pathways include Wnt/β-catenin, PI3K/AKT/mTOR, AhR, TGF-β, calcium signaling, EGFR, ERK1/2, JAK/STAT, HIF1α, NF-κB, and Nrf2 pathways. 3 The prodeath pathways modulated by ROS include JNK, p38, ASK1, p53, ATG4, PARP1, ATM, and AMP-activated protein kinase (AMPK) pathways. 3 Prosurvival pathways, when hyperactivated, driven by moderate increase in ROS, are considered to induce pro-oncogenic phenomena, while prodeath pathways, when initiated under excessive ROS, are considered to exert antitumor activity. Interestingly, categorically assigning whether ROS activate or inhibit a specific pathway is overly simplistic. For example, while moderate ROS often drive tumorigenic processes by enhancing prosurvival signaling, high ROS levels can inhibit these same pathways, such as PI3K/AKT, leading to growth arrest or cell death. 62 , 63 Again, it is not uncommon for prosurvival signaling pathways to also induce the expression of cell death-related molecules; for example, JAK/STAT signaling promotes proliferation but can also mediate necroptosis via ZBP1-RIPK3-MLKL activation in the absence of RIPK1. 64 Thus, ROS-mediated signaling is highly context dependent, influenced by ROS concentration, cellular metabolic state, and intrinsic genetic factors, underscoring the complex and dynamic interplay between redox balance and cancer biology.

ROS, cell cycle regulation, and carcinogenesis

ROS are key regulators of the cell cycle, with their effects determined by concentration, duration, and cellular context. In the G1 phase, ROS-mediated oxidation/phosphorylation of cyclin-dependent kinase 2 (CDK2) promotes its activation, facilitating the G1/S transition. 65 Interestingly, Auranofin-induced H 2 O 2 inhibits cyclin D-CDK4/6 activity by inducing disulfide bond formation between CDK4 and cyclin D, reducing cell proliferation. 66 During the S phase, ROS modulate CDK2-cyclin A activity and intra-S phase checkpoints, with mitochondrial ROS accelerating replication onset. 67 A moderate increase in ROS levels may increase CDK2 activity, which is vital for bypassing senescence and enabling cancer cell immortalization. 67 Conversely, in the G2/M transition (particularly redox-sensitive), sustained ROS have also been reported to oxidize and inactivate Cdc25 phosphatases, preventing CDK1 activation and blocking mitotic entry, potentially leading to cell death. 68 Moreover, excessive ROS hyperphosphorylate Aurora A, disrupting spindle assembly, 69 and oxidize APC/C components like APC11, inhibiting cyclin B degradation and prolonging mitotic arrest. 70

Additionally, physiological levels of ROS, particularly H 2 O 2, can modulate numerous prosurvival pathways and transcription factors involved in cell cycle progression. For example, Wnt/β-catenin signaling promotes β-catenin nuclear translocation, where it interacts with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors to activate the expression of target genes regulating cell proliferation, such as c-Myc and cyclin D1. 71 AhR translocates to the nucleus, forms a complex with ARNT, and binds to xenobiotic response elements (XREs) or dioxin response elements (DREs) located in the promoter regions of target genes involved in cell cycle progression and proliferation. 72 However, the ability of the AhR pathway to induce a G1/S cell cycle block, as evidenced following human cytomegalovirus (HCMV) infection, highlights the need for further research considering its role in various cancers and cellular contexts. 72 TGF-β enhances cyclin D1 transcription via β-catenin signaling, enhancing cyclin D1 promoter activity. 73 Ca²⁺ signaling activates transcription factors such as the DREAM complex and heat shock transcription factors (HSFs), driving immediate early gene (IEG) expression. 74 These IEGs are responsible for transitioning cells from a resting state (G0) back into the cell cycle, initiating proliferation. HIF1α promotes cell growth by enhancing glycolysis under hypoxia and regulating growth factors like IGF-2 to support proliferation and survival. 75 Once activated, EGFR triggers multiple downstream pathways, including the Ras-Raf-MAPK pathway and the PI3K-AKT pathway, ultimately leading to cell division and growth. 76 JAKs phosphorylate receptors and STAT proteins, leading to STAT dimerization and nuclear translocation to drive transcription of genes for growth, proliferation, and survival. 77 NF-κB promotes the G1-S transition by upregulating cyclin D1 and inhibiting p53, driving cell growth and apoptosis resistance. 67

The PI3K/AKT pathway is a key signaling cascade linked to cell proliferation and is often dysregulated in cancer. Regarding PI3K/AKT pathway, activated PI3K phosphorylates PIP2 into PIP3, which recruits AKT to the plasma membrane, where it is phosphorylated at Thr308 and Ser473, triggering full activation. 78 AKT activation regulates cell survival, growth, and metabolism by inhibiting p27, activating cAMP-response element binding protein (CREB), inactivating tuberous sclerosis complex 2 (TSC2), sequestering FOXO in the cytoplasm, and engaging a feedback loop with mTORC2 (AKT and mTORC2 form a critical feedback loop in which mTORC2 activates AKT by phosphorylating it at serine (Ser)473. This increased AKT activity might subsequently promote further mTORC2 stimulation). 79 These coordinated activities collectively promote protein synthesis and cell cycle progression. The ERK pathway activates kinases such as p90RSK and MSK1, which phosphorylate CREB at Ser133. 80 When CREB is phosphorylated, it acts as a transcriptional activator of various genes involved in cell growth and proliferation, including c-Myc and CDK1. As described earlier, hyperactivation of these pathways due to increases in ROS levels may contribute to carcinogenesis.

Conversely, excessive ROS concentrations can exert an antitumor effect by either modulating prodeath signaling pathways or inhibiting prosurvival pathways. For example, supraphysiological levels of ROS induces G1 arrest by stabilizing c-Fos binding to chromatin, suppressing Fra-1-mediated cyclin D1 expression, and activating p21 through the ATM/p53 signaling pathway. 81 During S-phase, oxidative DNA damage, including 8-oxoG lesions and strand breaks, activates the MRN-ATM-Chk2 cascade, halting replication to allow repair via p53/p21 activation. 82 Besides, drug-induced ROS can inhibit the PI3K/AKT pathway to suppress cancer cell proliferation by disrupting key pathways critical for tumor growth and survival, as evidenced by studies with (+)-anthrabenzoxocinone in NSCLC and 6-methoxydihydrosanguinarine in breast cancer. 62 , 63 While the exact basis for this paradoxical role remains unclear, excessive ROS levels induced by these drugs may underlie their inhibitory effects (Fig. 2c ).

ROS and angiogenesis

Elevated ROS levels (particularly NOX4-induced H 2 O 2 ) promote angiogenesis through redox-mediated pathways, with HIF1α playing a central role by directly upregulating VEGF and angiogenic factors like angiopoietin-2 and endothelin-1 (EDN1), particularly in colon cancer. 83 AKT-mediated FOXO inhibition prevents VEGF suppression while enhancing Sp1-driven VEGF transcription. 78 Wnt/β-catenin signaling similarly activates VEGF and EDN1 expression via TCF/LEF complexes, as evidenced in HEK293T cells. 84 In addition to activating VEGF, NF-κB initiates interleukin-8 (IL-8) and matrix metalloproteinase 9 (MMP9), and interacts with the PI3K pathway to enhance the expression of angiogenic factor with G patch and FHA domains 1 (AGGF1). 85 TGF-β1 induces angiogenesis primarily by enhancing VEGF secretion under hypoxia and upregulating signaling proteins such as Smad3/4 and HIF1α, which further increase VEGF transcriptional activity through histone acetyltransferase (p300), emphasizing the role of chromatin remodeling. 86 TGF-β1 also upregulates Flt-1, a key VEGF receptor, further amplifying the angiogenic response.

EGFR signaling promotes the Ras-Raf-MAPK pathway or recruits tumor-infiltrating neutrophils via IL-8, which enhances the permeability of newly formed vessels, facilitating tumor cell migration. 76 Neutrophils also deliver a specialized form of MMP9 that enzymatically activates VEGF. Under hypoxia, STAT3 forms transcriptional complexes with HIF1α, CBP/p300, and Ref- 1 /APE to enhance VEGF expression, as observed in multiple cancers. 87 STAT3 also directly binds to the VEGF promoter, as observed in NSCLC, and regulates MMP2 and MMP9 secretion, facilitating ECM degradation and angiogenesis. 88 Additionally, cofactors like HIF1α and Sp1 collaborate with STAT3 in endothelial cells to further promote VEGF expression, supporting angiogenesis 87 (Fig. 3a ). Fig. 3 a The mechanism of the ROS-mediated induction of angiogenesis. ROS induce angiogenesis primarily through redox-mediated pathways, particularly under hypoxic conditions. HIF1α plays a central role by upregulating VEGF and other angiogenic factors, such as angiopoietin-2 and endothelin-1 (EDN1). AKT activation inhibits FOXO proteins, preventing VEGF suppression, while enhancing Sp1-mediated VEGF transcription. Stabilized β-catenin interacts with TCF/LEF complexes to drive VEGF and EDN1 expression. NF-κB enhances angiogenesis by inducing IL-8, MMP9, and AGGF1 expression. TGF-β1 increases VEGF secretion under hypoxia and facilitates promoter activation via Smad3/4 and HIF1α, supported by chromatin remodeling through p300. EGFR signaling promotes angiogenesis via the Ras-Raf-MAPK pathway or neutrophil-mediated VEGF activation. Additionally, under hypoxic conditions, STAT3 forms transcriptional complexes with HIF1α and co-factors such as Sp1 to enhance VEGF expression and regulate ECM degradation through MMP2 and MMP9, further driving vascular growth. b The mechanism of ROS-mediated induction of metastasis. ROS activate Wnt/β-catenin signaling, enabling the nuclear translocation of β-catenin and its interaction with transcription factors such as ZEB1/2 and SNAIL to repress epithelial markers and promote mesenchymal traits. PI3K/AKT signaling stimulates mTORC2, a key regulator of EMT. TGF-β signaling disrupts cell polarity through TβRII-mediated Par6 phosphorylation and Smurf1-dependent RhoA degradation, while inducing miR-155 to weaken tight junctions. Paradoxically, it also activates RhoA and mTORC2 to promote stress fiber formation, EMT, and motility via the upregulation of SNAIL, SLUG, and ZEB, driving mesenchymal transition. ROS-mediated calcium signaling activates calcineurin, which modulates NFAT to induce ZEB1/2 expression, thereby enhancing mesenchymal marker expression (e.g., N-cadherin and vimentin) while repressing E-cadherin. EGFR signaling triggers the Ras-Raf-MAPK and PI3K-AKT pathways to regulate EMT markers, whereas hypoxia-induced HIF1α activates transcription factors such as TWIST and ZEB1 to induce mesenchymal traits. Additionally, activated STATs enhance EMT by upregulating matrix metalloproteinases (MMPs) and EMT-related transcription factors, such as SNAIL, TWIST, and ZEB1. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). VEGF vascular endothelial growth factor, FOXO forkhead box O (transcription factor), TCF/LEF T-cell factor/Lymphoid enhancer factor, MMP9 matrix metalloproteinase-9, AGGF1 angiogenic factor with G-patch and FHA domains 1, ZEB1/2 zinc finger E-box-binding homeobox 1/2, NFAT nuclear factor of activated T cells, TWIST twist-related protein (transcription factor)

Conversely, excessive ROS can inhibit VEGF signaling by damaging receptors and depleting NO• through ONOO − formation, disrupting vasodilation and endothelial function. 89 ROS may also activate antiangiogenic pathways, such as p53-mediated production of thrombospondin-1. 90 Furthermore, elevated ROS levels can trigger endothelial apoptosis via mitochondrial dysfunction and caspase activation. 91 The ability of excessive ROS to inhibit angiogenesis is now being leveraged in the development of ROS-mediated cancer therapeutics.

ROS and metastasis

Moderate ROS levels promote metastasis and cancer cell invasion by hyperactivating prosurvival pathways like Wnt/β-atenin pathway, which drives EMT through β-catenin’s nuclear interaction with transcription factors such as ZEB1/2 and SNAIL to repress epithelial markers. 92 PI3K/AKT activation triggers mTORC2, a key regulator of EMT, 79 whereas TGF-β signaling disrupts cell polarity via Par6 phosphorylation by TGF-β type II receptor (TβRII) and RhoA degradation, which is mediated by Smurf1, and induces miR-155 expression to destabilize tight junctions. 93 Interestingly, TGF-β signaling activates RhoA, promoting stress fiber formation to enhance migration and invasion, while its activation of mTORC2 further supports RhoA activity, facilitating EMT and cell motility. 94 Additionally, TGF-β signaling activates SNAIL, SLUG, and ZEB, thus promoting a more migratory mesenchymal phenotype. 94 Calcium signaling through calcineurin activates the nuclear factor of activated T cell (NFAT), which translocates into the nucleus to induce ZEB1/2 expression, modulating E-cadherin downregulation and N-cadherin and vimentin upregulation. 95 EGFR activation triggers the MAPK and PI3K-AKT pathways, which directly regulate the expression of mesenchymal and epithelial markers. 76 HIF1α drives EMT via TWIST and ZEB1, 96 whereas activated STATs promote MMP expression and the expression of EMT-associated transcription factors such as SNAIL, TWIST, and ZEB1. 88 A recent study reported that chronic oxidative stress disrupts the circadian rhythm of neutrophils and promotes neutrophil extracellular trap (NET) formation via glucocorticoid release, creating a metastasis-supporting microenvironment. 97

Conversely, excessive ROS have been well documented to inhibit metastasis in several studies. GPX2-knockdown-induced ROS suppress gastric cancer progression and metastasis by disrupting the KYNU-Kyn-AhR signaling pathway, 98 which is known to promote metastasis, as evidenced in chronic lymphocytic leukemia (CLL) in mice. 99 Similarly, a cholesterol oxidase-loaded Co–PN3 single-atom nanozyme effectively suppresses tumor metastasis by enhancing ROS generation 100 (Fig. 3b ).

ROS and drug resistance

Moderate levels of ROS are linked to the upregulation of drug efflux pumps like P-gp and MRP1. ROS regulate several signaling pathways involved in regulating drug efflux pumps. For example, β-catenin, after nuclear translocation, upregulates the expression of drug resistance genes such as ABCB1 (encoding P-gp) and ABCC1 (encoding MRP1). 101 The PI3K/AKT pathway promotes multidrug resistance by upregulating ABCB1, ABCC1, and ABCG2 (encoding BCRP), and activating antiapoptotic proteins like X-linked inhibitor of apoptosis (XIAP). 102 HIF1α activates H19 transcription in NSCLC cells, with long noncoding RNA H19 overexpression linked to increased P-gp and MRP1 expression. 103 Furthermore, the EGFR and ERK pathways induce p-gp expression by activating PI3K signaling, while TGF-β1 enhances P-gp through the HOTAIR/miR-145 axis, providing a novel mechanism for drug resistance in cancer. 104 , 105 A study demonstrated that oxidative stress-induced Nrf2 promotes drug efflux by upregulating ABCG2, as observed in biliary tract cancer cells. 106 Interestingly, targeting the Nrf2 pathway to overcome drug resistance in liver cancer involves the induction of excessive ROS. 107 Another recent study suggested that the 2D-CuPd nanozyme overcomes Tamoxifen resistance in breast cancer by leveraging the ROS-mediated inhibition of the PI3K/AKT/mTOR pathway. 108 Many other studies are also exploring the vulnerability of cancer cells to excessive ROS to overcome drug resistance. (Fig. 4a ). Fig. 4 a The mechanism of ROS-mediated induction of drug resistance. Elevated levels of ROS are linked to the upregulation of drug efflux pumps such as P-glycoprotein (P-gp) and MRP1 through the regulation of multiple signaling pathways, including Wnt/β-catenin, EGFR, ERK, TGF-β, PI3K/AKT, HIF1α, and MAPK pathways. ROS-induced β-catenin translocates to the nucleus, where it enhances the expression of drug resistance genes such as ABCB1 (P-gp) and ABCC1 (MRP1) by interacting with transcription factors. The PI3K/AKT pathway further drives multidrug resistance by upregulating ABC transporters, including ABCG2 (BCRP), and activating antiapoptotic proteins such as XIAP, which promote tumor survival, proliferation, and metastasis. Hypoxia-induced HIF1α increases P-gp and MRP1 expression via H19 transcription, with TGF-β1 contributing through the HOTAIR/miR-145 axis. Additionally, the activation of Nrf2 by ROS promotes drug efflux by enhancing ABCG2 transporter expression. EGFR and ERK pathways also contribute to the upregulation of P-gp and MRP1 via PI3K signaling, further enhancing the resistance phenotype. b Interplay between ROS and immunomodulation. In the tumor microenvironment, excessive ROS accumulation results in immune suppression, impairing T-cell responses, promoting the apoptosis of cytotoxic CD8 + tumor-infiltrating lymphocytes and natural killer cells, and upregulating immune checkpoints such as PD-L1 via FGFR1 signaling, thus suppressing T-cell activity and enabling immune evasion of cancer cells. ROS also favor the survival of immunosuppressive cells like myeloid-derived suppressor cells and M2 macrophages, further suppressing immune responses. ROS contribute to immune dysfunction by impairing T-cell receptor functionality. Additionally, ROS enhance the TGF-β/Smad2/3 pathway and induce NF-kB activation, suppressing antitumor immunity, promoting Treg and MDSC expansion, and stabilizing HIF1α, which fosters a hypoxia-driven immunosuppressive microenvironment, thereby promoting cancer progression and immune evasion. Moderate ROS play a pivotal role in immune stimulation by promoting T-cell proliferation and interleukin secretion. Moderate ROS levels activate nuclear factors of activated T cells, stimulating IL-2 and IL-4 secretion, while ROS can also revitalize exhausted CD8 + T cells through LDHA-driven glycolysis. ROS modulate key TCR signaling pathways, including calcium, NF-kB, ERK1/2, and mTOR pathways, enhancing T-cell activation, proliferation, and metabolic reprogramming. Furthermore, ROS-mediated activation of AhR supports the transition of effector T cells into memory T cells. Additionally, ROS reduce FOXP3 stability, thereby decreasing suppressive function of Tregs. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). P-gp P-glycoprotein, MRP1 multidrug resistance-associated protein 1 (encoded by ABCC1), ABC ATP-binding cassette, XIAP X-linked inhibitor of apoptosis protein, FGFR1 fibroblast growth factor receptor 1, Treg regulatory T cell, MDSC myeloid-derived suppressor cell, LDHA lactate dehydrogenase A, TCR T-cell receptor, FOXP3 forkhead box P3

ROS in immunosuppression

In the tumor microenvironment (TME), excessive ROS exert profound immunosuppressive effects, undermining antitumor immunity and promoting cancer progression. Cancer cells, cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs) are major contributors to elevated ROS levels, which suppress T-cell responses and promote the apoptosis of T cells due to their weak antioxidant systems. 109 ROS impair the function of cytotoxic CD8 + tumor-infiltrating lymphocytes (TILs) by inducing mitochondrial dysfunction, which reduces their ability to attack cancer cells. 110 Similarly, natural killer (NK) cells are rendered less effective, as ROS increase their apoptosis and functional impairment. 111 Furthermore, ROS contribute to the upregulation of immune checkpoint molecules like PD-L1 on cancer cells via FGFR1 signaling, suppressing T-cell activity and enabling immune evasion. 112 ROS also favor the survival of immunosuppressive cells such as MDSCs and M2 macrophages, which have enhanced antioxidant capacities, allowing them to thrive under oxidative conditions. 113 Through nitration and nitrosylation, ROS impair antigen presentation and TCR functionality, exacerbating immune dysfunction. 114 Hydrogen sulfide, an RSS, promotes regulatory T (Treg) cell differentiation by activating FOXP3. 115 ROS enhance the TGF-β/Smad2/3 pathway and induce NF-κB activation, collectively suppressing antitumor immunity by inhibiting cytotoxic T cells and NK cells, promoting the expansion of Tregs and MDSCs, and upregulating immune checkpoints like PD-1 and PD-L1. 116 Additionally, ROS stabilize HIF1α, promoting immunosuppression in NSCLC through inducing EMT, reducing CD8 + TILs, and activating the HIF1α/LOXL2 pathway, which fosters a hypoxia-driven immunosuppressive microenvironment 117 (Fig. 4b ).

Conversely, the immunostimulatory role of moderate levels of ROS is also well evidenced. ROS, including O 2 •⁻, H 2 O 2 , and OH•, serve as critical signaling molecules that bolster immune responses through their role in both innate and adaptive immunity. Upon T-cell receptor (TCR) activation, mitochondrial oxidative phosphorylation (OXPHOS) and NOXs are upregulated, leading to increased ROS production, which fuels T-cell proliferation and interleukin (IL) secretion. 118 Moderate ROS levels also activate NFAT to stimulate IL-2 secretion, promoting T-cell proliferation and survival. 119 Besides, ROS can also induce the type 2 cytokine Fc–IL-4, which revitalizes exhausted CD8 + T cells by increasing LDHA-driven glycolysis and NAD+ generation, effectively restoring their antitumor activity. 120 ROS play crucial modulatory roles in amplifying distal TCR pathways, including Ca 2+ -calcineurin-NFAT, IKK-NF-κB, Ras-ERK1/2, and mTOR cascades, which in turn enhance T-cell activation, proliferation, and cytokine production (e.g., IL-2). 121 Additionally, ROS-activated AhR in effector T cells supports their transition into memory T cells, ensuring long-term immune surveillance. 122 Peroxynitrite stimulates TLR4 and NF-κB activation and cytokines (release of TNF-α, IL-1β, and IL-8) 123 , and NOX-induced ROS play a role in inflammasome activation, such as the NLRP3 inflammasome, which drives caspase activity and cytokine production to enhance immune cell recruitment and function. 124 Additionally, the loss of transmembrane p24 trafficking protein 4 (TMED4)-induced ROS reduces FOXP3 stability and the suppressive function of Tregs in an IRE1α/XBP1 axis–dependent manner 125 (Fig. 4b ).

ROS, cellular metabolism and cancer

Carbohydrate metabolism

ROS modulate cancer metabolism by influencing multiple pathways critical for tumor survival and proliferation. In glycolysis, ROS oxidize GAPDH and PKM2, altering their activity, thereby inhibiting glucose uptake, while simultaneously enhancing glucose uptake and metabolism through HIF1α stabilization. 126 Interestingly, inhibition of GADPH and PKM2 redirects glucose-6-phosphate (G6P) flux away from glycolysis and towards the oxidative arm of the PPP, which produces NADPH, thereby boosting NADPH production to counter oxidative stress. 127 In mitochondria, ROS impact the TCA cycle by oxidizing enzymes such as aconitase and α-ketoglutarate dehydrogenase (αKGDH), modulating metabolic flux, whereas superoxide generated at the ETC amplifies redox signaling. 128 Glutaminolysis supports ROS detoxification by enhancing glutathione regeneration. ROS directly oxidize the glutaminase protein, altering its structure and function, and modulating metabolic pathways, including elevated mitochondrial ROS production, which further affects glutaminase activity. Interestingly, ROS can increase glutaminase activity by activating p53, which increases GLS2 expression and activity. 129 Additionally, serine‒glycine one-carbon metabolism (SGOC) provides NADPH and nucleotides, with Nrf2 upregulating this pathway to mitigate oxidative damage. 130 Cancer cells balance ROS levels to promote redox signaling and survival while avoiding oxidative stress, a vulnerability that therapies targeting these pathways aim to exploit, selectively inducing oxidative damage and cell death in tumors (Fig. 5a ). Fig. 5 a ROS in carbohydrate and lipid metabolism. ROS modulate cancer metabolism by altering key pathways essential for tumor survival and proliferation. In glycolysis, ROS oxidize GAPDH and PKM2, inhibiting their activity and redirecting glucose flux from glycolysis to the oxidative pentose phosphate pathway (PPP), thereby increasing NADPH production to combat oxidative stress. Simultaneously, ROS stabilize HIF1α, enhancing glucose uptake and metabolism. In mitochondria, ROS impair TCA cycle enzymes such as aconitase and α-ketoglutarate dehydrogenase, and superoxide from the ETC amplifies redox signaling. In glutaminolysis, ROS oxidize glutaminase and, via p53 activation, upregulate GLS2 to support glutathione regeneration. ROS also influence serine‒glycine one-carbon metabolism (SGOC), with Nrf2 upregulating this pathway to generate NADPH and nucleotides. In lipid metabolism, elevated ROS activate AMPK, which inhibits ACC, reducing malonyl-CoA levels and increasing fatty acid oxidation (FAO). This shift sustains ATP and NADPH production, supporting tumor survival and therapy resistance. However, ROS also induce lipid peroxidation, attacking PUFAs, generating 4-HNE, which forms toxic adducts with proteins, leading to dysfunction. b ROS in nucleic acid metabolism. ROS significantly impact nucleic acid metabolism through direct oxidative damage and modulation of transcriptional, epigenetic, and posttranscriptional processes. ROS regulate redox-sensitive transcription factors such as Nrf2, NF-κB, HIF1α, and FOXO via posttranslational modifications (PTMs) or upstream signaling pathways, influencing the expression of genes and ncRNAs. ROS-induced activation of Nrf2 leads to the expression of ncRNAs, some of which promote tumorigenesis, therapeutic resistance or regulated cell death. Epigenetically, ROS alter DNA and histone methylation and acetylation through effects on enzymes like DNMTs, HATs, HDACs, and sirtuins. Redox modifications such as S-nitrosylation and S-glutathionylation modulate chromatin structure and gene accessibility, while mitochondrial ROS influence the NAD + /NADH ratio, which governs sirtuin activity. Furthermore, ROS induce epigenetic regulation through oxidative DNA lesions such as 8-oxo-dG and promote RNA modifications, including N6-methyladenosine, which alter mRNA stability and translation, contributing to drug resistance. c ROS in protein metabolism. Redox signaling tightly regulates protein metabolism by modulating protein synthesis, folding, and degradation. H₂O₂ impairs protein synthesis by activating oxidative stress-sensitive kinases such as PERK and GCN2, leading to eIF2 phosphorylation and translation repression, and by inhibiting mTORC1, which stabilizes 4EBP1–eIF4E interaction, blocking translation initiation. In the ER, protein folding depends on redox-regulated disulfide bond formation catalyzed by Ero1 and PDI, both using redox-active cysteines. H 2 O 2 also influences protein degradation by enhancing immunoproteasome formation via IFN-γ signaling and promoting 20S proteasome activity through S-glutathionylation. Additionally, ROS induce protein carbonylation—irreversible oxidative damage, disrupting proteostasis and driving tumor progression. However, excessive ROS can also trigger ER stress, which overwhelms cancer cell defenses, exerting potential antitumor effects. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). GAPDH glyceraldehyde-3-phosphate dehydrogenase, PKM2 pyruvate kinase M2, αKGDH α-ketoglutarate dehydrogenase, GLS2 glutaminase 2, ACC acetyl-CoA carboxylase, PERK protein kinase R-like ER kinase, GCN2 general control nonderepressible 2, eIF2 eukaryotic initiation factor 2, 4EBP1 eukaryotic translation initiation factor 4E-binding protein 1, eIF4E eukaryotic translation initiation factor 4E, Ero1 endoplasmic reticulum oxidoreductin 1, PDI protein disulfide isomerase

Lipid metabolism

Elevated ROS activate AMPK, which phosphorylates and inhibits acetyl-CoA carboxylase (ACC), reducing malonyl-CoA levels and thereby relieving the inhibition of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme in fatty acid oxidation (FAO). 131 This metabolic shift promotes FAO, leading to increased ATP production and regeneration of NADPH via TCA cycle-linked pathways. In many tumors, enhanced FAO provides metabolic flexibility, sustaining ATP and NADPH levels during oxidative and metabolic stress, which promotes survival, therapy resistance, and metastatic potential. 132 Concurrently, ROS, particularly OH•, initiate lipid peroxidation by attacking polyunsaturated fatty acids (PUFAs) within cellular membranes. This peroxidation process leads to the formation of 4-hydroxy-2-nonenal (4-HNE). 133 4-HNE readily forms covalent adducts with nucleophilic amino acid residues—particularly cysteine, histidine, and lysine—through Michael addition or Schiff base formation, frequently resulting in protein misfolding, unfolding, or aggregation. Notably, in glioma cells, fatty acid-binding protein 7 (FABP7) binds and internalizes PUFAs to promote lipid droplet formation, whereas deletion of FABP7 decreases lipid droplets accumulation and leads to elevated ROS levels 6 (Fig. 5a ).

Nucleic acid metabolism

ROS significantly influence nucleic acid metabolism through direct oxidative modifications and by regulating transcriptional, epigenetic, and posttranscriptional mechanisms.

Redox regulation of transcription

ROS modulate the activity of redox-sensitive transcription factors (TFs), such as Nrf2, NF-κB, HIF1α, and FOXO, either through posttranslational modifications (PTMs) or by impacting upstream signaling pathways (such as Keap1 in Nrf2 signaling, IKK in NF-κB signaling, and PHD2 in HIF1α signaling). 134 Under ROS stress, Nrf2 binds to ARE, which then induces noncoding RNA (ncRNA). While ncRNAs play a major role in therapeutic resistance, they can function as regulated cell death (RCD) accelerators that modulate therapeutic sensitivity. Besides, translation of ncRNAs can produce unwanted peptides in ROS-associated diseases, including cancer. Aberrant polyadenylation events within introns of tumor suppressor genes such as DICER1 and FOXN3 result in the production of truncated proteins lacking essential tumor-suppressive functions, thereby promoting tumorigenesis. 135 Additionally, certain long ncRNAs (lncRNAs) can be translated into peptides bearing hydrophobic C-terminal tails, enabling their localization to cellular membranes, where they may act as tumor-associated antigens. 136 Interestingly, normal cells and cancer cells seem to have different lncRNA transcripts in response to H 2 O 2 stress, which might contribute to the different sensitivities to ROS observed in normal and cancer cells. ROS-induced PTMs also activate NF-κB signaling, leading to the upregulation of the antiapoptotic proteins BCL-XL and IAP 137 (Fig. 5b ).

Redox regulation of epigenetics

Redox signaling exerts long-term cellular effects through epigenetic mechanisms, including DNA and histone methylation, acetylation, and other PTMs. Mito-ROS regulate the expression of DNA methyltransferases (DNMTs), leading to changes in the expression of oxidative stress-related genes. 138 Furthermore, the methyl donor of epigenetic methylation is from methionine metabolism, which can also be regulated by H 2 O 2 . Acetylation of histones at lysine residues serves as a transcriptional activator. This reaction is catalyzed by histone acetylases (HATs) using acetyl-CoA as a donor substrate. Histone deacetylases (HDACs), on the other hand, are regulated by redox modifications—for instance, S-nitrosylation of HDAC2 at cysteine residues induces its release from chromatin, which promotes chromatin remodeling and transcriptional activation of nearby genes. 9 Furthermore, S-glutathionylation of histone 3 affects nucleosome stability and alters chromatin structure, which enhances the binding of the replication machinery to DNA. 139 Sirtuins are an additional class of NAD + -dependent HDACs whose activity is indirectly redox-regulated through their dependence on the NAD + /NADH ratio maintained by the TCA cycle and affected by mitochondrial ROS production. 140 Besides, 8-oxo-2′-deoxyguanosine, a product of DNA oxidation, functions as an epigenetic modifier that regulates gene expression. Additionally, RNA modification is a posttranscriptional event that can be regulated by ROS. 6 The generation of N6-methyladenosine is a very common type of RNA modification affected by H 2 O 2 through the activation of methyltransferases or demethylases. 141 Notably, N6-methyladenosine modification can alter the stability and translational efficiency of mRNAs, leading to drug resistance (Fig. 5b ).

Protein metabolism

Redox signaling intricately regulates protein metabolism at multiple stages, including protein synthesis, folding, and degradation. ROS, particularly H 2 O 2 , negatively influence protein synthesis by inducing phosphorylation of eukaryotic initiation factor (eIF2) via oxidative stress-sensitive kinases such as PERK and GCN2, thereby repressing translation. 142 Additionally, H 2 O 2 suppresses mTORC1 activity, reducing phosphorylation of 4EBP1, which then binds eIF4E, preventing interaction with eIF4G, thereby blocking translation initiation. In the ER, protein folding is redox-regulated through the formation of structural disulfide bonds, which are catalyzed by Ero1 and PDI, both of which utilize redox-active cysteine residues. 143 H 2 O 2 also modulates protein degradation by promoting the formation of the immunoproteasome through IFN-γ signaling, which involves dissociation of the 19S regulatory particle from the 20S core, assisted by Hsp70. 144 Moreover, H 2 O 2 enhances proteasome activity via S-glutathionylation of cysteine residues in the 20S subunit. 145 ROS also induce protein carbonylation by oxidizing amino acid residues such as proline, arginine, lysine, and threonine, forming reactive carbonyl groups—markers of irreversible oxidative damage. 146 Accumulation of carbonylated proteins disrupts proteostasis and contributes to tumor progression; however, excessive ROS-induced ER stress can also exert antitumor effects by overwhelming cancer cell survival mechanisms (Fig. 5c ).

ROS and cell death

The specific type of RCD that cancer and immune cells undertake in response to ROS stress is determined by the intrinsic genetic wiring, metabolic state, and level and type of ROS. Intrinsic apoptosis occurs in stressed epithelial or cancer cells via mitochondrial BAX/BAK activation and caspase-9-mediated pathways when antioxidant defenses fail but the apoptotic machinery remains intact. 147 Superoxide and hydroxyl radicals drive intrinsic apoptosis by disrupting mitochondrial membrane potential, whereas H 2 O 2 promotes extrinsic apoptosis by inducing c-FLIP ubiquitination and proteasomal degradation, enabling caspase-8 activation. Extrinsic apoptosis dominates as ROS synergize with death receptor signaling (e.g., TNFR/Fas), activating caspase-8 through DISC formation. 148

Necroptosis and extrinsic apoptosis share initial signaling pathways involving death receptors such as TNFR1 or Fas, but necroptosis occurs in caspase-8-deficient contexts (e.g., inflamed tissues or resistant cancers) via RIPK1/RIPK3/MLKL activation. 149 Under specific conditions, ROS can bypass these pathways to induce pyroptosis, driven by inflammasome activation (e.g., NLRP3) in response to PAMPs/DAMPs, the predominance of inflammatory caspases (caspase-1/4/5/11) over caspase-8 or RIPK3, and cell-specific mechanisms prioritizing cytokine release (IL-1β/IL-18) in immune cells like macrophages. 150 In such cases, ROS-activated inflammasomes cleave gasdermin-D to form membrane pores, enabling pyroptosis while suppressing apoptosis and necroptosis through mechanisms like c-FLIP degradation or RIPK1 ubiquitination.

Ferroptosis, characterized by GPX4 inhibition and iron-dependent lipid peroxidation, occurs in iron-rich cells such as glioblastomas and neurons, and is often triggered by decreased SLC7A11 expression or cystine depletion. 151 In contrast, disulfidptosis arises in cancer cells under glucose deprived conditions with high SLC7A11 expression, leading to cystine accumulation, disulfide stress, and cytoskeletal collapse, ultimately resulting in cell death. 152

Oxeiptosis occurs when extreme oxidative damage causes lysosomal membrane permeabilization, particularly when other death pathways are impaired. 153 In contrast, cuproptosis, which is regulated by cuproptosis-related genes (CRGs), is promoted by genes such as FDX1, LIAS, and PDHA1, which increase cellular sensitivity, whereas genes like MTF1 and CDKN2A reduce sensitivity. 154 Cells with mutations affecting Fe-S cluster formation or stability are especially vulnerable to cuproptosis because of weakened mitochondrial function and increased susceptibility to copper-induced toxicity. 155 And ROS-induced NETosis occurs when tumor-derived factors like cytokines and DAMPs activate neutrophils via NOX2, resulting in excessive ROS production. 156

Apoptosis

Excessive intracellular ROS activate proapoptotic BH3-only proteins (e.g., BAD, BIM, PUMA, NOXA), which displace antiapoptotic BCL-2 family members (e.g., BCL-2, BCL-XL), enabling BAX/BAK activation and mitochondrial outer membrane permeabilization (MOMP). 157 This releases cytochrome c and apoptogenic factors such as AIF, Smac/Diablo, and endonuclease G, initiating apoptosome formation and caspase (-9, -3, -6, and -7) activation. 158 Effector caspases then cleave cellular proteins, causing DNA fragmentation, cytoskeletal dismantling, and controlled cell death.

In addition, ROS modulate several signaling pathways to promote apoptosis. These pathways include the ASK1 pathway, which initiates proapoptotic signaling through JNK and p38 pathways, leading to the phosphorylation of proapoptotic proteins like BAD, BIM, and BAX. 159 PARP1 also activates BAX and BAK, contributing to apoptosis via mitochondrial dysfunction and chromatin remodeling. 160 Additionally, PARP1 drives apoptosis via interactions with signaling molecules such as apoptosis-inducing factor (AIF), p53, caspase-3, caspase-7, and ATM. 161 ATG4 plays a significant role in apoptosis, as ATG4 may shift cells from survival to apoptosis when autophagy is inhibited. 162 Additionally, p53, through its activation by AMPK, ATM and other stress-related pathways, promotes BAX, PUMA, and NOXA, 163 whereas TGF-β enhances the expression of BIK while downregulating BCL-XL, causing an increased apoptotic response. 164 HIF1α binds to the hypoxia-responsive element (HRE) of the BCL-2 interacting protein 3 (BNIP3) gene, upregulating the expression of this apoptosis-inducing factor in various cancers. 165 ROS also interact with calcium signaling at the mitochondrial–ER interface, where Ca 2+ surges induce mitochondrial swelling and rupture via disrupted ion exchange and adenine nucleotide translocase (ANT) channel dysfunction. 166 Besides, Ca 2+ overload activates calpain, which cleaves BCL-2 proteins and activates BID and AIF, thereby promoting apoptosis. Ca 2+ -activated calcineurin dephosphorylates BAD, enhancing its proapoptotic activity. 166

ROS promote extrinsic apoptosis by accelerating the ubiquitin-mediated degradation of c-FLIP, thereby enhancing DISC formation and caspase-8 activation through adapter proteins such as Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD). ROS also activate pathways such as the AhR, p53, JNK, and ASK1 pathways, enabling extrinsic apoptosis. Recent findings revealed that ROS-driven AhR/CYP1B1 signaling induces Fas via p53 activation, contributing to 6PPDQ-induced cardiac dysfunction in zebrafish embryos. 167 Additionally, p53 can bypass classical death receptors by upregulating Reprimo (RPRM), which activates the Hippo–YAP/TAZ–p73 axis, leading to the expression of proapoptotic genes. 168 JNK and ASK1 modulate death receptor signaling, amplifying extrinsic apoptosis. 169

Moderate levels of ROS, on the other hand, inhibit apoptosis by activating prosurvival pathways such as the PI3K/AKT, ERK, and NF-κB pathways. The PI3K/AKT pathway inactivates BAD and BAX while also suppressing caspase-9 and caspase-3 activation. 170 Similarly, ERK signaling phosphorylates and neutralizes BAD, BIM, and BMF (Ser77), preventing their interaction with BCL-2 family proteins and enhancing the expression of BCL-2 and BCL-XL. 171 Additionally, NF-κB upregulates antiapoptotic genes, including FLIP, BCL-XL, c-IAP, XIAP, TRAF1, and TRAF2, further blocking cell death 172 (Fig. 6a ). Fig. 6 a The mechanism of ROS-mediated induction of apoptosis. Excessive intracellular ROS induce apoptosis by modulating key signaling molecules, such as ASK1, PARP1, ATG4, p53, JNK, p38, AMPK, ATM, and calcium signaling, in a context-dependent manner. In the intrinsic (mitochondrial) pathway, ROS activate proapoptotic BH3-only proteins (e.g., BAD, BID, BIM, PUMA, NOXA), displacing antiapoptotic BCL-2 family members (e.g., BCL-2, BCL-XL) and triggering mitochondrial outer membrane permeabilization (MOMP). This leads to cytochrome c release, apoptosome formation, caspase-9 activation, and downstream executioner caspases (3, 6, 7), with AIF, Smac/Diablo, and HtrA2/Omi further amplifying apoptosis. ASK1 activates JNK/p38, enhancing BAX activation via phosphorylation of BAD, BIM, and BAX. PARP1 promotes apoptosis through BAX/BAK activation and chromatin remodeling, while its cleavage by caspases conserves ATP. ROS-induced mitochondrial Ca 2+ overload activates calpain- and AIF-mediated DNA fragmentation; calcineurin dephosphorylates BAD, inhibiting BCL-XL. In contrast, moderate ROS levels activate survival pathways (PI3K/AKT, ERK, and NF-κB). ROS also promote extrinsic apoptosis by degrading c-FLIP, enhancing DISC formation and caspase-8 activation via FADD and TRADD. Additionally, ROS activate AhR/p53 signaling to induce Fas, and p53 can trigger extrinsic-like apoptosis via Reprimo-mediated Hippo–YAP/TAZ-p73 activation. b The mechanism of ROS-mediated induction of autophagy, necroptosis, and ferroptosis. ROS regulate multiple cell death and survival pathways in a context-dependent manner. During autophagy, H 2 O 2 oxidizes ATG4 under starvation, enhancing LC3/ATG8 lipidation and autophagosome formation. ROS also activate MAPK pathways, with JNK upregulating Beclin 1 and modulating LC3, whereas p38β phosphorylates ULK1 (Ser555) to initiate autophagy, especially in cancer. p53 induces the expression of autophagy-related genes (Beclin 1, DRAM), and ROS-activated TRP channels (e.g., TRPM2) promote Beclin 1 phosphorylation via CaMKII. PARP1 activation from DNA damage triggers AMPK, suppresses mTOR, and promotes autophagy. In necroptosis, ROS enhance RIPK1/RIPK3 aggregation and necrosome formation, while sustained JAK/STAT signaling upregulates ZBP1, driving necroptosis via MLKL or apoptosis via caspase-8. RIPK3 also links necroptosis to metabolism through GLUD1. Additionally, ROS might induce necrosis by initiating the PI3K/AKT pathway. In ferroptosis, ROS inhibit the xCT system, deplete GSH, impair GPX4, and promote lipid peroxidation. Dysregulated iron metabolism (TFR1, ferritin) drives Fenton reactions. p53 suppresses SLC7A11 and promotes iron accumulation via FDXR, whereas AhR signaling modulates ferroptosis via SLC7A11. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). AIF apoptosis-inducing factor, DISC death-inducing signaling complex, FADD Fas-associated death domain protein, TRADD TNF receptor-associated death domain protein, DRAM damage-regulated autophagy modulator, CaMKII calcium/calmodulin-dependent protein kinase II, MLKL mixed lineage kinase domain-like pseudokinase, GLUD1 glutamate dehydrogenase 1, FDXR ferredoxin reductase

Autophagy

Autophagy is a tightly regulated cellular degradation process in which lysosomes eliminate protein aggregates, damaged organelles, and invading pathogens. 173 ATG4 uniquely regulates autophagy by processing and deconjugating LC3/ATG8-PE. ROS-induced ATG4 oxidation enhances LC3 lipidation and early autophagosome formation, 174 although phagophore growth can occur independently of LC3/ATG8. 162 ROS also regulate autophagy indirectly through the activation of MAPKs, including JNK and p38. 175 JNK phosphorylates c-Jun, enhancing transcription of Beclin 1, crucial for autophagosome formation. and regulates LC3, facilitating autophagy. 176 p38β MAPK induces autophagy by phosphorylating ULK1 at Ser555, particularly in response to cancer-related stimuli. 177 The p53 pathway induces autophagy by upregulating Beclin 1 and damage-regulated autophagy modulator (DRAM). 178 ROS-Ca 2+ signaling also facilitates autophagy via calcium-permeable ion channels such as those of the transient receptor potential (TRP) family. 179 TRPV1 mediates prosurvival autophagy in thymocytes in response to capsaicin, 180 whereas TRPC1-driven Ca 2+ entry triggers autophagy under hypoxia and nutrient deprivation. 181 Additionally, TRPM2 induces Beclin 1 phosphorylation at Ser90 via CaMKII, increasing hepatocyte vulnerability to cell death during oxidative stress. 181 Besides, In response to oxidative DNA damage, PARP1 activates AMPK, which in turn suppresses mTOR signaling—a key inhibitor of autophagy. 5 This pathway induces a prosurvival form of autophagy in NPC cells (Fig. 6b ).

Interestingly, autophagy might modulate ROS to promote cancer cell survival and drug resistance, depending on the context. In pancreatic cancer, autophagy mitigates Tetrandrine-induced ROS, preserving mitochondria and reducing apoptosis, thereby contributing to drug resistance. 182 HIF1α-BNIP3-mediated mitophagy reduces mitochondrial ROS and NLRP3 inflammasome activation, which is protective in conditions like renal fibrosis but potentially promotes tumor progression. 183 Therefore, context-based autophagy targeting could be a potential antineoplastic therapeutic strategy.

Necroptosis

ROS amplify RIPK1 activation via a feedback loop. TNF-α-induced RIPK3 activation generates ROS, which promote RIPK1 autophosphorylation at Ser161 and facilitate the formation of disulfide bond-linked aggregates through cysteines 257, 268, and 586. 184 This enhances RIPK1 recruitment of RIPK3, further increasing ROS production and driving necrosome formation. Additionally, ROS oxidize RIPK1 and reduce the levels and activation of executioner caspases-3, -6, and -7, priming the hyperglycemic shift from apoptosis to necroptosis before TNF-α engages death receptors. 185 Besides, ROS-driven JAK/STAT signaling upregulates Z-DNA binding protein 1 (ZBP1), which forms a complex with RIPK3 in the absence of RIPK1, triggering MLKL-mediated necroptosis. 64 Notably, RIPK3 links necroptotic signaling to cellular metabolism by interacting with glutamate dehydrogenase 1 (GLUD1), which catalyzes the conversion of glutamate to alpha-ketoglutarate. 186 Interestingly, insulin-induced ROS might induce necrosis by initiating PI3K/AKT, a prosurvival pathway, 187 suggesting context-specific ROS modulation of necroptosis (Fig. 6b ).

Ferroptosis

This process begins with the inhibition of the cysteine/glutamate antiporter system xCT, which is composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) and limits the extracellular cysteine uptake required for GSH synthesis. 188 Depletion of GSH impairs GPX4, halting the detoxification of lipid hydroperoxides and triggering unchecked lipid peroxidation 189 . Lipid peroxides react with ferrous iron (Fe 2+ ) through Fenton reactions, generating ROS that damage cellular membranes. 190 Dysregulated iron metabolism, characterized by increased transferrin receptor 1 (TFR1) expression and decreased ferritin levels, leads to iron overload and further amplifies ROS production. 190 Antioxidant systems, including ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH2)-vitamin K hydroquinone (VKH2), dihydroorotate dehydrogenase (DHODH)-CoQH2, and GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4), provide protection by mitigating oxidative damage and inhibiting ferroptosis. 188

Under excessive ROS, p53 plays a crucial role in promoting ferroptosis by negatively regulating SLC7A11, leading to decreased GSH and increased sensitivity to ferroptosis by limiting the antioxidant capacity of cells. 191 Additionally, p53 influences iron homeostasis through enzymes like ferredoxin reductase (FDXR), enhancing iron accumulation, which is pivotal for ferroptosis. 192 Paradoxically, ROS can modulate ferroptosis by regulating SLC7A11 expression through the Nrf2-mediated pathway. 193 Interestingly, a recent study identified a GPX4- and FSP1-independent regulation of ferroptosis involving the phospholipid-modifying enzymes MBOAT1 and MBOAT2, which are regulated by sex hormones. 194 Ferroptosis may induce immunosuppression, as ferroptosis in MDSCs results in the release of oxygenated lipids that impair T-cell function (Fig. 6b ).

Disulfidptosis

Disulfidptosis is a form of PCD induced by glucose starvation in SLC7A11-overexpressing cells, where reduced NADPH production impairs cysteine-to-cystine conversion, causing cysteine accumulation and disulfide stress. 195 Excessive OH• depletes NADPH, leading to abnormal disulfide bond formation in actin cytoskeletal proteins, resulting in F-actin aggregation, cytoskeletal contraction, detachment from the plasma membrane, and structural disruption, ultimately culminating in cell death. 196 Besides, ROS might induce disulfidptosis by regulating the JNK and NF-κB pathways. 197 , 198 Recent studies have shown that cells with high disulfidptosis scores are more vulnerable to glucose deprivation 199 . This metabolic vulnerability can enhance sensitivity to certain anticancer drugs, although in some contexts, disulfidptosis induction might paradoxically contribute to drug resistance in cultured cells through adaptive stress responses 199 (Fig. 7a ). Fig. 7 a The mechanism of ROS-mediated induction of disulfidptosis, pyroptosis, oxeiptosis, NETosis, and cuproptosis. In disulfidptosis, glucose starvation in SLC7A11-overexpressing cells causes ROS-mediated NADPH depletion, impairing cysteine-to-cystine conversion, resulting in abnormal disulfide bond formation in cytoskeletal proteins and structural collapse. ROS-induced JNK and NF-κB signaling may further regulate disulfidptosis. In pyroptosis, ROS activate the NLRP3 inflammasome via TXNIP dissociation, leading to caspase-1-mediated cleavage of gasdermin (GSDM) pore formation and the release of proinflammatory cytokines. ROS also oxidize mitochondrial membranes and activate the JNK-caspase pathway, enhancing pyroptosis or, conversely, inhibiting it through PI3K/AKT-mTORC2 signaling. Oxeiptosis is triggered when ROS oxidize KEAP1, releasing PGAM5, which dephosphorylates AIFM1 to initiate this caspase-independent cell death that selectively eliminates ROS-damaged cells. In NETosis, ROS generated by NOX or mitochondria activate MAPKs and PAD4, promoting chromatin decondensation and the release of neutrophil extracellular traps (NETs), which contribute to chronic inflammation and cancer progression. Finally, in cuproptosis, ROS exacerbate oxidative stress through copper redox cycling, causing toxic hydroxyl radical production, aggregation of lipoylated TCA cycle proteins, and mitochondrial dysfunction. b Mechanisms of ROS-mediated modulation of Wnt/β-catenin, PI3K/AKT, Nrf2, and JAK/STAT signaling pathways. In PI3K/AKT signaling, ROS oxidize cysteine residues in phosphatases such as PTEN, PTP1B, SHP2, and PP2A, inhibiting their activity and sustaining AKT activation. In Wnt signaling, ROS oxidatively inactivate nucleoredoxin (NRX), releasing its suppression of disheveled (Dvl) and enabling Wnt/β-catenin pathway activation. ROS also trigger Nrf2 signaling by directly oxidizing Keap1 or through Mst1/Mst2 autophosphorylation, which inhibits Keap1; Nrf2 is then phosphorylated at Ser40 by PKCδ to become transcriptionally active. In JAK/STAT signaling, ROS initiate the phosphorylation of JAK2 and TYK2, promoting inflammation and tumor progression. Additionally, ROS activate c-Abl in vascular smooth muscle cells, which phosphorylates PKCδ and subsequently PYK2, leading to JAK2 transphosphorylation. Oxidation of Cys215 in PTP1B inhibits its phosphatase activity, prolonging STAT activation and amplifying oncogenic signaling. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). NLRP3 NLR family pyrin domain containing 3, TXNIP thioredoxin-interacting protein, PGAM5 phosphoglycerate mutase family member 5, AIFM1 apoptosis-inducing factor mitochondria-associated 1, PAD4 protein arginine deiminase 4, PTEN phosphatase and tensin homolog, PTP1B protein tyrosine phosphatase 1B, PP2A protein phosphatase 2A, PKCδ protein kinase C delta, PYK2 proline-rich tyrosine kinase 2

Pyroptosis

ROS play dual roles in pyroptosis, which is mediated by inflammasomes and gasdermin proteins (GSDMs). 200 , 201 Under ROS stress, thioredoxin-interacting protein (TXNIP) dissociates from TRX and activates NLR family pyrin domain containing 3 (NLRP3) inflammasomes, leading to caspase-1 activation and GSDMD cleavage, forming membrane pores and releasing proinflammatory cytokines. 202 , 203 Mito-ROS oxidize GSDMD cysteine residues, enhancing its cleavage by caspase-1/caspase-11. 204 Interestingly, NLRP3 and GSDM pore formation in the mitochondrial membrane can induce ROS production by causing mitochondrial dysfunction. 205 Iron-induced ROS recruit BAX to mitochondria via translocase of outer mitochondrial membrane 20 (TOMM20), promoting cytochrome C release, caspase-3 activation, GSDME cleavage and pyroptosis. 206 ROS-induced TNF signaling can also drive RIPK/FADD-mediated caspase-8 activation to cleave GSDMD or GSDMC and induce pyroptosis. 207 ROS elevate intracellular Ca 2+ levels, triggering ER stress, Caspase-3 activation, and GSDME-mediated pyroptosis in TNBC cells. 208 Additionally, ROS can trigger the ASK1-JNK-caspase-3-GSDME pathway to promote pyroptosis. 209 Interestingly, ROS can inhibit pyroptosis through the PI3K/AKT-mTORC2 pathway, suppressing ASK1 activation. ROS-p53 signaling transcriptionally upregulates GSDME and caspases, switching apoptosis to pyroptosis. 210 ROS stress can activate NF-κB, which induces the expression of inflammasome-associated genes. Additionally, ROS-induced AhR signaling can either activate the NLRP3 inflammasome, 211 or inhibit macrophage pyroptosis by upregulating ornithine decarboxylase 1 (Odc-1), enhancing polyamine biosynthesis (e.g., spermine), which suppresses K + efflux and inflammasome assembly, as observed in ulcerative colitis patients 212 (Fig. 7a ).

However, acute NLRP3 activation induces tumor-suppressive pyroptosis and antitumor immunity, whereas chronic activation promotes metastasis through IL-1β/IL-18-driven inflammation. 213 Notably, GSDME expression enhances tumor cell phagocytosis by tumor-associated macrophages and boosts the activity of tumor-infiltrating natural killer cells and CD8 + T lymphocytes, amplifying the antitumor immune response. 214

Oxieptosis

ROS oxidize specific cysteine residues (e.g., Cys151, Cys273, and Cys288) on KEAP1, which acts as a cellular ROS sensor. 215 At low to moderate ROS levels, KEAP1 releases Nrf2, while at excessive ROS levels, KEAP1 releases PGAM5, a mitochondrial serine‒threonine phosphatase that dephosphorylates AIFM1 at Ser116 to activate the oxeiptosis pathway. 216 This caspase-independent cell death process selectively removes ROS-damaged cells, preventing inflammation and preserving tissue homeostasis (Fig. 7a ).

NETosis

ROS induce NETosis through both NOX-dependent and NOX-independent mechanisms. In NOX-dependent NETosis, NOX generates ROS, activating the MAPKs-ERK, p38 MAPK, and JNK pathways. 217 This promotes the migration of myeloperoxidase (MPO) and neutrophil elastase (NE) to the nuclear envelope, where NE partially degrades histones, leading to chromatin decondensation and the release of neutrophil extracellular traps (NETs). 6 In NOX-independent NETosis, ROS are produced by mitochondria and are triggered by stimuli such as calcium ionophores or ultraviolet light. 218 Elevated calcium activates peptidyl arginine deiminase 4 (PAD4), causing histone citrullination, chromatin decondensation, and NET formation. 6 Both pathways highlight ROS as key initiators of NETosis.

NETosis promotes chronic inflammation and cancer progression by inducing DNA damage, proliferation, and angiogenesis via MMP9 and VEGF. 219 It facilitates metastasis via IL-17/granulocyte colony-stimulating factor (G-CSF) signaling, high mobility group box 1 (HMGB1) activation, and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated adhesion. 220 NETosis shifts neutrophils to a protumor N2 phenotype, promoting an immunosuppressive TME, EMT, and chemoresistance. 221 NETs shield tumor cells from immune detection, driving immunotherapy resistance via PD-L1 expression, T-cell exhaustion, and IL-8-mediated immunosuppression, while NETosis in the hypoxic TME enhances chromatin decondensation, tumor cell trapping, and immune evasion, making NETs a critical therapeutic target 221 (Fig. 7a ).

Cuproptosis

ROS induce cuproptosis through Fenton-like reactions, where copper cycles between Cu + and Cu 2+ , generating toxic OH• that damages biomolecule and disrupts mitochondrial function. 222 This oxidative stress promotes copper accumulation, leading to the aggregation of lipoylated TCA cycle proteins and the loss of iron‒sulfur cluster proteins—key hallmarks of cuproptosis. In cancer, this mechanism exploits the heightened copper demand and metabolic vulnerabilities of tumor cells, particularly those reliant on OXPHOS. 222 By selectively targeting cancer cells with copper ionophores like Elesclomol or ROS-inducing agents, including radiotherapy or combination therapy, cuproptosis can be triggered, offering a promising strategy to overcome cancer. 223 , 224 However, balancing copper toxicity and therapeutic efficacy remains critical to minimize off-target effects while maximizing anticancer outcomes (Fig. 7a ).

ROS selectivity in signaling pathway modulation

ROS activate various signaling pathways through selective interactions dictated by the chemistry of specific ROS and the biochemical properties of target molecules. O 2 •⁻ reacts selectively, reducing transition metals and forming ONOO⁻ with nitric oxide, while also damaging Fe–S cluster enzymes critical to metabolism. 11 , 225 H 2 O 2 is less reactive but selectively oxidizes cysteine residues with low pKa values and reacts with transition metals to generate OH•. 12 OH• is highly indiscriminate, reacts at near diffusion-controlled rates and drives oxidative damage. 226 ONOO⁻ reacts with thiols, metals, and CO₂, generating oxidants such as NO 2 • and CO 3 •⁻. 225 ¹O 2 is a nonradical but highly reactive species, central to photobiological and oxidative processes. 11

The redox potential of specific residues, particularly cysteine, plays a critical role in ROS selectivity. Cysteine residues with low pKa values (e.g., 4.7–5.4) are more nucleophilic and prone to oxidation. For instance, the catalytic cysteine in PTPs has a low pKa because of the Cys-X5-Arg motif, making them highly susceptible to oxidation by H 2 O 2 , leading to the formation of sulfenic acid (SOH), disulfide bonds (S‒S), or sulfenyl-amide (S‒N) bonds. 227 Proteins containing redox-sensitive motifs, such as the CXXC motif in nucleoredoxin (NRX) or TRX, are preferential targets for ROS. 228 These motifs are structurally designed to sense and respond to redox changes. For example, the oxidation of Cys205 and Cys208 in NRX disrupts its interaction with disheveled (Dvl), stabilizing β-catenin and activating the Wnt/β-catenin pathway. The sensitivity of cysteine residues to redox changes is influenced by their steric accessibility and the pKa value of their thiol groups. Typically, the pKa value of free cysteine is approximately 8.2. However, when cysteine residues are located near positively charged residues, their pKa decreases to less than 6.5, increasing their susceptibility to oxidation. 229 This shift in pKa is associated with the transformation of redox-sensitive thiols into potent nucleophiles in the presence of basic residues. Cellular redox state might modulate the sensitivity of specific molecules to ROS and subsequent reactions. For example, reducing conditions strengthen some interactions (e.g., NRX-Dvl), and oxidizing conditions weaken them in modulating the Wnt/β-catenin pathway. 230 Proteins such as TRX and glutaredoxin (GRX) might modulate ROS interactions by reducing oxidized cysteine residues, thereby restoring protein function. For example, TRX reduces oxidized ASK1, preventing its activation, whereas GRX regulates the redox state of proteins like Ras, influencing MAPK signaling. 58

Mechanism of the ROS-mediated modulation of signaling pathways

PI3K/AKT/mTOR pathway

ROS enhance PI3K/AKT signaling by suppressing PTEN through H 2 O 2 -induced oxidation (Cys124/Cys71) or Ser380 phosphorylation, inhibiting membrane binding, 231 forming disulfide bridges and promoting migratory shifts. 232 Interestingly, PTEN degradation also occurs independently of H 2 O 2 , as observed in pancreatic cancer cells with elevated prostaglandin production via 5-LOX and COX-2 overexpression. 232 , 233 H 2 O 2 also oxidizes cysteines in PTPs, enabling receptor tyrosine kinase (RTK) phosphorylation, 234 Insulin-induced ROS inhibit PTP1B, preventing insulin pathway dephosphorylation and promoting PI3K/AKT signaling. 235 H 2 O 2 also increases threonine phosphorylation in Caco-2 cells by downregulating PP2A via oxidation of its redox-sensitive Cys266 and Cys269, forming inhibitory disulfide bonds, 236 particularly through oxidation of the B55α isoform. 237 Notably, some studies suggest that ROS-mediated inhibition of the PI3K pathway regulates cell death and enhances chemotherapy sensitivity in cancers, although the exact mechanisms are unclear 238 , 239 (Table 1 , Fig. 7b ). Table 1 List of signaling pathways mediated by ROS with mechanistic highlights Signaling pathway Role in cancer signaling Signaling intermediate Site Modification Mechanistic aspect Refs. PI3K/AKT Drug resistance, Cancer cell proliferation, Metastasis PTEN Cys124 Cys71 -S-S- By inhibiting all these phosphatases, ROS activate PI3K/AKT signaling. 231 PTP1B Cys215 S-N-R 235 PP2A Cys266 Cys269 -S-S- 236 AhR Cell survival and proliferation, EMT, Cell death 2-Oxindole, IDO1 – – ROS initiate 2-Oxindole, which in turn activates IDO1. Activated IDO1 then catalyzes the Trp transformation into Kyn. Upon interaction with AhR, Kyn promotes activation and nuclear translocation of AhR. 258 , 259 Tryptophan – FICZ ROS induce photo-transformation of Trp into FICZ, which in turn activates and transfers AhR to the nucleus. 257 EGFR Tumor cell proliferation, Drug resistance NA Tyr845 Phosphorylation ROS directly activate EGFR by phosphorylation on its Tyr845 residue. 280 NA Cys797 R–S–OH ROS activate EGFR by oxidative modification of Cys797 residue on EGFR. 281 PTEN Cys124, Cys71 -S-S- ROS inactivate phosphatase like PTEN by oxidizing Cys124 and Cys71, thereby activating EGFR. 231 TGF-β Drug Resistance, Cell proliferation, Autophagy LAP-β Met253 Conformational Change ROS induce Met-oxidation of LAP-β, triggering a structural change that results in the initiation of TGF-β. 249 MMP2 & 9 Cys73 R–S–OH ROS oxidize the thiol residues in MMPs into sulfenic acid, leading to their activation. Activated MMPs then oxidize LAP-β to release TGF-β. Cys73 was suggested to be associated with the MMP regulation. 250 Wnt/β-catenin Tumor progression, Migration, Metastasis NRX Cys205 Cys208 -S-S- ROS induce oxidation followed by inactivation of NRX that interacts with Dvl and decline their inhibitory activity on the destruction complex. NRX intervention leads to interaction between Dvl and Wnt and activates Wnt/β-catenin signaling. 71 HIF1α Cell proliferation, Angiogenesis, Metastasis, Apoptosis PHD Fe 2+ Fe 3+ H 2 O 2 inhibit the binding of ferrous iron to prolyl hydroxylases (PHDs) and upregulation of PHDs. Inhibition of PHDs results in initiation of HIF1α. 251 Succinate – – Under Hypoxia, SDH inverse catalysis induced succinate accumulation inhibits PHD activity by impeding the decarboxylation of α-ketoglutarate to succinate, a co-reaction required for HIF1α hydroxylation, thereby raising HIF1α expression. Though ROS association with succinate level is ill-defined, simultaneous re-oxidization of accumulated succinate by SDH produces mtROS. 252 NA Cys520/Cys533 S-nitrosylation ROS directly induce HIF1α through oxidative alteration of its Cys520/(Cys533 in mouse). 253 AMPK, ATM, PI3K/Akt, and MAPK See AMPK, ATM, PI3K/Akt, and MAPK See AMPK, ATM, PI3K/Akt, and MAPK signaling ROS may activate HIF1α through AMPK, ATM, PI3KAkt, and MAPK-induced phosphorylation of different residues of the HIF1α transactivation domain. 254 , 255 Nrf2 Cancer cell survival, Drug resistance Keap1 Cys151 -S-S- ROS induce Cys-oxidative modification and inactivation of Keap1, an inhibitory protein of Nrf2. The accumulated cytoplasmic Nrf2 then undergoes phosphorylation on Ser40 by caspase-3 initiated PKCδ and gets activated. 59 Mst1/Mst2 Thr183 Thr180 Phosphorylation Under oxidative stress, Mst1/Mst2 gets autophosphorylated on Thr180 and Thr183 residues. Activated Mst1/2 then inhibits Keap1, thereby activating Nrf2. 242 JAK/STAT Inflammation, Angiogenesis, Cancer, Metastasis JAK2 Tyr1007 Tyr1008 Phosphorylation ROS can directly activate JAK2 through tyrosine phosphorylation, which in turn activates the STAT factor. 77 TYK2 Tyr1054 Tyr1055 Phosphorylation ROS phosphorylate TYK2 on its tyrosine residues and initiates TYK2, which then potentiates STAT signaling. 77 PTP1B Cys215 S-N-R By inhibiting STAT repressor protein, PTP1B through Cys-oxidation, ROS initiate JAK/STAT signaling. 248 SRC Cys185 Cys277 Cys-SOH ROS activate SRC kinase through Cys-oxidative modification, thereby accelerating JAK/STAT signaling. 247 PKCδ Tyr512 Tyr523 Phosphorylation ROS activate JAK through PKCδ phosphorylation that, in turn, phosphorylates PYK2, which then transphosphorylates JAK. Activated JAK then switches on the STAT factor. 245 ERK1/2 Drug resistance, Metastasis EGFR Tyr845 Phosphorylation ROS activate EGFR by Tyr phosphorylation or Cys oxidation. Activated EGFR then modulates SH2- Grb2-SOS, where SOS initiates Ras by catalyzing the GTP binding to Ras. Ras then initiates Raf, which in turn potentiates MEK1/2 that activates ERK1/2. 280 Cys797 R–S–OH 281 SRC Kinase Cys185 and Cys277 Cys-SOH ROS activate SRC kinase through oxidative modification of cysteine residues. Activated SRC kinases then initiate Raf-1 directly through phosphorylation of their Tyr340/341 residue or EGFR mediated activation, leading to subsequent activation of ERK1/2. 247 Ras Cys118 R–S–OH ROS activate ERK in Ras-dependent manner (by activating Ras through Cys118 oxidation), which is independent of EGFR initiation. 281 DUSP-3 Cys124 R–S–OH ROS inhibit the ERK inhibitory phosphatase, DUSP3, through Cys124 oxidation, resulting in ERK activation. 287 ASK1 Autophagy TRX Cys32, Cys35 -S-S- ROS degrade TRX, an ASK1 inhibitory protein, through Cys oxidation, resulting in its dissociation from ASK1. 289 , 291 ASK1/2 Thr838. Thr806 Oligomerization and Phosphorylation ROS induce homo-oligomerization of ASK1, followed by autophosphorylation at Thr838, while hetero-oligomerization involves the autophosphorylation of ASK2 at Thr806. Subsequent phosphorylation of Thr838 residue of ASK1 by ASK2. 291 JNK Autophagy MAPKKKs (MEKK1/2/3/4, ASK-1 and MLK) – Phosphorylation ROS activate MAPKKKs through phosphorylation, which in turn activate MAPKKs like MKK3/4/6/7 through phosphorylation of Ser/Thr residues. Activated MEKs switch on JNK through phosphorylation of its critical TPY motif. 288 ASK1 – – ROS activate ASK1 directly through dimerization and subsequent phosphorylation or indirectly through TRX inhibition. Activated ASK1 then initiates JNK signaling. 291 GSTPs Arg70, Arg74, Asp90, Asp94, Thr67 Dimerization GSTP that tether JNK to repress JNK are oligomerized by ROS, thereby activating JNK. 290 P38 Autophagy, Inhibition of drug resistance MAPKKKs (ASK1, MEKK1/2/3/4 and MLK3) – Phosphorylation ROS phosphorylate and activate MAPKKKs, which in turn activates MAPKKs like MEK3/6. Activated MEKs induce dual phosphorylation of p38 on its critical threonine and tyrosine residues. 288 p38α Cys119, Cys162 -S-S- ROS phosphorylate both the p38α and MKK3 and mediates heterodimerization (forming a disulfide bond) between Cys104 of MKK3 and Cys119 and Cys162 of p38α, leading to p38α overexpression. 292 PARP1 Cell death signaling PARP1 Leu698 and Leu701 Relieving autoinhibition Upon ROS-induced DNA damage, PARP1 HD autoinhibition domain is unfolded by redistributing Leu698 and Leu701 out of the HD interior, thereby promoting the DNA binding of PARP1 and subsequent auto PARylation. 293 HPF1 – – Under oxidative DNA damage, HPF1-PARP1 binding mediates ADP-ribosylation of serine residues within the histone and PARP1. Besides, HPF1 remodels the active site of PARP1 by forming Arg239-Glu284 that jointly act as an active site for ser-ADP-ribosylation. 294 , 296 ATM DNA damage repair, Autophagy PRDX2, TRX1 Cys2991 of ATM -S-S- In the presence of ROS, PRDX2, and TRXR1 oxidize the Cys2991 residue on ATM, which then undergoes autophosporylation at Ser1981 residue, leading to complete activation of ATM. 297 P53 Apoptosis, Cell cycle blockage, Genome maintenance ATM Cys2991 -S-S- ROS-activated ATM initiates p53 on Ser15 and simultaneously activates CHK2, which then potentiates p53 by phosphorylating their Ser20 residue. 297 JNK See (JNK) See JNK Upon ROS-mediated activation, JNK phosphorylates p53 on Ser20 and Thr81, resulting in p53 activation. 300 P38 See (p38) See p38 ROS-induced p38 MAPK induces phosphorylation of p53 on Ser15, 33, 37 and 46, leading to p53 initiation. 299 ASK1 See ASK1 See ASK1 ROS induce transactivation of p53 in ASK1- JNK/p38 dependent way. 291 AMPK Tumor suppression AMP/ADP Thr172 of AMPK Phosphorylation Under oxidative stress, a decrease in ATP level increases AMP/ADP level and promotes AMP/AMPK-γ subunit binding, resulting in increased ROS mediated Thr172 of AMPK-α subunit phosphorylation followed by AMPK activation. 302 Ca 2+ Thr172 of AMPK Phosphorylation Hypoxia-induced ROS promote calcium levels, which involves the initiation of CaMKKβ that induces phosphorylation of AMPK Thr172 residue, thereby activating AMPK potentiation. 302 NA Cys299 Cys304 -S-S- ROS directly induce Cys oxidation of AMPK and potentiates AMPK. 303 NF-κB Pro-tumorigenic signaling, Drug resistance, Tumor progression, Cell death IKKβ Cys179 S-glutathionylation Excessive ROS oxidize the Cys179 residue on IKKβ to inhibit the activation of IKK, thereby inhibiting NF-κB activation, which results in declined pro-cancer signaling. 269 NA Cys62 S-glutathionylation A high level of ROS directly oxidize Cys62 of NF-κB, thereby reducing the DNA binding capacity of NF-κB. 264 IKKβ Ser177 Ser181 Phosphorylation TNF-α induced ROS oxidize LC8 to promote degradation of IκB on its Ser32 and Ser36 residues by activated IKK. Degradation of IKβ upregulates the initiation as well as nuclear relocation of NF-κB. 262 IKKα Ser176 Ser180 Phosphorylation IL-1β induced ROS activate NIK, which phosphorylates IKKα on its serine residue. Activated IKKα induces phosphorylation and ubiquitination on several serine residues of p100 to generate the NF-κB protein p52. 270 IκBα Tyr42 Phosphorylation ROS induce phosphorylation of IκBα, which in turn phosphorylates p65 and promotes its nuclear translocation. 263 ATG4 Autophagy NA Cys81 R–S–OH ROS directly oxidize the Cys77 residue of ATG4 into sulfenic acid or both the Cys77 and Cys81, forming a disulfide bond, thus inhibiting ATG4 activity and consequently promoting autophagy. 272 Cys77 Cys81 -S-S- 272 Cys292 Cys361 -S-S- ROS induce oxidation of Cys292 and Cys361 of ATG4B, inhibiting its autophagy inducing effectivity. 273 Ca 2+ Tumorigenesis, Autophagy TRPA1 Cys421 Cys621 Cys641 Cys665 -S-S- ROS activate TRP channels through Cys oxidative modification, except for TRPM2, which involves ADP-ribose tethering to the nudix-box sequence motif (NUDT9-H), and TRPML1, which undergoes Cys palmitoylation. Activated TRP channels then induce calcium ion signaling. While the majority of the TRP channel-mediated Ca 2+ influx is involved in pro-tumorigenic signaling, the Calcium channel activated by TRPM2 and TRPML1 have autophagic function. 277 TRPV1 Cys616 Cys621 S-nitrosylation 275 Cys258 Cys742 -S-S- TRPM2 Glu829 Arg845 NAD production 278 TRPC5 Cys553 Cys558 S-nitrosylation 276 MCOLN1/ TRPML1 Cys565 Cys566 Cys567 Palmitoylation 279 ROS Reactive oxygen species, PI3K Phosphoinositide 3-kinase, AKT Protein kinase B, Wnt Wingless and int, Nrf2 Nuclear factor erythroid 2–related factor 2, PTEN Phosphatase and Tensin homolog, PTP1B Protein tyrosine phosphatase 1B, PP2A Protein phosphatase 2A, Keap1 Kelch like-ECH-associated protein 1, Mst1/Mst2 macrophage-stimulating 1/2, PKCδ Protein kinase C δ, JAK Janus kinase, STAT Signal transducers and activators of transcription, TYK Tyrosine Kinases, Tyr Tyrosine, PYK2 Proline-rich tyrosine kinase 2, IDO1 Indoleamine-2,3-dioxygenase-1, Trp Tryptophan, Kyn kynurenine, FICZ 6-formylindolo[3,2-b]carbazole, AHR Aryl hydrocarbon receptor, TGF-β Transforming Growth Factor-β, LAP Latency-associated peptide, MMP Matrix metalloproteinase, Met Methionine, Cys Cysteine, PHDs Prolyl hydroxylases, SDH Succinate dehydrogenase, AMPK AMP-activated protein kinase, ATM Ataxia telangiectasia mutated, MAPK Mitogen-activated protein kinase, IκB Inhibitory κB, IKK IκB kinases, NF-κB Nuclear Factor kappa B, ATG4 Autophagy-related 4, TNFα Tumor Necrosis Factor α, IL-1β Interleukin-1β, TRPV1 Transient Receptor Potential Vanilloid 1, TRPC5 Transient Receptor Potential Channel 5, TRPA1 Transient receptor potential ankyrin 1, TRPM2 Transient Receptor Potential Melastatin 2, TRPML1 Transient Receptor Potential Mucolipin 1, EGFR Epidermal growth factor Receptor, ERK1/2 Extracellular-regulated kinase 1/2, ASK1 Apoptosis Signal-regulating Kinase 1, JNK c-Jun N-terminal Kinase, SRC kinase Proto-oncogene tyrosine-protein kinase, DUSP3 Dual specificity protein phosphatase 3, MAPKKK Mitogen Activated Protein (MAP) kinase kinase kinase, MKK Mitogen-activated protein kinase kinase, MEK Mitogen-activated protein kinase, Tyr Tyrosine, Cys Cysteine, Ser Serine, Thr Threonine, ATM Ataxia-telangiectasia mutated, CHK2 Checkpoint kinase 2, AMP Adenosine monophosphate, ADP Adenosine diphosphate, ATP Adenosine triphosphate, AMPK AMP-activated protein kinase, MAPK Mitogen Activated Protein kinase, CaMKKβ Calmodulin-dependent protein kinase β, PARP Poly (ADP-ribose) polymerase, DNA Deoxyribonucleic acid, Arg arginine, Glu Glutamic acid, HPF1 Histone PARylation factor 1, HD Helical Domain

Wnt/β-catenin pathway

NOX1 generates H 2 O 2 , which oxidizes the Cys205 and Cys208 residues of NRX. 71 This oxidation inactivates NRX, which normally binds to disheveled (Dvl) and represses its ability to inhibit the β-catenin destruction complex, thereby enabling it to stabilize β-catenin, facilitating ROS-driven Wnt/β-catenin signaling. 71 Thus, a redox-dependent interaction between NRX and Dvl is essential for Wnt/β-catenin signaling modulation by ROS (Table 1 , Fig. 7b ). Interestingly, NRX can indirectly promote β-catenin signaling by modulating Dvl stability. KLHL12, an E3 ubiquitin ligase adapter, targets Dvl for proteasomal degradation, negatively affecting the canonical Wnt pathway. However, reduced levels of NRX disrupt the interaction between KLHL12 and Dvl, preventing Dvl degradation and preserving the pool of Dvl necessary for sustaining Wnt/β-catenin signaling. 240

Nrf2 pathway

Under stress, ROS oxidize Keap1’s cysteine-rich domain (Cys151), 59 disrupting its interaction with Nrf2 and activating Nrf2. Consequently, Nrf2 levels increase in the cytoplasm, where Caspase-3-cleaved PKCδ further activates Nrf2 via Ser40 phosphorylation, enabling its nuclear translocation to activate ARE expression. 241 Mitochondrial ROS activate macrophage-stimulating 1/2 (Mst1/2) kinases via autophosphorylation at Thr183/Thr180. 242 Activated Mst1/2 relocates with Keap1 to mitochondria, phosphorylating its N-terminus, disabling Keap1 dimerization and subsequent Nrf2 activation 243 (Table 1 , Fig. 7b ).

JAK/STAT pathway

ROS, particularly H 2 O 2 , activate JAK2 and TYK2 signaling by phosphorylating JAK2 (Tyr1007/1008) and TYK2 (Tyr1054/1055), 77 leading to STAT activation via Tyr705 phosphorylation. 244 In vascular smooth muscle cells, ROS activate c-Abl, which phosphorylates PKCδ (Tyr512/523), 245 leading to PYK2 phosphorylation (Tyr402/579) and subsequent JAK2 transphosphorylation. 246 Additionally, ROS activate SRC kinase through Cys-oxidative modification, initiating JAK/STAT signaling. 247 Besides, ROS oxidize PTP1B, inhibiting its phosphatase activity and thereby preventing dephosphorylation of signaling components such as the IL-4 receptor, which prolongs STAT signaling 248 (Table 1 , Fig. 7b ).

TGF-β pathway

Ionizing radiation-induced ROS activate latent TGF-β1 by oxidizing Met253 in its LAP, triggering conformational changes, suggesting the isoform specificity of ROS in TGF-β activation. 249 This isoform-specific activation is due to variations in LAP homology (34–38%), despite the high similarity (75%) among TGF-β cytokines. ROS can activate LTGF-β indirectly by potentiating MMP2 and MMP9, which modify thiol residues (e.g., Cys73) to sulfenic acid, 250 activating MMPs, leading to LAP cleavage and the release of active TGF-β in the ECM (Table 1 , Fig. 8a ). Fig. 8 a Mechanisms of ROS mediated regulation of AhR, TGF-β, HIF1α, NF-κB, ATG4, and calcium signaling pathways. ROS-derived 2-oxindole activates IDO1, converting tryptophan to kynurenine (Kyn), which binds and activates AhR, while ROS-induced FICZ formation similarly triggers AhR nuclear translocation. In the TGF-β pathway, ROS oxidize methionine residues in LAP-β and activate MMPs, which further release TGF-β by oxidizing LAP-β, with Cys73 involved in MMP regulation. ROS stabilize HIF1α by inhibiting prolyl hydroxylases (PHDs), with succinate accumulation and oxidative modifications at Cys520 enhancing HIF1α levels, along with phosphorylation by AMPK, ATM, PI3K/Akt, and MAPK. NF-κB activation is promoted via IKKβ phosphorylation (Ser177/181) by TAK1, IκBα degradation (Ser32/36), and dynein light chain oxidation, enabling p65 nuclear translocation; however, excessive ROS oxidize NF-κB p50 (Cys62) and IKKβ (Cys179), inhibiting DNA binding and proteasome function, thereby dampening signaling. ROS also activate the noncanonical NF-κB pathway via NIK and IKKα phosphorylation (Ser176/180) and modulate NF-κB via the PI3K/PTEN/Akt axis. In autophagy, ROS oxidize Cys77/Cys81 and Cys292/Cys361 in ATG4/ATG4B, inhibiting their activity and enhancing autophagy. ROS also regulate calcium signaling by oxidizing cysteines in TRP channels (e.g., TRPV1, TRPC5, and TRPA1), promoting Ca 2+ influx, with TRPA1 activation linked to tumorigenesis. ROS activate TRPM2 via Glu829 and Arg845, generating NAD and ADP-ribose to stimulate Ca 2+ entry and cell death, and enhance antitumor calcium signaling through palmitoylation of Cys565–567 in MCOLN1 (TRPML1), amplifying ROS-mediated Ca 2+ responses. b Mechanistic action of ROS in modulating EGFR, p53, AMPK, ATM, PARP1, ERK1/2, ASK1, p38, and JNK-dependent pathways. ROS directly activate EGFR via phosphorylation at Tyr845 and oxidation of Cys797, and indirectly by inhibiting PTEN through oxidation of Cys124 and Cys71. EGFR then initiates Ras–Raf–MEK–ERK signaling, with ROS enhancing Ras activation via Cys118 oxidation, activating SRC, and inhibiting DUSP3 via Cys124 oxidation, collectively sustaining ERK1/2 activation. In JNK signaling, ROS degrade TRX, releasing ASK1 through autophosphorylation at Thr838/Thr806, which then activates MAPKKs (MKK3/4/6/7), leading to JNK activation. ROS-induced GSTP oligomerization releases its inhibitory hold on JNK, while oxidative inhibition of MKPs further amplifies JNK signaling. For p38 activation, ROS promote MAPKKK phosphorylation and activate MEK3/6, inducing dual phosphorylation of p38, while also increasing p38α/MKK3 dimerization. ROS activate ATM by oxidizing Cys2991 via PRDX2/TRX1, triggering Ser1981 autophosphorylation; activated ATM phosphorylates p53 at Ser15 and activates CHK2, which phosphorylates p53 at Ser20. JNK and p38 further phosphorylate p53 at Ser20, Thr81, and Ser15/33/37/46, enhancing its tumor-suppressive functions. ROS activate AMPK by increasing AMP/ADP levels, promoting γ subunit binding and Thr172 phosphorylation of the α subunit, with additional activation via CaMKKβ under hypoxia and direct Cys oxidation. Upon ROS-induced DNA damage, PARP1 undergoes conformational changes allowing DNA binding and autoPARylation, while HPF1 reshapes the PARP1 active site to facilitate serine ADP-ribosylation of histones, driving chromatin remodeling and repair. This figure was created in BioRender. tonu, r. (2025) ( https://BioRender.com/0q9bi92 ). IDO1 indoleamine 2,3-dioxygenase 1, MMPs matrix metalloproteinases, IKKβ inhibitor of nuclear factor kappa-B kinase subunit beta, TAK1 TGF-β-activated kinase 1, IκBα NF-kappa-B inhibitor alpha, NIK IKKα inhibitor of nuclear factor kappa-B kinase subunit alpha, TRP transient receptor potential, DUSP3 dual-specificity phosphatase 3, MAPKKs (MKK3/4/6/7) mitogen-activated protein kinase kinases, MEK3/6 MAPK/ERK kinase 3/6, CHK2 checkpoint kinase 2, CaMKKβ calcium/calmodulin-dependent protein kinase kinase beta, HPF1 histone PARylation factor 1

HIF1α pathway

ROS regulate HIF1α by oxidizing Fe 2+ to Fe 3+ , which inhibits prolyl hydroxylases (PHDs) that degrade HIF1α via hydroxylation. 251 Notably, PHDs use iron, ascorbate, oxygen, and 2-oxoglutarate to hydroxylate and inhibit HIF1α, while ROS disrupt these interactions, causing HIF1α accumulation. Hypoxia-induced mito-ROS, particularly H 2 O 2, can also regulate HIF1α by promoting succinate accumulation (which inhibits PHD expression) via the reverse succinate dehydrogenase (SDH) activity. 252 Additionally, nitric oxide (NO) induces HIF1α expression by S-nitrosylating Cys800 or Cys520, preventing its binding to the Von Hippel‒Lindau (VHL) protein and proteasomal degradation. 253 ROS can also indirectly activate HIF1α through pathways such as the AMPK, PI3K/AKT, and MAPK pathways, which phosphorylate HIF1α at specific residues (e.g., Ser419, Ser641, and Ser643) 254 , 255 (Table 1 , Fig. 8a ).

AhR pathway

ROS, especially H 2 O 2 , activate the AhR pathway by accelerating the production of endogenous ligands like FICZ and kynurenine (Kyn). 256 Kou et al. reported that H 2 O 2 increases oxindole levels, a tryptophan catabolite, with its major form, 2-oxindole, effectively activating the AhR pathway. 257 Besides, H 2 O 2 and 2-oxindole were observed to promote PD-L1 and indoleamine-2,3-dioxygenase-1 (IDO1), two immune checkpoint proteins. 257 In glioma cells, IDO1 and TDO were shown to infuse the transformation of Trp into Kyn, followed by AhR activation. 258 , 259 Opitz et al. reported that Kyn is an endogenous oncometabolite that has the potential to activate AhR. 258 Moreover, UV-induced ROS phototransform Trp into FICZ, a potent AhR ligand, highlighting the role of ROS in modulating the tumor milieu via AhR signaling. 257 (Table 1 , Fig. 8a ).

NF-κB pathway

The NF-κB pathway involves five proteins (p50/p105, p52/p100, p65/RelA, RelB, and c-Rel) and operates through two pathways: the canonical pathway, triggered by receptors like TLRs and TNFR, activates p50-RelA via IKKβ and NEMO, while the noncanonical pathway, initiated by BAFF-Rs, activates p52-RelB through NIK and IKKα. 260 NF-κB is typically inhibited by IκB proteins, which are degraded upon phosphorylation by IKKs, enabling NF-κB activation.

ROS, like H 2 O 2 and superoxide, act as activators or inhibitors of NF-κB, while NF-κB has pro- or antioxidant effects depending on oxidative stress levels. Superoxide and H 2 O 2 activate TAK1, which phosphorylates IKKβ at Ser177 and Ser181, enabling IKKβ to degrade IκBα at Ser32 and Ser36, triggering NF-κB signaling. 261 TNF-α-induced ROS oxidize the dynein light chain (LC8), enabling its binding to IκB and promoting IκBα degradation by IKK, leading to NF-κB activation. 262 Besides, externally added H 2 O 2 directly phosphorylates IκBα at Tyr42 via SYK/SRC kinases, which induces the phosphorylation and nuclear translocation of the p65 protein. 263

Excessive ROS, on the other hand, oxidize the Cys62 residue of NF-κB p50, reducing its DNA binding ability; Notably, this residue is prone to oxidation in the cytoplasm but sensitive to reduction in the nucleus. 264 Moreover, prolonged and excessive ROS production may inactivate the proteasome, which plays a key role in degrading IκB, an inhibitor of NF-κB. 263 , 265 H 2 O 2 reduces TNF-α-induced IKK activity by oxidizing cysteine residues, impairing IκB degradation and diminishing NF-κB activation. 266 The same outcome was reported in the case of arsenite 267 and nitric oxide, 268 as the Cys179 residue of IKKβ was oxidized, 269 causing the inhibition of IKK.

In case of noncanonical pathway, IL-1β-induced H 2 O 2 activates NIK, leading to IKKα phosphorylation (Ser176/Ser180), which converts p100 to p52, initiating NF-κB. 270 Moreover, H 2 O 2 was also shown to mediate NF-kB activation in an IKK-dependent way by regulating the PI3K/PTEN/AKT signaling cascade. 271 However, this interaction remains debated owing to the complexity of the crosstalk between ROS and NF-κB signaling, as well as the variable outcomes in different experimental models (Table 1 , Fig. 8a ).

ATG4 pathway

H 2 O 2 can induce the oxidation of the Cys81 (in the vicinity of the catalytic Cys77) residue of ATG4A and ATG4B into sulfenic acid or through reversible oxidation of Cys77 and Cys81 into disulfide bridges. 272 However, Zheng et al. identified Cys292 and Cys361 as key sites of ATG4B oxidation function and subsequent autophagy mediation. 273 Interestingly, Zheng et al. also reported that H 2 O 2 treatment-induced oxidative modification of the Cys292 and Cys361 residues of ATG4 to restrict LC3 lipidation, leading to autophagy inhibition. 273 The discrepancy between these studies is due to varied autophagy-inducing systems and levels of ROS 274 (Table 1 , Fig. 8a ).

Calcium pathway

Several studies have reported ROS-induced Cys oxidation and subsequent overexpression of different TRP channels, which in turn activate Ca 2+ . influx. For instance, ROS oxidize the Cys616, Cys621/Cys258 and Cys742 residues of TRPV1; 275 the Cys553 and Cys558 residues of TRPC5; 276 and the Cys621, Cys421, Cys641 and Cys665 residues of TRPA1. 277 H₂O₂ activates TRPM2 by targeting Glu829 and Arg845, producing NAD metabolites such as ADP-ribose, which opens calcium channels and induces cell death. 278 ROS-mediated Ca 2+ activation in antitumorigenic signaling involves the potentiation of the Ca 2+ emission channel mucolipin-1 (MCOLN1/TRPML1) through palmitoylation of cysteine residues Cys565, Cys566, and Cys567 within the L564CCC motif on its C-terminal tail. 279 However, it remains unclear whether all three cysteine residues undergo palmitoylation or if modifications to Cys565 and Cys567 are sufficient to optimize Cys566 palmitoylation (Table 1 , Fig. 8a ).

EGFR pathway

ROS promote ligand-independent initiation of EGFR in several ways, involving EGFR phosphorylation at the Tyr845 residue, 280 and/or inhibition of EGFR inhibitory PTPs (at Cys124 and Cys71) and/or Cys797 oxidation of EGFR. 281 Interestingly, EGFR T790M activation was observed to promote NOX2-regulated ROS formation, which in turn promoted the oxidation of the Cys797 and Met790 residues of EGFR. 282 , 283 While Met790 oxidation is reversible, Cys797 oxidation on EGFR T790M further upregulates EGFR-NOX2, which increases ROS production, resulting in aberrant EGFR expression. This excessive phosphorylation of EGFR with a disrupted dimer structure leads to the development of TKI resistance in ROS-exposed EGFR-sensitive NSCLC cell lines. 282 , 283 On the other hand, high ROS levels have been reported to induce apoptosis and surmount TKI resistance, as when exposed to excessive ROS, ASK1 potentiation results in the initiation of JNK and p38 MAPK and the induction of apoptosis. 284 Leung et al. suggested that Sanguinarine aggregated excessive ROS by promoting the activation of NOX3 and consequential inactivation of MsrA and Cys peroxidation of EGFR T790M in EGFR-modulated TKI-resistant cells, which ultimately led to EGFR degradation and cell death 284 (Table 1 , Fig. 8b ).

Ras/MAPK (ERK) pathway

The most prominent mechanism of ROS-mediated ERK activation starts with the potentiation of EGFR. Once activated, EGFR interacts with SHC, leading to Tyr317 phosphorylation, which facilitates Grb2 binding and the formation of the SHC-Grb2-SOS complex, which is modulated by hydrogen peroxide. 281 After relocating to the plasma membrane, SOS activates Ras by promoting GTP binding. 281 Activated Ras initiates Raf, which phosphorylates MEK1 (Ser218, Ser222) or MEK2 (Ser222, Ser226), and MEK1/2 then activates ERK by phosphorylating Tyr185 and Thr183. 285 In addition, SRC kinases activated by ROS mediate ERK activation via Raf or EGFR signaling. 286 Furthermore, ROS can mediate the Ras-dependent activation of ERK by oxidizing the Cys118 residue of Ras. In addition, commensal bacterium-induced ROS oxidize DUSP3 Cys124, relieving ERK inhibition and activating ERK 287 (Table 1 , Fig. 8b ).

JNK (MAPK) pathway

ROS-induced JNK pathway activation involves MAPKKK (MEKK1/2/3/4, MLK, and ASK1)-induced phosphorylation of a MAPKK (MEK3/4/6/7) at Ser or Thr residues, which then phosphorylates a highly critical Thr-Pro-Tyr (TPY) motif of JNK, leading to the induction and nuclear translocation of JNK. 288 ROS reversibly oxidize TRX at the Cys32 and Cys35 residues, dissociating it from ASK1 (activation), which, in turn, activates JNK. 289 Additionally, ROS dimerize GSTP, disrupting its ability to suppress JNK, thereby enhancing JNK activity, with potential dimerization sites at Arg70, Arg74, Asp90, Asp94, and Thr67. 290 Besides, ROS directly activate ASK1 through homo-oligomerization and autophosphorylation at Thr838 or hetero-oligomerization with ASK2, where ASK2 phosphorylates Thr838 of ASK1 after its own autophosphorylation at Thr806 291 (Table 1 , Fig. 8b ).

p38 (MAPK) pathway

ROS-induced p38 activation mechanism involves several initial proteins involved in the JNK pathway, such as ASK1. ROS directly or indirectly affect ASK1, MEKK1/2/3/4, and MLK3, which subsequently activate MEK3/6 (highly conserved in the p38 pathway). 288 MEK activation further induces double phosphorylation of a critical TPY motif of p38 on tyrosine and threonine residues. 288 Besides, ROS have been found to mediate heterodimerization between Cys104 of MKK3 and Cys119 and Cys162, which forms a disulfide bond between p38α and MKK3, leading to p38α overexpression 292 (Table 1 , Fig. 8b ).

PARP1 pathway

Four PARP-1 domains—F1, F3, WGR, and CAT (catalytic)—are crucial for DNA damage-dependent activity, whereas the CAT domain, comprising the Helical Domain (HD) and ADP-ribosyltransferase (ART), is vital for activation. 293

Under oxidative stress, ROS-induced DNA damage triggers HD unfolding via a “leucine switch” (Leu698 and Leu701 repositioning), relieving autoinhibition and enabling PARP1 DNA binding and autoPARylation. 293 Regulatory factors like histone PARylation factor 1 (HPF1) modulate PARP1 activity during stress-induced DNA damage. HPF1 interacts with several critical residues (Trp1014, Ser1012, Leu985, His826, and Leu1013) in the catalytic domain of PARP1 through its Lys307, Asp283, Cys285, Phe268, and Phe280 residues in the C-terminal domain. 294 – 296 This binding induces ADP-ribosylation of serine residues in the HD domain of PARP1 (Ser499, Ser507, and Ser519). 295 , 296 HPF1 also recruits Arg239 to position Glu284 for serine ADP-ribosylation, relieving PARP1 HD autoinhibition. The PARP1-HPF1 complex enhances ADP-ribosylation on Asp/Glu/Ser residues in histones, PARP1, and chromatin factors 294 , 296 (Table 1 , Fig. 8b ).

ATM pathway

At moderate ROS levels, a few enzymes like PRDX2 and TRX1, can induce chemical alteration of the Cys2991 residue on ATM to generate a reversible disulfide bond. 297 Upon dimerization, ATM undergoes autophosphorylation at the Ser1981 residue, leading to the initiation of ATM. 298 Under excessive ROS levels, ATM triggers downstream sites such as p53 and checkpoint kinase 2 (CHK2) for activation even when the DNA damage response (DDR) is absent, indicating that the activation pathway has no impact on the role of ATM at a certain level, whereas ATM has many other functions independent of the DDR 297 (Table 1 , Fig. 8b ).

p53 pathway

Upon oxidative DNA damage, ROS-activated ATM autophosphorylates and activates p53 (via Ser15 phosphorylation) and CHK2, which further phosphorylates p53 at Ser20. 299 Stress-activated JNK and p38MAPK have also been shown to affect p53 activation upon exposure to H 2 O 2 . 299 p38 MAPK has been found to induce the phosphorylation of p53 at Ser15, 33, 37, and 46, 299 whereas JNK has been implicated in the phosphorylation of p53 at the Thr81 and Ser20 residues. 300 As mentioned earlier, H 2 O 2 expression results in dimerization and subsequent initiation of ASK1, which initiates p38 MAPK and JNK, stabilizing p53. 288 Notably, DNA damage-induced p53 activation is typically modulated by ATM, whereas redox signaling-dependent p53 activation is regulated by p38 MAPK signaling. 299 Although diamide-induced ROS initiate both JNK and p38 MAPK, p53 activation by diamide is regulated entirely by p38 MAPK. 299 Interestingly, while H 2 O 2 activates all the ATM, JNK, and p38 MAPK signaling, H 2 O 2 -induced p53 activation requires only ATM and JNK 299 (Table 1 , Fig. 8b ).

AMPK pathway

H 2 O 2 activates AMPK in HEK-293 cells via an AMP/ADP-dependent pathway involving mitochondrial respiratory chain inhibition. 301 Another mechanism by which hypoxia-induced ROS activate AMPK is via an AMP-independent pathway involving Ca 2+ release from the ER. Stromal interaction molecule 1 (STIM1) detects ER calcium depletion, translocates to ER-plasma membrane junctions, and activates Ca 2+ release-activated channels (CRAC) by tethering Orai proteins, triggering CaMKKβ activation, which phosphorylates AMPK at Thr172. 302 In addition, H 2 O 2 directly activates AMPK in HEK-293 cells by oxidatively modifying Cys299 and Cys304 of the AMPKα subunit 303 (Table 1 , Fig. 8b ).

However, Hinchy et al. reported decreased AMPK activity after 30 min of H 2 O 2 addition, as ATP/ADP ratios were restored and PRDX-SO 2/3 formation was increased. 304 The underlying mechanism might be that oxidative stress oligomerizes PRDXs, which may compete with other cellular proteins for thioredoxin-catalyzed cysteine thiol reduction.

Exploring ROS and ROS-driven mechanisms for therapeutic targeting

In pancreatic cancer, oxidative stress initially activates TIGAR and Nrf2 for survival, but prolonged stress reduces TIGAR, increases ROS, and promotes metastasis. 305 Blocking antioxidants delays tumor initiation but accelerates metastasis, whereas antioxidant intervention (e.g., N-acetyl-L-cysteine) suppresses metastasis in TIGAR-deficient models. In melanoma and lung cancer, antioxidants have been shown to promote metastasis, underscoring the potential efficacy of a pro-oxidant approach in this context. 306 , 307

Additionally, the dual roles of ROS enable the development of context-specific therapeutic strategies, ranging from ROS induction to scavenging, for combination cancer therapies. Cancer cells exhibit exceptional mitochondrial plasticity and metabolic reprogramming, allowing them to adapt to the nutrient-deficient tumor microenvironment and evade single-agent therapies by activating alternative survival pathways. 308 Although excessive ROS can effectively induce cancer cell death and serve as a promising anticancer strategy, they may also cause immunosuppression. Thus, combining ROS-elevating therapies with immunotherapy could optimize outcomes by counteracting immune suppression while targeting cancer cell resilience.

Targeting downstream molecules critical for ROS-mediated pathways, such as the NRX (Wnt/β-catenin), IKK (NF-κB), and ASK1 (MAPK) pathways, might be a potential antitumor therapeutic strategy. By targeting these signaling nodes, this strategy precisely modulates ROS-driven pathways, counteracting ROS-induced signaling without necessarily altering ROS levels. Finally, the heterogeneity of redox responses across cancer types, patients, and stages emphasizes the need for personalized approaches. A comprehensive set of parameters—including redox status, antioxidant enzyme expression, cell signaling profiles, and cancer-specific signaling—constituting a “redox signaling signature” for individual patients, is currently awaiting development. 309 Notably, regardless of the therapeutic strategy, ROS-targeted therapies fall into two main categories: modulating redox adaptation mechanisms (antioxidant defenses) and targeting ROS-generating systems (e.g., NOX, iNOS, and mitochondria).

Therapeutic leverage of ROS depletion in chemoprevention and cancer treatment

Antioxidants are commonly used as over-the-counter supplements to prevent cancer or in combination with chemo-/radiotherapy to reduce side effects and improve patients’ quality of life during treatment. This section and Table 2 summarize antioxidant agents with antineoplastic potential that modulate ROS in cancer and their ROS-mediated mechanisms of action. Table 2 Antioxidant agents with antineoplastic potential that modulate ROS in cancer and their ROS-mediated mechanisms of action Antioxidants Current status in Cancer therapy Indications Drug Target Key findings/ROS suppressive anticancer mechanism Refs. Phase NCT/NDA ID Status N-Acetyl-L-cysteine (NAC) II NCT04481035 Active, not recruiting Neurofibromatosis type 1 Glutathione synthetase NAC → ↓ROS → ↓p-AKT → ↓Telomerase activity → ↓Cell viability. 310 PCS: SMMC-7721 HCC cell lines Hepatocellular carcinoma Diphenylene iodonium PCS: Colon cancer cell lines Colitis-associated Colon cancer NOX DPI→ ↓ROS → ↓NF-κB/STAT3/ERK → ↓M1 macrophages → ↓Inflammation → ↓Tumor number/size/load, ↓ High-grade neoplasia. 312 GKT137831 PCS: NSCLC cells NSCLC NOX1/4 GKT137831 → ↓ NOX4 → ↓ROS → ↓YY1 → ↓IL-8 → ↓PD-L1 → ↓Angiogenesis/Tumor growth → ↑TKIs sensitivity. 313 Setanaxib (Optimized Successor of GKT137831) PCS: CAF-rich murine tumor models Lung, colon, Breast cancer NOX4 Setanaxib → ↓NOX4 in CAFs → ↓ROS → CAF “Normalization” →↓Immune suppression → ↑CD8, T-cell infiltration → Overcoming αPD-1/PD-L1 resistance. 314 Cyclodiaryl-iodonium (CDAI) PCS: PDX model Pancreatic cancer NOX CDAI → ↓NOX → ↓Non-mtROS, ↑mtROS (via ΔΨm depolarization) → ↓Respiration/↓Glycolysis →↓p53/NF-κB/GnRH → Selective tumor cell death. 315 Fangchinoline (Fan) PCs: NSCLC cells NSCLC NOX4 Fan → ↓NOX4 → ↓ROS → ↓AKT/mTOR signaling → EMT reversal → ↓Invasion & Migration → ↓Metastasis. 316 Vitamin E I NCT00985777 Completed Pancreatic Exocrine Neoplasia Peroxyl radicals Vitamin E → ↑Caspase-3 activation → Selective apoptosis in neoplastic cells → Tumor suppression. 317 Lycopene PCS: PANC-1 cell lines Pancreatic cancer Singlet oxygen ( 1 O 2 ) Lycopene → ↓ROS/OCR → ↓MMP → ↓NF-κB activation → ↓cIAP1/cIAP2/survivin → ↑BAX/BCL-2 ratio → ↑Caspase-3 → Apoptosis. 321 Dimethyl fumarate II NCT02546440 Completed Cutaneous T-cell lymphoma Keap1 ↓mSWAT score, ↓NF-κB, ↓Pruritus 322 Sulforaphane II NCT00843167 Completed Breast cancer ↓Ki-67 in DCIS tissue 324 NA NCT01265953 Completed Prostate cancer ↓AMACR, ↓ARLNC1 (Genes linked to prostate cancer pathogenesis) 325 Resveratrol I NCT00433576 Withdrawn Colorectal cancer 39%↑Caspase-3 326 I NCT00920803 Completed Colorectal cancer 5%↓Ki-67 327 Bardoxolone-methyl (CDDO-Me, RTA402) I NCT00508807 Completed Advanced solid tumors ↑Nrf2, ↑NQO1/γ-GCS, ↓NF-κB/STAT3, ↓Cyclin D1/COX-2/iNOS, ↑TUNEL, 10×↑Macrophages. 331 I NCT00529438 Completed Advanced malignancies ↑NQO1, ↓NF-κB, ↓Cyclin D1 332 L-NMMA I/II NCT02834403 Completed TNBC iNOS 45.8% OR, 27% CR, ↓M2 markers, ↓IL-6/IL-10, ↑CD15+ Neutrophils, ↓Tumor arginase. 340 ROS Reactive Oxygen Species, ↓ Inhibition/Depletion, ↑ Activation/Release, HCC Hepatocellular Carcinoma, NOX NADPH Oxidase, DPI Diphenyleneiodonium, NF-κB Nuclear Factor kappa-light-chain-enhancer of activated B cells, STAT3 Signal Transducer and Activator of Transcription 3, ERK Extracellular Signal-Regulated Kinase, AML Acute Myeloid Leukemia, MRC Mitochondrial Respiratory Chain, ΔΨm Mitochondrial Membrane Potential, OXPHOS Oxidative Phosphorylation, PDX Patient-Derived Xenograft, mtROS Mitochondrial ROS, GnRH Gonadotropin-Releasing Hormone, GSH Glutathione, SOD Superoxide Dismutase, CAT Catalase, MDA Malondialdehyde, AOPP Advanced Oxidation Protein Products, BCL-2 B-cell Lymphoma 2, BAX BCL-2-associated X protein, HLECs Human Lymphatic Endothelial Cells, CCL21 Chemokine (C-C motif) Ligand 21, NSCLC Non-Small Cell Lung Cancer, YY1 Yin Yang 1, IL-8 Interleukin-8, PD-L1 Programmed Death-Ligand 1, TKIs Tyrosine Kinase Inhibitors, CAFs Cancer-Associated Fibroblasts, αPD-1/PD-L1 Anti-PD-1/PD-L1, TNBC Triple-Negative Breast Cancer, pSTAT3 Phosphorylated STAT3, OCR Oxygen Consumption Rate, MMP Matrix Metalloproteinase, cIAP1/2 Cellular Inhibitor of Apoptosis Protein 1/2, mSWAT Modified Severity-Weighted Assessment Tool, AMACR Alpha-Methylacyl-CoA Racemase, ARLNC1 Androgen Receptor-regulated Long Non-Coding RNA 1, DCIS Ductal Carcinoma In Situ, NQO1 NAD(P)H Quinone Dehydrogenase 1, γ-GCS Gamma-Glutamylcysteine Synthetase, COX-2 Cyclooxygenase-2, iNOS Inducible Nitric Oxide Synthase, TUNEL Terminal deoxynucleotidyl transferase dUTP Nick End Labeling, OR Objective Response, CR Complete Response

Modulation of GSH metabolism

N-acetyl-L-cysteine (NAC) supports GSH metabolism by providing cysteine for GSH replenishment. A preclinical study suggested its selective anticancer potential by depleting ROS below the levels required for telomerase activation, disrupting redox homeostasis, and suppressing cancer cell proliferation. 310 Interestingly, NAC paradoxically lowers the GSH/GSSG ratio, as cancer cells require some ROS to maintain antioxidant capacity. Besides, reduced glutathione and NOV-002 are being clinically investigated for their potential to improve the quality of life of patients receiving chemo-/radiotherapy.

Inhibition of NOX-mediated ROS generation

Agents capable of targeting NOXs to scavenge ROS could offer considerable potential for cancer therapy. Among several small-molecule NOX inhibitors, Ebselen is under clinical study for mitigating chemotherapy-induced toxicity. 311 Diphenylene iodonium (DPI) suppresses early tumorigenesis in colitis-associated cancer by inhibiting ROS-driven NF-κB, STAT3, and ERK pathways, reducing inflammation. 312 GKT137831 disrupts the NOX4-ROS-YY1-IL-8-PD-L1 axis, lowering IL-8 and PD-L1 levels to impair angiogenesis, immune evasion, and Gefitinib resistance. 313 The optimized successor of GKT137831, Setanaxib, overcomes αPD-1/PD-L1 resistance by targeting NOX4 in cancer-associated fibroblasts, reversing their immunosuppressive phenotype, and enhancing CD8 + T-cell infiltration. 314 Cyclodiaryl-iodonium (CDAI) kills pancreatic cancer cells by blocking NOX, reducing nonmitochondrial ROS while inducing lethal mitochondrial ROS, disrupting energy metabolism and triggering p53/NF-κB/GnRH pathway chaos with minimal toxicity. 315 Fangchinoline inhibits NSCLC metastasis by reversing EMT and suppressing the NOX4-ROS-AKT-mTOR pathway. 316

Direct ROS scavenging

ROS scavengers directly neutralize ROS by donating electrons or hydrogen atoms. ROS scavengers, such as Vitamin E, Vitamin C, Vitamin D, Melatonin, Carotenoids, and Lycopene, interact with ROS by donating electrons or hydrogen atoms to free radicals. To date, numerous studies have explored the antineoplastic potential of ROS scavengers. Among them, a phase I clinical trial ( NCT00985777 ) provided evidence that Tocotrienol (Vitamin E) may induce apoptosis in PDAC cells. 317 Regarding anti-inflammatory activity, Vitamin D3 has been reported to decrease TNF-α-induced inflammation in lung epithelial cells through a reduction in mitochondrial fission and mitophagy. 318 A study reported that Melatonin inhibits angiogenesis by downregulating the HIF1α/ROS/VEGF pathway in HUVECs, 319 while its pro-oxidant activity may also contribute to anticancer effects, highlighting a context-dependent mechanism that warrants further investigation. 320 A phase II trial ( NCT00450749 ) suggested that Lycopene may slow prostate cancer growth, although the results were inconclusive. In PANC-1 cells, lycopene inhibits ROS-mediated NF-κB signaling and induces apoptosis. 321

Keap1 inhibition

Keap1 inhibition activates Nrf2 to upregulate antioxidant enzymes that neutralize ROS. For example, in cutaneous T-cell lymphoma (CTCL), DMF therapy has shown clinical efficacy by lowering mSWAT scores, relieving pruritus, and inhibiting NF-κB, as demonstrated in the NCT02546440 trial. 322 Sulforaphane targets Cys151 to inhibit the Keap1–Nrf2 interaction, boosting NAD(P)H:NQO1 expression and reducing lung inflammation in vivo. 323 A clinical trial ( NCT00843167 ) revealed that Sulforaphane reduces the expression of Ki-67 and other proliferation markers in DCIS and high-risk lung cancer patients. 324 Another trial ( NCT01265953 ) revealed that Sulforaphane downregulates the prostate cancer-associated genes AMACR and ARLNC1. 325 Besides DMF and Sulforaphane, other Keap1 inhibitors include Resveratrol, Quercetin, RTA-402, and RTA-408. Resveratrol induces caspase-3-mediated apoptosis (39% increase; NCT00920803 ) and reduces Ki-67-linked proliferation (5% decrease; NCT00433576 ) in hepatic metastases and colorectal cancer. 326 , 327 Quercetin activates Nrf2/Keap1 to reduce ROS, 328 while inducing ROS-dependent cell death in malignant cells, 329 , 330 underscoring its potential as both a chemopreventive and chemotherapeutic agent. Bardoxolone methyl (RTA 402) upregulates Nrf2 targets, suppresses NF-κB and cyclin D1, and induces tumor regression in advanced cancers. In trials ( NCT00529438 , NCT00508807 ), it achieved responses in several hematologic and solid tumors, with stabilization lasting 6–12 months. 331 , 332 Omaveloxolone (RTA 408) has also been reported to induce time- and dose-dependent activation of Nrf2 antioxidant genes ( NCT02029729 ). In addition, Genistein and Procyanidin B2 reduce carcinogen-induced ROS and DNA damage via Nrf2/ARE signaling in bronchial epithelial cells. 333

Utilization of SOD mimetics

Although SOD mimics have a lower rate constant than natural SOD enzymes, they effectively function in extracellular fluids lacking antioxidant enzymes. SOD mimics include Metalloporphyrins, Mn (II) polyamines, Mn(III) salens, Mn(III) corroles, and Mn(IV) biliverdins. 334 The Mn(II)-based compound GC4419 showed safety but no remission in mCRPC ( NCT01080352 ). Additionally, certain SOD mimics like Motexafin gadolinium, act as both prooxidative and antioxidative agents.

Xanthine oxidoreductase (XOR) inhibition

Inhibiting XOR (Xanthine oxidase and Xanthine dehydrogenase) offers a promising cancer therapeutic approach for reducing ROS generation during purine catabolism, thereby mitigating DNA damage, inflammation, and tumor progression. 335 Preclinical studies have shown that XOR inhibition enhances the effectiveness of the TKIs currently used in clinics against BCR-ABL in CML. 336 Hericium erinaceus , an edible mushroom, may treat breast cancer by inhibiting Xanthine oxidase, scavenging ROS, and suppressing cancer cell growth with minimal impact on normal cells. 337

iNOS inhibition

iNOS (inducible NOS) is highly overexpressed in many cancers and is correlated with poor prognosis in TNBC, making it a promising biomarker and therapeutic target. 338 Therefore, inhibiting iNOS can reduce ROS production, suppress tumor growth, and modulate immune responses. Andrographolide was shown to exert antitumor activity across multiple cancers by inhibiting iNOS. 339 In the NCT02834403 trial, combining L-NMMA with Taxane showed efficacy in treating chemorefractory breast cancer, particularly in advanced cases, with manageable toxicity. 340

Therapeutic leverage of ROS elevation in cancer treatment

Since the 1950s, various strategies/drug research have been implemented based on this concept, such as administering ROS or ROS-generating enzymes to tumor cell lines or murine models with tumors. 335 As documented in this section and Table 3 , antineoplastic agents/methods with ROS-inducing potential and their ROS-mediated antitumor mechanisms—compiled from sources including the FDA database ( www.fda.gov ), ClinicalTrials.gov, and DrugBank ( http://go.drugbank.com )—demonstrate diverse mechanisms of action ranging from metabolic interference to direct oxidative damage. Table 3 Antineoplastic agents/methods with ROS-inducing potential and their ROS-mediated antitumor mechanisms Name Clinal trial (CT)/FDA approval/PCS Indication Target Key findings/ROS-mediated anticancer mechanism Refs. Phase NDA/NCT ID Status Buthionine sulfoximine (BSO) I NCT00002730 Completed Neuroblastoma GSH BSO → ↓GSH→ Disrupted ETC →↓ΔΨm →↑ROS→Cell death. 342 Imexon 1 NCT00327288 Completed NSCLC, breast, prostate cancer Imexon → Binds thiols (↓GSH) →↑ROS → ↓Δψm →Apoptosis. 343 OSamp PCS: SW620 Colon cancer xenograft mouse model Colon cancer OSamp → Esterase/acid hydrolysis → ↓GSH + ↑ROS → ↓ΔΨm → Cyt c release → ↑Caspase-3, ↓STAT3 → Apoptosis. 344 LBL21 PCS: multiple cancer models NSCLC LBL21 → ↓ GSH → ↑ ROS →↓ΔΨm →↓CSC-SP cells →↓Tumor growth. 346 PEITC NA NCT03034603 Completed Head and neck cancer GSH, ETC-III, UPR ↓GSH, reactivation of p53, ↑SD response, ↑PFS. 347 Benzoyloxy dibenzyl carbonate (B2C) PCS: Multiple cancer xenograft mouse models Various cancers GSH B2C→ ↓GSH → ↑ROS → ↓ΔΨm → Caspase-3/PARP1 activation, BCL-2 cleavage → Apoptosis. 348 ACZ2 PCS: GC Xenograft mouse model Gastric cancer GSH, TRXR1 ACZ2 → ↓GSH/TRXR1 → ↑ROS → ↑PERK/EIF2α/ATF4/CHOP → ER stress → Apoptosis, Autophagy. 349 PX-12 II NCT00417287 Terminated Advanced pancreatic cancer TRX1 PX-12 → ↓TRX1 → ↑ROS → ↑Lipid peroxidation→ Ferroptosis. 353 I NCT00736372 Completed Metastatic cancer Arsenic trioxide NA NDA: 021248 (For RA) NA Leukemia TRXR1 ATO →↓ TRX1 → ASK1 activation → ↑SEK1 & JNK → ↑Apoptosis signaling. 355 Auranofin II NCT01419691 Completed Lymphocytic leukemia Ovarian cancer TRXR Auranofin → ↓TRXR → ↑ROS →↓ΔΨm → Caspase-3/7 activation, DNA damage → Apoptosis. 356 I NCT01747798 Completed Motexafin gadolinium (MGD) II NCT00134186 Completed Kidney neoplasms TRX MGD → ↓ TRX → ↑ ROS/ Oxidative stress →↓DNA repair → Apoptosis. 357 II NCT00129844 Completed NSCLC WZ35 (curcumin-derived analogs) PCS: Human gastric cancer cell lines Gastric cancer TRXR WZ35 → binds TRXR (Sec-498) → ↓ TRXR → ↑ROS→ Apoptosis → Cell death. 358 Piperlongumine (PL) PCS: Colorectal cancer cells Colorectal cancer TRXR, GSH PL →↓TRXR/GSH →↑mtROS → DNA damage, G2/M cell cycle arrest → ↑RT efficacy. 359 Shikonin PCS: NSCLC cells NSCLC TRXR1 Shikonin → Binds TRXR1 (Sec498) → ↓TRXR → Retains NOX activity → ↑ O 2 • − → ↑ ROS → Necroptosis. 360 LW-216 PCS: NCI-H460 Lung cancer xenograft mouse model NSCLC TRXR1 LW-216 → Binds TRXR1 (Arg371/Gly442) → ↓TRXR1 → ↑ROS → DNA damage → Apoptosis. 361 6-Shogaol PCS: HeLa cells Cervical cancer TRXR 6-Shogaol → ↓TRXR1 → ↑ROS → Apoptosis → Selective cytotoxicity (HeLa > Normal cells). 362 Nitrovin PCS: Zebrafish xenograft model Glioblastoma TRXR Nitrovin → Cytoplasmic vacuolation, ↑ROS → ↑MAPK, ↓Alix → Paraptosis (Caspase-3 independent) → Cell death. 363 ATN-224 II NCT00405574 Unknown Prostate cancer Superoxide Dismutase1 (SOD1) ATN-224 → ↓SOD1 → ↑ROS → ↓ΔΨm → Cell death. 364 , 365 TRIM22 PCS: Breast cancer cell lines Breast cancer TRIM22 → ↓CCS → ↓SOD1 → ↑ ROS → ↓STAT3→ ↓Tumor growth. 366 ARQ761 I NCT01502800 Completed Advanced solid tumors NQO1 ARQ761 →Futile redox cycling →↑ O 2 • − /H 2 O 2 → DSB → PARP1 hyperactivation → ↓NAD + /ATP → Apoptosis. 367 IP-DNQ PCS: NQO1 + pancreatic cancer cells Pancreatic cancer IP-DNQ → ↑ROS → DSB → PARP1 hyperactivation → Mitochondrial catastrophe, G2/M arrest → Apoptosis/Necrosis. 370 Cryptotanshinone (CTS) PCS: NQO1 high-expressing H460 lung cancer xenograft mouse model Lung cancer CTS → Binds NQO1 → ↑ROS → ↑JNK1/2 + PARP → ↑Iron/Ca 2+ → ↑ATP/NAD + → Necrosis. 371 Daphnetin (Daph) PCS: Ovarian cancer mouse xenograft model Ovarian cancer Daph → ↓NQO1 → ↑ROS → ↓TFR/ ↑ SLC40A1/ ↓ SLC7A11/ ↓ GPX4 → Fe 2+ accumulation, Lipid peroxidation → Ferroptosis. 372 CB-839 CT: Multiple cancers (Combination Therapy) Different cancers Glutaminase CB-839 → ↓Glutamate → ↓GSH synthesis → ↑ROS → Oxidative stress → Cancer cell death. 129 BIX01294 PCS: PDAC cells PDAC BIX01294 → ↓KDM6B → ↑Repressive histone marks (H3K27me3) at GLS promoter → ↓GLS → ↓Glutamine metabolism → ↑NADP + /NADPH ratio + ↓GSH → ↑ROS → ↑Caspase → Apoptosis. 374 2-DG I NCT00247403 Withdrawn Prostate cancer, solid tumors, intracranial neoplasms Hexokinase (Glycolysis) 2-DG → ↓Hexokinase→ ↓Glycolysis→ ↑ROS → ↑Caspase → Apoptosis. 375 Chloroquine (CQ) PCS: colorectal cancer HCT-116 cells Colorectal cancer CQ → ↓PDK1 → ↓Glycolysis →↓Δψm → ↑ROS → Apoptosis. 376 Lenvatinib PCS: HCC xenograft mouse models HCC GPX2 Lenvatinib → ↓β-catenin nuclear translocation → ↓GPX2 → ↑ROS→ apoptosis → HCC cell death. 377 FIN56 PCS: Bladder cancer cells Bladder cancer GPX4 protein FIN56 → ↓ GPX4 protein → ↑ROS→Autophagy→Ferroptosis. 378 Sulfasalazine PCS: Several cancer types Multiple cancers xCT/GPX4 SAS →↓xCT/GPX4 → ↑ROS → Ferroptosis. 379 Erastin PCS: Several cancer types Multiple cancers xCT/GSH/GPX4 Erastin →↓xCT/GPX4 → ↓ GSH → ↑ROS/MDA → Ferroptosis. 381 1,2-Dioxolane (FINO2) PCS: HT-1080 Fibrosarcoma GPX4 FINO2 → ↓ GPX4 (indirectly), ↓Co-Q10, ↑Iron oxidation→ ↑ROS → ↑ LPO→ Ferroptosis. 382 Bortezomib FDA Approved, NDA ID: 215441 Multiple myeloma Proteosome Bortezomib → ↓26S proteasome → ↑UPA → ↑ROS → NF-κB modulation → ↑NOXA → BCL-2 phosphorylation → p53 stabilization → ↑Caspase → Apoptosis. 384 CEP-18770 PCS: DAOY and UW228-2 cell lines Medulloblastoma CEP-18770 →↓Proteasome → ↑UPA → ↑ ER stress/ROS → p73 stabilization → DNA damage (γH2AX) →↑Caspase → Apoptosis → MB cell death. 386 Tryptanthrin (TRYP) PCS: Huh7 Liver cancer xenograft mouse model Liver cancer GSTP1 TRYP → ↓GSTP1 → ↑ROS → DNA damage → ↑NF-κB → SASP → Senescence→ ↑Susceptibility to apoptosis by ABT263 (BCL-2 inhibitor). 388 β-Sitosterol PCS: OC Xenograft mouse model Ovarian cancer ASS1/Nrf2 β-Sitosterol → Targets ASS1 → ↑Nrf2-Keap1 interaction → ↑Nrf2 ubiquitination/degradation → ↓HO-1/NQO1 → ↑ROS → ↑PTEN → ↓p-AKT → OC cell death. 390 ZIO-101 I NCT00592046 Completed Hematologic cancer NOX, mitochondrial disruption ZIO-101 → ↑ NOX (p67PHOX/ p47PHOX) →↑ROS → ↓ΔΨm→Cell death. 56 , 391 GNF362 PCs: Glioblastoma cell lines Glioblastoma ITPKB/NOX GNF362 → ↓ ITPKB-mediated NOX suppression→ ↑ NOX→ ↑ ROS → Restored TMZ sensitivity → Cancer cell death. 392 Elesclomol I NCT00827203 Suspended Solid tumors mitochondrial metabolism Elesclomol → Cu ( 2+ ) shuttling → Mitochondrial Cu (II) accumulation → ↑ROS → FDX1 reduces Cu ( 2+ ) to Cu ( + ) → Lipoylated DLAT oligomerization → Cuproptosis. 393 Fenretinide NA NCT02075177 NA Neuroblastoma ETC-II Fenretinide→ ↑mtROS (Complex II-dependent) → Cytoplasmic vacuolization (endosome accumulation) → Dynamin-dependent vesicle formation → Cell death (apoptosis/vacuole-associated). 394 Atovaquone PCS: Fhit-deficient lung cancer cell line Lung cancer ETC-III Atovaquone → ↓ETC -III → ↑mtROS → DNA damage → Apoptosis. 395 PDT III NCT00472108 Completed Basal cell carcinoma ¹O₂ m-THPC-PDT or VP-PDT→ Generates ¹O 2 /free radicals → ↑ROS → ↑ JNK →Autophagy/Apoptosis →Cell death. 401 III NCT00473343 Completed III NCT00472043 Completed CT Clinical Trial, PCS Preclinical Study, SAS Sulfasalazine, TRXR Thioredoxin Reductase, TRX Thioredoxin, GSH Glutathione, ROS Reactive Oxygen Species, ↓ Inhibition/Depletion, ↑ Activation/Release, ΔΨm Mitochondrial Membrane Potential, AIF Apoptosis-Inducing Factor, CG Calycosin-7-glucoside, SOD1 Superoxide Dismutase 1, CcOX Cytochrome c Oxidase, Nrf2 Nuclear Factor Erythroid 2–Related Factor 2, HO-1 Heme Oxygenase-1, GCLC Glutamate-Cysteine Ligase Catalytic Subunit, CCS Copper Chaperone of SOD1, GCLM Glutamate-Cysteine Ligase Modifier Subunit, EMT Epithelial-Mesenchymal Transition, DSB Double-Strand Break, PARP1 Poly(ADP-ribose) Polymerase 1, NAD+ Nicotinamide Adenine Dinucleotide, ATP Adenosine Triphosphate, IP-DNQ Isopentyl-Deoxynyboquinone, CTS Cryptotanshinone, NQO1 NAD(P)H Quinone Dehydrogenase 1, JNK1/2 c-Jun N-terminal Kinase 1/2, Daph Daphnetin, TFR Transferrin Receptor, SLC40A1 Ferroportin, SLC7A11 Solute Carrier Family 7 Member 11 xCT, GPX4 Glutathione Peroxidase 4, KDM6B Lysine Demethylase 6B, H3K27me3 Histone H3 Lysine 27 Trimethylation, GLS Glutaminase, GLUT1/4 Glucose Transporter 1/4, HK1/2 Hexokinase 1/2, PANoptosis Pyroptosis-Apoptosis-Necroptosis Hybrid Cell Death, GPX2 Glutathione Peroxidase 2, Co-Q10 Coenzyme Q10, LPO Lipid Peroxidation, UPA Ubiquitinated Protein Accumulation, NF-κB Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells, NOXA Phorbol-12-Myristate-13-Acetate-Induced Protein 1, p27/p21 Cyclin-Dependent Kinase Inhibitors, LC3-II Microtubule-Associated Protein 1A/1B-Light Chain 3-II, γH2AX Phosphorylated H2A Histone Family Member X, p73 Tumor Protein p73, GSTP1 Glutathione S-Transferase Pi 1, SASP Senescence-Associated Secretory Phenotype, Chac1 Glutathione-Specific Gamma-Glutamylcyclotransferase 1, MDA Malondialdehyde, Keap1 Kelch-like ECH-Associated Protein 1, HIF1α Hypoxia-Inducible Factor 1-Alpha, IRP1 Iron Regulatory Protein 1, SIT β-Sitosterol, ASS1 Argininosuccinate Synthase 1, OC Ovarian Cancer, PL Piperlongumine, mtROS Mitochondrial Reactive Oxygen Species, FDX1 Ferredoxin 1, DLAT Dihydrolipoamide S-Acetyltransferase, PTX1 Paclitaxel-Resistant Cell Line, PDT Photodynamic Therapy, ¹ O 2 Singlet Oxygen

GSH depletion

GSH inhibition causes severe ROS accumulation and increased oxidative stress, leading to cancer cell death. 341 BSO, a gamma-glutamylcysteine synthetase inhibitor, disrupts redox balance and sensitizes cancer cells to chemotherapy, 342 while Imexon generates ROS, causing DNA damage and apoptosis in multiple myeloma. 343 The hybrid anticancer drug OSamp depletes glutathione and generates ROS, selectively inducing oxidative stress and apoptosis in cancer. 344 Similarly, PEITC, a cruciferous phytochemical, selectively kills cancer cells by targeting GSH (along with ETC-III and the UPR) to induce ROS-mediated cell death, 345 with its synthetic analog LBL21 targeting stem-like cancer cells in NSCLC. 346 A trial revealed that Nutri-PEITC jelly improved PFS and quality of life in advanced oral cancer patients, which was correlated with p53 levels. 347 Benzoyloxy dibenzyl carbonate (B2C) generates Quinone Methide (QM) intermediates (GSH scavengers) upon hydrolysis, depleting GSH, enhancing ROS accumulation, and showing anticancer therapeutic potential. 348 Additionally, a recent study identified ACZ2 as a dual GSH/TRXR inhibitor, demonstrating its potential as a ROS-targeted therapeutic against gastric cancer. 349 Besides, DMF, another KEAP1-inhibiting antioxidant, paradoxically depletes GSH in MS patients, increasing ROS and mitochondrial stress to induce caspase-mediated memory T-cell apoptosis, thereby reducing neuroinflammation ( NCT02461069 ). 350 Many other studies have also reported ROS inducing potential of DMF, 351 , 352 suggesting selective anti-inflammatory mechanism of DMF that warrants further investigation.

Thioredoxin inhibition

The dysregulated TRX system often drives tumor progression and therapy resistance, making its targeted inhibition a potent ROS-mediated anticancer strategy. PX-12, a TRX1 inhibitor that binds to Cys73 of TRX, has shown promise across various cancers in preclinical and early clinical trials. 353 Another TRX1 inhibitor, Diallyl Trisulfide (Allitridin), a garlic-derived compound, inhibits TRX1 via Michael addition (Cys32 and Cys35), radiosensitizing glioblastoma. 354 Arsenic trioxide (ATO), an FDA-approved APL treatment, 355 and the repurposed antirheumatic drugs, Auranofin (AF) and Motexafin gadolinium (MGd) inhibit TRXR, inducing ROS to exert antitumor activity. 356 , 357 Curcumin has demonstrated anticancer activity through TRXR inhibition in preclinical and early clinical studies. 358 Piperlongumine (a dual TRXR/GSH inhibitor) demonstrates selective cytotoxicity in colon cancer. 359 Shikonin’s dual inhibition of TRXR and PKM2 induces necroptosis, whereas Nrf2 hyperactivation mediates resistance, which can be reversed through metabolic targeting. 360 Novel agents such as LW-216 (Sec498-targeted TRXR1 degradation), 361 6-shogaol (selenocysteine inhibition), 362 and Nitrovin induce caspase-3-independent paraptosis via MAPK/Alix modulation. 363

SOD inhibition

Inhibiting SOD, especially SOD1, prevents superoxide conversion, increasing ROS, thereby selectively targeting cancer cells. ATN-224 (Tetrathiomolybdate), a copper-chelating agent, depletes cellular copper, a cofactor essential for SOD1 activity, causing oxidative stress and cancer cell death, with promising preclinical and clinical results. 364 , 365 A recent study suggested that the E3 ligase TRIM22 functions as a tumor suppressor in breast cancer by degrading CCS (copper chaperone of SOD1), thereby reducing the copper supply to SOD1, impairing SOD1 activity, increasing ROS levels, and suppressing STAT3-dependent oncogenic pathways. 366

NQO1 inhibition

NQO1, overexpressed in cancers but minimally expressed in normal tissues, offers a tumor-specific therapeutic target through redox cycling, generating cytotoxic ROS. β- Lapachone (ARQ761) induces DNA damage, PARP1 hyperactivation, and apoptosis in an NQO1-dependent manner ( NCT02514031 ). 367 Another NQO1 substrate, ARQ501, was shown to cause stable disease in a phase 1 trial, 368 and DNQ is 10-fold more potent than β-lapachone. 369 However, these agents cause methemoglobinemia, a limitation overcome by DNQ derivative Isopentyl-DNQ (IP-DNQ) in pancreatic cancer. 370 Cryptotanshinone (CTS) binds NQO1 noncatalytically, triggering ROS/JNK1/iron/PARP/calcium-mediated necrosis, 371 while Daphnetin inhibits NQO1 to induce ferroptosis in ovarian cancer. 372

Inhibition of glutamine (Gln) metabolism

Inhibiting glutamine metabolism disrupts GSH and NADPH synthesis, elevating ROS, which impairs tumor growth and induces cancer cell death. 129 Glutaminase inhibitors, such as CB-839 (Telaglenastat), BPTES, and Compound 968, disrupt Gln metabolism, depleting GSH and increasing ROS to induce cancer cell death. 129 Additionally, the ASCT2 inhibitor, V-9302 blocks Gln uptake, impairing tumor growth and enhancing immunity via ROS-mediated B7H3 degradation. 373 A novel glutaminase inhibitor, BIX01294, suppresses pancreatic cancer by inhibiting KDM6B-mediated glutaminase expression, thereby disrupting redox balance. 374

Glycolysis inhibition

Glycolysis inhibitors (2-DG, Metformin, Lonidamine, and 3-BP) target hexokinase to disrupt the Warburg effect in cancer cells, impairing energy production and inducing ROS-mediated selective cell death. 375 In a recent study, Chloroquine (CQ) was found to inhibit hypoxia-induced growth of colorectal cancer cells by suppressing glycolysis and NAD⁺ production through PDK1 inhibition. 376 This leads to mitochondrial dysfunction, excessive ROS generation, reduced membrane potential, and apoptosis via PARP cleavage and caspase activation. Despite their antitumor efficacy, glycolysis inhibitors lack selectivity because of the role of glycolysis in normal cells; targeting cancer-specific isoforms (e.g., PKM2) or using nanocarriers could enhance specificity and reduce toxicity.

Inhibition of GPXs

GPX inhibition disrupts redox balance, inducing oxidative stress and offering a ROS-targeted cancer therapy approach. 14 For instance, Lenvatinib blocks GPX2 in liver cancer, causing ROS buildup and apoptosis. 377 Similarly, targeting xCT/GPX4, a critical regulator of lipid peroxidation, with compounds such as FIN56, Erastin, Sulfasalazine and RSL3 induces ferroptosis. 378 – 381 Interestingly, a recent study suggested that RSL3 may induce cell death primarily through the inhibition of TRXR1 rather than the suppression of GPX4, highlighting the need for further studies to elucidate the precise mechanisms by which RSL3 triggers ferroptosis. 380 FINO2 indirectly inhibits GPX4 activity (unlike Erastin and RSL3) without depleting GPX4 protein (unlike FIN56), while also oxidizing iron to drive ferroptosis. 382

Inhibition of the ubiquitin–proteasome pathway

Proteasome inhibitors represent a promising anticancer strategy by disrupting protein homeostasis and inducing ROS. 383 Bortezomib treats multiple myeloma by blocking the 26S proteasome, increasing ROS, and upregulating proapoptotic proteins such as NOXA. 384 Disulfiram (in combination with copper) has been shown to inhibit both the proteasome and SOD1, amplifying oxidative stress. 222 Experimental inhibitors such as MG132, Epoxomicin, Marizomib, and Lactacystin also induce ROS-dependent apoptosis across various cancers. 385 Another novel proteasome inhibitor, CEP-18770, demonstrates superior and more sustained dose-dependent suppression of tumor proteasome activity than Bortezomib in medulloblastoma. 386

GSTP inhibition

Overexpression of GSTP is frequently observed in multiple cancers, positioning it as a compelling therapeutic target for ROS-driven anticancer strategies. 387 While known inhibitors (e.g., Ethacrynic Acid derivatives, NBDHEX, TLK199, LAS17, and CNBSF) exist, their ROS-linked mechanisms remain incompletely characterized. 387 A recent study identified GSTP1 as the target of Tryptanthrin (TRYP), which binds and inhibits GSTP1, triggering ROS accumulation, DDR, and senescence initiation. 388

Nrf2 inhibition

Nrf2, frequently overexpressed in therapy-resistant cancers, represents a promising therapeutic target for ROS-mediated anticancer strategies, as demonstrated by Tamoxifen-resistant breast cancer cells that develop irradiation cross-resistance through Nrf2-driven antioxidant upregulation and a glycolytic shift, with Nrf2 inhibition restoring radiosensitivity in both cellular models and patient tumors ( NCT00738777 ). 389 This approach is further validated by the agent β-Sitosterol, which indirectly modulates Nrf2 through ASS1 and then induces ROS-mediated cell death in ovarian cancer. 390

NOX activation

NOX activation drives ROS generation in cancer therapy, exemplified by ZIO-101 (Darinaparsin), which induces NOX-mediated ROS production and mitochondrial disruption, triggering apoptosis in hematologic and solid tumors. 391 While its precise mechanism—including potential NOX subunit (e.g., p67phox, p47phox) involvement—requires further elucidation, ZIO-101’s dual action of ROS induction and mitochondrial impairment effectively promotes cancer cell death. 56 , 391 A study on recurrent glioblastoma observed that elevated inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB)—due to reduced Trim25-mediated degradation—suppresses NOX enzyme activity, lowering ROS production and enabling resistance to Temozolomide (TMZ). Depleting ITPKB or inhibiting it with GNF362 reactivated NOX, increased ROS levels, and restored TMZ sensitivity in resistant GBM cells. 392

Targeting ETC

Elesclomol and Fenretinide exploit this mechanism: Elesclomol binds to mitochondrial copper, disrupting ETC function and increasing ROS, 393 whereas Fenretinide interferes with mitochondrial complex II to elevate superoxide. 394 Loss of Fhit protein is observed in most cancers. Atovaquone, a repurposed antimalarial drug, acts as a selective OXPHOS inhibitor by targeting the CoQ10-dependent mitochondrial complex III, causing electron leakage, ROS production, and cell death, as observed in Fhit-deficient lung cancer cell lines. 395 Phenformin, a metformin analog, inhibits complex I to generate ROS and shows promise in preclinical and early-phase trials for treating HCC and glioma. 396

Pharmacological ascorbate

Ascorbate (vitamin C) acts as a pro-oxidant under certain conditions, generating ROS in the presence of transition metals like iron. 397 In a Phase II trial ( NCT02420314 ) for advanced NSCLC, Ascorbate combined with Carboplatin and Paclitaxel inhibited tumor growth through H₂O₂ generation, iron modulation (higher transferrin linked to improved PFS), and immune activation (4.2-fold increase in CD8 + T cells), achieving a 34.2% response rate and a 12.8-month median OS. 398 Another trial ( NCT02344355 ) in glioblastoma patients reported improved survival (19.6 vs. 14.6 months), with the greatest benefit in IDH-mutant tumors (53.1 months) and those with high MRI-detected iron, where vitamin C-induced Fe 3+ reduction to Fe 2+ enhanced chemo-radiation sensitivity. 397

Conventional anticancer agents

Chemotherapeutic drugs (e.g., Doxorubicin, Paclitaxel, Cyclophosphamide, and 5-Fluorouracil) often induce ROS via a secondary mechanism (including mitochondrial dysfunction, DNA damage, depletion of NAD + and ATP, and destabilization of microtubules) to enhance their cytotoxic effects. 399 That their anticancer efficacy can be regulated by exposure to antioxidants suggests that their ROS-inducing capacity can be exploited for developing cancer therapies. Ionizing radiation (IR) produces ROS via water radiolysis, causing oxidative damage. 400 PDT employs photosensitizers that generate ROS, primarily ¹O 2 , upon light activation, causing oxidative damage and inducing cancer cell death. 401 PDT has shown efficacy in Phase III trials for basal cell carcinoma, improving tumor reduction and quality of life, but is limited by light penetration depth and photosensitivity. A previous study suggested that MLu (lutetium texaphyrin), an analog of MGd, acts as a photodynamic sensitizer under light irradiation to generate excessive ROS, which activate caspase-3. Caspase-3 then cleaves GSDME, releasing its pore-forming N-terminal fragment, thereby leading to pyroptosis. 402

In addition to conventional approaches, several strategies targeting metabolic vulnerabilities and stress response pathways have emerged as promising ROS-mediated antitumor therapies. ER stress induction—via agents like Bortezomib or natural compounds such as Triptolide—triggers UPR activation and ROS-mediated cell death in malignancies with a high proteostatic burden. 403 IDH1/2 inhibition disrupts NADPH homeostasis, weakens redox defenses and induces oxidative damage. Vorasidenib, a brain-penetrant IDH1/2 inhibitor, showed efficacy in a Phase III trial for IDH-mutant glioma ( NCT04164901 ) by reducing GSH, increasing ROS, and enhancing therapeutic effects. 404 DDR pathway inhibitors (e.g., ATM, CHK1, and PARP inhibitors) exacerbate oxidative stress by impairing repair processes and antioxidant functions. 405

ROS-responsive pathway/cellular process-targeted therapy: potential targets

This approach is particularly relevant in diseases like cancer, where ROS dysregulation promotes pathological modulation of cellular processes/pathways. This section and Table 4 include different potential targets specific to different ROS-mediated cellular processes or pathways, as well as potential therapeutic strategies for mitigating cancer. Table 4 Potential targets and therapeutic strategies for different ROS mediated cellular processes and pathways Pathway/cellular process Potential target Potential therapeutic strategy Refs. PI3K/AKT, EGFR, JAK/STAT, and ERK1/2 PTPs PTP activation 231 Wnt/β-catenin NRX NRX activation 71 ERK MEK (1/2) MEK (1/2) inhibition 285 JNK ASK1 ASK1 activation 288 p38 JAK/STAT JAK2 JAK2 inhibition 77 Apoptosis BCL-2 family, caspase family Cellular context-based modulation 157 , 158 Ferroptosis xCT, GPX4, FSP1, DHODH, GCH1 Cellular context-based modulation 188 Pyroptosis NLRP3 inflammasome, GSDMD, caspase family, and NF-κB Cellular context-based modulation 202 , 203 Necroptosis RIPK1/3, MLKL Cellular context-based modulation 184 NETosis MPO, NE, PAD4 Cellular context-based modulation 6 , 217 Oxieptosis KEAP1-PGAM5-AIFM1 Cellular context-based modulation 216 PI3K/AKT Phosphoinositide 3-Kinase/Protein Kinase B, EGFR Epidermal Growth Factor Receptor, JAK/STAT Janus Kinase/Signal Transducer and Activator of Transcription, ERK1/2 Extracellular Signal-Regulated Kinase 1/2, NF-kB Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells, Wnt/β-catenin Wingless-related integration site/β-catenin, ERK Extracellular Signal-Regulated Kinase, JNK c-Jun N-terminal Kinase, NRX Nucleoredoxin, MEK (1/2) Mitogen-Activated Protein Kinase Kinase 1/2, ASK1 Apoptosis Signal-Regulating Kinase 1, JAK2 Janus Kinase 2, xCT Cystine/Glutamate Transporter (SLC7A11 subunit), GPX4 Glutathione Peroxidase 4, FSP1 Ferroptosis Suppressor Protein 1, DHODH Dihydroorotate Dehydrogenase, GCH1 GTP Cyclohydrolase 1, NLRP3 inflammasome NOD-LRR- Pyrin Domain-Containing Protein 3 inflammasome, GSDMD Gasdermin D, RIPK1/3 Receptor-Interacting Protein Kinase 1/3, MLKL Mixed Lineage Kinase Domain-Like Pseudokinase, MPO Myeloperoxidase, NE Neutrophil Elastase, PAD4 Peptidyl Arginine Deiminase 4, Keap1 Kelch-like ECH-Associated Protein 1, PGAM5 Phosphoglycerate Mutase 5, AIFM1 Apoptosis-Inducing Factor Mitochondrial 1

Potential targets in the ROS-responsive pathway

As PTP inhibition might modulate several oncogenic pathways, developing small molecules to activate or protect PTPs from oxidative modification offers therapeutic potential. A study observed TRXR1 to exhibit potential in protecting PTP1B from oxidative inhibition by H 2 O 2 . 406 NRX, a redox-sensitive regulator of Dvl proteins, modulates Wnt/β-catenin signaling; its ROS-mediated inactivation promotes excessive self-renewal of hematopoietic stem/progenitor cells (HSPCs) in myelodysplastic syndrome (MDS). 407 Although no direct activators exist, antioxidants (e.g., NAC, Ascorbic acid) and redox modulators (e.g., Ebselen, Curcumin) may influence NRX activity. Notably, as a TRX subfamily member, NRX itself supports antioxidant defense by protecting enzymes like catalase from ROS-induced oxidation, enhancing H 2 O 2 detoxification. 408 Furthermore, its downregulation might reduce β-catenin levels and cause a carcinogenic shift, 240 warranting further exploration of its therapeutic potential in redox control and Wnt signaling.

Targeting JAK2 in JAK/STAT pathway might offer a promising strategy to disrupt the ROS-STAT pathway. JAK2 inhibitors such as AG490 and Ruxolitinib reverse ROS-induced STAT activation and mitigate pSTAT3-driven ICAM-1 and PD-L1 induction. 409 Similarly, inhibiting Ras and MEK1/2 offers another anticancer therapeutic approach by blocking the ROS-ERK pathway. For example, Alendronate sodium blocks Ras prenylation to induce G1 arrest and apoptosis by inhibiting ROS-mediated ERK1/2 signaling. 410 The MEK inhibitor PD98059 suppresses ROS-induced ERK1/2 activation, reducing glial fibrillary acidic protein (GFAP) expression (a marker of gliosis). 411

Targeting ASK1 activation in the JNK and p38 pathways represents another potential therapeutic strategy, as various compounds can induce apoptosis through the ROS-ASK1-JNK/p38 axis. Flexicaulin triggers ROS/ASK1/JNK activation in esophageal cancer, 412 while Quercetin induces AMPK-α, ASK1, and p38/caspase-dependent apoptosis. 413 Daidzein and Gefitinib synergistically promote c-Jun translocation via this axis. 414 Additionally, Catechol-containing polyphenols induce ROS via tyrosinase-mediated oxidation, triggering ASK1/JNK/p38 signaling and apoptosis in A375 melanoma cells. 415

Potential targets in ROS-responsive cellular processes

The BCL-2 family and caspase family are potential therapeutic targets in ROS-mediated apoptosis. 157 , 158 Targeting these molecules involves many pathways and molecules, including ER stress pathways (UPR sensors, CHOP, and calcium signaling), p53 tumor suppressors (which regulate the BAX/BCL-2 balance), mitochondrial apoptosis (cytochrome c release and caspase activation), and antioxidant systems (TRXR inhibition and GSH depletion). 44 , 157 , 158 Therefore, therapeutic strategies involve ROS-inducing agents (prooxidant drugs, TRXR/GSH inhibitors), ER stress inducers, p53 reactivators, and combination therapies (e.g., with PARP inhibitors or immunotherapy).

The ferroptosis defense network includes multiple parallel antioxidant systems—xCT/GPX4, FSP1/CoQ10, DHODH, and GCH1/BH4—which prevent lipid peroxidation, presenting key therapeutic targets. Besides xCT/GPX4 inhibition (by Erastin/Sulfasalazine/RSL3), 379 – 381 FSP1 inhibitors (iFSP1, Liproxstatin-1) and DHODH blockers (TPP-brequinar/B2, Leflunomide) disrupt organelle membranes and mitochondrial antioxidants, respectively. 416 – 419 GCH1 suppression (by Gambogenic acid) amplifies ROS by depleting BH4, as evidenced in NSCLC. 420 Notably, multitarget agents like Brequinar (DHODH/FSP1) exploit the system’s redundancy, selectively targeting cancer cells, especially in OXPHOS-dependent or immunotherapy-resistant malignancies. 421 The NLRP3 inflammasome-GSDMD-caspase-1/NF-κB axis represents a pivotal but context-dependent target in ROS-mediated pyroptosis, but NLRP3 has dual roles in disease pathogenesis. 422 Therefore, precision modulation is critical: inhibitors (MCC950) for inflammatory diseases versus activators (Saikosaponin-D, Baicalin) for immunogenic tumor killing. 422 – 424 Additionally, emerging agents like Gambogic acid targets ROS/caspase-3/GSDME, while Shikonin, GEFT, and Paris saponin-7 modulate ROS-GSDM signaling to induce pyroptosis in several cancers. 425 – 428

Targeting the Keap1/PGAM5/AIFM1 axis in ROS-mediated oxieptosis could selectively amplify oxidative stress to induce programmed cell death in cancer cells, offering a novel therapeutic strategy. In cancer cells, including CRC cells, ROS inducers like Sanguinarine (SNG) trigger Keap1-PGAM5-dependent cytotoxicity by inducing oxieptosis. 216

RIPK1/3 and MLKL, as central mediators of necroptosis, are promising therapeutic targets in ROS-driven necroptosis. 184 However, RIPK1 modulation is governed by phosphorylation, with activation driven by autophosphorylation at Ser161 and Ser166 and ROS-induced modifications. 429 Conversely, inhibitory phosphorylation by TAK1, MAP kinase-activated protein kinase 2 (MAPKAPK2), IKKα/β (at Ser320/Ser321, Ser336, and Ser25), and ULK1 (at Ser357) restrains RIPK1-mediated cell death, 430 suggesting residue-specific modulation of these targets. Additionally, agents like Acetylshikonin, RETRA, and Erigeron breviscapus induce RIPK1/RIPK3/MLKL-dependent necroptosis, indicating their antitumor potential. 431 – 433

MPO, NE, and PAD4 are key targets in ROS-mediated NETosis. While in early-stage cancers, antitumor N1 neutrophils dominate, suggesting that NETosis induction could enhance tumor cell killing, 434 its inhibition in advanced stages can block protumor N2 neutrophil effects. ROS scavengers like Kaempferol suppress NETosis and reduce lung metastasis in a mouse breast tumor model by targeting the ROS-PAD4 pathway. 435

Targeting cancer vulnerabilities via a combination approach

ROS-modulating combination therapies have become integral components of many adjuvant and neoadjuvant cancer treatment regimens, addressing the complexity and adaptability of ROS-mediated cancer cell biology. The anticancer combination therapeutic strategies leveraging ROS for anticancer effects are discussed in this section and in Table 5 . The data concerning the antitumorigenic strategies have been collected from www.fda.gov , http://clinicaltrials.gov , http://go.drugbank.com , and different works of literature. Table 5 List of anticancer combination therapeutic strategies leveraging ROS for anticancer effects Combination Compound(s)/techniques Key findings/ROS-mediated antitumor mechanism Current status in cancer therapy Refs. Coinhibition of TRXR and GLS Auranofin (Au) + CB-839 Auranofin + CB-839 → ↑TRXR1 & glutamine→ ↑ROS → ↓Viability in Glutamine-free media & MYC-high HGSOC cells PCS: HGSOC PDX models 436 Coinhibition of TRXR and GSH Auranofin + Loss of GSR (GSH Pathway) GSR (GSH pathway) loss + Auranofin → ↑ROS (synergistic oxidative stress) → Apoptosis → ↑Sensitivity of NSCLC cells to TRXR inhibition PCS: NSCLC cells 437 Coinhibition of thioredoxin system and SOD Auranofin + ATN-224 Auranofin + ATN-224 → ↑ROS → Resensitization to β-lapachone PCS: A549 NSCLC cells (KEAP1 MUT ) 438 Coinhibition of TRXR and GSTP Auranofin + Piperlongumine (PPL) Au +PPL→ ↓GSTP1 → ↑ROS & nM-range ↓IC 50 vs. Au alone PCS: Glioblastoma stem cells (GSCs) 439 Coinhibition of TRX and proteasome Auranofin + Bortezomib Auranofin + Bortezomib → GSH depletion via ATF4/CHAC1 axis/↑ROS → Proteotoxic stress→ ER & mitochondria dilation→ Selective paraptosis in breast cancer cells with reduced toxicity risk PCS: Breast cancer cells 440 TRXR inhibition and chemotherapeutic drug Withaferin A + Sorafenib Withaferin A + Sorafenib→ ↓TRXR1 → ↑ROS → DNA/ER stress→ Apoptosis (ATF4-dependent) → HCC tumor suppression PCS: HCC xenograft models 441 TRXR inhibition and DDR targeting drugs Auranofin + Cyst(e)inase Auranofin + Cyst(e)inase→ 6–12× ↑ROS, 80-89% ↑ DSB, Significant ↑Cell death vs. Monotherapy PCS: Prostate cancer cell lines 442 TRXR inhibition and NP-based delivery system PL-Au@P-ZnO NRs + SDT PL-Au@P-ZnO NRs + US → 4.5× ↑ ROS vs. Untreated, ↓Cell Viability with dose PCS: MCF-7 cell lines 443 MbO 2 @Gd-NTs +RT MbO 2 @Gd-NTs +RT → 15.4× ↑ ROS, 11.8× ↑ DSBs, 1.2× ↑Apoptosis vs PBS + RT PCS: Lewis lung cancer xenograft model 444 CM-Coated MSNs/Ce6/Cur + PDT CAM-MSN/Ce6/Cur → Homologous targeting → ↓TRXR1/2, ↑PDT → ↑ROS → Tumor inhibition PCS: CAL-27 cell line 445 Mitochondria targeting drug and GPX inhibition Artemisinin + RSL3 Artemisinin + RSL3 → ↓GPX4 (Weak ↓GPX4 by Artemisinin) → ↑ROS →↑Ferroptosis, Apoptosis PCS: Breast cancer cells 446 Mitochondria targeting drug and NQO1 inhibition FRV–1 + Dicoumarol Dicoumarol + FRV-1 → D-state Complex I inhibition, ↓OXPHOS, ↓NQO → ↑mtROS → ↓ATP/Δψm → ↓Viability (vs FRV-1 alone) in NQO1 + cells PCS: NQO1-positive BC cells 447 Mitochondria and DDR targeting drugs Elesclomol + Rucaparib (Ru)/Talazoparib (Tala) Ruca/Tala + Elesclomol (Synthetic lethality) → 100× ↑Elesclomol sensitivity→ ↑ROS → ↓Viability in BRCA1-mutant (↓BER) vs. Wild-type PCS: BRCA1-mutated cancer cells 448 Mitochondria and ER stress targeting drugs EMT-NPs EMT-NPs → ER (↑IRE1α/ ↑ CHOP → ↑Ca 2+ ), Mitochondria (↓MMP → ↑Cyt c) →↑ROS →↑Caspase-12/3 → Apoptosis PCS: A549 NSCLC CDX and ovarian cancer PDX model 449 Mitochondria targeting SDT-proteasome inhibition IR-820@NBs + MG-132 + SDT IR-820@NBs + US + MG-132 (Synergistic tumor suppression) → ↓ΔΨm → ↑ROS →↑Apoptosis, ↑Autophagy → ↓Viability, ↓Migration/Invasion PCS: HEPG2 HCC cell lines 450 Mitochondria targeting drug with chemotherapeutic drug Elesclomol Sodium + Paclitaxel Elesclomol Sodium + Paclitaxel→ ↑ROS, 2× ↑PFS, 41.7% ↓ DPR, ↑OS vs. Paclitaxel alone CT, Phase II, Metastatic melanoma 451 76% ↑ PFS (in Normal LDH), NSD vs. Paclitaxel alone (in Elevated LDH) CT, Phase III, Metastatic melanoma 452 Mitochondria targeting drug and glycolysis inhibition Elesclomol + (2-DG/3-BP) Elesclomol + 2DG/3BP →↓Rapid ΔΨm, ↓Lactate →↑ROS → Additive ↑ cell death PCS: MCF7 and MDA-MB-231 breast cancer cells 453 EP13 + (Oxamate/2-DG) EP13 + Oxamate/2-DG→ ↓ETC I, ↓OXPHOS, ↓Glycolysis→ ↑ROS → ↓Cell viability PCS: MCF7 and MDA-MB-231 breast cancer cells 454 Mitochondria targeting drug and nanoparticle-based delivery system CAT/CPT-TPP/PEG-Ce6 (CTC) CTC Micelles → ↑Mitochondrial ROS → ↑ICD → ↓Tumor growth (Primary/Distant), Immune activation PCS: Hypoxic 4T1 TNBC mouse model 455 AuCu-Ce6-TPP (ACCT) ACCT + X-ray→ ¹O 2 /OH•, ↓(HIF1α/H 2 O 2 ) → ↓Hypoxia→ Cell death in 4T1 cells PCS: Hypoxic 4T1 TNBC mouse model 456 CuFe 2 O 4 - Metformin (MET)- BAY-876 (CFMB) CFMB → ↓GLUT1/ ↓ HK, ↓OXPHOS → ATP Crisis → ↑Cu + /↑Fe 2+ release → ↑OH• →Tumor death PCS: Hypoxic 4T1 TNBC mouse model 457 CeO 2−x -MET-GOx@PDA/BSA (CPGMB) CPGMB → ↓HK2/↓Glucose → ATP Crisis → H 2 O 2 → O 2 (hypoxia relief)/OH• → Tumor Ablation PCS: 4T1 breast cancer mouse model 458 TPP-GOX-CAT-PpIX (tGCP) tGCP →↓Glucose, ↑H 2 O 2 , ↑O 2 , ↑¹O 2 → ↑ROS →Apoptosis →Tumor Regression PCS: 4T1 breast cancer mouse model 459 NP@ESCu + anti-PD-L1 NP@ESCu + anti-PD-L1 → ROS-triggered ES/Cu release→ Cuproptosis, Immune reprogramming →Tumor regression PCS: Bladder cancer mouse model 460 TPP-T-Ce6- FX11 TPP-T-Ce6- FX11 → GSH-triggered release → ↓Glycolysis → ↑Mitochondrial ROS → ATP crisis → Tumor regression PCS: MCF-7 breast adenocarcinoma xenograft mice model 461 Glutaminase inhibition and chemotherapeutic drug CB-839 + Cabozantinib 42% ORR, 100% DCR, with 50% ORR CT, Phase I for mRCC 462 CB-839 + Azacitidine 70% CR CT, Phase Ib/II study for high-risk MDS 464 Dual inhibition of glutamine metabolism LL202 (GLS1i) + V9302 (ASCT2i LL202 + V9302(Synergy) → ↓Glutamine uptake/metabolism → Energy stress ( ↑ AMPK), ↓Nrf2/HO-1) → ↑ROS→ ↑DNA damage → ↓Proliferation PCS: Osimertinib-resistant H1975OR xenografts lung cancer model 465 Targeting glutamine metabolism and NQO1 BPTES/CB-839 + ß-Lap BPTES/CB-839 + ß-Lap → ↓NADPH, ↑ROS → DNA damage → PARP hyperactivation → NAD⁺ depletion → Apoptosis →↓PDA cell viability (KRAS MUT , NQO1-high) PCS: Pancreatic ductal adenocarcinomas (PDA) cell lines 466 Glutaminase inhibition and CAP/PDT C968-Ce6 (C9SN) C9SN → ↓GSH→ ↓ROS scavenging → ↑Oxidative stress → ↑Cell death/ICD → Neoantigen release → DC maturation → M2-to-M1 TAM polarization → CTL recruitment/activation PCS: 4T1 breast cancer mouse model 467 Coinhibition of glutamine and one-carbon metabolism BPTES + CBR-5884 (PHGDH inhibitor) BPTES + CBR-5884 +Lenvatinib/Sorafenib (Chemo Synergy) → ↓1 C metabolism, ↓Glutaminolysis → Cell cycle arrest, ↑ROS → ↓Proliferation → Cell death PCS: ATC cells 468 Glycolysis inhibition and chemotherapeutic drug 2-DG + Etoposide 2-DG + Etoposide →↓Glycolysis → ↓NADPH & ATP → ↑ ROS → ER stress → ERp57/Calreticulin exposure → Immunogenic cell death (ICD) → Tumor-specific T-cell activation → ↑Survival in immunocompetent mice PCS: Lymphoma 469 Coinhibition of TRX and glycolysis 2-DG + PX-12 2-DG + PX-12 (Synergistic) → ↓TRX1, ↓Glycolysis → ↑ROS → ↑2-DG cytotoxicity (in vitro/vivo) PCS: CRC cells 470 Coinhibition of glycolysis, TRX and GSH system 2-DG + Auranofin + BSO 2-DG + Auranofin + BSO → ↓TRXR, ↓GSH, ↓Glycolysis → ↑ROS → Apoptosis → ↓E-BCSCs, ↓M-BCSCs PSC: Breast cancer stem cells 471 GSH depletion and chemotherapy FeP@HCPT-HA FeP@HCPT-HA → Release of HCPT, Fe 2+ , Fe 3+ → ↑H 2 O 2 , ↓GSH→ ↑ROS → ↑Lipid peroxidation → Ferroptosis, Apoptosis PCS: CD44-overexpressing tumor cells 472 GSH depletion and PDT PEG(-b-PCL-Ce6)-b-PBEMA + Docetaxel (DTX) + PDT Polymeric Micelles +DTX + PDT (Light induced) → ↓GSH → ↑ROS → 1.24-2.39× ↓ IC 50 vs. free DTX, ↓Tumor volume vs. controls, 75% tumor necrosis, 70% apoptosis, ↓Ki-67/CD34 (In vivo) PCS: Syngeneic 4T1 breast cancer mouse model 473 GSH depletion and GLUT inhibition FCSP@876 MOFs FCSP@876 MOFs → ↑SLC7A11, ↑Cystine, ↓GLUT1→ ↓NADPH → ↓Cysteine, ↓GSH → ↓GPX4 → ↑ROS → Ferroptosis, Disulfidptosis → ↑Cell death (↓Ki67, ↓GPX4, ↑PTGS2) PCS: 4T1 breast cancer mouse model 474 GPX inhibition and chemotherapeutic drugs GPX4 inhibition + BRAFi ± EGFRi Targeting GPX4 + BRAFi ± EGFRi → ↓ GPX4 expression→ ↑ROS→ ↑Lipid peroxidation → Ferroptosis → Restored sensitivity to BRAFi ± EGFRi PCS: BRAFV600E colorectal cancer 475 Coinhibition of TRXR and GPX Jolkinolide B (JB) + GPX4i (RSL3/ML162) Jolkinolide B + RSL3/ML162 → ↓GPX4 → ↓TRXR1 overexpression (GPX4i induced) → ↑Lipid ROS → Ferroptosis/Apoptosis→ ↓GPX4i resistance (↑IC50) in Cisplatin-resistant bladder cancer cells PCS: Cisplatin-resistant bladder cancer cells 476 GPX inhibition and PDT/PTT Composite hydrogel (ZCND-Erastin/PAA: F127) ZCND + Erastin→ ↓HSP70 → ↓GPX4 → ↑ROS → Synergistic ferroptotic cell death PCS: 4T1 breast cancer mouse model 477 Coinhibition of GPX and Nrf2 Nrf2i (TRI/CP/ML385) + GPX4i (RSL3/ML210) ML385 + RSL3/ML210 → ↓Nrf2/GPX4 → ↑Lipid ROS → Ferroptosis/Apoptosis→ ↓Tumor growth, ↓Metastasis, ↓Ascites (no toxicity) vs. Vehicle/RSL3 alone (in vivo) PCS: ID8-Luc ovarian cancer model 478 GSTP inhibition and GSH depletion via NP delivery EA-SS-CHL (ECPP) ECPP → ↓GSH/GSTP-pi→ ↑ROS→ Oxidative stress → Apoptosis PCS: 4T1 breast cancer mouse model 479 Proteasome inhibition and chemotherapeutic drug Bortezomib (BTZ) + Actinomycin D (ActD) BTZ + ActD (Synergistic) → ↓Proteasome activity upregulation by ActD→ Proteotoxic stress → Impaired cell-cycle progression → Apoptosis → ↑ActD sensitivity PCS: Wilms tumor cells 480 Proteosome inhibition and CDT MIL-88-MG132@M MIL88-MG132@M → UPS blockade → ↑Ubiquitinated proteins→ ↓NF-κB/↑(p53-Ser536) → ↑ROS → ↑Apoptosis → ↓Tumor volume, ↓Cyclin D1/NF-κB, ↑Ubiquitin/p53, ↑DC maturation, ↑CTLs vs. Monotherapy (in vivo) PCS: CT-26 CRC-bearing mice model 481 Dual inhibition of ubiquitin–proteasome pathway Carfilzomib (CFZ) + Bortezomib (BZ) BZ + CFZ (Synergistic) → ↓Proteasome → ↑UPA → ↑ER stress/ROS → ↓MMP → ↑Caspase-3/8/9/12 → Apoptosis → 56.4% ↓Tumor vs. Monotherapy (in vivo) PCS: C57BL/6 melanoma xenograft model (mouse) 482 Coinhibition of glutaminase and proteasome V9302 + Carfilzomib V9302 + Carfilzomib→ ↓Glutamine metabolism (↓MYC/NRAS/GLS), ↓Proteasome → ↑ER stress, ↑ROS → Apoptosis (↑Caspase-3/PARP), Autophagy (↑LC3-II) PCS: PCM cell lines 483 Proteosome inhibition and Immune therapy IL-33+ Bortezomib (BTZ) IL-33 + BTZ(Synergistic) → ↓GSH → ↑ ROS→ ↓NF-κB-p65 nuclear translocation→ ↓Stemness (SOX2/MYC/OCT4) → ↑Apoptosis → ↓Tumor growth vs. BTZ alone PCS: U226B1 MM cell xenograft mouse model 485 Dual inhibition of GSTP and NQO1 MNPC (Inhibits NQO1 & GSTP1) MNPC → ↓GSH/GSSG → ↑ROS → Oxidative stress → Caspase-3 activation → Apoptosis, LDH release → ↓Tumor volume, ↑Survival PCS: Glioblastoma U87MG-EGFRvIII xenografts 486 Simultaneous targeting of NQO1 and SOD IB-DNQ + ATN-224 IB-DNQ + ATN224/KD → NQO1 futile cycling, ↓SOD1 → ↓O₂•− detox → 4×↑mtROS → ↓ΔΨm→ ↓ATP→ Cyt c release → ↑Caspase-3 → Apoptosis → ↓Tumor, ↓Metastasis vs. IB-DNQ (in vivo) PCS: TNBC xenograft models 487 NQO1 inhibition and chemotherapy Dicoumarol + Chemotherapeutic Drug Dicoumarol + Chemotherapeutic drug→ ↓ (DPP9 overexpression induced NQO1) → ↑ROS → Restored chemosensitivity PCS: Liver cancer cells 107 NQO1 exploitation and CDT NV-IONP-Lapa NV-IONP-Lapa → NQO1 catalysis, ↓GSH → Lapa → H₂O₂ → OH• (Fenton)→ ↑Oxidative stress→ Tumor apoptosis PCS: Ovarian cancer cells 488 NQO1 exploitation and DDR targeting drugs β-Lapachone + T2AA β-Lapachone + T2AA → ↓NQO1, ↓PCNA, ↓PARP1 hyperactivation (induced by β-Lapachone alone) →↑ DSBs, 5x↑H₂O₂ → ↑γ-H2AX foci→ ↓NAD + /ATP→ Necrosis → ↑Cell death vs. β-Lapachone PCS: LLC xenograft 489 β-Lapachone + Rucaparib β-Lapachone + Rucaparib→ ↓NQO1, ↓PARP1 hyperactivation (induced by β-Lapachone alone) →↑DSBs,↑H₂O₂ → ↑γ-H2AX foci → ↓NAD⁺/ATP loss → (Necrosis → Apoptosis) PCS: Pancreatic and NSCLC PDX models 490 Nrf2 inhibition and chemotherapeutic drug Tangeretin + Paclitaxel/AZD9291 (TKI) Tangeretin + Paclitaxel/AZD9291→ ↓Nrf2 (upregulated in resistant cells) →↑ROS → ↓P-gp → Chemo/TKI sensitization→ ↓Tumor growth PCS: A549/T lung cancer cells-derived xenografts 491 Nrf2 inhibition + PDT/PTT Brusatol/silica@MnO 2 /Ce6@PDA-PEG-FA Brusatol/silica@MnO 2 /Ce6@PDA-PEG-FA → ↓HSPs, ↓Nrf2, ↑ROS→ ↓GPX4/FTH → Ferroptosis→ Hypoxia- and hyperthermia-associated resistance in phototherapy PCS: Pancreatic cancer cells 492 DDR targeting drugs and ferroptosis induction PARPi (Olaparib) +Ferroptosis Inducers (Sulfasalazine) Sulfasalazine + Olaparib→ ↓PARP1, ↑p53, ↓SLC7A11 → ↓Cystine/GSH→ Lipid Peroxidation → Ferroptosis → ↓BRCA wild-type tumors PCS: BRCA-wild-type ovarian cancer cells 493 DDR targeting drugs and PDT ZTN@COF@Poloxamer–PDT/PARPi (Niraparib) ZTN@COF@Poloxamer–PDT/(Niraparib) (Synthetic lethality) → ↑ROS → DNA damage (&DNA repair inhibition) → Tumor apoptosis, Immune activation → ↓Metastasis PCS: Soft tissue sarcoma cells 494 NOX activation and chemotherapeutic drug Berbamine Hydrochloride (Ber) + Cisplatin Ber+ Cisplatin→ ↑NOX2 → Lysosomal alkalinization → Autophagy blockade (↑LC3-II/p62) → ↑ROS → MAPK activation → Apoptosis → ↑Cancer cell death PCS: Lung adenocarcinoma xenograft mouse model 496 Heat shock protein inhibition and chemotherapeutic drug Tubeimoside-I (TBM) + Oxaliplatin TBM + Oxaliplatin (Synergy)→ ↓HSPD1 → ↑ROS → ER stress, JNK/p38 activation → Apoptosis → ↓Tumor growth vs. Monotherapy PCS: CRC xenograft mouse model 498 Ferroptosis induction and PDT TBzT-CNQi + FSP1 inhibitor (iFSP1) TBzT-CNQi (membrane-targeting) + iFSP1→ ↑ROS, ↓FSP1 → ↓CoQ10 → ↑LPO → Immunogenic ferroptosis → ↑ICD → DC maturation, CD8 + T-cell recruitment → Tumor clearance PCS: 4T1 breast cancer mouse model 499 IDO1 inhibition and chemotherapeutic drug PTX@PoxMTP NPs PTX@PoxMTP NPs →1.5× ↑ROS, ↓IC50, 1.26×↑Apoptosis, 1.2× G2/M arrest, 1.1–1.5× ↑ HMGB1/ATP, 1.25–1.5×↑DCs maturation, ↓IDO1/kyn → Immune activation, ↓Tumor growth, ↓lung metastases, 3.7× ↑ CD8 + T cells, ↓Tregs/M2-TAMs, and ↑CD8+/Treg ratio vs. Free PTX PCS: 4T1 breast cancer bearing mice model with lung metastasis 500 Chemotherapeutic combination Sodium arsenite (NaAsO₂) + Chloroquine (CQ) + Dichloroacetate (DCA) NaAsO₂ + DCA + CQ → ↓Glycolysis (↓LDHA) → ↓Autophagy (↑LC3B by NaAsO₂, blocked by CQ) → ↑CAT, ↑SOD → ↓Lipid peroxidation (↓MDA) → ↓Tumor growth→ ↑Survival: 90% (combo) vs. 35% (control) PCS: 4NQO-induced OSCC mice model 501 Lipid metabolic reprogramming and immune checkpoint blockade Lipofermata + Anti-PD-L1 Lipofermata + Anti-PD-L1→ ↓FATP2 → ↓Lipid accumulation & ROS in MDSCs→ ↓Immunosuppression → ↑T-cell activation (↑CD107a, ↑IFN-γ) → ↓PD-L1 expression → ↑Tumor clearance PCS: LLC xenograft Mouse model 502 Antioxidant and chemotherapeutic drug Curcumin + Paclitaxel Curcumin + Paclitaxel → 60% ↑ ORR vs. Placebo CT, Phase II 503 TRX Thioredoxin, TRXR Thioredoxin Reductase, GLS Glutaminase, SOD Superoxide Dismutase, GSH Glutathione, GCLC Glutamate-Cysteine Ligase Catalytic Subunit, GSTP Glutathione-S-Transferase, PCS Pre-clinical Study, CT Clinical Trial, GPX Glutathione Peroxidase, HGSOC High-Grade Serous Ovarian Cancer, DMSO Dimethyl Sulfoxide, PI proteosome Inhibitors, BTZ Bortezomib, IXZ Ixazomib, DLZ Delanzomib, CRC Colorectal Cancer, HCC Hepatocellular Carcinoma, NSCLC Non-Small Cell Lung Cancer, GSC Glioma Stem Cell, ATF4 Activating Transcription Factor 4, DSB Double-Strand Break, RT Radiotherapy, Gy Gray (unit of radiation dose), PBS Phosphate-Buffered Saline, MbO 2 @Gd-NTs Oxygenated Myoglobin-Loaded Gadolinium Nanotubes, CM-Coated MSNs/Ce6/Cur CAL-27 Cancer Cell Membrane-Coated Mesoporous Silica Nanoparticles Co-Loaded with Chlorin e6 and Curcumin, PL-Au@P-ZnO NRs Piperlongumine-loaded, Au-decorated, poly(ethylene glycol)-coated zinc oxide nanorods, SDT Sonodynamic Therapy, Us Ultrasound, PFS Progression-Free Survival, OS Overall Survival, DPR Durable Prostate-specific antigen (PSA) Response, OXPHOS Oxidative Phosphorylation, ETC Electron Transport Chain, CPT Chemo-Photo Therapy, HIF1α Hypoxia-Inducible Factor 1-Alpha, GLUT1 Glucose Transporter 1, TPP-GOX-CAT-PpIX Triphenylphosphine-Conjugated Glucose Oxidase/Catalase/Protoporphyrin IX Hybrid System, NP@ESCu Nanoparticles with Elesclomol and Copper, TPP-T-Ce6- FX11 Triphenylphosphonium-Conjugated Chlorin e6 (T-Ce6) Co-Delivered with FX11, EMT-NPs Endoplasmic Reticulum (ER) and Mitochondria Dual-Targeting Nanoparticles, MMP Mitochondrial Membrane Potential, BER Base Excision Repair, PHGDH Phosphoglycerate Dehydrogenase, ASCT2 Alanine-Serine-Cysteine Transporter 2, PKM2 Pyruvate Kinase M2, AIF Apoptosis-Inducing Factor, AMPK AMP-Activated Protein Kinase, MYC MYC Proto-Oncogene, NRAS Neuroblastoma RAS Viral Oncogene Homolog, DCR Disease Control Rate, CR Complete Response, CAP Cold Atmospheric Plasma, CTL Cytotoxic T Lymphocyte, EA-SS-CHL Ethacrynic Acid Disulfide-Conjugated Chlorambucil (Prodrug), NV-IONP-Lapa Nanovesicle-Encapsulated Iron Oxide Nanoparticles Loaded with β-Lapachone, FCSP@876 MOFs Fe-Cu-SS metal–organic frameworks (MOFs) loaded with BAY876, GLUT Glucose Transporter, PSTG2 Prostaglandin-Endoperoxide Synthase 2, PCNA Proliferating cell nuclear antigen, T2AA T2 amino alcohol, SOX2 SRY-Box Transcription Factor 2, OCT4 Octamer-Binding Transcription Factor 4, MIL-88-MG132@M Macrophage Membrane-Coated-MG132-Loaded-NH₂-MIL-88(Fe)-Metal-Organic Framework, DHA Docosahexaenoic Acid, NIR Near-Infrared, TKI Tyrosine Kinase Inhibitor, MDR Multidrug Resistance, Brusatol/silica@MnO 2 / Ce6@PDA-PEG-FA Brusatol-loaded silica nanonetwork coated with manganese dioxide and chlorin e6, further functionalized with polydopamine-polyethylene glycol-folate, MAPK Mitogen-Activated Protein Kinase, ICG Indocyanine Green, HSPD1 Heat Shock Protein Family D (Hsp60) Member 1, CDT Chemodynamic Therapy, RDT Radiodynamic Therapy, PDT Photodynamic Therapy, MET Metformin, GNP Gold nanoparticles, PTT Photothermal Therapy, ΔΨm Mitochondrial depolarization, ↓ inhibition/depletion, ↑ activation/release, NV extracellular vesicle (EV) mimetic nanovesicles, IONPs Iron oxide nanoparticles, Lapa β-Lapachone, GM-CSF Granulocyte-Macrophage Colony-Stimulating Factor, STAT3 Signal Transducer and Activator of Transcription 3, FATP2 Fatty Acid Transport Protein 2, MDSC Myeloid-Derived Suppressor Cell, PTX@PoxMTP NPs Paclitaxel-loaded-ROS-responsive-1-MT-conjugated-PEGylated polyoxalate nanoparticles, PEG Polyethylene glycol, HMGB1 High Mobility Group Box 1, ATP Adenosine Triphosphate, IFN Interferon, TAM Tumor-Associated Macrophages, IDO1 Indoleamine 2,3-Dioxygenase 1, CRT Calreticulin, MDA Malondialdehyde, MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide, CAT Catalase, LDH Lactate Dehydrogenase, LC3B Microtubule-Associated Protein 1A/1B-Light Chain 3B, LPO Lipid Peroxidation, ICD Immunogenic Cell Death, FSP1 Ferroptosis Suppressor Protein 1, DC Dendritic Cell, PARP1 Poly(ADP-Ribose) Polymerase 1, ZTN@COF@poloxamer Zirconium-TCP NanoMOF@Covalent Organic Framework@Poloxamer Nanocapsules (where “TCP” Tetrakis(4-carboxyphenyl)porphyrin), SLC7A11 Solute Carrier Family 7 Member 11, BRCA Breast CAncer gene (BRCA1/BRCA2)

Combination therapeutic strategies targeting ROS elevation

TRX system in combination therapy

TRX inhibition often drives cancer cells to alternative metabolic pathways. 436 For example, in MYC-high HGSOC, TRX inhibition shifts cells to glutamine metabolism, and combining Auranofin with CB-839 exacerbates ROS accumulation and induces metabolic stress and apoptosis. 436 In NSCLC, the complementary roles of the TRX and GSH antioxidant systems are also evident, as simultaneous inhibition—via Auranofin treatment combined with GSR (GSH pathway) loss—synergistically elevates ROS levels, overwhelms cellular redox defenses, and triggers apoptosis, thereby sensitizing cancer cells to TRXR inhibition. 437 Additionally, in Nrf2-activated NSCLC with Keap1 mutations, resistance to β-lapachone arises from enhanced antioxidant defenses. Targeting the TRX system and SOD1 has been found to disrupt redox balance synergistically, amplifying β-lapachone-induced ROS, DNA damage, and cell death. 438

In glioblastoma, TRX inhibition by Auranofin upregulates GSTP1 as compensation, while Piperlongumine (PL) directly inhibits GSTP1, disabling the GSH system. Dual inhibition disrupts redox homeostasis, amplifies ROS, and lowers the IC50 to nanomolar levels, highlighting their potential for repurposing in glioblastoma therapy. 439 A recent study suggested that simultaneous inhibition of the TRX system (Auranofin) and the proteasome (Bortezomib) synergistically induces paraptosis in breast cancer cells by promoting GSH depletion through the ATF4/CHAC1 axis, leading to proteotoxic stress and characteristic dilation of the ER and mitochondria. 440 This combination selectively targets cancer cells at lower doses, offering an effective, less toxic strategy against apoptosis-resistant cancers. Inhibition of the TRX system has also been shown to effectively enhance chemosensitivity through ROS-dependent mechanisms. In HCC, Withaferin A synergizes Sorafenib to promote ROS-mediated ER stress, DNA damage, and apoptosis. 441 Targeting both the TRX system and the DDR has demonstrated promising outcomes across several cancers. A study demonstrated that Cyst(e)inase, an enzyme depleting L-cysteine/cystine, when combined with Auranofin, amplified ROS levels and DSBs, inhibiting prostate cancer growth. 442

Nanoparticle-driven combination therapies targeting the TRX system

TRXR inhibitors, including GNPs, Auranofin, CONPs, Curcumin derivatives, and others, are utilized as sensitizers in RT, PDT, CDT, and ultrasound (US) irradiation via nanoparticle-based delivery. This approach enhances treatment efficacy, overcomes resistance, and reduces required doses, minimizing side effects.

Gold nanoparticles (GNPs) act as nanoradiosensitizers, enhancing localized energy deposition and ROS generation, leading to DNA damage. A novel chemopiezocatalytic therapy using Piperlongumine (PL)-loaded, Auranofin (Au)-decorated, PEG-coated zinc oxide nanorods (PL-Au@P-ZnO NRs) leverages the piezoelectric properties of ZnO under US to generate ROS. 443 Auranofin enhances ROS via Fenton-like activity, and PL increases specificity, inducing selective tumor cell death. In vivo, PL-Au@P-ZnO NRs with US suppress tumor growth without causing systemic toxicity. 443

Motexafin Gadolinium (Xcytrin®), a Gadolinium (Gd 3+ )-coordinated Texaphyrin (Gd-Tex) radiosensitizer, has been investigated in clinical trials for glioblastoma multiforme and pancreatic cancer, but the outcomes remain unpublished. Limited efficacy has led to the development of Gd-Tex-lipid-based nanovesicles (Gd-NTs) for improved tumor accumulation and radiosensitization. 444 Incorporating O 2 -dependent myoglobin (Mb) into Gd-NTs (MbO₂@Gd-NTs) alleviates tumor hypoxia, amplifies Gd-Tex-induced ROS production, enhances radiosensitization, and induces long-term antitumor immune memory. 444

Curcumin is being evaluated as a radiosensitizer in prostate ( NCT01917890 ) and cervical cancer ( NCT05947513 ) but faces challenges due to its low bioavailability, short half-life, and HIFs, necessitating nanoparticle-based delivery systems. Preclinically, a biomimetic nanoplatform using mesoporous silica nanoparticles (MSNs) loaded with Chlorin e6 (Ce6) and Curcumin (Cur) and coated with cancer cell membranes (CMs) demonstrated enhanced tumor targeting and uptake in oral carcinoma. 445 Cur inhibited TRXR1, disrupting ROS defenses and amplifying Ce6-mediated ROS under laser irradiation, significantly inhibiting tumor growth.

Targeting mitochondria in combination therapy

Combining mitochondria-targeting drugs with ROS-modulating therapies effectively overcomes cancer cell metabolic plasticity and enhances efficacy through synergistic pathways compared to monotherapy. For instance, Artemisinin generates ROS and induces apoptosis while weakly inhibiting GPX4 to trigger mild ferroptosis. Combining Artemisinin with GPX4 inhibitor, RSL3 synergistically enhances ferroptosis, highlighting the potential of this combination for effective cancer therapy. 446 Targeting mitochondria and NQO1 may overcome drug resistance in NQO1-overexpressing BC. FRV-1 targets ETC-I, inducing ROS and mitochondrial dysfunction in NQO1-negative cells but is inactivated in NQO1-positive MCF7 cells. Combining FRV-1 with the NQO1 inhibitor Dicoumarol has been reported to restore sensitivity. 447

Mitochondria-DDR targeting combinations show synergistic lethality in BRCA1-mutated cancers. Defective base-excision repair (BER) sensitizes cells to mito-ROS damage, making Elesclomol effective; moreover, combining Elesclomolwith PARP inhibitors, Rucaparib or Talazoparib amplifies ROS-induced DNA damage and enhances synthetic lethality. 448 Targeting the ER and mitochondria have demonstrated anticancer efficacy in ovarian cancer. Dual-targeting nanoparticles (EMT-NPs), which synergistically induce ER stress and mitochondrial dysfunction by promoting Ca 2+ efflux, ROS production, and apoptosis, have recently been developed. 449 They also enhance imaging in xenograft models, offering a drug-free, precision cancer-related prognostic strategy. Finally, to overcome the limitations of IR-820, IR-820@NBs were developed, which target mitochondria under ultrasound to generate lethal ROS, 450 while in combination with proteasome inhibitors, MG-132 further enhances SDT efficacy by inducing apoptosis and autophagy in HCC cells.

Targeting mitochondria has shown promise in enhancing chemosensitivity. The Elesclomol–Paclitaxel combination exploits Elesclomol’s ROS generation and mitochondrial apoptosis induction capacity to sensitize cancer cells to Paclitaxel. This combination has been evaluated in several clinical trials. A Phase II trial in patients with metastatic melanoma revealed that compared with Paclitaxel alone, Elesclomol-Paclitaxel doubled the median PFS, reduced DPR by 41.7%, and improved OS. 451 However, a subsequent Phase III trial ( NCT00522834 ) in chemotherapy-naive advanced melanoma patients failed to show efficacy overall, although patients with normal lactate dehydrogenase (LDH) levels responded better. 452 These findings suggest the reliance of Elesclomol on OXPHOS, with the use of glycolysis inhibitors potentially enhancing its efficacy in high-LDH tumors. In support of this, a study in breast adenocarcinoma cells (MCF7 and MDA-MB-231) demonstrated greater cytotoxicity with Elesclomol and glycolysis inhibitors (2-DG or 3-BP) compared to single-agent therapies. 453 Similarly, EP13, an OXPHOS inhibitor targeting complex I, increased ROS levels and synergized with glycolysis inhibitors (Oxamate and 2-DG) in aggressive breast cancers. 454

Nanoparticle-driven combination therapies targeting mitochondria

Recent nanotechnology advances integrate mitochondria-targeted therapeutics with multimodal strategies to address hypoxia and enhance efficacy. A polymer micelle (CAT/CPT-TPP/PEG-Ce6, CTC) achieves triple-synergistic amplification of ROS via PDT and chemotherapy, inducing immunogenic cell death. 455 Another nanoparticle system, AuCu-Ce6-TPP (ACCT), combines RT, RDT, and CDT to combat hypoxia by integrating Ce6 for sensitization, Curcumin (Cu) for OH• generation and hypoxia alleviation, Auranofin (Au) for glutathione depletion, and triphenylphosphine (TPP) for mitochondrial targeting, demonstrating potent anticancer effects in hypoxic 4T1 cells. 456

The CFMB nanoplatform, loaded with Metformin (MET) and BAY-876 (BAY) on CuFe₂O₄ (CF), targets glycolysis and OXPHOS, depleting tumor energy via MET-mediated HK2 inhibition and mitochondrial disruption, and BAY-mediated GLUT1 inhibition. In high-GSH environments, CFMB releases Cu + /Fe 2+ , catalyzing H 2 O 2 into OH• to enhance CDT, with NIR light boosting ROS production and enabling PTT for tumor suppression without toxicity. 457 Similarly, the CPGMB nanoplatform, composed of polydopamine-coated CeO 2 -x nanorods co-loaded with MET and GOx, inhibits glycolysis via HK2 inhibition and glucose depletion. GOx-generated H 2 O 2 is converted to O 2 by Ce 4+ , alleviating hypoxia, while Ce 3+ transforms H 2 O 2 into OH• for CDT. 458 Another study developed a mitochondriona-targeted bioreactor using TPP, GOx, CAT, and protoporphyrin IX (PpIX) that integrates glucose (starvation therapy), oxygen generation, and PDT to amplify ROS production, inducing mitochondrial destruction and apoptosis with strong in vivo antitumor efficacy. 459

To address copper (Cu) ionophore limitations, a ROS-sensitive polymer (PHPM) was developed to coencapsulate Elesclomol (ES) and Cu, forming NP@ESCu nanoparticles. 460 Upon ROS-triggered release in cancer cells, ES and Cu synergistically amplify ROS, inducing cuproptosis and stimulating immune responses. In a bladder cancer model, NP@ESCu reprogrammed the tumor microenvironment and, when combined with anti-PD-L1, enhanced therapeutic efficacy. 460 Another bioreducible exosome with redox-cleavable diselenide linkers delivers mitochondria-targeting sonosensitizers (T-Ce6) and glycolysis inhibitors (FX11) to tumors. 461 Under US irradiation, T-Ce6 induces ROS-mediated mitochondrial damage, whereas FX11 inhibits glycolysis, amplifying antitumor effects of SDT.

Glutaminase inhibition in combination therapy

Glutaminase inhibition in combination with other ROS modulation pathways has been shown to be effective in overcoming therapeutic resistance in various cancers. In metastatic RCC, CB-839 plus Cabozantinib achieved a 42% ORR and 100% DCR ( NCT02071862 ), 462 with Phase II trials ongoing (NCT0342821). For PIK3CA-mutant CRC, CB-839 combined with Capecitabine improved PFS, even in fluoropyrimidine-resistant patients ( NCT02861300 ). 463 In high-risk MDS, CB-839 and Azacitidine achieved a 70% marrow complete response in a Phase Ib/II study ( NCT03047993 ). 464 Overcoming Osimertinib resistance in NSCLC involves targeting glutamine metabolism, as resistant cells are glutamine dependent. Dual inhibition of ASCT2 and GLS1 has been shown to outperform GLS1 inhibition alone, effectively combating resistance in preclinical models. 465 Additionally, high NQO1 expression in resistant cells supports redox homeostasis, contributing to resistance. Combining NQO1 targeting with glutamine metabolism inhibition offers a promising strategy to overcome resistance. 466 Moreover, a nanobooster, C9SN, comprising the glutaminase inhibitor C968 and the photosensitizer Chlorin e6, enhanced PDT efficacy by depleting GSH and inducing oxidative stress. 467 It triggered immunogenic cell death, CTL activation, and macrophage polarization, suppressing tumors and remodeling the tumor microenvironment. In anaplastic thyroid cancer (ATC), glutaminolysis inhibition alone induces growth arrest but not cell death due to compensatory ATF4-mediated one-carbon metabolism, which is amplified during progression from papillary to anaplastic thyroid cancer. Dual targeting of PHGDH, a key enzyme in one-carbon metabolism, and glutamine metabolism synergistically increases ROS, inducing growth arrest and sensitizing ATC cells to anticancer drugs. 468

Glycolysis inhibition in combination therapy

Combining glycolysis inhibition with oxidative stress modulation enhances therapy by sensitizing cancer cells to ROS-mediated damage and addressing metabolic reprogramming, resistance, and nonselectivity. For instance, 2-DG synergizes with Etoposide to increase cytotoxicity, promote tumor-specific T-cell activation, and induce immunogenic cell death. 469 Clinically, a Phase I study ( NCT00247403 ) explored 2-DG as a radiosensitizer for intracranial neoplasms but was withdrawn due to discontinuation of drug manufacturing. This combination disrupts mitochondrial integrity, induces ROS-mediated apoptosis, and suppresses the expression of EMT markers, offering a promising metabolic reprogramming strategy for BC treatment. Glycolysis inhibition in CRC is limited by systemic toxicity and resistance via TRX1 upregulation, which enhances SLC1A5 expression, glutamine transport, and GSH synthesis to counteract cytotoxicity. 470 TRX1 inhibitor PX-12 or SLC1A5 knockdown synergistically enhances the cytotoxic effects of 2-DG by disrupting redox balance in vitro and in vivo. 470 Moreover, while single treatments showed minimal efficacy, coinhibition of glycolysis (2-DG), TRX (Auranofin), and GSH (BSO) synergistically suppressed tumor growth, metastasis, and tumor-initiating capacity in TNBC patient-derived xenografts by inducing ROS-mediated apoptosis in both epithelial and mesenchymal breast cancer stem cells. 471

GSH depletion in combination therapy

GSH depletion enhances cancer therapy sensitivity. For example, the limited endogenous H 2 O 2 and elevated GSH levels in tumor cells reduce the effectiveness of the iron-based nanocarrier 10-hydroxycamptothecin (HCPT) in inducing ferroptosis. 472 To overcome this, a ferric phosphate nanotherapeutic system, FeP@HCPT-HA, was developed. FeP@HCPT-HA targets CD44-overexpressing tumor cells and degrades in the acidic tumor microenvironment to release HCPT, Fe 2+ , and Fe 3+ . The released Fe 3+ depletes GSH, downregulates GPX4, and enhances lipid peroxidation, whereas HCPT induces apoptosis and supplies H 2 O 2 for the Fe 2+ -mediated Fenton reaction. These synergistic mechanisms effectively induce ferroptosis and apoptosis, significantly inhibiting tumor growth. Additionally, to enhance PDT, a study designed a star-shaped polymer, PEG(-b-PCL-Ce6)-b-PBEMA, that boosts ROS generation, depletes GSH, and delivers chemotherapy. It combines PDT with Ce6 for ROS production, an H 2 O 2 -labile group for GSH depletion, and Doxorubicin delivery. This triple strategy significantly increased antitumor efficacy both in vitro and in vivo, suggesting a promising approach to amplify oxidative stress in cancer treatment. 473 A Phase I trial ( NCT00327288 ) evaluated Imexon-Docetaxel across various cancers to determine maximum tolerated dose, but the clinical outcomes are pending. Targeting GSH and glucose transporters also exploits the metabolic dependencies of cancer cells, suggesting a promising therapeutic approach. Cancers resist ferroptosis by upregulating SLC7A11 and increasing cysteine uptake and GSH synthesis. Glucose restriction causes cysteine accumulation and NADPH deficiency, triggering disulfidptosis. To exploit this vulnerability, FCSP@876 MOFs were developed, combining a ferroptosis-inducing MOF with the GLUT1 inhibitor BAY876. This nanoplatform induces two-pronged ROS attack: first, ferroptosis via lipid peroxidation, and second, disulfidptosis via glucose starvation-induced NADPH deficiency. 474

GPX inhibition in combination therapy

GPX4 inhibition overcomes therapeutic resistance, as evidenced in BRAFV600E colorectal cancer. GPX4 upregulation in response to BRAFi ± EGFRi therapy blocks therapy-induced ferroptosis and drives resistance. Targeting GPX4 restores ferroptosis, enhances the efficacy of BRAFi ± EGFRi, and overcomes resistance in in vitro, in vivo, organoid, and patient-derived xenograft models. 475 GPX-TRXR inhibition also overcomes cisplatin resistance in bladder cancer. 476 Combining the TRXR1 inhibitors jolkinolide B or Auranofin, with GPX4 inhibitors offers a promising strategy for overcoming cisplatin resistance. 476 Additionally, GPX inhibition may enhance PDT and PTT. To effectively eliminate residual tumor cells, a composite ZCND-Erastin/PAA:F127 hydrogel was developed, incorporating zinc-centered carbon nano-dodecahedrons (ZCND) and Erastin. 477 ZCND PDT/PTT generates ROS, which reduce HSP70, destabilizing GPX4 and promoting ferroptosis, while Erastin also destabilizes GPX4 to enhance ferroptosis. In vitro and in vivo studies confirmed that this hydrogel effectively suppressed tumor recurrence after surgical resection. Coinhibition of GPX and Nrf2 also has a synergistic effect on ovarian cancer, which is particularly susceptible to ferroptosis due to its “iron addiction.” A study showed that combining Nrf2 inhibitors (e.g., ML385) with GPX4 inhibitors synergistically suppressed ovarian cancer by inducing ROS accumulation, lipid peroxidation, and caspase-3 activation, promoting ferroptosis and apoptosis. 478 Coinhibition of GSTP and GSH enhances chemotherapy, as observed in a study on breast cancer, as Chlorambucil’s (CHL) efficacy is limited by GSH- and GSTP-pi-mediated resistance. A study developed a GSH-responsive prodrug (EA-SS-CHL) encapsulated in nanoparticles (ECPPs) that releases ethacrynic acid (EA) and CHL to deplete GSH, inhibit GSTP-pi, and amplify ROS, enhancing CHL’s cytotoxicity. 479

Proteasome inhibition in combination therapy

Bortezomib has been shown to increase the efficacy of Actinomycin D in Wilms tumor cells by disrupting protein homeostasis and restoring apoptosis. 480 Additionally, a Phase II trial ( NCT01769209 ) explored the ability of Bortezomib to induce ROS in ALL blast cells and its potential to improve chemotherapy outcomes; the findings remain unpublished. Proteosome inhibition sensitizes CDT by elevating ROS levels and, with a macrophage membrane coating, ensures targeted tumor accumulation, as evidenced in a study on mCRC. This study used the MIL-88-MG132@M nanoplatform to overcome TME-induced CDT resistance. 481 This Fe-MOF-based system, loaded with MG132, inhibited proteasome activity and NF-κB p65 phosphorylation, leading to the accumulation of proapoptotic proteins and the disruption of tumor homeostasis. Dual proteasome inhibition with Carfilzomib and Bortezomib has also demonstrated anticancer activity in melanoma while minimizing toxicity. A study showed that the low-dose Carfilzomib-Bortezomib combination amplifies antitumor effects through ROS-dependent apoptosis and ER stress, reducing Bortezomib-related toxicity. 482

Co-inhibition of Glutaminase and proteasome might overcome Proteasome inhibitors (PIs) resistance, as evidenced in plasma cell myeloma (PCM). Combining the ASCT2 inhibitor V9302 with Carfilzomib synergistically elevated ROS levels, induced apoptosis, and activated a catastrophic UPR characterized by the upregulation of spliced Xbp1, ATF3, and CHOP, enhancing cytotoxicity in both PI-sensitive and resistant PCM cells. 483 Coinhibition of the proteasome and Nrf2 can overcome proteasome inhibitor resistance by blocking the Nrf2-mediated antioxidant defense activated upon proteasome inhibition. For example, CuONPs inhibit proteasomes in vascular endothelial cells, inducing autophagy while stabilizing Nrf2 to increase antioxidant defenses. Conversely, Nrf2 inhibition blocks antioxidant gene activation, resulting in ROS accumulation, macromolecular damage, and cell death. 484 This approach shows potential for use in ROS-mediated cancer therapy, warranting further exploration. Immune therapy-PI combination might enhance PI sensitivity, as evidenced in multiple myeloma (MM), where IL-33 enhances Bortezomib sensitivity by inducing excessive ROS. 485 The IL-33-Bortezomib combination suppressed MM cell proliferation by boosting ROS levels, inhibiting NF-κB-p65 nuclear translocation, and downregulating the expression of stemness genes—effects reversed by the addition of ROS scavengers.

NQO1 inhibition in combination therapy

Coinhibition of GSTP1 and NQO1 shows antitumor potential in GBM, where EGFR mutations upregulate these enzymes to suppress ROS and drive tumor growth. The small-molecule inhibitor MNPC potently targets both NQO1 and GSTP1, disrupting redox homeostasis, elevating ROS, and inducing apoptosis in EGFRvIII-mutant GBM cells. 486 Additionally, therapy-resistant CSCs, including those in TNBC, rely on DPP9-upregulated Nrf2-mediated antioxidant defenses (NQO1, SOD1) to suppress ROS and survive. Targeting these vulnerabilities, the NQO1-bioactivatable agent IB-DNQ generates ROS to kill CSCs, with its efficacy enhanced by concurrent SOD1 inhibition, which is elevated in TNBC. 487

NQO1 inhibition may help overcome therapeutic resistance, as demonstrated in several preclinical and clinical trials. A study revealed that DPP9 promotes chemoresistance in liver cancer by binding to KEAP1, stabilizing Nrf2, and upregulating NQO1 expression to lower ROS and reduce chemotherapy efficacy. 107 Inhibiting NQO1 with Dicoumarol restores ROS accumulation and enhances the effectiveness of chemotherapy in liver cancer. ARQ761 is under clinical evaluation with Gemcitabine and Nab-paclitaxel ( NCT02514031 ) for treating NQO1-overexpressing tumors. A study enhanced CDT by using nanovesicles (NV-IONP-Lapa) loaded with iron oxide nanoparticles (IONPs) and β-Lapachone (Lapa). NQO1 catalyzed Lapa to generate H₂O₂, while IONPs released iron ions in the acidic tumor environment, converting H₂O₂ into cytotoxic OH• via the Fenton reaction. This system showed excellent tumor-targeting potential with minimal side effects, offering a promising approach for treating NQO1-overexpressing tumors. 488

Targeting DDR and NQO1 may synergistically enhance antitumor efficacy while minimizing β-Lapachone-associated toxicity. Combining β-Lapachone with proliferating cell nuclear antigen (PCNA) inhibitor T2AA blocks DNA repair complex assembly, exacerbates ROS-induced DSBs, and enhances antitumor efficacy, as shown in Lewis lung carcinoma models. 489 Similarly, combining the PARP inhibitor Rucaparib with β-Lapachone amplifies ROS generation and shifts the cell death mechanism from necrosis to caspase-dependent apoptosis, improving tumor-selective killing in NQO1-positive xenograft models. 490 A clinical trial ( NCT03575078 ) evaluating ARQ761 with Olaparib was initiated but withdrawn due to lack of patient enrollment.

Nrf2 inhibition in combination therapy

Nrf2 inhibition enhances antitumor therapy in various cancers by overcoming MDR linked to elevated ROS and Nrf2 levels. In a study on lung cancer, targeting the ROS/Nrf2 axis with Nrf2 siRNA or Tangeretin was shown to suppress Nrf2, overcome MDR (downregulating P-gp), and synergize with Paclitaxel and AZD9291 in A549/T xenografts. 491 Similarly, to overcome hypoxia- and hyperthermia-induced phototherapy resistance, a MnO₂- and Ce6/PDA-PEG-FA - decorated silica nanonetwork loaded with Brusatol was engineered. MnO₂ generated oxygen to amplify Ce6-mediated PDT and PDA-driven PTT while targeting HSPs, and Brusatol inhibited the Nrf2‒GPX4 axis, inducing ferroptosis and phototherapeutic efficacy. 492

Targeting DDR in combination therapy

Combining PARP inhibitors (PARPis) with ferroptosis inducers (FINs) may overcome PARPi resistance in BRCA-wild-type ovarian cancer. A study revealed that PARP inhibition induces ferroptosis via p53-mediated SLC7A11 downregulation, depleting glutathione and increasing ROS-driven lipid peroxidation in BRCA-mutant ovarian cancer. Ferroptosis suppression contributes to resistance in BRCA-wild-type cancers, while PARPi-FIN combinations synergistically enhance cytotoxicity in BRCA-proficient ovarian cancer models both in vitro and in vivo. 493 Additionally, to address soft tissue sarcoma resistance to PDT, ZTN@COF@poloxamer nanocapsules were developed, integrating a Zr-based MOF, the photosensitizer Tetrakis (4-carbethoxyphenyl) porphyrin, and the PARP inhibitor Niraparib, where light-activated ROS generation induces apoptosis, enhancing PDT efficacy and blocking DNA repair. 494

In addition, several other combination therapies targeting ROS promotion have been studied to overcome resistance to conventional anticancer agents. For example, recurrence in nasopharyngeal carcinoma often arises from radioresistance. A study showed that SOD2 knockdown amplifies radiation-induced superoxide production and lipid peroxidation, enhancing radiosensitivity via ferroptosis. 495 However, DHODH inhibition in SOD2-depleted cells reduced oxidative stress, lipid peroxidation, and ferroptosis, improving survival and colony formation, suggesting that DHODH activity sustains radiation-induced ferroptosis. Therefore, caution is needed when combining DHODH inhibitors with radiotherapy, as they may counteract radiosensitization. NOX activator, Berbamine Hydrochloride has also been found to synergize with Cisplatin in lung carcinoma cells by inducing excessive ROS, impairing lysosomal acidification via NOX2 recruitment, triggering MAPK-mediated apoptosis, and increasing cell death. 496 Photochemotherapy might be a promising strategy for precision nanotheranostics, as demonstrated by IMTD, a nanotheranostic coassembling ICG photosensitizer with Mannose (MAN)- Thioketal linker (TK)- Doxorubicin (DOX), for tumor-targeted, light/ROS-responsive photochemotherapy. IMTD prevents premature DOX leakage, enhances tumor accumulation via mannose receptor uptake, and enables spatiotemporal drug release through laser-triggered ROS generation and thioketal cleavage in vitro/in vivo. 497

Tubeimoside-I, a heat shock protein inhibitor, has been reported to synergize with Oxaliplatin in CRC by increasing ROS levels, downregulating HSPD1, and upregulating ER stress and MAPK pathways, thereby enhancing the anticancer effects of Oxaliplatin. 498 To overcome hypoxia and ROS limitations in tumor PDT, the cell membrane-targeting photosensitizer TBzT-CNQi was developed to generate ¹O 2 , OH•, and O 2 •⁻, inducing lipid peroxidation and enhancing ferroptosis. 499 Moreover, combining TBzT-CNQi with ferroptosis suppressor protein 1 inhibitor (iFSP1) downregulated FSP1, reduced CoQ10, and amplified lipid peroxidation, triggering immunogenic ferroptosis. This combination activated immune responses, increased CD8 + T cells, and reduced tumor-associated macrophages, offering a promising strategy for photodynamic immunotherapy in hypoxic tumors. Immunotherapy faces challenges from poor tumor immunogenicity and immunosuppressive microenvironments. ICD inducers like Paclitaxel (PTX) stimulate immunity via DAMP release but are limited by poor targeting and immunosuppressive effects. Building on synergistic ICD inducers and IDO inhibitors, a study developed ROS-responsive PTX@PoxMTP NPs to codeliver PTX and 1-MT (IDO inhibitor). 500 Tumor-specific ROS trigger PTX release, inducing ICD and amplifying ROS, whereas esterase-activated 1-MT disrupts the IDO1/kynurenine pathway to reduce immunosuppression. This synergy enhances dendritic cell maturation and T-cell infiltration, and suppresses Tregs and TAMs, resulting in robust tumor regression and metastasis control with minimal off-target effects.

Combination therapeutic strategies targeting ROS suppression

Several studies have investigated combination strategies to overcome resistance and improve tumor-specific responses by suppressing ROS levels. A novel regimen combining Sodium arsenite (NaAsO₂), Chloroquine (CQ), and Dichloroacetate (DCA) targets chemoresistance in oral squamous cell carcinoma (OSCC) by regulating ROS, autophagy, and glycolysis. NaAsO₂ induces cytotoxic ROS and inhibits glycolysis; DCA enhances this effect, while CQ blocks autophagy. This combination boosts antioxidant enzymes, restores redox balance, improves survival (90% vs. 35%), and reduces tumor progression in OSCC mouse models with minimal toxicity, offering a promising strategy against chemoresistance. 501

The efficacy of immune checkpoint blockade (ICB) is often limited by MDSC-mediated immunosuppression. Tumor-derived GM-CSF activates STAT3, upregulating Fatty Acid Transport Protein 2 (FATP2) to drive lipid accumulation and ROS production, critical for MDSC function. A study demonstrated that FATP2 inhibition with Lipofermata disrupted lipid metabolism, reduced ROS, and blocked MDSC suppression, enhancing antitumor responses. 502 This approach has synergized with anti-PD-L1 therapy by boosting CD8 + T-cell activity and restoring antitumor immunity, offering a metabolic reprogramming strategy to improve ICB efficacy.

In addition, many preclinical and clinical studies have been conducted and are ongoing to explore the antiproliferative, anti-invasive, antiangiogenic, and chemoresistance-modulating properties of antioxidants like Curcumin, Lycopene, and Vitamin C. A clinical trial ( NCT03072992 ) revealed that intravenous Curcumin (CUC-1®) combined with Paclitaxel significantly improved the ORR (51%) compared to placebo (33%), with an even greater effect in patients completing treatment. 503 Lycopene alone had no significant effect, but coadministration with Docetaxel showed low toxicity, favorable pharmacokinetics, and improved angiogenesis and IGF-1 signaling in metastatic prostate carcinoma (NCT0149519). 504

Personalized cancer treatment utilizing the ROS signature

ROS-related biomarkers are essential for personalized medicine because of the observed heterogeneity in redox responses across different cancer types, stages, and individuals with the same cancer. Protein carbonyls, arising from oxidative cleavage, deamination, and Michael addition, along with advanced glycation end products (AGEs) like carboxymethyl lysine (CML), are among these markers. 505 , 506 Additionally, lipid peroxidation products such as acrolein, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), and F2-isoprostanes (IsoPs) are also indicative of ROS-related damage. 506 , 507 Nucleic acid oxidation products like 8-oxo-dG (8-oxo-2’-deoxyguanosine) are commonly used biomarker for oxidative stress and DNA damage caused by ROS. 508 Elevated 8-oxo-dG indicates oxidative damage, and to date, many clinical studies have utilized plasma levels of 8-oxo-dG to monitor oxidative stress and DNA damage in cancer.

The thiol‒disulfide balance, representing the equilibrium between reduced thiols (-SH groups) and oxidized disulfides (-S‒S‒ bonds) in cells, serves as a redox biomarker. 509 In a study of 62 cervical cancer patients and 61 healthy women ( NCT04258553 ), Sezgin et al. reported a significant positive correlation between disulfide levels and cervical cancer stage, proposing thiol-disulfide balance as a potential early biomarker for this disease. 510 Antioxidant enzymes are key biomarkers of oxidative stress and are extensively studied as ROS-related indicators in numerous cancer clinical trials. 11 A study in ovarian cancer ( NCT03470857 ) reported that elevated SOD activity might be linked to increased ROS. Another study ( NCT01985113 ) reported that plasma TRX levels are significantly regulated in lung cancer patients (>7.1 U/mL), indicating its diagnostic potential.

Promoter methylation sites such as 5-methylcytosine (5-mC), RUNX3, DNMT1, and p16 are the key gene targets for hypermethylation induced by ROS, and their epigenetic alterations can serve as useful biomarkers for cancer diagnosis. 511 Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), play critical roles in regulating ROS-related pathogenesis, making them promising biomarkers and therapeutic targets in cancer. 512 For example, miR-373 functions as a redox regulator and promotes tumorigenesis in various cancers, while miR-371 is linked to cancer metastasis, drug resistance, and recurrent germ cell cancers ( NCT04435756 ). 513 Additionally, miR-155, linked to oxidative stress and tumorigenesis via the Nrf2 pathway, is targeted by Cobomarsen, a Phase II trial of a miR-155 inhibitor ( NCT03713320 ) for cutaneous T-cell lymphoma (CTL) and mycosis fungoides. 514 HOTAIR, a lncRNA, regulates chromatin structure and gene expression, promoting tumor progression and metastasis in breast, colorectal, and lung cancer. 515 Mitochondrial lncRNAs like ASncmtRNA, a redox sensor with oncogenic roles, are targeted by Andes-1537, an antisense oligonucleotide showing promise in Phase I trials ( NCT02508441 , NCT03985072 ) for solid tumors. 516 Conversely, miR-16 suppresses tumor growth by regulating oxidative stress and promoting apoptosis. In a Phase I trial ( NCT02369198 ), an EGFR-targeted miR-16 mimic showed promise in treating mesothelioma and NSCLC. 517 Another tumor suppressor involved in redox regulation, miR-34a, has been extensively tested in animal models. MRX34, a miR-34a mimic, was developed to assess its safety, pharmacokinetics, and pharmacodynamics in a Phase I trial ( NCT01829971 ). Besides, transcription factors like Nrf2 and p53 act as crucial ROS-related biomarkers in cancer diagnosis and treatment, balancing between protecting cells from oxidative stress and contributing to tumor growth under certain conditions.

Some ROS-related biomarkers that are clinically used to assess the redox state of the body or specific tissues and cells in cancer are listed in Table 6 . The data concerning the oxidative biomarkers have been collected from www.fda.gov , http://clinicaltrials.gov , http://go.drugbank.com , and different works of literature. Table 6 List of ROS-related biomarkers and their clinical implications in cancer Type of markers Name of markers Disease/condition Clinical trials Phase ID Status Protein carbonyls and advanced glycation end products Carboxymethyl Lysine (CML) Prostate cancer I/II NCT03712371 Terminated Breast cancer NA NCT04716764 Unknown Breast cancer NA NCT05265715 Completed Lipid peroxidation products F2-isoprostanes (F2-IsoPs) Lung cancer II NCT02719860 Completed Pancreatic cancer II NCT01515046 Terminated Prostate cancer I NCT00895115 Completed Breast cancer II/III NCT00393172 Completed Colon cancer NA NCT01470586 Completed Trans-4-hydroxy-2-nonenal (4-HNE) Liver cancer II NCT00513461 Completed Anal cancer I/II NCT03386500 Recruiting High-grade glioma Early I NCT04559685 Recruiting Pediatric cancer NA NCT05255445 Completed Malondialdehyde (MDA) Neoplasms NA NCT06247865 Completed Oral cancer NA NCT04267419 Completed Prostate cancer IV NCT02149628 Completed Breast cancer MA NCT00539422 Completed Polycystic ovary syndrome NA NCT02954120 Completed Liver cancer II/III NCT01964001 Completed Acute myeloid leukemia I/II NCT05580861 Recruiting NSCLC NA NCT04676009 Completed Gastrointestinal carcinoma NA NCT02871999 Completed Laryngeal cancer NA NCT05857202 Unknown Colon cancer NA NCT01596634 Completed Acrolein Smoking-related carcinoma II NCT05121051 Recruiting Lung cancer NA NCT03402230 Completed Nucleic acid oxidation products 8-oxo-2’-deoxyguanosine (8-oxo-dG) Colon cancer NA NCT03550885 Active, not recruiting Premalignant lesion NA NCT03830710 Completed Esophageal carcinoma II NCT01097304 Completed Lung cancer II NCT02719860 Completed Bladder cancer NA NCT03286699 Terminated Oral cancer NA NCT04372914 Completed Breast cancer NA NCT02938780 Completed Prostate cancer II NCT03824652 Recruiting Thiols Thiol-disulfide balance Cervix cancer NA NCT04258553 Completed Endometrium cancer NA NCT04175067 Completed Ovarian cancer NA NCT05011539 Completed Breast cancer NA NCT04479098 Completed Antioxidant enzymes Superoxide dismutase (SOD) Head and neck cancer NA NCT01771991 Completed Neoplasm NA NCT03470857 Completed Liver cancer II/III NCT01964001 Completed Prostate cancer NA NCT00898274 Completed Catalase (CAT) Polycystic ovarian syndrome NA NCT03792282 Completed Malignant neoplasm Early I NCT05985278 Recruiting Breast cancer NA NCT04354233 Recruiting Glutathione peroxidase (GPX) Hepatocellular carcinoma NA NCT04601961 Unknown Prostate cancer NA NCT01917890 Completed Head and neck cancer NA NCT05451576 Recruiting Glutathione reductase (GR) Breast cancer NA NCT03516253 Unknown Non-Hodgkin’s lymphoma NA NCT03260231 Unknown Glutathione S-transferases (GSTs) Cancer NA NCT01293591 Completed NSCLC NA NCT06140082 Not yet recruiting Polycystic ovarian syndrome IV NCT02027337 Unknown Thioredoxin reductase Lung cancer NA NCT01985113 Completed I NCT02166242 Completed NCT01980212 Completed Pancreatic cancer II NCT00417287 Terminated Rectal cancer NA NCT00972751 Completed Promoter methylation site 5-methylcytosine AML, MDS, CMML NA NCT03526666 Completed Colorectal cancer NA NCT04196803 Completed Lung adenocarcinoma NA NCT06477211 Completed RUNX3 Gastric adenocarcinoma II NCT00674167 Unknown Lung cancer II/III NCT02416739 Unknown Colorectal cancer NA NCT05638542 Unknown DNMT1 Gastric carcinoma NA NCT05811546 Unknown Glioma NA NCT04097535 Completed II NCT04765514 Recruiting NA NCT02997423 Completed p16 Lung cancer NA NCT01038492 Completed Barrett’s Esophagus III NCT01566474 Completed Cervical cancer NA NCT05049252 Unknown Ewing sarcoma NA NCT00898053 Completed Breast cancer NA NCT01138345 Completed Oral epithelial dysplasia NA NCT00835341 Completed Non-Hodgkin’s lymphoma NA NCT00026910 Completed Non-coding RNAs (ncRNA) miR-373 Breast cancer NA NCT04720508 Unknown miR-155 Bladder cancer NA NCT03591367 Completed miR-371 Germ cell cancer NA NCT04435756 Active, not recruiting HOTAIR Thyroid cancer NA NCT03469544 Unknown miR-16 Pleural mesothelioma lung cancer I NCT02369198 Completed miR-122 Liver cancer I/II NCT01646489 Completed I/II NCT01727934 Unknown I/II NCT01872936 Unknown I/II NCT01200420 Completed miR-155 T-cell lymphoma II NCT03713320 Terminated miR-34a Melanoma I NCT01829971 Terminated I NCT02862145 Withdrawn mtlncRNA Unresectable tumors I NCT02508441 Terminated I NCT03985072 Completed Transcription factors Nrf2 Head and neck cancer Early I NCT03182959 Completed Smoking-related carcinoma Early I NCT03402230 Completed p53 Acute myeloid lymphoma I NCT03855371 Unknown Esophageal cancer III NCT00525200 Completed

Conclusion and perspective

ROS play a dual role in mammalian cells and are essential yet potentially toxic to both normal and cancerous tissues, making selective targeting through ROS-modulating therapies inherently challenging. The “Threshold concept for cancer therapy” suggests that tumor cells, with higher inherent ROS levels, can be selectively targeted through pro-oxidant therapy, exploiting their impaired redox homeostasis. 518 However, the lack of comparable normal cell controls highlights the need for larger paired studies and in vivo investigations to validate its translational potential.

Developing antioxidant-based therapies poses significant challenges due to the antioxidant paradox. While antioxidants protect healthy cells by mitigating oxidative stress, cancer cells exploit elevated antioxidant levels for survival. 14 Nonspecificity presents another great challenge in developing this therapeutic regime. For example, NOX inhibitors like DPI and VAS3947 affect pathways beyond NOX. 519 DPI disrupts mitochondrial respiration, NOS, and other complexes, causing off-target superoxide bursts, while VAS3947 induces apoptosis via cysteine thiol alkylation, independent of NOX activity. These off-target effects can lead to misleading and unexpected outcomes in studies of NOX-related oxidative metabolism in cancer. Moreover, antioxidants like Ascorbate, Dimethyl Fumarate (DMF), and Lycopene can act as pro-oxidants or antioxidants depending on the cellular context. Given these challenges, antioxidant-based therapies may be better suited for cancer prevention, as cancer cells can exploit antioxidants for survival. Research should prioritize understanding their context-dependent pro-oxidant and antioxidant effects to improve selectivity. TME-based studies could increase treatment efficacy, addressing nonspecificity and resistance. For example, NOX4 promotes tumor growth and metastasis under hypoxic conditions, making selective NOX4 inhibitors potential treatments for hypoxia-inducible cancers. 520 Furthermore, in the absence of specific agents, genetic approaches like gene knockdown offer precision therapy.

Targeting ROS promotion faces challenges due to metabolic plasticity and off-target toxicity. While polypharmacology enhances versatility, achieving tumor selectivity remains difficult. The efficacy of ROS-inducing agents depends on tumor-specific genetics and metabolism. For example, RSL3, a GPX4 inhibitor, induces ferroptosis in pancreatic cancer but varies in effectiveness based on the KRAS mutations and metabolic adaptations. 521 Such observations underscore the necessity of developing context-specific therapies, which require the consideration of oncogenic drivers, metabolic dependencies, and redox regulation. ROS like H₂O₂ can amplify cancer cell death via bystander effects but may also harm normal cells, necessitating tissue- and systemic-level impact assessment.

Targeting ROS-dependent pathways for drug development is challenging because of the dual role, complex regulation, and context-dependent activity of ROS. Key considerations include several critical questions: Is the molecule’s regulation by ROS conserved, and what is its mode of regulation? How does it influence specific pathways, and what is the interplay between ROS and those pathways, including potential interference from other ROS-regulated molecules? Furthermore, does the target molecule affect a single pathway or multiple pathways? The tumor microenvironment (TME) adds another layer of complexity, as shown in cervical cancer cells: MEK inhibition (MEKi) modulates ROS differently across cell lines, with ERK reducing ROS in C33-A cells but increasing it in SiHa and CaSki cells. 522 Combined ROS and ERK inhibition showed synergistic effects on CaSki and HeLa cells but not on C33-A or SiHa cells, underscoring the context-dependent ROS-ERK interplay. These complexities highlight the importance of precisely understanding ROS–target interactions and pathway dynamics to effectively leverage ROS-dependent mechanisms while minimizing unintended effects.

Combination therapeutic strategies in cancer focus on ROS induction rather than suppression, primarily owing to the complex and context-dependent role of ROS in malignancy, as exemplified by the “Antioxidant Paradox”. ROS-inducing therapies, combined with chemotherapy or radiotherapy, offer promise by amplifying oxidative stress selectively. However, challenges like bioavailability, off-target effects, TME heterogeneity, and metabolic plasticity persist. 523 Nanoparticle delivery systems enable precise, TME-responsive drug release by exploiting high levels of ROS, altered pH, or elevated NQO1 levels in tumors. Hypoxia further complicates ROS-based therapies, but oxygen-independent strategies—such as Fenton-like metal catalysts (Fe/Cu), hypoxia-activated prodrugs (HAPs), SDT, and NQO1 bioactivatable drugs (e.g., β-Lapachone)—show particular promise. 524 Furthermore, a major hurdle in ROS-targeted cancer therapy is the translation of mechanistic insights into clinically viable drugs. To address this, combining gene-editing tools (e.g., CRISPR or RNAi) with conventional therapies offers a promising solution—enabling precise disruption of redox-regulating genes (e.g., NOX4 and HIF1α) while leveraging the broad cytotoxicity of chemotherapy.

With respect to ROS-related biomarkers for personalized treatment, measuring specific ROS biomarkers like F2-isoprostanes or 8-oxo-dG, along with oxidative damage products, enhances sensitivity but faces challenges due to the transient and fluctuating nature of ROS. 11 Stable isotopes and advanced techniques such as LC‒MS or UPLC‒MS/MS might improve detection accuracy, whereas real-time monitoring tools, such as fluorescence spectroscopy and electrochemical sensors, can capture dynamic ROS activity. 525 Tissue-specific analyses and redox modulators provide deeper insights into organ- or cell-specific ROS behavior. Recent advancements, including deep tissue fluorescence imaging, metabolomics, and mass spectrometry imaging, have enabled in vivo investigations of redox mechanisms in tumors, 526 but further research is needed to achieve full precision and efficacy. Ultimately, unraveling how redox modulation drives tumor initiation, progression, and resistance will guide the rational design of context specific, clinically relevant therapies that exploit tumor-specific redox vulnerabilities while minimizing harm to normal tissues.

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

Acknowledgements

This work was supported in part by a grant from the National Research Foundation of Korea (NRF-2020R1A2C201215513 to Y.H.), Republic of Korea. This study was also an outcome of the ‘Gyeongsangnam-do Regional Innovation System & Education (RISE-202502990001 to Y.H.)’ Project, supported by the Ministry of Education and Gyeongsangnam-do, Republic of Korea. Additional support was provided by the Frontier Inje Research for Science and Technology (FIRST), Republic of Korea. The authors would like to express their gratitude to all the members of the “Biological Clock & Aging Control” laboratory for their invaluable support and critical comments. The authors also extend special thanks to Professor Sungho Yang (PhD) and Tonusree Roy at Inje University for their support with the critical revision of graphical images.

Author contributions

Conceptualization, S.A., Y.H.; software, S.A., R.M., A.K.K.; investigation, S.A., Y.H.; formal analysis, S.A., Y.H.; resources, Y.H.; data curation, S.A., R.M., A.K.K., I.S.N.; P.L., H.I.; visualization, S.A., Y.H., R.M.; supervision, Y.H., W.W.; validation, Y.H., W.W.; project administration, S.A., Y.H.; funding acquisition, Y.H.; writing-original draft preparation, S.A., Y.H.; writing-review and editing, S.A., R.M., A.K.K., I.S.N., P.L., H.I., W.W., Y.H.; All the authors have read and approved the final manuscript.

Data availability

All data used and/or analyzed in this review are available within the article and the referenced sources.

Competing interests

The authors declare no competing interests.

References

1. Reuter S Gupta SC Chaturvedi MM Aggarwal BB Oxidative stress, inflammation, and cancer: How are they linked? Free Radic. Biol. Med. 2010 49 1603 1616 10.1016/j.freeradbiomed.2010.09.006 20840865 PMC2990475 Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic. Biol. Med. 49 , 1603–1616 (2010). 20840865 10.1016/j.freeradbiomed.2010.09.006 PMC2990475

2. Kalyanaraman B Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies Redox Biol. 2018 15 347 362 10.1016/j.redox.2017.12.012 29306792 PMC5756055 Kalyanaraman, B. et al. Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies. Redox Biol. 15 , 347–362 (2018). 29306792 10.1016/j.redox.2017.12.012 PMC5756055

3. Perillo B ROS in cancer therapy: the bright side of the moon Exp. Mol. Med. 2020 52 192 203 10.1038/s12276-020-0384-2 32060354 PMC7062874 Perillo, B. et al. ROS in cancer therapy: the bright side of the moon. Exp. Mol. Med. 52 , 192–203 (2020). 32060354 10.1038/s12276-020-0384-2 PMC7062874

4. Dash UC Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications Acta Pharm. Sin. B 2025 15 15 34 10.1016/j.apsb.2024.10.004 40041912 PMC11873663 Dash, U. C. et al. Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications. Acta Pharm. Sin. B 15 , 15–34 (2025). 40041912 10.1016/j.apsb.2024.10.004 PMC11873663

5. Chang H Zou Z Targeting autophagy to overcome drug resistance: further developments J. Hematol. Oncol. 2020 13 159 10.1186/s13045-020-01000-2 33239065 PMC7687716 Chang, H. & Zou, Z. Targeting autophagy to overcome drug resistance: further developments. J. Hematol. Oncol. 13 , 159 (2020). 33239065 10.1186/s13045-020-01000-2 PMC7687716

6. Glorieux C Liu S Trachootham D Huang P Targeting ROS in cancer: rationale and strategies Nat. Rev. Drug Discov. 2024 23 583 606 10.1038/s41573-024-00979-4 38982305 Glorieux, C., Liu, S., Trachootham, D. & Huang, P. Targeting ROS in cancer: rationale and strategies. Nat. Rev. Drug Discov. 23 , 583–606 (2024). 38982305 10.1038/s41573-024-00979-4

7. Xu J Chen H Qian H Wang F Xu Y Advances in the modulation of ROS and transdermal administration for anti-psoriatic nanotherapies J. Nanobiotechnol. 2022 20 448 10.1186/s12951-022-01651-y PMC9569062 36242051 Xu, J., Chen, H., Qian, H., Wang, F. & Xu, Y. Advances in the modulation of ROS and transdermal administration for anti-psoriatic nanotherapies. J. Nanobiotechnol. 20 , 448 (2022). 10.1186/s12951-022-01651-y PMC9569062 36242051

8. Sies H Jones DP Reactive oxygen species (ROS) as pleiotropic physiological signalling agents Nat. Rev. Mol. Cell Biol. 2020 21 363 383 10.1038/s41580-020-0230-3 32231263 Sies, H. & Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 21 , 363–383 (2020). 32231263 10.1038/s41580-020-0230-3

9. Lennicke C Cochemé HM Redox metabolism: ROS as specific molecular regulators of cell signaling and function Mol. Cell. 2021 81 3691 3707 10.1016/j.molcel.2021.08.018 34547234 Lennicke, C. & Cochemé, H. M. Redox metabolism: ROS as specific molecular regulators of cell signaling and function. Mol. Cell. 81 , 3691–3707 (2021). 34547234 10.1016/j.molcel.2021.08.018

10. Zheng Y Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications Cell Death Dis. 2024 15 859 10.1038/s41419-024-07244-x 39587094 PMC11589755 Zheng, Y. et al. Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications. Cell Death Dis. 15 , 859 (2024). 39587094 10.1038/s41419-024-07244-x PMC11589755

11. Murphy MP Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo Nat. Metab. 2022 4 651 662 10.1038/s42255-022-00591-z 35760871 PMC9711940 Murphy, M. P. et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nat. Metab. 4 , 651–662 (2022). 35760871 10.1038/s42255-022-00591-z PMC9711940

12. Sies H Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology Nat. Rev. Mol. Cell Biol. 2022 23 499 515 10.1038/s41580-022-00456-z 35190722 Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. 23 , 499–515 (2022). 35190722 10.1038/s41580-022-00456-z

13. Altomare A Lipid peroxidation derived reactive carbonyl species in free and conjugated forms as an index of lipid peroxidation: limits and perspectives Redox Biol. 2021 42 101899 10.1016/j.redox.2021.101899 33642248 PMC8113032 Altomare, A. et al. Lipid peroxidation derived reactive carbonyl species in free and conjugated forms as an index of lipid peroxidation: limits and perspectives. Redox Biol. 42 , 101899 (2021). 33642248 10.1016/j.redox.2021.101899 PMC8113032

14. An X Oxidative cell death in cancer: mechanisms and therapeutic opportunities Cell Death Dis. 2024 15 556 10.1038/s41419-024-06939-5 39090114 PMC11294602 An, X. et al. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis. 15 , 556 (2024). 39090114 10.1038/s41419-024-06939-5 PMC11294602

15. Koppenol, W. H. & Sies, H. Was hydrogen peroxide present before the arrival of oxygenic photosynthesis? The important role of iron(II) in the Archean ocean. Redox Biol . 69 , 103012 (2024). 10.1016/j.redox.2023.103012 PMC10808959 38183797

16. Loew O A New Enzyme of General Occurrence in Organisms Science 1900 11 701 702 10.1126/science.11.279.701 17751716 Loew, O. A New Enzyme of General Occurrence in Organisms. Science 11 , 701–702 (1900). 17751716 10.1126/science.11.279.701

17. Zuo J Redox signaling at the crossroads of human health and disease MedComm 2022 3 127 10.1002/mco2.127 PMC8971743 35386842 Zuo, J. et al. Redox signaling at the crossroads of human health and disease. MedComm 3 , 127 (2022). 10.1002/mco2.127 PMC8971743 35386842

18. Grosche J Meißner J Eble JA More than a syllable in fib-ROS-is: The role of ROS on the fibrotic extracellular matrix and on cellular contacts Mol. Aspects Med. 2018 63 30 46 10.1016/j.mam.2018.03.005 29596842 Grosche, J., Meißner, J. & Eble, J. A. More than a syllable in fib-ROS-is: The role of ROS on the fibrotic extracellular matrix and on cellular contacts. Mol. Aspects Med. 63 , 30–46 (2018). 29596842 10.1016/j.mam.2018.03.005

19. Sbarra AJ Karnovsky ML The Biochemical Basis of Phagocytosis: I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes J. Biol. Chem. 1959 234 1355 1362 10.1016/S0021-9258(18)70011-2 13654378 Sbarra, A. J. & Karnovsky, M. L. The Biochemical Basis of Phagocytosis: I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes. J. Biol. Chem. 234 , 1355–1362 (1959). 13654378

20. McCord JM Fridovich I Superoxide Dismutase J. Biol. Chem. 1969 244 6049 6055 10.1016/S0021-9258(18)63504-5 5389100 McCord, J. M. & Fridovich, I. Superoxide Dismutase. J. Biol. Chem. 244 , 6049–6055 (1969). 5389100

21. Commoner B Townsend J Pake GE Free radicals in biological materials Nature 1954 174 689 691 10.1038/174689a0 13213980 Commoner, B., Townsend, J. & Pake, G. E. Free radicals in biological materials. Nature 174 , 689–691 (1954). 13213980 10.1038/174689a0

22. HARMAN D Aging: a theory based on free radical and radiation chemistry J. Gerontol. 1956 11 298 300 10.1093/geronj/11.3.298 13332224 HARMAN, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11 , 298–300 (1956). 13332224 10.1093/geronj/11.3.298

23. Balaban RS Nemoto S Finkel T Mitochondria, Oxidants, and Aging Cell 2005 120 483 495 10.1016/j.cell.2005.02.001 15734681 Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, Oxidants, and Aging. Cell 120 , 483–495 (2005). 15734681 10.1016/j.cell.2005.02.001

24. Mittal CK Murad F Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3’,5’-monophosphate formation Proc. Natl Acad. Sci. USA 1977 74 4360 4364 10.1073/pnas.74.10.4360 22077 PMC431941 Mittal, C. K. & Murad, F. Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3’,5’-monophosphate formation. Proc. Natl Acad. Sci. USA 74 , 4360–4364 (1977). 22077 10.1073/pnas.74.10.4360 PMC431941

25. Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine (Oxford Univ. Press, 1991).

26. Mueller JH Growth-determining substances in bacteriological culture media Proc. Soc. Exp. Biol. Med. 1921 18 225 228 10.3181/00379727-18-113 Mueller, J. H. Growth-determining substances in bacteriological culture media. Proc. Soc. Exp. Biol. Med. 18 , 225–228 (1921).

27. Van Patten SM Oxidation of Methionine Residues in Antithrombin: Effects on biological activity and heparin binding J. Biol. Chem. 1999 274 10268 10276 10.1074/jbc.274.15.10268 10187813 Van Patten, S. M. et al. Oxidation of Methionine Residues in Antithrombin: Effects on biological activity and heparin binding. J. Biol. Chem. 274 , 10268–10276 (1999). 10187813 10.1074/jbc.274.15.10268

28. Brot N Weissbach L Werth J Weissbach H Enzymatic reduction of protein-bound methionine sulfoxide Proc. Natl Acad. Sci. USA 1981 78 2155 2158 10.1073/pnas.78.4.2155 7017726 PMC319302 Brot, N., Weissbach, L., Werth, J. & Weissbach, H. Enzymatic reduction of protein-bound methionine sulfoxide. Proc. Natl Acad. Sci. USA 78 , 2155–2158 (1981). 7017726 10.1073/pnas.78.4.2155 PMC319302

29. Lescure A Gautheret D Carbon P Krol A Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif J. Biol. Chem. 1999 274 38147 38154 10.1074/jbc.274.53.38147 10608886 Lescure, A., Gautheret, D., Carbon, P. & Krol, A. Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif. J. Biol. Chem. 274 , 38147–38154 (1999). 10608886 10.1074/jbc.274.53.38147

30. Lin Z Free methionine-(R)-sulfoxide reductase from Escherichia coli reveals a new GAF domain function Proc. Natl Acad. Sci. USA 2007 104 9597 9602 10.1073/pnas.0703774104 17535911 PMC1887594 Lin, Z. et al. Free methionine-(R)-sulfoxide reductase from Escherichia coli reveals a new GAF domain function. Proc. Natl Acad. Sci. USA 104 , 9597–9602 (2007). 17535911 10.1073/pnas.0703774104 PMC1887594

31. Drazic A Methionine oxidation activates a transcription factor in response to oxidative stress Proc. Natl Acad. Sci. USA 2013 110 9493 9498 10.1073/pnas.1300578110 23690622 PMC3677443 Drazic, A. et al. Methionine oxidation activates a transcription factor in response to oxidative stress. Proc. Natl Acad. Sci. USA 110 , 9493–9498 (2013). 23690622 10.1073/pnas.1300578110 PMC3677443

32. Green DR Reed JC Mitochondria and Apoptosis Science 1998 281 1309 1312 10.1126/science.281.5381.1309 9721092 Green, D. R. & Reed, J. C. Mitochondria and Apoptosis. Science 281 , 1309–1312 (1998). 9721092 10.1126/science.281.5381.1309

33. Scherz-Shouval R Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4 EMBO J. 2007 26 1749 1760 10.1038/sj.emboj.7601623 17347651 PMC1847657 Scherz-Shouval, R. et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26 , 1749–1760 (2007). 17347651 10.1038/sj.emboj.7601623 PMC1847657

34. Cho YS Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation Cell 2009 137 1112 1123 10.1016/j.cell.2009.05.037 19524513 PMC2727676 Cho, Y. S. et al. Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation. Cell 137 , 1112–1123 (2009). 19524513 10.1016/j.cell.2009.05.037 PMC2727676

35. Stockwell BR Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications Cell 2022 185 2401 2421 10.1016/j.cell.2022.06.003 35803244 PMC9273022 Stockwell, B. R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185 , 2401–2421 (2022). 35803244 10.1016/j.cell.2022.06.003 PMC9273022

36. Hirschhorn T Stockwell BR The development of the concept of ferroptosis Free Radic. Biol. Med. 2019 133 130 143 10.1016/j.freeradbiomed.2018.09.043 30268886 PMC6368883 Hirschhorn, T. & Stockwell, B. R. The development of the concept of ferroptosis. Free Radic. Biol. Med. 133 , 130–143 (2019). 30268886 10.1016/j.freeradbiomed.2018.09.043 PMC6368883

37. Barton J Nanoscale Dynamic Readout of a Chemical Redox Process Using Radicals Coupled with Nitrogen-Vacancy Centers in Nanodiamonds ACS Nano 2020 14 12938 12950 10.1021/acsnano.0c04010 32790348 Barton, J. et al. Nanoscale Dynamic Readout of a Chemical Redox Process Using Radicals Coupled with Nitrogen-Vacancy Centers in Nanodiamonds. ACS Nano 14 , 12938–12950 (2020). 32790348 10.1021/acsnano.0c04010

38. Oliveira ASF Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations J. Chem. Theory Comput. 2024 20 385 395 10.1021/acs.jctc.3c00785 38150288 PMC10782445 Oliveira, A. S. F. et al. Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations. J. Chem. Theory Comput. 20 , 385–395 (2024). 38150288 10.1021/acs.jctc.3c00785 PMC10782445

39. Jinnouchi R Karsai F Kresse G Machine learning-aided first-principles calculations of redox potentials NPJ Comput. Mater. 2024 10 107 10.1038/s41524-024-01295-6 Jinnouchi, R., Karsai, F. & Kresse, G. Machine learning-aided first-principles calculations of redox potentials. NPJ Comput. Mater. 10 , 107 (2024).

40. Li X Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers J. Hematol. Oncol. 2013 6 19 10.1186/1756-8722-6-19 23442817 PMC3599349 Li, X. et al. Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J. Hematol. Oncol. 6 , 19 (2013). 23442817 10.1186/1756-8722-6-19 PMC3599349

41. Sousa T Gouveia M Travasso RDM Salvador A How abundant are superoxide and hydrogen peroxide in the vasculature lumen, how far can they reach? Redox Biol. 2022 58 102527 10.1016/j.redox.2022.102527 36335761 PMC9640316 Sousa, T., Gouveia, M., Travasso, R. D. M. & Salvador, A. How abundant are superoxide and hydrogen peroxide in the vasculature lumen, how far can they reach? Redox Biol. 58 , 102527 (2022). 36335761 10.1016/j.redox.2022.102527 PMC9640316

42. Radi R Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine Proc. Natl Acad. Sci. USA 2018 115 5839 5848 10.1073/pnas.1804932115 29802228 PMC6003358 Radi, R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proc. Natl Acad. Sci. USA 115 , 5839–5848 (2018). 29802228 10.1073/pnas.1804932115 PMC6003358

43. Jo DS Park NY Cho D-H Peroxisome quality control and dysregulated lipid metabolism in neurodegenerative diseases Exp. Mol. Med. 2020 52 1486 1495 10.1038/s12276-020-00503-9 32917959 PMC8080768 Jo, D. S., Park, N. Y. & Cho, D.-H. Peroxisome quality control and dysregulated lipid metabolism in neurodegenerative diseases. Exp. Mol. Med. 52 , 1486–1495 (2020). 32917959 10.1038/s12276-020-00503-9 PMC8080768

44. Bhattarai KR The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling Exp. Mol. Med. 2021 53 151 167 10.1038/s12276-021-00560-8 33558590 PMC8080639 Bhattarai, K. R. et al. The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling. Exp. Mol. Med. 53 , 151–167 (2021). 33558590 10.1038/s12276-021-00560-8 PMC8080639

45. Wang L Wang C Oxidative protein folding fidelity and redoxtasis in the endoplasmic reticulum Trends Biochem. Sci. 2023 48 40 52 10.1016/j.tibs.2022.06.011 35871147 Wang, L. & Wang, C. Oxidative protein folding fidelity and redoxtasis in the endoplasmic reticulum. Trends Biochem. Sci. 48 , 40–52 (2023). 35871147 10.1016/j.tibs.2022.06.011

46. Ponsero AJ Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip Mol. Cell 2017 67 962 973 10.1016/j.molcel.2017.08.012 28918898 PMC5772773 Ponsero, A. J. et al. Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip. Mol. Cell 67 , 962–973 (2017). 28918898 10.1016/j.molcel.2017.08.012 PMC5772773

47. Forrester SJ Kikuchi DS Hernandes MS Xu Q Griendling KK Reactive oxygen species in metabolic and inflammatory signaling Circ. Res. 2018 122 877 902 10.1161/CIRCRESAHA.117.311401 29700084 PMC5926825 Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q. & Griendling, K. K. Reactive oxygen species in metabolic and inflammatory signaling. Circ. Res. 122 , 877–902 (2018). 29700084 10.1161/CIRCRESAHA.117.311401 PMC5926825

48. Germon ZP Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies Sci. Signal. 2023 16 eabp9586 10.1126/scisignal.abp9586 36976863 Germon, Z. P. et al. Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies. Sci. Signal. 16 , eabp9586 (2023). 36976863 10.1126/scisignal.abp9586

49. Hole PS Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling Blood 2013 122 3322 3330 10.1182/blood-2013-04-491944 24089327 Hole, P. S. et al. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood 122 , 3322–3330 (2013). 24089327 10.1182/blood-2013-04-491944

50. Gobert AP Wilson KT Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise Free Radic. Biol. Med. 2017 105 16 27 10.1016/j.freeradbiomed.2016.09.024 27682363 PMC5366100 Gobert, A. P. & Wilson, K. T. Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise. Free Radic. Biol. Med. 105 , 16–27 (2017). 27682363 10.1016/j.freeradbiomed.2016.09.024 PMC5366100

51. Jamieson KL Endo T Darwesh AM Samokhvalov V Seubert JM Cytochrome P450-derived eicosanoids and heart function Pharmacol. Ther. 2017 179 47 83 10.1016/j.pharmthera.2017.05.005 28551025 Jamieson, K. L., Endo, T., Darwesh, A. M., Samokhvalov, V. & Seubert, J. M. Cytochrome P450-derived eicosanoids and heart function. Pharmacol. Ther. 179 , 47–83 (2017). 28551025 10.1016/j.pharmthera.2017.05.005

52. Osaki M Oshimura M Ito H PI3K–Akt pathway: its functions and alterations in human cancer Apoptosis 2004 9 667 676 10.1023/B:APPT.0000045801.15585.dd 15505410 Osaki, M., Oshimura, M. & Ito, H. PI3K–Akt pathway: its functions and alterations in human cancer. Apoptosis 9 , 667–676 (2004). 15505410 10.1023/B:APPT.0000045801.15585.dd

53. Nakanishi A Wada Y Kitagishi Y Matsuda S Link between PI3K/AKT/PTEN pathway and NOX protein in diseases Aging Dis 2014 5 203 211 24900943 10.14336/AD.2014.0500203 PMC4037312 Nakanishi, A., Wada, Y., Kitagishi, Y. & Matsuda, S. Link between PI3K/AKT/PTEN pathway and NOX protein in diseases. Aging Dis 5 , 203–211 (2014). 24900943 10.14336/AD.2014.0500203 PMC4037312

54. Bhattacharyya A Chattopadhyay R Mitra S Crowe SE Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases Physiol. Rev. 2014 94 329 354 10.1152/physrev.00040.2012 24692350 PMC4044300 Bhattacharyya, A., Chattopadhyay, R., Mitra, S. & Crowe, S. E. Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases. Physiol. Rev. 94 , 329–354 (2014). 24692350 10.1152/physrev.00040.2012 PMC4044300

55. Huang J Fe(II) Redox Chemistry in the Environment Chem. Rev. 2021 121 8161 8233 10.1021/acs.chemrev.0c01286 34143612 Huang, J. et al. Fe(II) Redox Chemistry in the Environment. Chem. Rev. 121 , 8161–8233 (2021). 34143612 10.1021/acs.chemrev.0c01286

56. Li X Precise modulation and use of reactive oxygen species for immunotherapy Sci. Adv. 2024 10 eadl0479 10.1126/sciadv.adl0479 38748805 PMC11095489 Li, X. et al. Precise modulation and use of reactive oxygen species for immunotherapy. Sci. Adv. 10 , eadl0479 (2024). 38748805 10.1126/sciadv.adl0479 PMC11095489

57. Tebay LE Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease Free Radic. Biol. Med. 2015 88 108 146 10.1016/j.freeradbiomed.2015.06.021 26122708 PMC4659505 Tebay, L. E. et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med. 88 , 108–146 (2015). 26122708 10.1016/j.freeradbiomed.2015.06.021 PMC4659505

58. Yang B Lin Y Huang Y Shen YQ Chen Q Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases Redox Biol. 2024 70 103032 10.1016/j.redox.2024.103032 38232457 PMC10827563 Yang, B., Lin, Y., Huang, Y., Shen, Y. Q. & Chen, Q. Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases. Redox Biol. 70 , 103032 (2024). 38232457 10.1016/j.redox.2024.103032 PMC10827563

59. Chun K Raut PK Kim D Surh Y Role of chemopreventive phytochemicals in Nrf2-mediated redox homeostasis in humans Free Radic. Biol. Med. 2021 172 699 715 10.1016/j.freeradbiomed.2021.06.031 34214633 Chun, K., Raut, P. K., Kim, D. & Surh, Y. Role of chemopreventive phytochemicals in Nrf2-mediated redox homeostasis in humans. Free Radic. Biol. Med. 172 , 699–715 (2021). 34214633 10.1016/j.freeradbiomed.2021.06.031

60. Xu L Massagué J Nucleocytoplasmic shuttling of signal transducers Nat. Rev. Mol. Cell Biol. 2004 5 209 219 10.1038/nrm1331 14991001 Xu, L. & Massagué, J. Nucleocytoplasmic shuttling of signal transducers. Nat. Rev. Mol. Cell Biol. 5 , 209–219 (2004). 14991001 10.1038/nrm1331

61. Baptiste N Prives C p53 in the Cytoplasm: A Question of Overkill? Cell 2004 116 487 489 10.1016/S0092-8674(04)00164-3 14980216 Baptiste, N. & Prives, C. p53 in the Cytoplasm: A Question of Overkill? Cell 116 , 487–489 (2004). 14980216 10.1016/s0092-8674(04)00164-3

62. Zhang L 6-Methoxydihydrosanguinarine induces apoptosis and autophagy in breast cancer MCF-7 cells by accumulating ROS to suppress the PI3K/AKT/mTOR signaling pathway Phytother. Res. 2023 37 124 139 10.1002/ptr.7601 36116140 Zhang, L. et al. 6-Methoxydihydrosanguinarine induces apoptosis and autophagy in breast cancer MCF-7 cells by accumulating ROS to suppress the PI3K/AKT/mTOR signaling pathway. Phytother. Res. 37 , 124–139 (2023). 36116140 10.1002/ptr.7601

63. Li X-Q Cheng X-J Wu J Wu K-F Liu T Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer Cell. Mol. Biol. Lett. 2024 29 58 10.1186/s11658-024-00578-6 38649803 PMC11036658 Li, X.-Q., Cheng, X.-J., Wu, J., Wu, K.-F. & Liu, T. Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer. Cell. Mol. Biol. Lett. 29 , 58 (2024). 38649803 10.1186/s11658-024-00578-6 PMC11036658

64. Ingram JP ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence of RIPK1 J. Immunol. 2019 203 1348 1355 10.4049/jimmunol.1900216 31358656 PMC6702065 Ingram, J. P. et al. ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence of RIPK1. J. Immunol. 203 , 1348–1355 (2019). 31358656 10.4049/jimmunol.1900216 PMC6702065

65. Kirova DG A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase Dev. Cell 2022 57 1712 1727 10.1016/j.devcel.2022.06.008 35809563 PMC9616724 Kirova, D. G. et al. A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase. Dev. Cell 57 , 1712–1727 (2022). 35809563 10.1016/j.devcel.2022.06.008 PMC9616724

66. Knight H Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation Circ. Res. 2023 133 966 988 10.1161/CIRCRESAHA.122.321836 37955182 PMC10699508 Knight, H. et al. Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation. Circ. Res. 133 , 966–988 (2023). 37955182 10.1161/CIRCRESAHA.122.321836 PMC10699508

67. Yang H Reprogramming cellular senescence and aging clocks for advanced cancer immunotherapy Mol. Cancer 2025 24 237 10.1186/s12943-025-02459-8 41039629 PMC12492661 Yang, H. et al. Reprogramming cellular senescence and aging clocks for advanced cancer immunotherapy. Mol. Cancer 24 , 237 (2025). 41039629 10.1186/s12943-025-02459-8 PMC12492661

68. Boutros R Lobjois V Ducommun B CDC25 phosphatases in cancer cells: key players? Good targets? Nat. Rev. Cancer 2007 7 495 507 10.1038/nrc2169 17568790 Boutros, R., Lobjois, V. & Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat. Rev. Cancer 7 , 495–507 (2007). 17568790 10.1038/nrc2169

69. Wang G-F Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation Free Radic. Biol. Med. 2017 103 177 187 10.1016/j.freeradbiomed.2016.12.031 28017898 Wang, G.-F. et al. Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation. Free Radic. Biol. Med. 103 , 177–187 (2017). 28017898 10.1016/j.freeradbiomed.2016.12.031

70. Chang T-S Jeong W Lee D-Y Cho C-S Rhee SG The RING-H2–finger protein APC11 as a target of hydrogen peroxide Free Radic. Biol. Med. 2004 37 521 530 10.1016/j.freeradbiomed.2004.05.006 15256223 Chang, T.-S., Jeong, W., Lee, D.-Y., Cho, C.-S. & Rhee, S. G. The RING-H2–finger protein APC11 as a target of hydrogen peroxide. Free Radic. Biol. Med. 37 , 521–530 (2004). 15256223 10.1016/j.freeradbiomed.2004.05.006

71. Yochum GS Sherrick CM MacPartlin M Goodman RH A β-catenin/TCF-coordinated chromatin loop at MYC integrates 5′ and 3′ Wnt-responsive enhancers Proc. Natl Acad. Sci. USA 2009 107 145 150 10.1073/pnas.0912294107 19966299 PMC2806753 Yochum, G. S., Sherrick, C. M., MacPartlin, M. & Goodman, R. H. A β-catenin/TCF-coordinated chromatin loop at MYC integrates 5′ and 3′ Wnt-responsive enhancers. Proc. Natl Acad. Sci. USA 107 , 145–150 (2009). 19966299 10.1073/pnas.0912294107 PMC2806753

72. Naseri-Nosar P Nogalski MT Shenk T The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression Proc. Natl Acad. Sci. USA 2021 118 e2026336118 10.1073/pnas.2026336118 33723080 PMC8000196 Naseri-Nosar, P., Nogalski, M. T. & Shenk, T. The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression. Proc. Natl Acad. Sci. USA 118 , e2026336118 (2021). 33723080 10.1073/pnas.2026336118 PMC8000196

73. Li T-F Transforming Growth Factor-β Stimulates Cyclin D 1 Expression through Activation of β-Catenin Signaling in Chondrocytes J. Biol. Chem. 2006 281 21296 21304 10.1074/jbc.M600514200 16690606 PMC2649822 Li, T.-F. et al. Transforming Growth Factor-β Stimulates Cyclin D 1 Expression through Activation of β-Catenin Signaling in Chondrocytes. J. Biol. Chem. 281 , 21296–21304 (2006). 16690606 10.1074/jbc.M600514200 PMC2649822

74. Dewenter M von der Lieth A Katus HA Backs J Calcium Signaling and Transcriptional Regulation in Cardiomyocytes Circ. Res. 2017 121 1000 1020 10.1161/CIRCRESAHA.117.310355 28963192 Dewenter, M., von der Lieth, A., Katus, H. A. & Backs, J. Calcium Signaling and Transcriptional Regulation in Cardiomyocytes. Circ. Res. 121 , 1000–1020 (2017). 28963192 10.1161/CIRCRESAHA.117.310355

75. Masoud GN Li W HIF-1α pathway: role, regulation and intervention for cancer therapy Acta Pharm. Sin. B 2015 5 378 389 10.1016/j.apsb.2015.05.007 26579469 PMC4629436 Masoud, G. N. & Li, W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B 5 , 378–389 (2015). 26579469 10.1016/j.apsb.2015.05.007 PMC4629436

76. Liu Q EGFR-TKIs resistance via EGFR-independent signaling pathways Mol. Cancer 2018 17 53 10.1186/s12943-018-0793-1 29455669 PMC5817859 Liu, Q. et al. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol. Cancer 17 , 53 (2018). 29455669 10.1186/s12943-018-0793-1 PMC5817859

77. Philips RL The JAK–STAT pathway at 30: Much learned, much more to do Cell 2022 185 3857 3876 10.1016/j.cell.2022.09.023 36240739 PMC9815833 Philips, R. L. et al. The JAK–STAT pathway at 30: Much learned, much more to do. Cell 185 , 3857–3876 (2022). 36240739 10.1016/j.cell.2022.09.023 PMC9815833

78. Hassan D AKT kinases as therapeutic targets J. Exp. Clin. Cancer Res. 2024 43 313 10.1186/s13046-024-03207-4 39614261 PMC11606119 Hassan, D. et al. AKT kinases as therapeutic targets. J. Exp. Clin. Cancer Res. 43 , 313 (2024). 39614261 10.1186/s13046-024-03207-4 PMC11606119

79. Hua H Targeting Akt in cancer for precision therapy J. Hematol. Oncol. 2021 14 128 10.1186/s13045-021-01137-8 34419139 PMC8379749 Hua, H. et al. Targeting Akt in cancer for precision therapy. J. Hematol. Oncol. 14 , 128 (2021). 34419139 10.1186/s13045-021-01137-8 PMC8379749

80. Anjum R Blenis J The RSK family of kinases: emerging roles in cellular signalling Nat. Rev. Mol. Cell Biol. 2008 9 747 758 10.1038/nrm2509 18813292 Anjum, R. & Blenis, J. The RSK family of kinases: emerging roles in cellular signalling. Nat. Rev. Mol. Cell Biol. 9 , 747–758 (2008). 18813292 10.1038/nrm2509

81. Shaulian E Karin M Shaulian E Karin M AP-1 in cell proliferation and survival Oncogene 2001 20 2390 2400 10.1038/sj.onc.1204383 11402335 Shaulian, E., Karin, M., Shaulian, E. & Karin, M. AP-1 in cell proliferation and survival. Oncogene 20 , 2390–2400 (2001). 11402335 10.1038/sj.onc.1204383

82. Lee J-H Ataxia Telangiectasia-Mutated (ATM) Kinase Activity Is Regulated by ATP-driven Conformational Changes in the Mre11/Rad50/Nbs1 (MRN) Complex J. Biol. Chem. 2013 288 12840 12851 10.1074/jbc.M113.460378 23525106 PMC3642328 Lee, J.-H. et al. Ataxia Telangiectasia-Mutated (ATM) Kinase Activity Is Regulated by ATP-driven Conformational Changes in the Mre11/Rad50/Nbs1 (MRN) Complex. J. Biol. Chem. 288 , 12840–12851 (2013). 23525106 10.1074/jbc.M113.460378 PMC3642328

83. Watts ER Walmsley SR Inflammation and Hypoxia: HIF and PHD Isoform Selectivity Trends Mol. Med. 2019 25 33 46 10.1016/j.molmed.2018.10.006 30442494 Watts, E. R. & Walmsley, S. R. Inflammation and Hypoxia: HIF and PHD Isoform Selectivity. Trends Mol. Med. 25 , 33–46 (2019). 30442494 10.1016/j.molmed.2018.10.006

84. Fernández JG Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription Mol. Cancer 2014 13 209 10.1186/1476-4598-13-209 25204429 PMC4177250 Fernández, J. G. et al. Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription. Mol. Cancer 13 , 209 (2014). 25204429 10.1186/1476-4598-13-209 PMC4177250

85. Si W Angiotensin II Increases Angiogenesis by Nf-κB-mediated Transcriptional Activation of Angiogenic Factor Aggf1 Arterioscler. Thromb. Vasc. Biol. 2018 38 abstr. 501 10.1161/atvb.38.suppl_1.501 PMC6103173 29641288 Si, W. et al. Angiotensin II Increases Angiogenesis by Nf-κB-mediated Transcriptional Activation of Angiogenic Factor Aggf1. Arterioscler. Thromb. Vasc. Biol. 38 , abstr. 501 (2018). 10.1096/fj.201701543RR PMC6103173 29641288

86. Nam E-H Park S-R Kim P-H TGF-β1 induces mouse dendritic cells to express VEGF and its receptor (Flt-1) under hypoxic conditions Exp. Mol. Med. 2010 42 606 613 10.3858/emm.2010.42.9.059 20631490 PMC2947018 Nam, E.-H., Park, S.-R. & Kim, P.-H. TGF-β1 induces mouse dendritic cells to express VEGF and its receptor (Flt-1) under hypoxic conditions. Exp. Mol. Med. 42 , 606–613 (2010). 20631490 10.3858/emm.2010.42.9.059 PMC2947018

87. Gray MJ HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas Oncogene 2005 24 3110 3120 10.1038/sj.onc.1208513 15735682 Gray, M. J. et al. HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24 , 3110–3120 (2005). 15735682 10.1038/sj.onc.1208513

88. Yang Y Enalapril overcomes chemoresistance and potentiates antitumor efficacy of 5-FU in colorectal cancer by suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins Cell Death Dis. 2020 11 477 10.1038/s41419-020-2675-x 32581212 PMC7314775 Yang, Y. et al. Enalapril overcomes chemoresistance and potentiates antitumor efficacy of 5-FU in colorectal cancer by suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins. Cell Death Dis. 11 , 477 (2020). 32581212 10.1038/s41419-020-2675-x PMC7314775

89. Andrabi SM Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications Adv. Sci. 2023 10 2303259 10.1002/advs.202303259 PMC10602574 37632708 Andrabi, S. M. et al. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications. Adv. Sci. 10 , 2303259 (2023). 10.1002/advs.202303259 PMC10602574 37632708

90. Lawler J Counter regulation of tumor angiogenesis by vascular endothelial growth factor and thrombospondin-1 Semin. Cancer Biol. 2022 86 126 135 10.1016/j.semcancer.2022.09.006 36191900 Lawler, J. Counter regulation of tumor angiogenesis by vascular endothelial growth factor and thrombospondin-1. Semin. Cancer Biol. 86 , 126–135 (2022). 36191900 10.1016/j.semcancer.2022.09.006

91. Pang B Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction Angiogenesis 2024 27 623 639 10.1007/s10456-024-09938-4 39060773 PMC11564294 Pang, B. et al. Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction. Angiogenesis 27 , 623–639 (2024). 39060773 10.1007/s10456-024-09938-4 PMC11564294

92. Tufail M Jiang C-H Li N Wnt signaling in cancer: from biomarkers to targeted therapies and clinical translation Mol. Cancer 2025 24 107 10.1186/s12943-025-02306-w 40170063 PMC11963613 Tufail, M., Jiang, C.-H. & Li, N. Wnt signaling in cancer: from biomarkers to targeted therapies and clinical translation. Mol. Cancer 24 , 107 (2025). 40170063 10.1186/s12943-025-02306-w PMC11963613

93. Zhang YE Non-Smad pathways in TGF-β signaling Cell Res. 2009 19 128 139 10.1038/cr.2008.328 19114990 PMC2635127 Zhang, Y. E. Non-Smad pathways in TGF-β signaling. Cell Res. 19 , 128–139 (2009). 19114990 10.1038/cr.2008.328 PMC2635127

94. Motizuki M Yokoyama T Saitoh M Miyazawa K The Snail signaling branch downstream of the TGF-β/Smad3 pathway mediates Rho activation and subsequent stress fiber formation J. Biol. Chem. 2024 300 105580 10.1016/j.jbc.2023.105580 38141763 PMC10821601 Motizuki, M., Yokoyama, T., Saitoh, M. & Miyazawa, K. The Snail signaling branch downstream of the TGF-β/Smad3 pathway mediates Rho activation and subsequent stress fiber formation. J. Biol. Chem. 300 , 105580 (2024). 38141763 10.1016/j.jbc.2023.105580 PMC10821601

95. Li X Calcineurin-NFAT Signaling Critically Regulates Early Lineage Specification in Mouse Embryonic Stem Cells and Embryos Cell Stem Cell 2011 8 46 58 10.1016/j.stem.2010.11.027 21211781 Li, X. et al. Calcineurin-NFAT Signaling Critically Regulates Early Lineage Specification in Mouse Embryonic Stem Cells and Embryos. Cell Stem Cell 8 , 46–58 (2011). 21211781 10.1016/j.stem.2010.11.027

96. Shang T Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance J. Hematol. Oncol. 2025 18 32 10.1186/s13045-025-01684-4 40102937 PMC11921735 Shang, T. et al. Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance. J. Hematol. Oncol. 18 , 32 (2025). 40102937 10.1186/s13045-025-01684-4 PMC11921735

97. He X-Y Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment Cancer Cell 2024 42 474 486 10.1016/j.ccell.2024.01.013 38402610 PMC11300849 He, X.-Y. et al. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell 42 , 474–486 (2024). 38402610 10.1016/j.ccell.2024.01.013 PMC11300849

98. Xu H Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism Oncogene 2023 42 1994 2006 10.1038/s41388-023-02708-4 37138031 PMC10256612 Xu, H. et al. Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism. Oncogene 42 , 1994–2006 (2023). 37138031 10.1038/s41388-023-02708-4 PMC10256612

99. Sadik A IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression Cell 2020 182 1252 1270 10.1016/j.cell.2020.07.038 32818467 Sadik, A. et al. IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 182 , 1252–1270 (2020). 32818467 10.1016/j.cell.2020.07.038

100. Liu Y Multi-Enzyme Co-Expressed Nanomedicine for Anti-Metastasis Tumor Therapy by Up-Regulating Cellular Oxidative Stress and Depleting Cholesterol Adv. Mater. 2024 36 2307752 10.1002/adma.202307752 37734072 Liu, Y. et al. Multi-Enzyme Co-Expressed Nanomedicine for Anti-Metastasis Tumor Therapy by Up-Regulating Cellular Oxidative Stress and Depleting Cholesterol. Adv. Mater. 36 , 2307752 (2024). 10.1002/adma.202307752 37734072

101. Schulz JA Hartz AMS Bauer B ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery Pharmacol. Rev. 2023 75 815 853 10.1124/pharmrev.120.000025 36973040 PMC10441638 Schulz, J. A., Hartz, A. M. S. & Bauer, B. ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery. Pharmacol. Rev. 75 , 815–853 (2023). 36973040 10.1124/pharmrev.120.000025 PMC10441638

102. Liu R PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers Cell Death Dis 2020 11 797 10.1038/s41419-020-02998-6 32973135 PMC7515865 Liu, R. et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis 11 , 797 (2020). 32973135 10.1038/s41419-020-02998-6 PMC7515865

103. Arabpour, M. & Rezaei, N. The role of noncoding RNAs in drug resistance of cancers. In Handbook of Cancer and Immunology (ed. Rezaei, N.) 1–26 (Springer International Publishing, 2022).

104. Raju GSR HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer Mol. Cancer 2023 22 65 10.1186/s12943-023-01765-3 36997931 PMC10061914 Raju, G. S. R. et al. HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer. Mol. Cancer 22 , 65 (2023). 36997931 10.1186/s12943-023-01765-3 PMC10061914

105. Jiang L Wang P Sun Y-J Wu Y-J Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway J. Exp. Clin. Cancer Res. 2019 38 265 10.1186/s13046-019-1251-7 31215501 PMC6580523 Jiang, L., Wang, P., Sun, Y.-J. & Wu, Y.-J. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway. J. Exp. Clin. Cancer Res. 38 , 265 (2019). 31215501 10.1186/s13046-019-1251-7 PMC6580523

106. Zhan M Variants in oxidative stress-related genes affect the chemosensitivity through Nrf2-mediated signaling pathway in biliary tract cancer EBioMedicine 2019 48 143 160 10.1016/j.ebiom.2019.08.037 31590928 PMC6838379 Zhan, M. et al. Variants in oxidative stress-related genes affect the chemosensitivity through Nrf2-mediated signaling pathway in biliary tract cancer. EBioMedicine 48 , 143–160 (2019). 31590928 10.1016/j.ebiom.2019.08.037 PMC6838379

107. Zhou Y DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells Redox Biol. 2024 75 103292 10.1016/j.redox.2024.103292 39094401 PMC11345690 Zhou, Y. et al. DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells. Redox Biol. 75 , 103292 (2024). 39094401 10.1016/j.redox.2024.103292 PMC11345690

108. Jiang W 2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway Biomaterials 2023 294 121986 10.1016/j.biomaterials.2022.121986 36623325 Jiang, W. et al. 2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway. Biomaterials 294 , 121986 (2023). 36623325 10.1016/j.biomaterials.2022.121986

109. Xiang H Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma Cancer Immunol. Res. 2020 8 436 450 10.1158/2326-6066.CIR-19-0507 32075803 Xiang, H. et al. Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma. Cancer Immunol. Res. 8 , 436–450 (2020). 32075803 10.1158/2326-6066.CIR-19-0507

110. Lisci M Griffiths GM Arming a killer: mitochondrial regulation of CD8+ T cell cytotoxicity Trends Cell Biol. 2023 33 138 147 10.1016/j.tcb.2022.05.007 35753961 Lisci, M. & Griffiths, G. M. Arming a killer: mitochondrial regulation of CD8+ T cell cytotoxicity. Trends Cell Biol. 33 , 138–147 (2023). 35753961 10.1016/j.tcb.2022.05.007

111. Renken S Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress J. Immunother. Cancer 2022 10 e004458 10.1136/jitc-2021-004458 35738800 PMC9226989 Renken, S. et al. Targeting of Nrf2 improves antitumoral responses by human NK cells, TIL and CAR T cells during oxidative stress. J. Immunother. Cancer 10 , e004458 (2022). 35738800 10.1136/jitc-2021-004458 PMC9226989

112. Glorieux C Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling Redox Biol. 2021 38 101780 10.1016/j.redox.2020.101780 33171331 PMC7658718 Glorieux, C. et al. Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling. Redox Biol. 38 , 101780 (2021). 33171331 10.1016/j.redox.2020.101780 PMC7658718

113. Shah R Ibis B Kashyap M Boussiotis VA The role of ROS in tumor infiltrating immune cells and cancer immunotherapy Metabolism 2024 151 155747 10.1016/j.metabol.2023.155747 38042522 PMC10872310 Shah, R., Ibis, B., Kashyap, M. & Boussiotis, V. A. The role of ROS in tumor infiltrating immune cells and cancer immunotherapy. Metabolism 151 , 155747 (2024). 38042522 10.1016/j.metabol.2023.155747 PMC10872310

114. Griswold-Prenner I Unveiling the human nitroproteome: protein tyrosine nitration in cell signaling and cancer J. Biol. Chem. 2023 299 105038 10.1016/j.jbc.2023.105038 37442231 PMC10413360 Griswold-Prenner, I. et al. Unveiling the human nitroproteome: protein tyrosine nitration in cell signaling and cancer. J. Biol. Chem. 299 , 105038 (2023). 37442231 10.1016/j.jbc.2023.105038 PMC10413360

115. Oberholtzer N H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response Sci. Adv. 2024 10 eadp1152 10.1126/sciadv.adp1152 39546607 PMC11566994 Oberholtzer, N. et al. H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response. Sci. Adv. 10 , eadp1152 (2024). 39546607 10.1126/sciadv.adp1152 PMC11566994

116. Bu MT Chandrasekhar P Ding L Hugo W The roles of TGF-β and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors Pharmacol. Ther. 2022 240 108211 10.1016/j.pharmthera.2022.108211 35577211 PMC10956517 Bu, M. T., Chandrasekhar, P., Ding, L. & Hugo, W. The roles of TGF-β and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors. Pharmacol. Ther. 240 , 108211 (2022). 35577211 10.1016/j.pharmthera.2022.108211 PMC10956517

117. Luo F HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer Cancer Lett. 2022 531 39 56 10.1016/j.canlet.2022.01.027 35090965 Luo, F. et al. HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer. Cancer Lett. 531 , 39–56 (2022). 35090965 10.1016/j.canlet.2022.01.027

118. Morris G Gevezova M Sarafian V Maes M Redox regulation of the immune response Cell Mol. Immunol. 2022 19 1079 1101 10.1038/s41423-022-00902-0 36056148 PMC9508259 Morris, G., Gevezova, M., Sarafian, V. & Maes, M. Redox regulation of the immune response. Cell Mol. Immunol. 19 , 1079–1101 (2022). 36056148 10.1038/s41423-022-00902-0 PMC9508259

119. Mak TW Glutathione Primes T Cell Metabolism for Inflammation Immunity 2017 46 675 689 10.1016/j.immuni.2017.03.019 28423341 Mak, T. W. et al. Glutathione Primes T Cell Metabolism for Inflammation. Immunity 46 , 675–689 (2017). 28423341 10.1016/j.immuni.2017.03.019

120. Feng B The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer Nature 2024 634 712 720 10.1038/s41586-024-07962-4 39322665 PMC11485240 Feng, B. et al. The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 634 , 712–720 (2024). 39322665 10.1038/s41586-024-07962-4 PMC11485240

121. Gallagher MP Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK Proc. Natl Acad. Sci. USA 2021 118 e2103795118 10.1073/pnas.2025825118 PMC8536361 34452995 Gallagher, M. P. et al. Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK. Proc. Natl Acad. Sci. USA 118 , e2103795118 (2021). 10.1073/pnas.2025825118 PMC8536361 34452995

122. Zhang H Sustained AhR activity programs memory fate of early effector CD8+ T cells Proc Natl Acad Sci USA 2024 121 e2317658121 10.1073/pnas.2317658121 38437537 PMC10945852 Zhang, H. et al. Sustained AhR activity programs memory fate of early effector CD8+ T cells. Proc Natl Acad Sci USA 121 , e2317658121 (2024). 38437537 10.1073/pnas.2317658121 PMC10945852

123. Ziegler K Chemical modification of pro-inflammatory proteins by peroxynitrite increases activation of TLR4 and NF-κB: Implications for the health effects of air pollution and oxidative stress Redox Biol. 2020 37 101581 10.1016/j.redox.2020.101581 32739154 PMC7767743 Ziegler, K. et al. Chemical modification of pro-inflammatory proteins by peroxynitrite increases activation of TLR4 and NF-κB: Implications for the health effects of air pollution and oxidative stress. Redox Biol. 37 , 101581 (2020). 32739154 10.1016/j.redox.2020.101581 PMC7767743

124. Liu J Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy J. Hematol. Oncol. 2023 16 116 10.1186/s13045-023-01512-7 38037103 PMC10687997 Liu, J. et al. Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy. J. Hematol. Oncol. 16 , 116 (2023). 38037103 10.1186/s13045-023-01512-7 PMC10687997

125. Jiang Z TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models J. Clin. Invest. 2024 135 e179874 10.1172/JCI179874 39480507 PMC11684806 Jiang, Z. et al. TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models. J. Clin. Invest. 135 , e179874 (2024). 39480507 10.1172/JCI179874 PMC11684806

126. Wang R-H Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2 Nat. Commun. 2024 15 7463 10.1038/s41467-024-51875-9 39198443 PMC11358145 Wang, R.-H. et al. Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2. Nat. Commun. 15 , 7463 (2024). 39198443 10.1038/s41467-024-51875-9 PMC11358145

127. Loopmans S The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes Nat. Metab. 2025 7 182 195 10.1038/s42255-024-01187-5 39794539 PMC11774761 Loopmans, S. et al. The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes. Nat. Metab. 7 , 182–195 (2025). 39794539 10.1038/s42255-024-01187-5 PMC11774761

128. Mansilla S Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango Free Radic. Biol. Med. 2023 197 71 84 10.1016/j.freeradbiomed.2023.01.028 36738801 Mansilla, S. et al. Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango. Free Radic. Biol. Med. 197 , 71–84 (2023). 36738801 10.1016/j.freeradbiomed.2023.01.028

129. Jin J Byun J-K Choi Y-K Park K-G Targeting glutamine metabolism as a therapeutic strategy for cancer Exp. Mol. Med. 2023 55 706 715 10.1038/s12276-023-00971-9 37009798 PMC10167356 Jin, J., Byun, J.-K., Choi, Y.-K. & Park, K.-G. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp. Mol. Med. 55 , 706–715 (2023). 37009798 10.1038/s12276-023-00971-9 PMC10167356

130. Sun W Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers Biomark. Res. 2023 11 48 10.1186/s40364-023-00487-4 37147729 PMC10161514 Sun, W. et al. Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers. Biomark. Res. 11 , 48 (2023). 37147729 10.1186/s40364-023-00487-4 PMC10161514

131. Zhou Z Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria Sci. Adv. 2025 10 eadl0389 10.1126/sciadv.adl0389 PMC10990287 38569044 Zhou, Z. et al. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria. Sci. Adv. 10 , eadl0389 (2025). 10.1126/sciadv.adl0389 PMC10990287 38569044

132. Tufail M Jiang C-H Li N Altered metabolism in cancer: insights into energy pathways and therapeutic targets Mol. Cancer 2024 23 203 10.1186/s12943-024-02119-3 39294640 PMC11409553 Tufail, M., Jiang, C.-H. & Li, N. Altered metabolism in cancer: insights into energy pathways and therapeutic targets. Mol. Cancer 23 , 203 (2024). 39294640 10.1186/s12943-024-02119-3 PMC11409553

133. Zhong H Yin H Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: Focusing on mitochondria Redox Biol. 2015 4 193 199 10.1016/j.redox.2014.12.011 25598486 PMC4803793 Zhong, H. & Yin, H. Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: Focusing on mitochondria. Redox Biol. 4 , 193–199 (2015). 25598486 10.1016/j.redox.2014.12.011 PMC4803793

134. Krishnamoorthy J Downregulation of PERK activity and eIF2α serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells Cell Death Dis. 2018 9 254 10.1038/s41419-018-0326-2 29449538 PMC5833713 Krishnamoorthy, J. et al. Downregulation of PERK activity and eIF2α serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells. Cell Death Dis. 9 , 254 (2018). 29449538 10.1038/s41419-018-0326-2 PMC5833713

135. Matsusaki M Regulation of plant ER oxidoreductin 1 (ERO1) activity for efficient oxidative protein folding J. Biol. Chem. 2019 294 18820 18835 10.1074/jbc.RA119.010917 31685660 PMC6901294 Matsusaki, M. et al. Regulation of plant ER oxidoreductin 1 (ERO1) activity for efficient oxidative protein folding. J. Biol. Chem. 294 , 18820–18835 (2019). 31685660 10.1074/jbc.RA119.010917 PMC6901294

136. Reeg S The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome Free Radic. Biol. Med. 2016 99 153 166 10.1016/j.freeradbiomed.2016.08.002 27498116 PMC5201141 Reeg, S. et al. The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome. Free Radic. Biol. Med. 99 , 153–166 (2016). 27498116 10.1016/j.freeradbiomed.2016.08.002 PMC5201141

137. Demasi M Redox regulation of the proteasome via S-glutathionylation Redox Biol. 2014 2 44 51 10.1016/j.redox.2013.12.003 PMC3881202 24396728 Demasi, M. et al. Redox regulation of the proteasome via S-glutathionylation. Redox Biol. 2 , 44–51 (2014). 10.1016/j.redox.2013.12.003 PMC3881202 24396728

138. Hawkins CL Davies MJ Detection, identification, and quantification of oxidative protein modifications J. Biol. Chem. 2019 294 19683 19708 10.1074/jbc.REV119.006217 31672919 PMC6926449 Hawkins, C. L. & Davies, M. J. Detection, identification, and quantification of oxidative protein modifications. J. Biol. Chem. 294 , 19683–19708 (2019). 31672919 10.1074/jbc.REV119.006217 PMC6926449

139. Lee S-H Widespread intronic polyadenylation inactivates tumour suppressor genes in leukemia Nature 2018 561 127 131 10.1038/s41586-018-0465-8 30150773 PMC6527314 Lee, S.-H. et al. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukemia. Nature 561 , 127–131 (2018). 30150773 10.1038/s41586-018-0465-8 PMC6527314

140. Kesner JS Noncoding translation mitigation Nature 2023 617 395 402 10.1038/s41586-023-05946-4 37046090 PMC10560126 Kesner, J. S. et al. Noncoding translation mitigation. Nature 617 , 395–402 (2023). 37046090 10.1038/s41586-023-05946-4 PMC10560126

141. Karin M Lin A NF-κB at the crossroads of life and death Nat. Immunol. 2002 3 221 227 10.1038/ni0302-221 11875461 Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nat. Immunol. 3 , 221–227 (2002). 11875461 10.1038/ni0302-221

142. Ying Z Short-term mitochondrial permeability transition pore opening modulates histone lysine methylation at the early phase of somatic cell reprogramming Cell Metab 2018 28 935 945 10.1016/j.cmet.2018.08.001 30174306 Ying, Z. et al. Short-term mitochondrial permeability transition pore opening modulates histone lysine methylation at the early phase of somatic cell reprogramming. Cell Metab 28 , 935–945 (2018). 30174306 10.1016/j.cmet.2018.08.001

143. Nott A Watson PM Robinson JD Crepaldi L Riccio A S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons Nature 2008 455 411 415 10.1038/nature07238 18754010 Nott, A., Watson, P. M., Robinson, J. D., Crepaldi, L. & Riccio, A. S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455 , 411–415 (2008). 18754010 10.1038/nature07238

144. García-Giménez JL Histone H3 glutathionylation in proliferating mammalian cells destabilizes nucleosomal structure Antioxid. Redox Signal. 2013 19 1305 1320 10.1089/ars.2012.5021 23541030 PMC3791047 García-Giménez, J. L. et al. Histone H3 glutathionylation in proliferating mammalian cells destabilizes nucleosomal structure. Antioxid. Redox Signal. 19 , 1305–1320 (2013). 23541030 10.1089/ars.2012.5021 PMC3791047

145. Gandhirajan RK Cysteine S-glutathionylation promotes stability and activation of the Hippo downstream effector transcriptional co-activator with PDZ-binding motif (TAZ) J. Biol. Chem. 2016 291 11596 11607 10.1074/jbc.M115.712539 27048650 PMC4882430 Gandhirajan, R. K. et al. Cysteine S-glutathionylation promotes stability and activation of the Hippo downstream effector transcriptional co-activator with PDZ-binding motif (TAZ). J. Biol. Chem. 291 , 11596–11607 (2016). 27048650 10.1074/jbc.M115.712539 PMC4882430

146. Yu F Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response Nucleic Acids Res. 2021 49 5779 5797 10.1093/nar/gkab415 34048572 PMC8191756 Yu, F. et al. Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response. Nucleic Acids Res. 49 , 5779–5797 (2021). 34048572 10.1093/nar/gkab415 PMC8191756

147. Tang D The molecular machinery of regulated cell death Cell Res. 2019 29 347 364 10.1038/s41422-019-0164-5 30948788 PMC6796845 Tang, D. et al. The molecular machinery of regulated cell death. Cell Res. 29 , 347–364 (2019). 30948788 10.1038/s41422-019-0164-5 PMC6796845

148. Nguyen TT Mitochondria-associated programmed cell death as a therapeutic target for age-related disease Exp. Mol. Med. 2023 55 1595 1619 10.1038/s12276-023-01046-5 37612409 PMC10474116 Nguyen, T. T. et al. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease. Exp. Mol. Med. 55 , 1595–1619 (2023). 37612409 10.1038/s12276-023-01046-5 PMC10474116

149. Roberts JZ Crawford N Longley DB The role of Ubiquitination in Apoptosis and Necroptosis Cell Death Differ. 2022 29 272 284 10.1038/s41418-021-00922-9 34912054 PMC8817035 Roberts, J. Z., Crawford, N. & Longley, D. B. The role of Ubiquitination in Apoptosis and Necroptosis. Cell Death Differ. 29 , 272–284 (2022). 34912054 10.1038/s41418-021-00922-9 PMC8817035

150. Faria SS NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer J. Biomed. Sci. 2021 28 26 10.1186/s12929-021-00724-8 33840390 PMC8040227 Faria, S. S. et al. NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer. J. Biomed. Sci. 28 , 26 (2021). 33840390 10.1186/s12929-021-00724-8 PMC8040227

151. Chen F Ferroptosis: principles and significance in health and disease J. Hematol. Oncol. 2024 17 41 10.1186/s13045-024-01564-3 38844964 PMC11157757 Chen, F. et al. Ferroptosis: principles and significance in health and disease. J. Hematol. Oncol. 17 , 41 (2024). 38844964 10.1186/s13045-024-01564-3 PMC11157757

152. Chen, J. et al. Disulfidptosis decoded: a journey through cell death mysteries, regulatory networks, disease paradigms and future directions. Biomark. Res . 12 , 45 (2024). 10.1186/s40364-024-00593-x PMC11059647 38685115

153. Scaturro P Pichlmair A Oxeiptosis- A cell death pathway to mitigate damage caused by radicals Cell Death Differ. 2018 25 1191 1193 10.1038/s41418-018-0134-3 29844568 PMC6030169 Scaturro, P., Pichlmair, A. & Oxeiptosis-, A. cell death pathway to mitigate damage caused by radicals. Cell Death Differ. 25 , 1191–1193 (2018). 29844568 10.1038/s41418-018-0134-3 PMC6030169

154. Chong W Clinical features and molecular landscape of cuproptosis signature-related molecular subtype in gastric cancer iMeta 2024 3 e190 10.1002/imt2.190 38898987 PMC11183172 Chong, W. et al. Clinical features and molecular landscape of cuproptosis signature-related molecular subtype in gastric cancer. iMeta 3 , e190 (2024). 38898987 10.1002/imt2.190 PMC11183172

155. Trivedi A Understanding cuproptosis through FDX1-mediated lipoylation and proteotoxic stress in Channa punctatus J. Hazard. Mater. Adv. 2025 19 100788 Trivedi, A. et al. Understanding cuproptosis through FDX1-mediated lipoylation and proteotoxic stress in Channa punctatus . J. Hazard. Mater. Adv. 19 , 100788 (2025).

156. Manoj H Cytokine signalling in formation of neutrophil extracellular traps: implications for health and diseases Cytokine Growth Factor Rev. 2024 81 27 39 10.1016/j.cytogfr.2024.12.001 39681501 Manoj, H. et al. Cytokine signalling in formation of neutrophil extracellular traps: implications for health and diseases. Cytokine Growth Factor Rev. 81 , 27–39 (2024). 39681501 10.1016/j.cytogfr.2024.12.001

157. Aranovich A Differences in the mechanisms of proapoptotic BH3 proteins binding to BCL-XL and BCL-2 quantified in live MCF-7 cells Mol. Cell 2012 45 754 763 10.1016/j.molcel.2012.01.030 22464442 Aranovich, A. et al. Differences in the mechanisms of proapoptotic BH3 proteins binding to BCL-XL and BCL-2 quantified in live MCF-7 cells. Mol. Cell 45 , 754–763 (2012). 22464442 10.1016/j.molcel.2012.01.030

158. Ren Y Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis Mol. Cancer 2023 22 130 10.1186/s12943-023-01831-w 37563639 PMC10413697 Ren, Y. et al. Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis. Mol. Cancer 22 , 130 (2023). 37563639 10.1186/s12943-023-01831-w PMC10413697

159. Gitego N Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis Nat. Commun. 2023 14 8381 10.1038/s41467-023-44084-3 38104127 PMC10725471 Gitego, N. et al. Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis. Nat. Commun. 14 , 8381 (2023). 38104127 10.1038/s41467-023-44084-3 PMC10725471

160. He R Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression Mol. Cancer 2024 23 267 10.1186/s12943-024-02172-y 39614268 PMC11606237 He, R. et al. Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression. Mol. Cancer 23 , 267 (2024). 39614268 10.1186/s12943-024-02172-y PMC11606237

161. Fang Y Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy Cancer Cell 2019 35 851 867 10.1016/j.ccell.2019.05.001 31185210 PMC6642675 Fang, Y. et al. Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy. Cancer Cell 35 , 851–867 (2019). 31185210 10.1016/j.ccell.2019.05.001 PMC6642675

162. Nguyen TN ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system Mol. Cell 2021 81 2013 2030 10.1016/j.molcel.2021.03.001 33773106 Nguyen, T. N. et al. ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system. Mol. Cell 81 , 2013–2030 (2021). 33773106 10.1016/j.molcel.2021.03.001

163. Shen J Wang Q Mao Y Gao W Duan S Targeting the p53 signaling pathway in cancers: molecular mechanisms and clinical studies MedComm 2023 4 e288 10.1002/mco2.288 37256211 PMC10225743 Shen, J., Wang, Q., Mao, Y., Gao, W. & Duan, S. Targeting the p53 signaling pathway in cancers: molecular mechanisms and clinical studies. MedComm 4 , e288 (2023). 37256211 10.1002/mco2.288 PMC10225743

164. Pandya V BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer Cell Death Dis. 2020 11 448 10.1038/s41419-020-2654-2 32528057 PMC7289861 Pandya, V. et al. BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer. Cell Death Dis. 11 , 448 (2020). 32528057 10.1038/s41419-020-2654-2 PMC7289861

165. Zhang L HIF-1alpha activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death Free Radic. Biol. Med. 2007 43 117 127 10.1016/j.freeradbiomed.2007.04.005 17561100 PMC2048659 Zhang, L. et al. HIF-1alpha activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death. Free Radic. Biol. Med. 43 , 117–127 (2007). 17561100 10.1016/j.freeradbiomed.2007.04.005 PMC2048659

166. Görlach A Bertram K Hudecova S Krizanova O Calcium and ROS: a mutual interplay Redox Biol. 2015 6 260 271 10.1016/j.redox.2015.08.010 26296072 PMC4556774 Görlach, A., Bertram, K., Hudecova, S. & Krizanova, O. Calcium and ROS: a mutual interplay. Redox Biol. 6 , 260–271 (2015). 26296072 10.1016/j.redox.2015.08.010 PMC4556774

167. Jiang Y Zhang M Li J Hu K Chen T AHR/cyp1b1 signaling-mediated extrinsic apoptosis contributes to 6PPDQ-induced cardiac dysfunction in zebrafish embryos Environ. Pollut. 2024 345 123467 10.1016/j.envpol.2024.123467 38311157 Jiang, Y., Zhang, M., Li, J., Hu, K. & Chen, T. AHR/cyp1b1 signaling-mediated extrinsic apoptosis contributes to 6PPDQ-induced cardiac dysfunction in zebrafish embryos. Environ. Pollut. 345 , 123467 (2024). 38311157 10.1016/j.envpol.2024.123467

168. Takikawa M Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway Proc. Natl Acad. Sci. USA 2025 122 e2413126122 10.1073/pnas.2413126122 39913207 PMC11831151 Takikawa, M. et al. Extrinsic induction of apoptosis and tumor suppression via the p53–Reprimo–Hippo–YAP/TAZ–p73 pathway. Proc. Natl Acad. Sci. USA 122 , e2413126122 (2025). 39913207 10.1073/pnas.2413126122 PMC11831151

169. Song J Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury Exp. Mol. Med. 2013 45 e69 10.1038/emm.2013.134 24357833 PMC3880461 Song, J. et al. Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp. Mol. Med. 45 , e69 (2013). 24357833 10.1038/emm.2013.134 PMC3880461

170. Wang Z P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway Nucleic Acids Res. 2023 51 1687 1706 10.1093/nar/gkad001 36727434 PMC9976905 Wang, Z. et al. P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway. Nucleic Acids Res. 51 , 1687–1706 (2023). 36727434 10.1093/nar/gkad001 PMC9976905

171. Shao Y Aplin AE ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity Cell Death Dis. 2012 3 e253 10.1038/cddis.2011.137 22258404 PMC3270271 Shao, Y. & Aplin, A. E. ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death Dis. 3 , e253 (2012). 22258404 10.1038/cddis.2011.137 PMC3270271

172. Li Y Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers Drug Resist. Updat. 2024 73 101042 10.1016/j.drup.2023.101042 38219532 Li, Y. et al. Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers. Drug Resist. Updat. 73 , 101042 (2024). 38219532 10.1016/j.drup.2023.101042

173. Zhao YG Codogno P Zhang H Machinery, regulation and pathophysiological implications of autophagosome maturation Nat. Rev. Mol. Cell Biol. 2021 22 733 750 10.1038/s41580-021-00392-4 34302147 PMC8300085 Zhao, Y. G., Codogno, P. & Zhang, H. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat. Rev. Mol. Cell Biol. 22 , 733–750 (2021). 34302147 10.1038/s41580-021-00392-4 PMC8300085

174. Martens S Fracchiolla D Activation and targeting of ATG8 protein lipidation Cell Discov. 2020 6 23 10.1038/s41421-020-0155-1 32377373 PMC7198486 Martens, S. & Fracchiolla, D. Activation and targeting of ATG8 protein lipidation. Cell Discov. 6 , 23 (2020). 32377373 10.1038/s41421-020-0155-1 PMC7198486

175. Ornatowski W Complex interplay between autophagy and oxidative stress in the development of pulmonary disease Redox Biol. 2020 36 101679 10.1016/j.redox.2020.101679 32818797 PMC7451718 Ornatowski, W. et al. Complex interplay between autophagy and oxidative stress in the development of pulmonary disease. Redox Biol. 36 , 101679 (2020). 32818797 10.1016/j.redox.2020.101679 PMC7451718

176. Jiang G-M The relationship between autophagy and the immune system and its applications for tumor immunotherapy Mol. Cancer 2019 18 17 10.1186/s12943-019-0944-z 30678689 PMC6345046 Jiang, G.-M. et al. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol. Cancer 18 , 17 (2019). 30678689 10.1186/s12943-019-0944-z PMC6345046

177. Slobodnyuk K Autophagy-induced senescence is regulated by p38α signaling Cell Death Dis. 2019 10 376 10.1038/s41419-019-1607-0 31092814 PMC6520338 Slobodnyuk, K. et al. Autophagy-induced senescence is regulated by p38α signaling. Cell Death Dis. 10 , 376 (2019). 31092814 10.1038/s41419-019-1607-0 PMC6520338

178. Crighton D DRAM, a p53-Induced Modulator of Autophagy, Is Critical for Apoptosis Cell 2006 126 121 134 10.1016/j.cell.2006.05.034 16839881 Crighton, D. et al. DRAM, a p53-Induced Modulator of Autophagy, Is Critical for Apoptosis. Cell 126 , 121–134 (2006). 16839881 10.1016/j.cell.2006.05.034

179. Iqbal MJ Interplay of oxidative stress, cellular communication and signaling pathways in cancer Cell Commun. Signal. 2024 22 7 10.1186/s12964-023-01398-5 38167159 PMC10763046 Iqbal, M. J. et al. Interplay of oxidative stress, cellular communication and signaling pathways in cancer. Cell Commun. Signal. 22 , 7 (2024). 38167159 10.1186/s12964-023-01398-5 PMC10763046

180. Das CK Banerjee I Mandal M Pro-survival autophagy: An emerging candidate of tumor progression through maintaining hallmarks of cancer Semin. Cancer Biol. 2020 66 59 74 10.1016/j.semcancer.2019.08.020 31430557 Das, C. K., Banerjee, I. & Mandal, M. Pro-survival autophagy: An emerging candidate of tumor progression through maintaining hallmarks of cancer. Semin. Cancer Biol. 66 , 59–74 (2020). 31430557 10.1016/j.semcancer.2019.08.020

181. Sukumaran P Sun Y Vyas M Singh B TRPC1-mediated Ca2+ entry is essential for the regulation of hypoxia and nutrient depletion-dependent autophagy Cell Death Dis. 2015 6 e1674 10.1038/cddis.2015.7 25741599 PMC4385947 Sukumaran, P., Sun, Y., Vyas, M. & Singh, B. TRPC1-mediated Ca2+ entry is essential for the regulation of hypoxia and nutrient depletion-dependent autophagy. Cell Death Dis. 6 , e1674 (2015). 25741599 10.1038/cddis.2015.7 PMC4385947

182. Wang Y Xu T Wang H Xia G Huang X Inhibition of autophagy induced by tetrandrine promotes the accumulation of reactive oxygen species and sensitizes efficacy of tetrandrine in pancreatic cancer Cancer Cell Int. 2024 24 241 10.1186/s12935-024-03410-5 38987818 PMC11238362 Wang, Y., Xu, T., Wang, H., Xia, G. & Huang, X. Inhibition of autophagy induced by tetrandrine promotes the accumulation of reactive oxygen species and sensitizes efficacy of tetrandrine in pancreatic cancer. Cancer Cell Int. 24 , 241 (2024). 38987818 10.1186/s12935-024-03410-5 PMC11238362

183. Li J HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome Cell Death Dis. 2023 14 200 10.1038/s41419-023-05587-5 36928344 PMC10020151 Li, J. et al. HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome. Cell Death Dis. 14 , 200 (2023). 36928344 10.1038/s41419-023-05587-5 PMC10020151

184. Zhang Y RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome Nat. Commun. 2017 8 14329 10.1038/ncomms14329 28176780 PMC5309790 Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8 , 14329 (2017). 28176780 10.1038/ncomms14329 PMC5309790

185. Deragon MA Mitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis Cell Death Discov. 2020 6 132 10.1038/s41420-020-00370-3 33298902 PMC7693268 Deragon, M. A. et al. Mitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis. Cell Death Discov. 6 , 132 (2020). 33298902 10.1038/s41420-020-00370-3 PMC7693268

186. Zhou Y RIPK3 signaling and its role in regulated cell death and diseases Cell Death Discov. 2024 10 200 10.1038/s41420-024-01957-w 38684668 PMC11059363 Zhou, Y. et al. RIPK3 signaling and its role in regulated cell death and diseases. Cell Death Discov. 10 , 200 (2024). 38684668 10.1038/s41420-024-01957-w PMC11059363

187. Wu Y-T Hui-Ling T Qing H Choon-Nam O Shen H-M Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy Autophagy 2009 5 824 834 10.4161/auto.9099 19556857 Wu, Y.-T., Hui-Ling, T., Qing, H., Choon-Nam, O. & Shen, H.-M. Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy 5 , 824–834 (2009). 19556857 10.4161/auto.9099

188. Tang D Chen X Kang R Kroemer G Ferroptosis: molecular mechanisms and health implications Cell Res. 2021 31 107 125 10.1038/s41422-020-00441-1 33268902 PMC8026611 Tang, D., Chen, X., Kang, R. & Kroemer, G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 31 , 107–125 (2021). 33268902 10.1038/s41422-020-00441-1 PMC8026611

189. Yu Y Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases Cell Death Discov. 2021 7 193 10.1038/s41420-021-00579-w 34312370 PMC8313570 Yu, Y. et al. Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov. 7 , 193 (2021). 34312370 10.1038/s41420-021-00579-w PMC8313570

190. Zheng X Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy Exp. Hematol. Oncol. 2023 12 65 10.1186/s40164-023-00427-w 37501213 PMC10375783 Zheng, X. et al. Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy. Exp. Hematol. Oncol. 12 , 65 (2023). 37501213 10.1186/s40164-023-00427-w PMC10375783

191. Xu R Wang W Zhang W Ferroptosis and the bidirectional regulatory factor p53 Cell Death Discov. 2023 9 197 10.1038/s41420-023-01517-8 37386007 PMC10310766 Xu, R., Wang, W. & Zhang, W. Ferroptosis and the bidirectional regulatory factor p53. Cell Death Discov. 9 , 197 (2023). 37386007 10.1038/s41420-023-01517-8 PMC10310766

192. Zhang Y Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2 Genes Dev. 2017 31 1243 1256 10.1101/gad.299388.117 28747430 PMC5558926 Zhang, Y. et al. Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev. 31 , 1243–1256 (2017). 28747430 10.1101/gad.299388.117 PMC5558926

193. He F ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis J. Hepatol. 2023 79 362 377 10.1016/j.jhep.2023.03.016 36996941 PMC11332364 He, F. et al. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. J. Hepatol. 79 , 362–377 (2023). 36996941 10.1016/j.jhep.2023.03.016 PMC11332364

194. Liang D Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones Cell 2023 186 2748 2764 10.1016/j.cell.2023.05.003 37267948 PMC10330611 Liang, D. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186 , 2748–2764 (2023). 37267948 10.1016/j.cell.2023.05.003 PMC10330611

195. Yan Y SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells Nat. Commun. 2023 14 3673 10.1038/s41467-023-39401-9 37339981 PMC10281978 Yan, Y. et al. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells. Nat. Commun. 14 , 3673 (2023). 37339981 10.1038/s41467-023-39401-9 PMC10281978

196. Su T “Resource-Conserving” engineered nanoparticles Mediate disulfidptosis by overcoming resistance to ferroptosis for antitumor immunotherapy Chem. Eng. J. 2024 500 157409 10.1016/j.cej.2024.157409 Su, T. et al. “Resource-Conserving” engineered nanoparticles Mediate disulfidptosis by overcoming resistance to ferroptosis for antitumor immunotherapy. Chem. Eng. J. 500 , 157409 (2024).

197. Brancaccio M First evidence of dermo-protective activity of marine sulfur-containing histidine compounds Free Radic. Biol. Med. 2022 192 224 234 10.1016/j.freeradbiomed.2022.09.017 36174879 Brancaccio, M. et al. First evidence of dermo-protective activity of marine sulfur-containing histidine compounds. Free Radic. Biol. Med. 192 , 224–234 (2022). 36174879 10.1016/j.freeradbiomed.2022.09.017

198. Liu X Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis Nat. Cell Biol. 2023 25 404 414 10.1038/s41556-023-01091-2 36747082 PMC10027392 Liu, X. et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat. Cell Biol. 25 , 404–414 (2023). 36747082 10.1038/s41556-023-01091-2 PMC10027392

199. Zhao D Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy Redox Biol. 2023 68 102966 10.1016/j.redox.2023.102966 38035663 PMC10698012 Zhao, D. et al. Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy. Redox Biol. 68 , 102966 (2023). 38035663 10.1016/j.redox.2023.102966 PMC10698012

200. Evavold CL Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway Cell 2021 184 4495 4511 10.1016/j.cell.2021.06.028 34289345 PMC8380731 Evavold, C. L. et al. Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway. Cell 184 , 4495–4511 (2021). 34289345 10.1016/j.cell.2021.06.028 PMC8380731

201. Devant P Gasdermin D pore-forming activity is redox-sensitive Cell Rep. 2023 42 112008 10.1016/j.celrep.2023.112008 36662620 PMC9947919 Devant, P. et al. Gasdermin D pore-forming activity is redox-sensitive. Cell Rep. 42 , 112008 (2023). 36662620 10.1016/j.celrep.2023.112008 PMC9947919

202. Tschopp J Schroder K NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 2010 10 210 215 10.1038/nri2725 20168318 Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10 , 210–215 (2010). 20168318 10.1038/nri2725

203. Shi J Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death Nature 2015 526 660 665 10.1038/nature15514 26375003 Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526 , 660–665 (2015). 26375003 10.1038/nature15514

204. Miao N Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus Nat. Commun. 2023 14 872 10.1038/s41467-023-36522-z 36797275 PMC9935630 Miao, N. et al. Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus. Nat. Commun. 14 , 872 (2023). 36797275 10.1038/s41467-023-36522-z PMC9935630

205. Rogers C Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation Nat. Commun. 2019 10 1689 10.1038/s41467-019-09397-2 30976076 PMC6459836 Rogers, C. et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10 , 1689 (2019). 30976076 10.1038/s41467-019-09397-2 PMC6459836

206. Zhou B Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis Cell Res. 2018 28 1171 1185 10.1038/s41422-018-0090-y 30287942 PMC6274649 Zhou, B. et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 28 , 1171–1185 (2018). 30287942 10.1038/s41422-018-0090-y PMC6274649

207. Demarco B Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality Sci. Adv. 2020 6 eabc3465 10.1126/sciadv.abc3465 33208362 PMC7673803 Demarco, B. et al. Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Sci. Adv. 6 , eabc3465 (2020). 33208362 10.1126/sciadv.abc3465 PMC7673803

208. Liang, C. et al. Hypericin photoactivation induces triple-negative breast cancer cell pyroptosis by targeting the ROS/CALR/Caspase-3/GSDME pathway. J. Adv. Res. 77 , 669–688 (2025). 10.1016/j.jare.2025.01.042 PMC12627876 39870303

209. Xiang C CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer Cell Death Dis. 2024 15 662 10.1038/s41419-024-07035-4 39256356 PMC11387770 Xiang, C. et al. CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer. Cell Death Dis. 15 , 662 (2024). 39256356 10.1038/s41419-024-07035-4 PMC11387770

210. Chen W Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling J. Exp. Clin. Cancer Res. 2024 43 248 10.1186/s13046-024-03168-8 39215364 PMC11363528 Chen, W. et al. Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling. J. Exp. Clin. Cancer Res. 43 , 248 (2024). 39215364 10.1186/s13046-024-03168-8 PMC11363528

211. Yuan J PM2.5 exacerbates nasal epithelial barrier dysfunction in allergic rhinitis by inducing NLRP3-mediated pyroptosis via the AhR/CYP1A1/ROS axis J. Hazard. Mater. 2025 492 138145 10.1016/j.jhazmat.2025.138145 40209413 Yuan, J. et al. PM2.5 exacerbates nasal epithelial barrier dysfunction in allergic rhinitis by inducing NLRP3-mediated pyroptosis via the AhR/CYP1A1/ROS axis. J. Hazard. Mater. 492 , 138145 (2025). 40209413 10.1016/j.jhazmat.2025.138145

212. Gao Y Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis Theranostics 2024 14 4218 4239 10.7150/thno.95749 39113799 PMC11303072 Gao, Y. et al. Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis. Theranostics 14 , 4218–4239 (2024). 39113799 10.7150/thno.95749 PMC11303072

213. Sharma BR Kanneganti T-D NLRP3 inflammasome in cancer and metabolic diseases Nat. Immunol. 2021 22 550 559 10.1038/s41590-021-00886-5 33707781 PMC8132572 Sharma, B. R. & Kanneganti, T.-D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol. 22 , 550–559 (2021). 33707781 10.1038/s41590-021-00886-5 PMC8132572

214. Zhang Z Gasdermin E suppresses tumour growth by activating anti-tumour immunity Nature 2020 579 415 420 10.1038/s41586-020-2071-9 32188940 PMC7123794 Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579 , 415–420 (2020). 32188940 10.1038/s41586-020-2071-9 PMC7123794

215. Suzuki T Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1 Cell Rep. 2019 28 746 758 10.1016/j.celrep.2019.06.047 31315052 Suzuki, T. et al. Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1. Cell Rep. 28 , 746–758 (2019). 31315052 10.1016/j.celrep.2019.06.047

216. Pallichankandy S Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine Cell Death Discov. 2023 9 94 10.1038/s41420-023-01376-3 36914635 PMC10011521 Pallichankandy, S. et al. Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine. Cell Death Discov. 9 , 94 (2023). 36914635 10.1038/s41420-023-01376-3 PMC10011521

217. Liu Z Dou Y Lu C Han R He Y Neutrophil extracellular traps in tumor metabolism and microenvironment Biomark. Res. 2025 13 12 10.1186/s40364-025-00731-z 39849606 PMC11756210 Liu, Z., Dou, Y., Lu, C., Han, R. & He, Y. Neutrophil extracellular traps in tumor metabolism and microenvironment. Biomark. Res. 13 , 12 (2025). 39849606 10.1186/s40364-025-00731-z PMC11756210

218. Chen Y The role of neutrophil extracellular traps in cancer progression, metastasis and therapy Exp. Hematol. Oncol. 2022 11 99 10.1186/s40164-022-00345-3 36384979 PMC9667637 Chen, Y. et al. The role of neutrophil extracellular traps in cancer progression, metastasis and therapy. Exp. Hematol. Oncol. 11 , 99 (2022). 36384979 10.1186/s40164-022-00345-3 PMC9667637

219. Aldabbous L Neutrophil extracellular traps promote angiogenesis Arterioscler. Thromb. Vasc. Biol. 2016 36 2078 2087 10.1161/ATVBAHA.116.307634 27470511 Aldabbous, L. et al. Neutrophil extracellular traps promote angiogenesis. Arterioscler. Thromb. Vasc. Biol. 36 , 2078–2087 (2016). 27470511 10.1161/ATVBAHA.116.307634

220. Ma Y Wei J He W Ren J Neutrophil extracellular traps in cancer MedComm 2024 5 e647 10.1002/mco2.647 39015554 PMC11247337 Ma, Y., Wei, J., He, W. & Ren, J. Neutrophil extracellular traps in cancer. MedComm 5 , e647 (2024). 39015554 10.1002/mco2.647 PMC11247337

221. Shen Y Neutrophils and neutrophil extracellular traps: double-edged swords in cancer pathophysiology and therapy resistance Cell Commun. Signal. 2025 23 476 10.1186/s12964-025-02458-8 41185017 PMC12581448 Shen, Y. et al. Neutrophils and neutrophil extracellular traps: double-edged swords in cancer pathophysiology and therapy resistance. Cell Commun. Signal. 23 , 476 (2025). 41185017 10.1186/s12964-025-02458-8 PMC12581448

222. Vo TTT The crosstalk between copper-induced oxidative stress and cuproptosis: a novel potential anticancer paradigm Cell Commun. Signal. 2024 22 353 10.1186/s12964-024-01726-3 38970072 PMC11225285 Vo, T. T. T. et al. The crosstalk between copper-induced oxidative stress and cuproptosis: a novel potential anticancer paradigm. Cell Commun. Signal. 22 , 353 (2024). 38970072 10.1186/s12964-024-01726-3 PMC11225285

223. Lei G Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance Cancer Cell 2025 43 1076 1092 10.1016/j.ccell.2025.03.031 40215978 PMC12151758 Lei, G. et al. Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance. Cancer Cell 43 , 1076–1092 (2025). 40215978 10.1016/j.ccell.2025.03.031 PMC12151758

224. Chen M Three Birds with One Stone: Copper Ions Assisted Synergistic Cuproptosis/Chemodynamic/Photothermal Therapy by a Three-Pronged Approach Adv. Healthc. Mater. 2024 13 2401567 10.1002/adhm.202401567 38962848 Chen, M. et al. Three Birds with One Stone: Copper Ions Assisted Synergistic Cuproptosis/Chemodynamic/Photothermal Therapy by a Three-Pronged Approach. Adv. Healthc. Mater. 13 , 2401567 (2024). 10.1002/adhm.202401567 38962848

225. Möller MN Detection and quantification of nitric oxide-derived oxidants in biological systems J. Biol. Chem. 2019 294 14776 14802 10.1074/jbc.REV119.006136 31409645 PMC6779446 Möller, M. N. et al. Detection and quantification of nitric oxide-derived oxidants in biological systems. J. Biol. Chem. 294 , 14776–14802 (2019). 31409645 10.1074/jbc.REV119.006136 PMC6779446

226. Halliwell B Adhikary A Dingfelder M Dizdaroglu M Hydroxyl radical is a significant player in oxidative DNA damage: In vivo Chem. Soc. Rev. 2021 50 8355 8360 10.1039/D1CS00044F 34128512 PMC8328964 Halliwell, B., Adhikary, A., Dingfelder, M. & Dizdaroglu, M. Hydroxyl radical is a significant player in oxidative DNA damage: In vivo. Chem. Soc. Rev. 50 , 8355–8360 (2021). 34128512 10.1039/d1cs00044f PMC8328964

227. Lo Conte M Carroll KS The Redox Biochemistry of Protein Sulfenylation and Sulfinylation J. Biol. Chem. 2013 288 26480 26488 10.1074/jbc.R113.467738 23861405 PMC3772195 Lo Conte, M. & Carroll, K. S. The Redox Biochemistry of Protein Sulfenylation and Sulfinylation. J. Biol. Chem. 288 , 26480–26488 (2013). 23861405 10.1074/jbc.R113.467738 PMC3772195

228. Jeong W Chang T-S Boja ES Fales HM Rhee SG Roles of TRP14, a Thioredoxin-related Protein in Tumor Necrosis Factor-α Signaling Pathways J. Biol. Chem. 2004 279 3151 3159 10.1074/jbc.M307959200 14607843 Jeong, W., Chang, T.-S., Boja, E. S., Fales, H. M. & Rhee, S. G. Roles of TRP14, a Thioredoxin-related Protein in Tumor Necrosis Factor-α Signaling Pathways. J. Biol. Chem. 279 , 3151–3159 (2004). 14607843 10.1074/jbc.M307959200

229. Liou G Chiang Y-C Wang Y Weng J-K Mechanistic basis for the evolution of chalcone synthase catalytic cysteine reactivity in land plants J. Biol. Chem. 2018 293 18601 18612 10.1074/jbc.RA118.005695 30291143 PMC6290136 Liou, G., Chiang, Y.-C., Wang, Y. & Weng, J.-K. Mechanistic basis for the evolution of chalcone synthase catalytic cysteine reactivity in land plants. J. Biol. Chem. 293 , 18601–18612 (2018). 30291143 10.1074/jbc.RA118.005695 PMC6290136

230. Funato Y Michiue T Asashima M Miki H The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled Nat. Cell Biol. 2006 8 501 508 10.1038/ncb1405 16604061 Funato, Y., Michiue, T., Asashima, M. & Miki, H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled. Nat. Cell Biol. 8 , 501–508 (2006). 16604061 10.1038/ncb1405

231. Zhang Y Redox regulation of tumor suppressor PTEN in cell signaling Redox Biol. 2020 34 101553 10.1016/j.redox.2020.101553 32413744 PMC7226887 Zhang, Y. et al. Redox regulation of tumor suppressor PTEN in cell signaling. Redox Biol. 34 , 101553 (2020). 32413744 10.1016/j.redox.2020.101553 PMC7226887

232. Hopkins BD Hodakoski C Barrows D Mense SM Parsons RE PTEN function: The long and the short of it Trends Biochem. Sci. 2014 39 183 190 10.1016/j.tibs.2014.02.006 24656806 PMC4043120 Hopkins, B. D., Hodakoski, C., Barrows, D., Mense, S. M. & Parsons, R. E. PTEN function: The long and the short of it. Trends Biochem. Sci. 39 , 183–190 (2014). 24656806 10.1016/j.tibs.2014.02.006 PMC4043120

233. Chikara S Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment Cancer Lett. 2018 413 122 134 10.1016/j.canlet.2017.11.002 29113871 Chikara, S. et al. Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett. 413 , 122–134 (2018). 29113871 10.1016/j.canlet.2017.11.002

234. Lennicke C Cochemé HM Redox regulation of the insulin signalling pathway Redox Biol. 2021 42 101964 10.1016/j.redox.2021.101964 33893069 PMC8113030 Lennicke, C. & Cochemé, H. M. Redox regulation of the insulin signalling pathway. Redox Biol. 42 , 101964 (2021). 33893069 10.1016/j.redox.2021.101964 PMC8113030

235. Yang CY Active-site cysteine 215 sulfonation targets protein tyrosine phosphatase PTP1B for Cullin1 E3 ligase-mediated degradation Free Radic. Biol. Med. 2023 194 147 159 10.1016/j.freeradbiomed.2022.11.041 36462629 Yang, C. Y. et al. Active-site cysteine 215 sulfonation targets protein tyrosine phosphatase PTP1B for Cullin1 E3 ligase-mediated degradation. Free Radic. Biol. Med. 194 , 147–159 (2023). 36462629 10.1016/j.freeradbiomed.2022.11.041

236. Raman D Pervaiz S Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression Redox Biol. 2019 27 101105 10.1016/j.redox.2019.101105 30686777 PMC6859563 Raman, D. & Pervaiz, S. Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression. Redox Biol. 27 , 101105 (2019). 30686777 10.1016/j.redox.2019.101105 PMC6859563

237. Manning BD Toker A AKT/PKB Signaling: Navigating the Network Cell 2017 169 381 405 10.1016/j.cell.2017.04.001 28431241 PMC5546324 Manning, B. D. & Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 169 , 381–405 (2017). 28431241 10.1016/j.cell.2017.04.001 PMC5546324

238. Liu Y Inhibition of PI3K/AKT signaling via ROS regulation is involved in rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells Int. J. Biol. Sci. 2021 17 589 602 10.7150/ijbs.49514 33613115 PMC7893580 Liu, Y. et al. Inhibition of PI3K/AKT signaling via ROS regulation is involved in rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells. Int. J. Biol. Sci. 17 , 589–602 (2021). 33613115 10.7150/ijbs.49514 PMC7893580

239. Wen C ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin Cell Death Dis. 2019 10 809 10.1038/s41419-019-2035-x 31649256 PMC6813365 Wen, C. et al. ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin. Cell Death Dis. 10 , 809 (2019). 31649256 10.1038/s41419-019-2035-x PMC6813365

240. Funato Y Nucleoredoxin sustains Wnt/β-catenin signaling by retaining a pool of inactive dishevelled protein Curr. Biol. 2010 20 1945 1952 10.1016/j.cub.2010.09.065 20970343 Funato, Y. et al. Nucleoredoxin sustains Wnt/β-catenin signaling by retaining a pool of inactive dishevelled protein. Curr. Biol. 20 , 1945–1952 (2010). 20970343 10.1016/j.cub.2010.09.065

241. Bloom DA Jaiswal AK Phosphorylation of Nrf2 at Ser40 by Protein Kinase C in Response to Antioxidants Leads to the Release of Nrf2 from INrf2, but Is Not Required for Nrf2 Stabilization/Accumulation in the Nucleus and Transcriptional Activation of Antioxidant Response Element-mediated NAD(P)H:Quinone Oxidoreductase-1 Gene Expression J. Biol. Chem. 2003 278 44675 44682 10.1074/jbc.M307633200 12947090 Bloom, D. A. & Jaiswal, A. K. Phosphorylation of Nrf2 at Ser40 by Protein Kinase C in Response to Antioxidants Leads to the Release of Nrf2 from INrf2, but Is Not Required for Nrf2 Stabilization/Accumulation in the Nucleus and Transcriptional Activation of Antioxidant Response Element-mediated NAD(P)H:Quinone Oxidoreductase-1 Gene Expression. J. Biol. Chem. 278 , 44675–44682 (2003). 12947090 10.1074/jbc.M307633200

242. Yin Y The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy Acta Pharm. Sin. B 2023 13 1956 1975 10.1016/j.apsb.2023.01.015 37250161 PMC10213817 Yin, Y. et al. The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy. Acta Pharm. Sin. B 13 , 1956–1975 (2023). 37250161 10.1016/j.apsb.2023.01.015 PMC10213817

243. Wang P Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis Nat. Commun. 2019 10 755 10.1038/s41467-019-08680-6 30765703 PMC6376064 Wang, P. et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat. Commun. 10 , 755 (2019). 30765703 10.1038/s41467-019-08680-6 PMC6376064

244. Sriram K Benkovic SA Hebert MA Miller DB O’Callaghan JP Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J. Biol. Chem. 2004 279 19936 19947 10.1074/jbc.M309304200 14996842 Sriram, K., Benkovic, S. A., Hebert, M. A., Miller, D. B. & O’Callaghan, J. P. Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J. Biol. Chem. 279 , 19936–19947 (2004). 14996842 10.1074/jbc.M309304200

245. Sun X Wu F Datta R Kharbanda S Kufe D Interaction between Protein Kinase C δ and the c-Abl Tyrosine Kinase in the Cellular Response to Oxidative Stress J. Biol. Chem. 2000 275 7470 7473 10.1074/jbc.275.11.7470 10713049 Sun, X., Wu, F., Datta, R., Kharbanda, S. & Kufe, D. Interaction between Protein Kinase C δ and the c-Abl Tyrosine Kinase in the Cellular Response to Oxidative Stress. J. Biol. Chem. 275 , 7470–7473 (2000). 10713049 10.1074/jbc.275.11.7470

246. Lakkakorpi PT Bett AJ Lipfert L Rodan GA Duong LT PYK2 Autophosphorylation, but Not Kinase Activity, Is Necessary for Adhesion-induced Association with c-Src, Osteoclast Spreading, and Bone Resorption J. Biol. Chem. 2003 278 11502 11512 10.1074/jbc.M206579200 12514172 Lakkakorpi, P. T., Bett, A. J., Lipfert, L., Rodan, G. A. & Duong, L. T. PYK2 Autophosphorylation, but Not Kinase Activity, Is Necessary for Adhesion-induced Association with c-Src, Osteoclast Spreading, and Bone Resorption. J. Biol. Chem. 278 , 11502–11512 (2003). 12514172 10.1074/jbc.M206579200

247. Heppner D Direct cysteine sulfenylation drives activation of the Src kinase Nat. Commun. 2018 9 4522 10.1038/s41467-018-06790-1 30375386 PMC6207713 Heppner, D. et al. Direct cysteine sulfenylation drives activation of the Src kinase. Nat. Commun. 9 , 4522 (2018). 30375386 10.1038/s41467-018-06790-1 PMC6207713

248. Sharma P Redox Regulation of Interleukin-4 Signaling Immunity 2008 29 551 564 10.1016/j.immuni.2008.07.019 18957266 PMC2631209 Sharma, P. et al. Redox Regulation of Interleukin-4 Signaling. Immunity 29 , 551–564 (2008). 18957266 10.1016/j.immuni.2008.07.019 PMC2631209

249. Xu X Transforming growth factor-β in stem cells and tissue homeostasis Bone Res. 2018 6 2 10.1038/s41413-017-0005-4 29423331 PMC5802812 Xu, X. et al. Transforming growth factor-β in stem cells and tissue homeostasis. Bone Res. 6 , 2 (2018). 29423331 10.1038/s41413-017-0005-4 PMC5802812

250. Chang CH Pauklin S ROS and TGFβ: from pancreatic tumour growth to metastasis J. Exp. Clin. Cancer Res. 2021 40 152 10.1186/s13046-021-01960-4 33941245 PMC8091747 Chang, C. H. & Pauklin, S. ROS and TGFβ: from pancreatic tumour growth to metastasis. J. Exp. Clin. Cancer Res. 40 , 152 (2021). 33941245 10.1186/s13046-021-01960-4 PMC8091747

251. Yuan X Ruan W Bobrow B Carmeliet P Eltzschig HK Targeting hypoxia-inducible factors: therapeutic opportunities and challenges Nat. Rev. Drug Discov. 2024 23 175 200 10.1038/s41573-023-00848-6 38123660 PMC12337356 Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P. & Eltzschig, H. K. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat. Rev. Drug Discov. 23 , 175–200 (2024). 38123660 10.1038/s41573-023-00848-6 PMC12337356

252. Yang J-X Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation J. Exp. Clin. Cancer Res. 2024 43 169 10.1186/s13046-024-03094-9 38880883 PMC11181580 Yang, J.-X. et al. Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α activation. J. Exp. Clin. Cancer Res. 43 , 169 (2024). 38880883 10.1186/s13046-024-03094-9 PMC11181580

253. Li F Regulation of HIF-1α Stability through S-Nitrosylation Mol. Cell 2007 26 63 74 10.1016/j.molcel.2007.02.024 17434127 PMC2905600 Li, F. et al. Regulation of HIF-1α Stability through S-Nitrosylation. Mol. Cell 26 , 63–74 (2007). 17434127 10.1016/j.molcel.2007.02.024 PMC2905600

254. Mylonis I Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1α J. Biol. Chem. 2006 281 33095 33106 10.1074/jbc.M605058200 16954218 Mylonis, I. et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1α. J. Biol. Chem. 281 , 33095–33106 (2006). 16954218 10.1074/jbc.M605058200

255. Zhao Y ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway Mol. Cancer 2017 16 79 10.1186/s12943-017-0648-1 28407774 PMC5390360 Zhao, Y. et al. ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway. Mol. Cancer 16 , 79 (2017). 28407774 10.1186/s12943-017-0648-1 PMC5390360

256. Stone TW Williams RO Modulation of T cells by tryptophan metabolites in the kynurenine pathway Trends Pharmacol. Sci. 2023 44 442 456 10.1016/j.tips.2023.04.006 37248103 Stone, T. W. & Williams, R. O. Modulation of T cells by tryptophan metabolites in the kynurenine pathway. Trends Pharmacol. Sci. 44 , 442–456 (2023). 37248103 10.1016/j.tips.2023.04.006

257. Kou Z Oxidative stress modulates expression of immune checkpoint genes via activation of AhR signaling Toxicol. Appl. Pharmacol. 2022 457 116314 10.1016/j.taap.2022.116314 36368423 PMC10166770 Kou, Z. et al. Oxidative stress modulates expression of immune checkpoint genes via activation of AhR signaling. Toxicol. Appl. Pharmacol. 457 , 116314 (2022). 36368423 10.1016/j.taap.2022.116314 PMC10166770

258. Opitz CA An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor Nature 2011 478 197 203 10.1038/nature10491 21976023 Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478 , 197–203 (2011). 21976023 10.1038/nature10491

259. Labadie BW Bao R Luke JJ Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan–kynurenine–aryl hydrocarbon axis Clin. Cancer Res. 2019 25 1462 1471 10.1158/1078-0432.CCR-18-2882 30377198 PMC6397695 Labadie, B. W., Bao, R. & Luke, J. J. Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan–kynurenine–aryl hydrocarbon axis. Clin. Cancer Res. 25 , 1462–1471 (2019). 30377198 10.1158/1078-0432.CCR-18-2882 PMC6397695

260. Zhang T Ma C Zhang Z Zhang H Hu H NF-κB signaling in inflammation and cancer MedComm 2021 2 618 653 10.1002/mco2.104 34977871 PMC8706767 Zhang, T., Ma, C., Zhang, Z., Zhang, H. & Hu, H. NF-κB signaling in inflammation and cancer. MedComm 2 , 618–653 (2021). 34977871 10.1002/mco2.104 PMC8706767

261. Stephenson A The inhibitor of κB kinase β (IKKβ) phosphorylates IκBα twice in a single binding event through a sequential mechanism J. Biol. Chem. 2022 299 102796 10.1016/j.jbc.2022.102796 36528060 PMC9843440 Stephenson, A. et al. The inhibitor of κB kinase β (IKKβ) phosphorylates IκBα twice in a single binding event through a sequential mechanism. J. Biol. Chem. 299 , 102796 (2022). 36528060 10.1016/j.jbc.2022.102796 PMC9843440

262. Jung Y Kim H Sun HM Sue GR Jeong W Dynein light chain LC8 negatively regulates NF-κB through the redox-dependent interaction with IκBα J. Biol. Chem. 2008 283 23863 23871 10.1074/jbc.M803072200 18579519 PMC3259766 Jung, Y., Kim, H., Sun, H. M., Sue, G. R. & Jeong, W. Dynein light chain LC8 negatively regulates NF-κB through the redox-dependent interaction with IκBα. J. Biol. Chem. 283 , 23863–23871 (2008). 18579519 10.1074/jbc.M803072200 PMC3259766

263. Pakjoo M Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors Cell Commun. Signal. 2024 22 105 10.1186/s12964-023-01433-5 38331801 PMC10851565 Pakjoo, M. et al. Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors. Cell Commun. Signal. 22 , 105 (2024). 38331801 10.1186/s12964-023-01433-5 PMC10851565

264. Zhu Z Inhibition of nuclear thioredoxin aggregation attenuates PM2.5-induced NF-κB activation and pro-inflammatory responses Free Radic. Biol. Med. 2019 130 206 214 10.1016/j.freeradbiomed.2018.10.438 30420332 Zhu, Z. et al. Inhibition of nuclear thioredoxin aggregation attenuates PM2.5-induced NF-κB activation and pro-inflammatory responses. Free Radic. Biol. Med. 130 , 206–214 (2019). 30420332 10.1016/j.freeradbiomed.2018.10.438

265. Wu M Sustained oxidative stress inhibits NF-κB activation partially via inactivating the proteasome Free Radic. Biol. Med. 2009 46 62 69 10.1016/j.freeradbiomed.2008.09.021 18948189 PMC2688728 Wu, M. et al. Sustained oxidative stress inhibits NF-κB activation partially via inactivating the proteasome. Free Radic. Biol. Med. 46 , 62–69 (2009). 18948189 10.1016/j.freeradbiomed.2008.09.021 PMC2688728

266. Korn SH Wouters EFM Vos N Janssen-Heininger YMW Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase J. Biol. Chem. 2001 276 35693 35700 10.1074/jbc.M104321200 11479295 Korn, S. H., Wouters, E. F. M., Vos, N. & Janssen-Heininger, Y. M. W. Cytokine-induced activation of nuclear factor-kappa B is inhibited by hydrogen peroxide through oxidative inactivation of IkappaB kinase. J. Biol. Chem. 276 , 35693–35700 (2001). 11479295 10.1074/jbc.M104321200

267. Kapahi P Inhibition of NF-κB activation by arsenite through reaction with a critical cysteine in the activation loop of IκB kinase J. Biol. Chem. 2000 275 36062 36066 10.1074/jbc.M007204200 10967126 Kapahi, P. et al. Inhibition of NF-κB activation by arsenite through reaction with a critical cysteine in the activation loop of IκB kinase. J. Biol. Chem. 275 , 36062–36066 (2000). 10967126 10.1074/jbc.M007204200

268. Reynaert NL Nitric Oxide Represses Inhibitory B Kinase through S-Nitrosylation Proc. Natl. Acad. Sci. USA. 2004 101 8945 8950 10.1073/pnas.0400588101 15184672 PMC428452 Reynaert, N. L. et al. Nitric Oxide Represses Inhibitory B Kinase through S-Nitrosylation. Proc. Natl. Acad. Sci. USA. 101 , 8945–8950 (2004). 15184672 10.1073/pnas.0400588101 PMC428452

269. Reynaert NL Dynamic redox control of NF-kappaB through glutaredoxin-regulated Proc. Natl. Acad. Sci. USA 2006 103 13086 13091 10.1073/pnas.0603290103 16916935 PMC1559757 Reynaert, N. L. et al. Dynamic redox control of NF-kappaB through glutaredoxin-regulated. Proc. Natl. Acad. Sci. USA 103 , 13086–13091 (2006). 16916935 10.1073/pnas.0603290103 PMC1559757

270. Li Q Engelhardt J Interleukin-1 Induction of NF B Is Partially Regulated by H2O2-mediated Activation of NF B-inducing Kinase J. Biol. Chem. 2006 281 1495 1505 10.1074/jbc.M511153200 16286467 Li, Q. & Engelhardt, J. Interleukin-1 Induction of NF B Is Partially Regulated by H2O2-mediated Activation of NF B-inducing Kinase. J. Biol. Chem. 281 , 1495–1505 (2006). 16286467 10.1074/jbc.M511153200

271. Morgan MJ Liu Z Crosstalk of reactive oxygen species and NF-κB signaling Cell Res. 2011 21 103 115 10.1038/cr.2010.178 21187859 PMC3193400 Morgan, M. J. & Liu, Z. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 21 , 103–115 (2011). 21187859 10.1038/cr.2010.178 PMC3193400

272. Laureano-Marín AM Abscisic acid-triggered persulfidation of the cys protease ATG4 mediates regulation of autophagy by sulfide Plant Cell 2020 32 3902 3920 10.1105/tpc.20.00766 33037147 PMC7721334 Laureano-Marín, A. M. et al. Abscisic acid-triggered persulfidation of the cys protease ATG4 mediates regulation of autophagy by sulfide. Plant Cell 32 , 3902–3920 (2020). 33037147 10.1105/tpc.20.00766 PMC7721334

273. Zheng X The protease activity of human ATG4B is regulated by reversible oxidative modification Autophagy 2020 16 1838 1850 10.1080/15548627.2019.1709763 31880198 PMC8386634 Zheng, X. et al. The protease activity of human ATG4B is regulated by reversible oxidative modification. Autophagy 16 , 1838–1850 (2020). 31880198 10.1080/15548627.2019.1709763 PMC8386634

274. Zhou J Full-coverage regulations of autophagy by ROS: from induction to maturation Autophagy 2022 18 1240 1255 10.1080/15548627.2021.1984656 34662529 PMC9225210 Zhou, J. et al. Full-coverage regulations of autophagy by ROS: from induction to maturation. Autophagy 18 , 1240–1255 (2022). 34662529 10.1080/15548627.2021.1984656 PMC9225210

275. Yoshida T Nitric oxide activates TRP channels by cysteine S-nitrosylation Nat. Chem. Biol. 2006 2 596 607 10.1038/nchembio821 16998480 Yoshida, T. et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2 , 596–607 (2006). 16998480 10.1038/nchembio821

276. Khare P The TRPC5 receptor as pharmacological target for pain and metabolic disease Pharmacol. Ther. 2024 263 108727 10.1016/j.pharmthera.2024.108727 39384022 Khare, P. et al. The TRPC5 receptor as pharmacological target for pain and metabolic disease. Pharmacol. Ther. 263 , 108727 (2024). 39384022 10.1016/j.pharmthera.2024.108727

277. Shimizu, S., Takahashi, N. & Mori, Y. Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology , Vol. 223 (eds Nilius, B. & Flockerzi, V.) Ch. 3 (Springer, 2014). 25296415

278. Kolisek M Beck A Fleig A Penner R Cyclic ADP-Ribose and Hydrogen Peroxide Synergize with ADP-Ribose in the Activation of TRPM2 Channels Mol. Cell 2005 18 61 69 10.1016/j.molcel.2005.02.033 15808509 Kolisek, M., Beck, A., Fleig, A. & Penner, R. Cyclic ADP-Ribose and Hydrogen Peroxide Synergize with ADP-Ribose in the Activation of TRPM2 Channels. Mol. Cell 18 , 61–69 (2005). 15808509 10.1016/j.molcel.2005.02.033

279. Xing Y Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway Autophagy 2022 18 1932 1954 10.1080/15548627.2021.2008752 34878954 PMC9450983 Xing, Y. et al. Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway. Autophagy 18 , 1932–1954 (2022). 34878954 10.1080/15548627.2021.2008752 PMC9450983

280. Giannoni E Redox regulation of anoikis: reactive oxygen species as essential mediators of cell survival Cell Death Differ. 2008 15 867 878 10.1038/cdd.2008.3 18259192 Giannoni, E. et al. Redox regulation of anoikis: reactive oxygen species as essential mediators of cell survival. Cell Death Differ. 15 , 867–878 (2008). 18259192 10.1038/cdd.2008.3

281. Weng MS Chang JH Hung WY Yang YC Chien MH The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance J. Exp. Clin. Cancer Res. 2018 37 61 10.1186/s13046-018-0728-0 29548337 PMC5857086 Weng, M. S., Chang, J. H., Hung, W. Y., Yang, Y. C. & Chien, M. H. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J. Exp. Clin. Cancer Res. 37 , 61 (2018). 29548337 10.1186/s13046-018-0728-0 PMC5857086

282. Sequist LV Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Sci. Transl. Med. 2011 3 75ra26 10.1126/scitranslmed.3002003 21430269 PMC3132801 Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3 , 75ra26 (2011). 21430269 10.1126/scitranslmed.3002003 PMC3132801

283. Heppner DE The NADPH oxidases DUOX1 and NOX2 play distinct roles in redox regulation of epidermal growth factor receptor signaling J. Biol. Chem. 2016 291 23282 23293 10.1074/jbc.M116.749028 27650496 PMC5087744 Heppner, D. E. et al. The NADPH oxidases DUOX1 and NOX2 play distinct roles in redox regulation of epidermal growth factor receptor signaling. J. Biol. Chem. 291 , 23282–23293 (2016). 27650496 10.1074/jbc.M116.749028 PMC5087744

284. Leung ELH Targeting tyrosine kinase inhibitor-resistant non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation Antioxid. Redox Signal. 2016 24 263 279 10.1089/ars.2015.6420 26528827 PMC4753639 Leung, E. L. H. et al. Targeting tyrosine kinase inhibitor-resistant non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation. Antioxid. Redox Signal. 24 , 263–279 (2016). 26528827 10.1089/ars.2015.6420 PMC4753639

285. Lavoie H Therrien M Regulation of RAF protein kinases in ERK signalling Nat. Rev. Mol. Cell Biol. 2015 16 281 298 10.1038/nrm3979 25907612 Lavoie, H. & Therrien, M. Regulation of RAF protein kinases in ERK signalling. Nat. Rev. Mol. Cell Biol. 16 , 281–298 (2015). 25907612 10.1038/nrm3979

286. Pelaz SG Tabernero A Src: coordinating metabolism in cancer Oncogene 2022 41 4917 4928 10.1038/s41388-022-02487-4 36217026 PMC9630107 Pelaz, S. G. & Tabernero, A. Src: coordinating metabolism in cancer. Oncogene 41 , 4917–4928 (2022). 36217026 10.1038/s41388-022-02487-4 PMC9630107

287. Wentworth C Alam MA Jones R Nusrat A Neish A Enteric Commensal Bacteria Induce Extracellular Signal-regulated Kinase Pathway Signaling via Formyl Peptide Receptor-dependent Redox Modulation of Dual Specific Phosphatase 3 J. Biol. Chem. 2011 286 38448 38455 10.1074/jbc.M111.268938 21921027 PMC3207424 Wentworth, C., Alam, M. A., Jones, R., Nusrat, A. & Neish, A. Enteric Commensal Bacteria Induce Extracellular Signal-regulated Kinase Pathway Signaling via Formyl Peptide Receptor-dependent Redox Modulation of Dual Specific Phosphatase 3. J. Biol. Chem. 286 , 38448–38455 (2011). 21921027 10.1074/jbc.M111.268938 PMC3207424

288. Cargnello M Roux PP Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases Microbiol. Mol. Biol. Rev. 2011 75 50 83 10.1128/MMBR.00031-10 21372320 PMC3063353 Cargnello, M. & Roux, P. P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 75 , 50–83 (2011). 21372320 10.1128/MMBR.00031-10 PMC3063353

289. Shu N Hägglund P Cai H Hawkins CL Davies MJ Modification of Cys residues in human thioredoxin-1 by p-benzoquinone causes inhibition of its catalytic activity and activation of the ASK1/p38-MAPK signalling pathway Redox Biol. 2020 29 101400 10.1016/j.redox.2019.101400 31926625 PMC6926358 Shu, N., Hägglund, P., Cai, H., Hawkins, C. L. & Davies, M. J. Modification of Cys residues in human thioredoxin-1 by p-benzoquinone causes inhibition of its catalytic activity and activation of the ASK1/p38-MAPK signalling pathway. Redox Biol. 29 , 101400 (2020). 31926625 10.1016/j.redox.2019.101400 PMC6926358

290. Okamura T Phosphorylation of glutathione s-transferase p1 (gstp1) by epidermal growth factor receptor (EGFR) promotes formation of the gstp1-c-jun n-terminal kinase (JNK) complex and suppresses JNK downstream signaling and apoptosis in brain tumor cells J. Biol. Chem. 2015 290 30866 30878 10.1074/jbc.M115.656140 26429914 PMC4692215 Okamura, T. et al. Phosphorylation of glutathione s-transferase p1 (gstp1) by epidermal growth factor receptor (EGFR) promotes formation of the gstp1-c-jun n-terminal kinase (JNK) complex and suppresses JNK downstream signaling and apoptosis in brain tumor cells. J. Biol. Chem. 290 , 30866–30878 (2015). 26429914 10.1074/jbc.M115.656140 PMC4692215

291. Takeda K Apoptosis Signal-regulating Kinase (ASK) 2 Functions as a Mitogen-activated Protein Kinase Kinase Kinase in a Heteromeric Complex with ASK1 J. Biol. Chem. 2007 282 7522 7531 10.1074/jbc.M607177200 17210579 Takeda, K. et al. Apoptosis Signal-regulating Kinase (ASK) 2 Functions as a Mitogen-activated Protein Kinase Kinase Kinase in a Heteromeric Complex with ASK1. J. Biol. Chem. 282 , 7522–7531 (2007). 17210579 10.1074/jbc.M607177200

292. Bassi R Redox-dependent dimerization of p38α mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3 J. Biol. Chem. 2017 292 16161 16173 10.1074/jbc.M117.785410 28739872 PMC5625047 Bassi, R. et al. Redox-dependent dimerization of p38α mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3. J. Biol. Chem. 292 , 16161–16173 (2017). 28739872 10.1074/jbc.M117.785410 PMC5625047

293. Dawicki-McKenna JM PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain Mol. Cell 2015 60 755 768 10.1016/j.molcel.2015.10.013 26626480 PMC4712911 Dawicki-McKenna, J. M. et al. PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. Mol. Cell 60 , 755–768 (2015). 26626480 10.1016/j.molcel.2015.10.013 PMC4712911

294. Suskiewicz MJ HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation Nature 2020 579 598 602 10.1038/s41586-020-2013-6 32028527 PMC7104379 Suskiewicz, M. J. et al. HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature 579 , 598–602 (2020). 32028527 10.1038/s41586-020-2013-6 PMC7104379

295. Bonfiglio JJ Serine ADP-Ribosylation Depends on HPF1 Mol. Cell 2017 65 932 940 10.1016/j.molcel.2017.01.003 28190768 PMC5344681 Bonfiglio, J. J. et al. Serine ADP-Ribosylation Depends on HPF1. Mol. Cell 65 , 932–940 (2017). 28190768 10.1016/j.molcel.2017.01.003 PMC5344681

296. Sun FH HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones Nat. Commun. 2021 12 1028 10.1038/s41467-021-21302-4 33589610 PMC7884425 Sun, F. H. et al. HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones. Nat. Commun. 12 , 1028 (2021). 33589610 10.1038/s41467-021-21302-4 PMC7884425

297. Lee J-H Paull TT Cellular functions of the protein kinase ATM and their relevance to human disease Nat. Rev. Mol. Cell Biol. 2021 22 796 814 10.1038/s41580-021-00394-2 34429537 Lee, J.-H. & Paull, T. T. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat. Rev. Mol. Cell Biol. 22 , 796–814 (2021). 34429537 10.1038/s41580-021-00394-2

298. Wu H Liu Q Shan X Gao W Chen Q ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4 Autophagy 2023 19 2062 2077 10.1080/15548627.2023.2170960 36752571 PMC10283418 Wu, H., Liu, Q., Shan, X., Gao, W. & Chen, Q. ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy 19 , 2062–2077 (2023). 36752571 10.1080/15548627.2023.2170960 PMC10283418

299. Shi T van Soest DMK Polderman PE Burgering BMT Dansen TB DNA damage and oxidant stress activate p53 through differential upstream signaling pathways Free Radic. Biol. Med. 2021 172 298 311 10.1016/j.freeradbiomed.2021.06.013 34144191 Shi, T., van Soest, D. M. K., Polderman, P. E., Burgering, B. M. T. & Dansen, T. B. DNA damage and oxidant stress activate p53 through differential upstream signaling pathways. Free Radic. Biol. Med. 172 , 298–311 (2021). 34144191 10.1016/j.freeradbiomed.2021.06.013

300. Oleinik N Krupenko N Krupenko S Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway Oncogene 2007 26 7222 7230 10.1038/sj.onc.1210526 17525747 Oleinik, N., Krupenko, N. & Krupenko, S. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene 26 , 7222–7230 (2007). 17525747 10.1038/sj.onc.1210526

301. Hawley SA Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation Cell Metab 2010 11 554 565 10.1016/j.cmet.2010.04.001 20519126 PMC2935965 Hawley, S. A. et al. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11 , 554–565 (2010). 20519126 10.1016/j.cmet.2010.04.001 PMC2935965

302. Park JM Lee DH Kim DH Redefining the role of AMPK in autophagy and the energy stress response Nat. Commun. 2023 14 2994 10.1038/s41467-023-38401-z 37225695 PMC10209092 Park, J. M., Lee, D. H. & Kim, D. H. Redefining the role of AMPK in autophagy and the energy stress response. Nat. Commun. 14 , 2994 (2023). 37225695 10.1038/s41467-023-38401-z PMC10209092

303. Zmijewski JW Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase J. Biol. Chem. 2010 285 33154 33164 10.1074/jbc.M110.143685 20729205 PMC2963401 Zmijewski, J. W. et al. Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J. Biol. Chem. 285 , 33154–33164 (2010). 20729205 10.1074/jbc.M110.143685 PMC2963401

304. Hinchy EC Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly J. Biol. Chem. 2018 293 17208 17217 10.1074/jbc.RA118.002579 30232152 PMC6222118 Hinchy, E. C. et al. Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J. Biol. Chem. 293 , 17208–17217 (2018). 30232152 10.1074/jbc.RA118.002579 PMC6222118

305. Cheung EC Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer Cancer Cell 2020 37 168 182 10.1016/j.ccell.2019.12.012 31983610 PMC7008247 Cheung, E. C. et al. Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer. Cancer Cell 37 , 168–182 (2020). 31983610 10.1016/j.ccell.2019.12.012 PMC7008247

306. Wiel C BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis Cell 2019 178 330 345 10.1016/j.cell.2019.06.005 31257027 Wiel, C. et al. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis. Cell 178 , 330–345 (2019). 31257027 10.1016/j.cell.2019.06.005

307. Gal K Antioxidants can increase melanoma metastasis in mice Sci. Transl. Med. 2015 7 308re8 26446958 10.1126/scitranslmed.aad3740 Gal, K. et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med. 7 , 308re8 (2015). 26446958 10.1126/scitranslmed.aad3740

308. Liu S Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer Mol. Cancer 2024 23 261 10.1186/s12943-024-02165-x 39574178 PMC11580516 Liu, S. et al. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer. Mol. Cancer 23 , 261 (2024). 39574178 10.1186/s12943-024-02165-x PMC11580516

309. Trachootham D Alexandre J Huang P Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 2009 8 579 591 10.1038/nrd2803 19478820 Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8 , 579–591 (2009). 19478820 10.1038/nrd2803

310. Li P NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells Redox Biol 2016 8 91 97 10.1016/j.redox.2015.12.001 26771767 PMC5022045 Li, P. et al. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells. Redox Biol 8 , 91–97 (2016). 26771767 10.1016/j.redox.2015.12.001 PMC5022045

311. Reis J A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action Redox Biol. 2020 32 101466 10.1016/j.redox.2020.101466 32105983 PMC7042484 Reis, J. et al. A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action. Redox Biol. 32 , 101466 (2020). 32105983 10.1016/j.redox.2020.101466 PMC7042484

312. Kuai Y An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer Theranostics 2020 10 6743 10.7150/thno.43938 32550901 PMC7295061 Kuai, Y. et al. An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer. Theranostics 10 , 6743 (2020). 32550901 10.7150/thno.43938 PMC7295061

313. Liu W-J Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC Drug Resist. Updat. 2023 70 100987 10.1016/j.drup.2023.100987 37392558 Liu, W.-J. et al. Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. Drug Resist. Updat. 70 , 100987 (2023). 37392558 10.1016/j.drup.2023.100987

314. Ford K NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors Cancer Res. 2020 80 1846 1860 10.1158/0008-5472.CAN-19-3158 32122909 PMC7611230 Ford, K. et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 80 , 1846–1860 (2020). 32122909 10.1158/0008-5472.CAN-19-3158 PMC7611230

315. Pang J A Cyclodiaryliodonium NOX Inhibitor for the Treatment of Pancreatic Cancer via Enzyme-Activatable Targeted Delivery by Sulfated Glycosaminoglycan Derivatives Adv. Healthc. Mater. 2023 12 2203011 10.1002/adhm.202203011 36841552 Pang, J. et al. A Cyclodiaryliodonium NOX Inhibitor for the Treatment of Pancreatic Cancer via Enzyme-Activatable Targeted Delivery by Sulfated Glycosaminoglycan Derivatives. Adv. Healthc. Mater. 12 , 2203011 (2023). 10.1002/adhm.202203011 36841552

316. Chen B Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ROS-related Akt-mTOR signaling pathway Cancer Lett. 2022 543 215783 10.1016/j.canlet.2022.215783 35700820 Chen, B. et al. Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ROS-related Akt-mTOR signaling pathway. Cancer Lett. 543 , 215783 (2022). 35700820 10.1016/j.canlet.2022.215783

317. Springett GM A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia EBioMedicine 2015 2 1987 1995 10.1016/j.ebiom.2015.11.025 26844278 PMC4703733 Springett, G. M. et al. A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia. EBioMedicine 2 , 1987–1995 (2015). 26844278 10.1016/j.ebiom.2015.11.025 PMC4703733

318. Chen Y-C Vitamin D3 decreases TNF-α-induced inflammation in lung epithelial cells through a reduction in mitochondrial fission and mitophagy Cell. Biol. Toxicol. 2022 38 427 450 10.1007/s10565-021-09629-6 34255241 PMC8275919 Chen, Y.-C. et al. Vitamin D3 decreases TNF-α-induced inflammation in lung epithelial cells through a reduction in mitochondrial fission and mitophagy. Cell. Biol. Toxicol. 38 , 427–450 (2022). 34255241 10.1007/s10565-021-09629-6 PMC8275919

319. Cheng J Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF Int. J. Mol. Med. 2019 43 945 955 30569127 10.3892/ijmm.2018.4021 PMC6317691 Cheng, J. et al. Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF. Int. J. Mol. Med. 43 , 945–955 (2019). 30569127 10.3892/ijmm.2018.4021 PMC6317691

320. Zou Z-W Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS Redox Biol. 2018 16 226 236 10.1016/j.redox.2018.02.025 29525603 PMC5854931 Zou, Z.-W. et al. Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS. Redox Biol. 16 , 226–236 (2018). 29525603 10.1016/j.redox.2018.02.025 PMC5854931

321. Jeong Y Lim JW Kim H Lycopene inhibits reactive oxygen species-mediated nf-kb signaling and induces apoptosis in pancreatic cancer cells Nutrients 2019 11 762 10.3390/nu11040762 30939781 PMC6521322 Jeong, Y., Lim, J. W. & Kim, H. Lycopene inhibits reactive oxygen species-mediated nf-kb signaling and induces apoptosis in pancreatic cancer cells. Nutrients 11 , 762 (2019). 30939781 10.3390/nu11040762 PMC6521322

322. Nicolay JP Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study Blood 2023 142 794 805 10.1182/blood.2022018669 37217183 PMC10644069 Nicolay, J. P. et al. Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study. Blood 142 , 794–805 (2023). 37217183 10.1182/blood.2022018669 PMC10644069

323. Crisman E KEAP1-NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential Med. Res. Rev. 2023 43 237 287 10.1002/med.21925 36086898 PMC10087726 Crisman, E. et al. KEAP1-NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential. Med. Res. Rev. 43 , 237–287 (2023). 36086898 10.1002/med.21925 PMC10087726

324. Zhang Z Atwell LL Farris PE Ho E Shannon J Associations between cruciferous vegetable intake and selected biomarkers among women scheduled for breast biopsies Public Health Nutr. 2016 19 1288 1295 10.1017/S136898001500244X 26329135 PMC10271091 Zhang, Z., Atwell, L. L., Farris, P. E., Ho, E. & Shannon, J. Associations between cruciferous vegetable intake and selected biomarkers among women scheduled for breast biopsies. Public Health Nutr. 19 , 1288–1295 (2016). 26329135 10.1017/S136898001500244X PMC10271091

325. Zhang Z Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial Nutr. Cancer 2020 72 74 87 10.1080/01635581.2019.1619783 31155953 PMC8244813 Zhang, Z. et al. Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial. Nutr. Cancer 72 , 74–87 (2020). 31155953 10.1080/01635581.2019.1619783 PMC8244813

326. Howells LM Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - Safety, pharmacokinetics, and pharmacodynamics Cancer Prev. Res. 2011 4 1419 1425 10.1158/1940-6207.CAPR-11-0148 PMC3173869 21680702 Howells, L. M. et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - Safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. 4 , 1419–1425 (2011). 10.1158/1940-6207.CAPR-11-0148 PMC3173869 21680702

327. Patel KR Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients Cancer Res. 2010 70 7392 7399 10.1158/0008-5472.CAN-10-2027 20841478 PMC2948608 Patel, K. R. et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 70 , 7392–7399 (2010). 20841478 10.1158/0008-5472.CAN-10-2027 PMC2948608

328. Luo X A novel anti-atherosclerotic mechanism of quercetin: Competitive binding to KEAP1 via Arg483 to inhibit macrophage pyroptosis Redox Biol. 2022 57 102511 10.1016/j.redox.2022.102511 36274522 PMC9596875 Luo, X. et al. A novel anti-atherosclerotic mechanism of quercetin: Competitive binding to KEAP1 via Arg483 to inhibit macrophage pyroptosis. Redox Biol. 57 , 102511 (2022). 36274522 10.1016/j.redox.2022.102511 PMC9596875

329. Ding L Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes Free Radic. Biol. Med. 2024 213 150 163 10.1016/j.freeradbiomed.2024.01.002 38190923 Ding, L. et al. Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes. Free Radic. Biol. Med. 213 , 150–163 (2024). 38190923 10.1016/j.freeradbiomed.2024.01.002

330. Wang Z-X Quercetin induces p53-independent cancer cell death through lysosome activation by the transcription factor EB and Reactive Oxygen Species-dependent ferroptosis Br. J. Pharmacol. 2021 178 1133 1148 10.1111/bph.15350 33347603 Wang, Z.-X. et al. Quercetin induces p53-independent cancer cell death through lysosome activation by the transcription factor EB and Reactive Oxygen Species-dependent ferroptosis. Br. J. Pharmacol. 178 , 1133–1148 (2021). 33347603 10.1111/bph.15350

331. Hong DS Phase I trial with a novel oral NF-κB/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies J. Clin. Oncol. 2025 26 3517 10.1200/jco.2008.26.15_suppl.3517 Hong, D. S. et al. Phase I trial with a novel oral NF-κB/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies. J. Clin. Oncol. 26 , 3517 (2025).

332. Hong DS A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas Clin. Cancer Res. 2012 18 3396 3406 10.1158/1078-0432.CCR-11-2703 22634319 PMC4494099 Hong, D. S. et al. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin. Cancer Res. 18 , 3396–3406 (2012). 22634319 10.1158/1078-0432.CCR-11-2703 PMC4494099

333. Suraweera TL Merlin JPJ Dellaire G Xu Z Rupasinghe HPV Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro Int. J. Mol. Sci. 2023 24 3676 10.3390/ijms24043676 36835090 PMC9961944 Suraweera, T. L., Merlin, J. P. J., Dellaire, G., Xu, Z. & Rupasinghe, H. P. V. Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro. Int. J. Mol. Sci. 24 , 3676 (2023). 36835090 10.3390/ijms24043676 PMC9961944

334. Tovmasyan A Reboucas J Benov L Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics Antioxid. Redox Signal. 2013 20 2416 2436 10.1089/ars.2013.5576 23964890 PMC4005499 Tovmasyan, A., Reboucas, J. & Benov, L. Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics. Antioxid. Redox Signal. 20 , 2416–2436 (2013). 23964890 10.1089/ars.2013.5576 PMC4005499

335. Casas AI On the Clinical Pharmacology of Reactive Oxygen Species Pharmacol. Rev. 2020 72 801 828 10.1124/pr.120.019422 32859763 Casas, A. I. et al. On the Clinical Pharmacology of Reactive Oxygen Species. Pharmacol. Rev. 72 , 801–828 (2020). 32859763 10.1124/pr.120.019422

336. Romo-González M Moreno-Paz S García-Hernández V Sánchez-Guijo F Hernández-Hernández Á Inhibition of xanthine oxidoreductase enhances the potential of tyrosine kinase inhibitors against chronic myeloid leukemia Antioxidants 2020 9 74 10.3390/antiox9010074 31952182 PMC7022995 Romo-González, M., Moreno-Paz, S., García-Hernández, V., Sánchez-Guijo, F. & Hernández-Hernández, Á Inhibition of xanthine oxidoreductase enhances the potential of tyrosine kinase inhibitors against chronic myeloid leukemia. Antioxidants 9 , 74 (2020). 31952182 10.3390/antiox9010074 PMC7022995

337. Thongkongkaew, T. et al. Anti-Xanthine Oxidase 5′-Hydroxyhericenes A–D from the Edible Mushroom Hericium erinaceus and Structure Revision of 3-[2,3-Dihydroxy-4-(hydroxymethyl)tetrahydrofuran-1-yl]-pyridine-4,5-diol. ACS Omega 8, 46284–46291 (2023).. 10.1021/acsomega.3c07792 PMC10701869 38075774

338. Chen T Unveiling the significance of inducible nitric oxide synthase: Its impact on cancer progression and clinical implications Cancer Lett. 2024 592 216931 10.1016/j.canlet.2024.216931 38701892 Chen, T. Unveiling the significance of inducible nitric oxide synthase: Its impact on cancer progression and clinical implications. Cancer Lett. 592 , 216931 (2024). 38701892 10.1016/j.canlet.2024.216931

339. Qu J Advances in ameliorating inflammatory diseases and cancers by andrographolide: Pharmacokinetics, pharmacodynamics, and perspective Med. Res. Rev. 2022 42 1147 1178 10.1002/med.21873 34877672 Qu, J. et al. Advances in ameliorating inflammatory diseases and cancers by andrographolide: Pharmacokinetics, pharmacodynamics, and perspective. Med. Res. Rev. 42 , 1147–1178 (2022). 34877672 10.1002/med.21873

340. Chung AW A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer Sci. Transl. Med. 2021 13 eabj5070 10.1126/scitranslmed.abj5070 34910551 Chung, A. W. et al. A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer. Sci. Transl. Med. 13 , eabj5070 (2021). 34910551 10.1126/scitranslmed.abj5070

341. Wang J Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response Int. J. Nanomed. 2024 19 2301 2315 10.2147/IJN.S440709 PMC10926878 38469056 Wang, J. et al. Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response. Int. J. Nanomed. 19 , 2301–2315 (2024). 10.2147/IJN.S440709 PMC10926878 38469056

342. Gencheva R Coppo L Arnér ESJ Ren X Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite Free Radic. Biol. Med. 2025 233 317 329 10.1016/j.freeradbiomed.2025.03.049 40180024 Gencheva, R., Coppo, L., Arnér, E. S. J. & Ren, X. Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite. Free Radic. Biol. Med. 233 , 317–329 (2025). 40180024 10.1016/j.freeradbiomed.2025.03.049

343. Dvorakova K Induction of mitochondrial changes in myeloma cells by imexon Blood 2001 97 3544 3551 10.1182/blood.V97.11.3544 11369649 Dvorakova, K. et al. Induction of mitochondrial changes in myeloma cells by imexon. Blood 97 , 3544–3551 (2001). 11369649 10.1182/blood.v97.11.3544

344. Han E Dual Stimuli-Activatable Oxidative Stress Amplifying Agent as a Hybrid Anticancer Prodrug Bioconjug. Chem. 2017 28 968 978 10.1021/acs.bioconjchem.6b00683 28192990 Han, E. et al. Dual Stimuli-Activatable Oxidative Stress Amplifying Agent as a Hybrid Anticancer Prodrug. Bioconjug. Chem. 28 , 968–978 (2017). 28192990 10.1021/acs.bioconjchem.6b00683

345. Li Z Targeting ferroptosis in breast cancer Biomark. Res. 2020 8 58 10.1186/s40364-020-00230-3 33292585 PMC7643412 Li, Z. et al. Targeting ferroptosis in breast cancer. Biomark. Res. 8 , 58 (2020). 33292585 10.1186/s40364-020-00230-3 PMC7643412

346. Wang J Inhibition of cancer growth in vitro and in vivo by a novel ros-modulating agent with ability to eliminate stem-like cancer cells Cell Death Dis. 2017 8 e2887 e2887 10.1038/cddis.2017.272 28640251 PMC5520927 Wang, J. et al. Inhibition of cancer growth in vitro and in vivo by a novel ros-modulating agent with ability to eliminate stem-like cancer cells. Cell Death Dis. 8 , e2887–e2887 (2017). 28640251 10.1038/cddis.2017.272 PMC5520927

347. Lam-Ubol A Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial Int. J. Mol. Sci. 2023 24 7824 10.3390/ijms24097824 37175527 PMC10177844 Lam-Ubol, A. et al. Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial. Int. J. Mol. Sci. 24 , 7824 (2023). 37175527 10.3390/ijms24097824 PMC10177844

348. Yoo D Glutathione-Depleting Pro-Oxidant as a Selective Anticancer Therapeutic Agent ACS Omega 2019 4 10070 10077 10.1021/acsomega.9b00140 31460099 PMC6648603 Yoo, D. et al. Glutathione-Depleting Pro-Oxidant as a Selective Anticancer Therapeutic Agent. ACS Omega 4 , 10070–10077 (2019). 31460099 10.1021/acsomega.9b00140 PMC6648603

349. Li Y The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress Biochem. Pharmacol. 2023 208 115404 10.1016/j.bcp.2022.115404 36592709 Li, Y. et al. The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress. Biochem. Pharmacol. 208 , 115404 (2023). 36592709 10.1016/j.bcp.2022.115404

350. Liebmann M Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity Brain 2021 144 3126 3141 10.1093/brain/awab307 34849598 PMC8634070 Liebmann, M. et al. Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity. Brain 144 , 3126–3141 (2021). 34849598 10.1093/brain/awab307 PMC8634070

351. Carlström KE Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes Nat. Commun. 2019 10 3081 10.1038/s41467-019-11139-3 31300673 PMC6626021 Carlström, K. E. et al. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat. Commun. 10 , 3081 (2019). 31300673 10.1038/s41467-019-11139-3 PMC6626021

352. Lückel C IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis Nat. Commun. 2019 10 5722 10.1038/s41467-019-13731-z 31844089 PMC6915776 Lückel, C. et al. IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nat. Commun. 10 , 5722 (2019). 31844089 10.1038/s41467-019-13731-z PMC6915776

353. Lin Y Radiotherapy-mediated redox homeostasis-controllable nanomedicine for enhanced ferroptosis sensitivity in tumor therapy Acta Biomater 2023 159 300 311 10.1016/j.actbio.2023.01.022 36642338 Lin, Y. et al. Radiotherapy-mediated redox homeostasis-controllable nanomedicine for enhanced ferroptosis sensitivity in tumor therapy. Acta Biomater 159 , 300–311 (2023). 36642338 10.1016/j.actbio.2023.01.022

354. Tian Y Diallyl trisulfide sensitizes radiation therapy on glioblastoma through directly targeting thioredoxin 1 Free Radic. Biol. Med. 2022 189 157 168 10.1016/j.freeradbiomed.2022.07.019 35921994 Tian, Y. et al. Diallyl trisulfide sensitizes radiation therapy on glioblastoma through directly targeting thioredoxin 1. Free Radic. Biol. Med. 189 , 157–168 (2022). 35921994 10.1016/j.freeradbiomed.2022.07.019

355. Kwan S Garnier N Miller WH Jr. Mann KK Abstract 4890: Arsenic trioxide induces apoptosis through the activation of ASK1 and is enhanced by a thioredoxin reductase inhibitor Cancer Res. 2012 72 4890 10.1158/1538-7445.AM2012-4890 Kwan, S., Garnier, N., Miller, W. H. Jr. & Mann, K. K. Abstract 4890: Arsenic trioxide induces apoptosis through the activation of ASK1 and is enhanced by a thioredoxin reductase inhibitor. Cancer Res. 72 , 4890 (2012).23002203

356. Yang M The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism Redox Biol. 2024 75 103245 10.1016/j.redox.2024.103245 38909408 PMC11254835 Yang, M. et al. The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism. Redox Biol. 75 , 103245 (2024). 38909408 10.1016/j.redox.2024.103245 PMC11254835

357. Evens AM Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells Blood 2005 105 1265 1273 10.1182/blood-2004-03-0964 15388578 Evens, A. M. et al. Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. Blood 105 , 1265–1273 (2005). 15388578 10.1182/blood-2004-03-0964

358. He W Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells J. Exp. Clin. Cancer Res. 2019 38 207 10.1186/s13046-019-1215-y 31113439 PMC6528260 He, W. et al. Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells. J. Exp. Clin. Cancer Res. 38 , 207 (2019). 31113439 10.1186/s13046-019-1215-y PMC6528260

359. Wang H Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems Cancer Lett. 2019 450 42 52 10.1016/j.canlet.2019.02.034 30790679 Wang, H. et al. Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems. Cancer Lett. 450 , 42–52 (2019). 30790679 10.1016/j.canlet.2019.02.034

360. Zhang Y Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling Free Radic. Biol. Med. 2022 180 52 62 10.1016/j.freeradbiomed.2021.12.314 34973363 Zhang, Y. et al. Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling. Free Radic. Biol. Med. 180 , 52–62 (2022). 34973363 10.1016/j.freeradbiomed.2021.12.314

361. Wang R Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production Neoplasia 2024 53 101004 10.1016/j.neo.2024.101004 38733769 PMC11104261 Wang, R. et al. Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production. Neoplasia 53 , 101004 (2024). 38733769 10.1016/j.neo.2024.101004 PMC11104261

362. Peng S Yu S Zhang J Zhang J 6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells Int. J. Mol. Sci. 2023 24 4966 10.3390/ijms24054966 36902397 PMC10003455 Peng, S., Yu, S., Zhang, J. & Zhang, J. 6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells. Int. J. Mol. Sci. 24 , 4966 (2023). 36902397 10.3390/ijms24054966 PMC10003455

363. Zhao L Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1) Biochem. Pharmacol. 2023 210 115487 10.1016/j.bcp.2023.115487 36893814 Zhao, L. et al. Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1). Biochem. Pharmacol. 210 , 115487 (2023). 36893814 10.1016/j.bcp.2023.115487

364. Glasauer A Sena LA Diebold LP Mazar AP Chandel NS Targeting SOD1 reduces experimental non-small-cell lung cancer J. Clin. Invest. 2014 124 117 128 10.1172/JCI71714 24292713 PMC3871252 Glasauer, A., Sena, L. A., Diebold, L. P., Mazar, A. P. & Chandel, N. S. Targeting SOD1 reduces experimental non-small-cell lung cancer. J. Clin. Invest. 124 , 117–128 (2014). 24292713 10.1172/JCI71714 PMC3871252

365. König S Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1 Cell Death Discov 2024 10 379 10.1038/s41420-024-02145-6 39187509 PMC11347576 König, S. et al. Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1. Cell Death Discov 10 , 379 (2024). 39187509 10.1038/s41420-024-02145-6 PMC11347576

366. Yang Y The E3 ligase TRIM22 functions as a tumor suppressor in breast cancer by targeting CCS for proteasomal degradation to inhibit STAT3 signaling Cancer Lett 2024 600 217157 10.1016/j.canlet.2024.217157 39127340 Yang, Y. et al. The E3 ligase TRIM22 functions as a tumor suppressor in breast cancer by targeting CCS for proteasomal degradation to inhibit STAT3 signaling. Cancer Lett 600 , 217157 (2024). 39127340 10.1016/j.canlet.2024.217157

367. Silvers MA The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1 pancreatic cancer cells, causing perturbation in central carbon metabolism J. Biol. Chem. 2017 292 18203 18216 10.1074/jbc.M117.813923 28916726 PMC5672043 Silvers, M. A. et al. The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1 pancreatic cancer cells, causing perturbation in central carbon metabolism. J. Biol. Chem. 292 , 18203–18216 (2017). 28916726 10.1074/jbc.M117.813923 PMC5672043

368. Blanco E β-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy Cancer Res. 2010 70 3896 3904 10.1158/0008-5472.CAN-09-3995 20460521 PMC2873165 Blanco, E. et al. β-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res. 70 , 3896–3904 (2010). 20460521 10.1158/0008-5472.CAN-09-3995 PMC2873165

369. Huang X An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis Cancer Res. 2012 72 3038 3047 10.1158/0008-5472.CAN-11-3135 22532167 PMC4795165 Huang, X. et al. An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis. Cancer Res. 72 , 3038–3047 (2012). 22532167 10.1158/0008-5472.CAN-11-3135 PMC4795165

370. Jiang L Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively Kill NQO1-Positive Pancreatic Cancer Cells Antioxid. Redox Signal. 2023 41 74 92 10.1089/ars.2022.0224 PMC11321107 37950707 Jiang, L. et al. Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively Kill NQO1-Positive Pancreatic Cancer Cells. Antioxid. Redox Signal. 41 , 74–92 (2023). 10.1089/ars.2022.0224 PMC11321107 37950707

371. Hou Y A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway Acta Pharm. Sin. B. 2025 15 991 1006 10.1016/j.apsb.2024.12.005 40177544 PMC11959885 Hou, Y. et al. A small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/Iron/PARP/calcium pathway. Acta Pharm. Sin. B. 15 , 991–1006 (2025). 40177544 10.1016/j.apsb.2024.12.005 PMC11959885

372. Ma N Zhang M Hu J Wei Z Zhang S Daphnetin induces ferroptosis in ovarian cancer by inhibiting NAD(P)H:Quinone oxidoreductase 1 (NQO1) Phytomedicine 2024 132 155876 10.1016/j.phymed.2024.155876 39032284 Ma, N., Zhang, M., Hu, J., Wei, Z. & Zhang, S. Daphnetin induces ferroptosis in ovarian cancer by inhibiting NAD(P)H:Quinone oxidoreductase 1 (NQO1). Phytomedicine 132 , 155876 (2024). 39032284 10.1016/j.phymed.2024.155876

373. Li Q Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity J. Biol. Chem. 2022 298 101753 10.1016/j.jbc.2022.101753 35189139 PMC8968643 Li, Q. et al. Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity. J. Biol. Chem. 298 , 101753 (2022). 35189139 10.1016/j.jbc.2022.101753 PMC8968643

374. Im SS BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics Mol. Metab. 2025 94 102113 10.1016/j.molmet.2025.102113 39961401 PMC11905835 Im, S. S. et al. BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics. Mol. Metab. 94 , 102113 (2025). 39961401 10.1016/j.molmet.2025.102113 PMC11905835

375. Wang X Harnessing glucose metabolism with nanomedicine for cancer treatment Theranostics 2024 14 6831 6882 10.7150/thno.100036 39479443 PMC11519798 Wang, X. et al. Harnessing glucose metabolism with nanomedicine for cancer treatment. Theranostics 14 , 6831–6882 (2024). 39479443 10.7150/thno.100036 PMC11519798

376. Mir IA Chloroquine sensitises hypoxic colorectal cancer cells to ROS-mediated cell death via structural disruption of pyruvate dehydrogenase kinase 1 Free Radic. Bio.l Med. 2025 227 656 666 10.1016/j.freeradbiomed.2024.12.026 39657842 Mir, I. A. et al. Chloroquine sensitises hypoxic colorectal cancer cells to ROS-mediated cell death via structural disruption of pyruvate dehydrogenase kinase 1. Free Radic. Bio.l Med. 227 , 656–666 (2025). 10.1016/j.freeradbiomed.2024.12.026 39657842

377. Tan W GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma J. Adv. Res. 2023 44 173 183 10.1016/j.jare.2022.03.012 36725188 PMC9936410 Tan, W. et al. GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma. J. Adv. Res. 44 , 173–183 (2023). 36725188 10.1016/j.jare.2022.03.012 PMC9936410

378. Sun Y Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells Cell Death Dis. 2021 12 1028 10.1038/s41419-021-04306-2 34716292 PMC8556316 Sun, Y. et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 12 , 1028 (2021). 34716292 10.1038/s41419-021-04306-2 PMC8556316

379. Dong Q Manganese-Based Redox Homeostasis Disruptor for Inducing Intense Ferroptosis/Apoptosis Through xCT Inhibition And Oxidative Stress Injury Adv. Healthc. Mater. 2023 12 2301453 10.1002/adhm.202301453 37531240 Dong, Q. et al. Manganese-Based Redox Homeostasis Disruptor for Inducing Intense Ferroptosis/Apoptosis Through xCT Inhibition And Oxidative Stress Injury. Adv. Healthc. Mater. 12 , 2301453 (2023). 10.1002/adhm.202301453 37531240

380. Cheff DM The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1 Redox Biol. 2023 62 102703 10.1016/j.redox.2023.102703 37087975 PMC10149367 Cheff, D. M. et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 62 , 102703 (2023). 37087975 10.1016/j.redox.2023.102703 PMC10149367

381. Yan R The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis Cell Res. 2022 32 687 690 10.1038/s41422-022-00642-w 35352032 PMC9253326 Yan, R. et al. The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis. Cell Res. 32 , 687–690 (2022). 35352032 10.1038/s41422-022-00642-w PMC9253326

382. Gaschler MM FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation Nat. Chem. Biol. 2018 14 507 515 10.1038/s41589-018-0031-6 29610484 PMC5899674 Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14 , 507–515 (2018). 29610484 10.1038/s41589-018-0031-6 PMC5899674

383. Zhou X Xu R Wu Y Zhou L Xiang T The role of proteasomes in tumorigenesis Genes Dis. 2024 11 101070 10.1016/j.gendis.2023.06.037 38523673 PMC10958230 Zhou, X., Xu, R., Wu, Y., Zhou, L. & Xiang, T. The role of proteasomes in tumorigenesis. Genes Dis. 11 , 101070 (2024). 38523673 10.1016/j.gendis.2023.06.037 PMC10958230

384. Din RU Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe Int. J. Mol. Sci. 2023 24 14646 10.3390/ijms241914646 37834095 PMC10572992 Din, R. U. et al. Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe. Int. J. Mol. Sci. 24 , 14646 (2023). 37834095 10.3390/ijms241914646 PMC10572992

385. Kim HJ Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux Autophagy 2021 17 961 979 10.1080/15548627.2020.1740529 32164484 PMC8078769 Kim, H. J. et al. Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux. Autophagy 17 , 961–979 (2021). 32164484 10.1080/15548627.2020.1740529 PMC8078769

386. Nath Varma S The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma Pharmaceutics 2024 16 672 10.3390/pharmaceutics16050672 38794334 PMC11124782 Nath Varma, S. et al. The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma. Pharmaceutics 16 , 672 (2024). 38794334 10.3390/pharmaceutics16050672 PMC11124782

387. Schultz M Dutta S Tew KD Inhibitors of glutathione S-transferases as therapeutic agents Adv. Drug Deliv. Rev. 1997 26 91 104 10.1016/S0169-409X(97)00029-X 10837536 Schultz, M., Dutta, S. & Tew, K. D. Inhibitors of glutathione S-transferases as therapeutic agents. Adv. Drug Deliv. Rev. 26 , 91–104 (1997). 10837536 10.1016/s0169-409x(97)00029-x

388. Zhang Y Tryptanthrin targets GSTP1 to induce senescence and increases the susceptibility to apoptosis by senolytics in liver cancer cells Redox Biol. 2024 76 103323 10.1016/j.redox.2024.103323 39180983 PMC11388193 Zhang, Y. et al. Tryptanthrin targets GSTP1 to induce senescence and increases the susceptibility to apoptosis by senolytics in liver cancer cells. Redox Biol. 76 , 103323 (2024). 39180983 10.1016/j.redox.2024.103323 PMC11388193

389. Reinema FV Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer Cancer Metab 2023 11 3 10.1186/s40170-023-00304-4 36755288 PMC9909892 Reinema, F. V. et al. Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer. Cancer Metab 11 , 3 (2023). 36755288 10.1186/s40170-023-00304-4 PMC9909892

390. Wang H β-Sitosterol targets ASS1 for Nrf2 ubiquitin-dependent degradation, inducing ROS-mediated apoptosis via the PTEN/PI3K/AKT signaling pathway in ovarian cancer Free Radic. Biol. Med. 2024 214 137 157 10.1016/j.freeradbiomed.2024.02.004 38364944 Wang, H. et al. β-Sitosterol targets ASS1 for Nrf2 ubiquitin-dependent degradation, inducing ROS-mediated apoptosis via the PTEN/PI3K/AKT signaling pathway in ovarian cancer. Free Radic. Biol. Med. 214 , 137–157 (2024). 38364944 10.1016/j.freeradbiomed.2024.02.004

391. Camacho LH Organic arsenic in patients (pts) with advanced solid tumors: Phase-1 results of zio-101 (s-dimethylarsino-glutathione) J. Clin. Oncol. 2007 25 3554 10.1200/jco.2007.25.18_suppl.3554 Camacho, L. H. et al. Organic arsenic in patients (pts) with advanced solid tumors: Phase-1 results of zio-101 (s-dimethylarsino-glutathione). J. Clin. Oncol. 25 , 3554 (2007).

392. Yan Y Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis Signal Transduct. Target. Ther. 2024 9 58 10.1038/s41392-024-01763-x 38438346 PMC10912509 Yan, Y. et al. Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis. Signal Transduct. Target. Ther. 9 , 58 (2024). 38438346 10.1038/s41392-024-01763-x PMC10912509

393. Gao J Novel insights into anticancer mechanisms of elesclomol: More than a prooxidant drug Redox Biol. 2023 67 102891 10.1016/j.redox.2023.102891 37734229 PMC10518591 Gao, J. et al. Novel insights into anticancer mechanisms of elesclomol: More than a prooxidant drug. Redox Biol. 67 , 102891 (2023). 37734229 10.1016/j.redox.2023.102891 PMC10518591

394. Brack E Fenretinide induces a new form of dynamin-dependent cell death in pediatric sarcoma Cell Death Differ. 2020 27 2500 2516 10.1038/s41418-020-0518-z 32144381 PMC7370225 Brack, E. et al. Fenretinide induces a new form of dynamin-dependent cell death in pediatric sarcoma. Cell Death Differ. 27 , 2500–2516 (2020). 32144381 10.1038/s41418-020-0518-z PMC7370225

395. Druck T Fhit–Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells Cell Death Dis. 2019 10 147 10.1038/s41419-019-1414-7 30770797 PMC6377664 Druck, T. et al. Fhit–Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells. Cell Death Dis. 10 , 147 (2019). 30770797 10.1038/s41419-019-1414-7 PMC6377664

396. Veiga SR Phenformin-induced mitochondrial dysfunction sensitizes hepatocellular carcinoma for dual inhibition of mTOR Clin. Cancer Res. 2018 24 3767 3780 10.1158/1078-0432.CCR-18-0177 29691292 Veiga, S. R. et al. Phenformin-induced mitochondrial dysfunction sensitizes hepatocellular carcinoma for dual inhibition of mTOR. Clin. Cancer Res. 24 , 3767–3780 (2018). 29691292 10.1158/1078-0432.CCR-18-0177

397. Petronek MS Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM Clin. Cancer Res. 2024 30 283 293 10.1158/1078-0432.CCR-22-3952 37773633 PMC10841843 Petronek, M. S. et al. Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM. Clin. Cancer Res. 30 , 283–293 (2024). 37773633 10.1158/1078-0432.CCR-22-3952 PMC10841843

398. Furqan M Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer Redox Biol. 2022 53 102318 10.1016/j.redox.2022.102318 35525024 PMC9079696 Furqan, M. et al. Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer. Redox Biol. 53 , 102318 (2022). 35525024 10.1016/j.redox.2022.102318 PMC9079696

399. Tocchetti CG From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview Antioxid. Redox. Signal. 2017 30 2110 2153 10.1089/ars.2016.6930 28398124 PMC6529857 Tocchetti, C. G. et al. From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview. Antioxid. Redox. Signal. 30 , 2110–2153 (2017). 28398124 10.1089/ars.2016.6930 PMC6529857

400. Forenzo C Larsen J Bridging clinical radiotherapy and space radiation therapeutics through reactive oxygen species (ROS)-triggered delivery Free Radic. Biol. Med. 2024 219 88 103 10.1016/j.freeradbiomed.2024.04.219 38631648 Forenzo, C. & Larsen, J. Bridging clinical radiotherapy and space radiation therapeutics through reactive oxygen species (ROS)-triggered delivery. Free Radic. Biol. Med. 219 , 88–103 (2024). 38631648 10.1016/j.freeradbiomed.2024.04.219

401. Song C Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway Cell Death Dis. 2020 11 938 10.1038/s41419-020-03136-y 33130826 PMC7603522 Song, C. et al. Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway. Cell Death Dis. 11 , 938 (2020). 33130826 10.1038/s41419-020-03136-y PMC7603522

402. Xu Y Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis Proc. Natl. Acad. Sci. 2024 121 e2314620121 10.1073/pnas.2314620121 38381784 PMC10907263 Xu, Y. et al. Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis. Proc. Natl. Acad. Sci. 121 , e2314620121 (2024). 38381784 10.1073/pnas.2314620121 PMC10907263

403. Chen P Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells Cancer Lett. 2024 587 216622 10.1016/j.canlet.2024.216622 38246224 Chen, P. et al. Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells. Cancer Lett. 587 , 216622 (2024). 38246224 10.1016/j.canlet.2024.216622

404. Mellinghoff IK Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma N. Engl. J. Med. 2023 389 589 601 10.1056/NEJMoa2304194 37272516 PMC11445763 Mellinghoff, I. K. et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N. Engl. J. Med. 389 , 589–601 (2023). 37272516 10.1056/NEJMoa2304194 PMC11445763

405. Srinivas US Tan BWQ Vellayappan BA Jeyasekharan AD ROS and the DNA damage response in cancer Redox Biol. 2019 25 101084 10.1016/j.redox.2018.101084 30612957 PMC6859528 Srinivas, U. S., Tan, B. W. Q., Vellayappan, B. A. & Jeyasekharan, A. D. ROS and the DNA damage response in cancer. Redox Biol. 25 , 101084 (2019). 30612957 10.1016/j.redox.2018.101084 PMC6859528

406. Dagnell M Thioredoxin reductase 1 and NADPH directly protect protein tyrosine phosphatase 1B from inactivation during H2O2 exposure J. Biol. Chem. 2017 292 14371 14380 10.1074/jbc.M117.793745 28684416 PMC5582832 Dagnell, M. et al. Thioredoxin reductase 1 and NADPH directly protect protein tyrosine phosphatase 1B from inactivation during H2O2 exposure. J. Biol. Chem. 292 , 14371–14380 (2017). 28684416 10.1074/jbc.M117.793745 PMC5582832

407. Basiorka AA The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype Blood 2016 128 2960 2975 10.1182/blood-2016-07-730556 27737891 PMC5179338 Basiorka, A. A. et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood 128 , 2960–2975 (2016). 27737891 10.1182/blood-2016-07-730556 PMC5179338

408. Kneeshaw S Nucleoredoxin guards against oxidative stress by protecting antioxidant enzymes Proc. Natl. Acad. Sci. 2017 114 8414 8419 10.1073/pnas.1703344114 28724723 PMC5547615 Kneeshaw, S. et al. Nucleoredoxin guards against oxidative stress by protecting antioxidant enzymes. Proc. Natl. Acad. Sci. 114 , 8414–8419 (2017). 28724723 10.1073/pnas.1703344114 PMC5547615

409. Charras A JAK Inhibitors and Oxidative Stress Control Front. Immunol. 2019 10 2814 10.3389/fimmu.2019.02814 31867003 PMC6908489 Charras, A. et al. JAK Inhibitors and Oxidative Stress Control. Front. Immunol. 10 , 2814 (2019). 31867003 10.3389/fimmu.2019.02814 PMC6908489

410. Feng Y Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling Toxicology 2024 508 153917 10.1016/j.tox.2024.153917 39137827 Feng, Y. et al. Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling. Toxicology 508 , 153917 (2024). 39137827 10.1016/j.tox.2024.153917

411. Zeng S Inhibiting the activation of MAPK (ERK1/2) in stressed Müller cells prevents photoreceptor degeneration Theranostics 2022 12 6705 10.7150/thno.71038 36185611 PMC9516241 Zeng, S. et al. Inhibiting the activation of MAPK (ERK1/2) in stressed Müller cells prevents photoreceptor degeneration. Theranostics 12 , 6705 (2022). 36185611 10.7150/thno.71038 PMC9516241

412. Huo JF Synthesis and in vitro and in vivo biological evaluation of novel derivatives of flexicaulin A as antiproliferative agents Eur. J. Med. Chem. 2020 208 112789 10.1016/j.ejmech.2020.112789 32883640 Huo, J. F. et al. Synthesis and in vitro and in vivo biological evaluation of novel derivatives of flexicaulin A as antiproliferative agents. Eur. J. Med. Chem. 208 , 112789 (2020). 32883640 10.1016/j.ejmech.2020.112789

413. Biswas P A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells Int. J. Mol. Sci. 2022 23 11746 10.3390/ijms231911746 36233051 PMC9569933 Biswas, P. et al. A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells. Int. J. Mol. Sci. 23 , 11746 (2022). 36233051 10.3390/ijms231911746 PMC9569933

414. Mhone TG Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity Int. J. Biol. Sci. 2022 18 3636 10.7150/ijbs.71870 35813479 PMC9254481 Mhone, T. G. et al. Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity. Int. J. Biol. Sci. 18 , 3636 (2022). 35813479 10.7150/ijbs.71870 PMC9254481

415. Ji Y Dai F Yan S Shi J-Y Zhou B Identification of Catechol-Type Diphenylbutadiene as a Tyrosinase-Activated Pro-oxidative Chemosensitizer against Melanoma A375 Cells via Glutathione S-Transferase Inhibition J. Agric. Food. Chem. 2019 67 9060 9069 10.1021/acs.jafc.9b02875 31339696 Ji, Y., Dai, F., Yan, S., Shi, J.-Y. & Zhou, B. Identification of Catechol-Type Diphenylbutadiene as a Tyrosinase-Activated Pro-oxidative Chemosensitizer against Melanoma A375 Cells via Glutathione S-Transferase Inhibition. J. Agric. Food. Chem. 67 , 9060–9069 (2019). 31339696 10.1021/acs.jafc.9b02875

416. Nakamura T Phase separation of FSP1 promotes ferroptosis Nature 2023 619 371 377 10.1038/s41586-023-06255-6 37380771 PMC10338336 Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619 , 371–377 (2023). 37380771 10.1038/s41586-023-06255-6 PMC10338336

417. Cheu JWS Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer Cell. Mol. Gastroenterol. Hepatol. 2023 16 133 159 10.1016/j.jcmgh.2023.03.001 36893885 PMC10230009 Cheu, J. W. S. et al. Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer. Cell. Mol. Gastroenterol. Hepatol. 16 , 133–159 (2023). 36893885 10.1016/j.jcmgh.2023.03.001 PMC10230009

418. Hai Y A novel mitochondria-targeting DHODH inhibitor induces robust ferroptosis and alleviates immune suppression Pharmacol. Res. 2024 202 107115 10.1016/j.phrs.2024.107115 38423231 Hai, Y. et al. A novel mitochondria-targeting DHODH inhibitor induces robust ferroptosis and alleviates immune suppression. Pharmacol. Res. 202 , 107115 (2024). 38423231 10.1016/j.phrs.2024.107115

419. Zhan M Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase Nat. Commun. 2023 14 3123 10.1038/s41467-023-38753-6 37253718 PMC10229567 Zhan, M. et al. Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase. Nat. Commun. 14 , 3123 (2023). 37253718 10.1038/s41467-023-38753-6 PMC10229567

420. Wang M Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis Pharmaceuticals 2025 18 374 10.3390/ph18030374 40143150 PMC11944504 Wang, M. et al. Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis. Pharmaceuticals 18 , 374 (2025). 40143150 10.3390/ph18030374 PMC11944504

421. Mishima E DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition Nature 2023 619 e9 e18 10.1038/s41586-023-06269-0 37407687 Mishima, E. et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619 , e9–e18 (2023). 37407687 10.1038/s41586-023-06269-0

422. Huang C Li J Wu R Li Y Zhang C Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives Mol. Cancer 2025 24 131 10.1186/s12943-025-02344-4 40319304 PMC12049004 Huang, C., Li, J., Wu, R., Li, Y. & Zhang, C. Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives. Mol. Cancer 24 , 131 (2025). 40319304 10.1186/s12943-025-02344-4 PMC12049004

423. Liu J Baicalin Induces Gastric Cancer Cell Pyroptosis through the NF-κB-NLRP3 Signaling Axis J. Cancer 2024 15 494 507 10.7150/jca.89986 38169542 PMC10758036 Liu, J. et al. Baicalin Induces Gastric Cancer Cell Pyroptosis through the NF-κB-NLRP3 Signaling Axis. J. Cancer 15 , 494–507 (2024). 38169542 10.7150/jca.89986 PMC10758036

424. Chen M Saikosaponin-D induces the pyroptosis of lung cancer by increasing ROS and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway J. Biochem. Mol Toxicol. 2023 37 e23444 10.1002/jbt.23444 37393521 Chen, M. et al. Saikosaponin-D induces the pyroptosis of lung cancer by increasing ROS and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway. J. Biochem. Mol Toxicol. 37 , e23444 (2023). 37393521 10.1002/jbt.23444

425. Qian X Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling Chin. Herb. Med. 2025 17 94 107 39949804 10.1016/j.chmed.2024.04.004 PMC11814252 Qian, X. et al. Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling. Chin. Herb. Med. 17 , 94–107 (2025). 39949804 10.1016/j.chmed.2024.04.004 PMC11814252

426. Ju X Shikonin triggers GSDME-mediated pyroptosis in tumours by regulating autophagy via the ROS–MAPK14/p38α axis Phytomedicine 2023 109 154596 10.1016/j.phymed.2022.154596 36610142 Ju, X. et al. Shikonin triggers GSDME-mediated pyroptosis in tumours by regulating autophagy via the ROS–MAPK14/p38α axis. Phytomedicine 109 , 154596 (2023). 36610142 10.1016/j.phymed.2022.154596

427. Zhang D Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells Biochem. Pharmacol. 2025 232 116695 10.1016/j.bcp.2024.116695 39643123 Zhang, D. et al. Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells. Biochem. Pharmacol. 232 , 116695 (2025). 39643123 10.1016/j.bcp.2024.116695

428. Yang F GEFT inhibits the GSDM-mediated proptosis signalling pathway, promoting the progression and drug resistance of rhabdomyosarcoma Cell Death Dis. 2024 15 867 10.1038/s41419-024-07243-y 39616223 PMC11608370 Yang, F. et al. GEFT inhibits the GSDM-mediated proptosis signalling pathway, promoting the progression and drug resistance of rhabdomyosarcoma. Cell Death Dis. 15 , 867 (2024). 39616223 10.1038/s41419-024-07243-y PMC11608370

429. Laurien L Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation Nat. Commun. 2020 11 1747 10.1038/s41467-020-15466-8 32269263 PMC7142081 Laurien, L. et al. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat. Commun. 11 , 1747 (2020). 32269263 10.1038/s41467-020-15466-8 PMC7142081

430. Cao X Targeting necroptosis: a promising avenue for respiratory disease treatment Cell Commun. Signal. 2024 22 418 10.1186/s12964-024-01804-6 39192326 PMC11350980 Cao, X. et al. Targeting necroptosis: a promising avenue for respiratory disease treatment. Cell Commun. Signal. 22 , 418 (2024). 39192326 10.1186/s12964-024-01804-6 PMC11350980

431. Lin S-S Acetylshikonin Induces Necroptosis via the RIPK1/RIPK3-Dependent Pathway in Lung Cancer Aging 2023 15 14900 10.18632/aging.205316 38126996 PMC10781480 Lin, S.-S. et al. Acetylshikonin Induces Necroptosis via the RIPK1/RIPK3-Dependent Pathway in Lung Cancer . Aging 15 , 14900 (2023). 38126996 10.18632/aging.205316 PMC10781480

432. Guo X Induction of RIPK3/MLKL-mediated necroptosis by Erigeron breviscapus injection exhibits potent antitumor effect Front. Pharmacol. 2023 14 1219362 10.3389/fphar.2023.1219362 37397499 PMC10311648 Guo, X. et al. Induction of RIPK3/MLKL-mediated necroptosis by Erigeron breviscapus injection exhibits potent antitumor effect. Front. Pharmacol. 14 , 1219362 (2023). 37397499 10.3389/fphar.2023.1219362 PMC10311648

433. Mohanty S RETRA induces necroptosis in cervical cancer cells through RIPK1, RIPK3, MLKL and increased ROS production Eur. J. Pharmacol. 2022 920 174840 10.1016/j.ejphar.2022.174840 35219733 Mohanty, S. et al. RETRA induces necroptosis in cervical cancer cells through RIPK1, RIPK3, MLKL and increased ROS production. Eur. J. Pharmacol. 920 , 174840 (2022). 35219733 10.1016/j.ejphar.2022.174840

434. Mousset A Bellone L Gaggioli C Albrengues J NETscape or NEThance: tailoring anti-cancer therapy Cancer Cell 2024 10 655 667 10.1016/j.trecan.2024.03.007 38664080 Mousset, A., Bellone, L., Gaggioli, C. & Albrengues, J. NETscape or NEThance: tailoring anti-cancer therapy. Cancer Cell 10 , 655–667 (2024). 10.1016/j.trecan.2024.03.007 38664080

435. Zeng J Kaempferol blocks neutrophil extracellular traps formation and reduces tumour metastasis by inhibiting ROS-PAD4 pathway J. Cell. Mol. Med. 2020 24 7590 7599 10.1111/jcmm.15394 32427405 PMC7339206 Zeng, J. et al. Kaempferol blocks neutrophil extracellular traps formation and reduces tumour metastasis by inhibiting ROS-PAD4 pathway. J. Cell. Mol. Med. 24 , 7590–7599 (2020). 32427405 10.1111/jcmm.15394 PMC7339206

436. Raninga PV Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma Mol. Ther. 2023 31 729 743 10.1016/j.ymthe.2022.12.011 36560881 PMC10014232 Raninga, P. V. et al. Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma. Mol. Ther. 31 , 729–743 (2023). 36560881 10.1016/j.ymthe.2022.12.011 PMC10014232

437. Yan X Inhibition of Thioredoxin/Thioredoxin Reductase Induces Synthetic Lethality in Lung Cancers with Compromised Glutathione Homeostasis Cancer Res. 2019 79 125 132 10.1158/0008-5472.CAN-18-1938 30401714 PMC7293542 Yan, X. et al. Inhibition of Thioredoxin/Thioredoxin Reductase Induces Synthetic Lethality in Lung Cancers with Compromised Glutathione Homeostasis. Cancer Res. 79 , 125–132 (2019). 30401714 10.1158/0008-5472.CAN-18-1938 PMC7293542

438. Torrente L Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone Redox Biol. 2020 30 101440 10.1016/j.redox.2020.101440 32007910 PMC6997906 Torrente, L. et al. Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone. Redox Biol. 30 , 101440 (2020). 32007910 10.1016/j.redox.2020.101440 PMC6997906

439. Jamali F Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells Antioxidants 2024 13 1201 10.3390/antiox13101201 39456455 PMC11504866 Jamali, F. et al. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells. Antioxidants 13 , 1201 (2024). 39456455 10.3390/antiox13101201 PMC11504866

440. Seo MJ Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells Cell Death Dis. 2023 14 42 10.1038/s41419-023-05586-6 36658130 PMC9852458 Seo, M. J. et al. Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells. Cell Death Dis. 14 , 42 (2023). 36658130 10.1038/s41419-023-05586-6 PMC9852458

441. Chen X Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells Phytomedicine 2024 128 155317 10.1016/j.phymed.2023.155317 38537439 Chen, X. et al. Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells. Phytomedicine 128 , 155317 (2024). 38537439 10.1016/j.phymed.2023.155317

442. Saha A Cysteine depletion sensitizes prostate cancer cells to agents that enhance DNA damage and to immune checkpoint inhibition J. Exp. Clin. Cancer Res. 2023 42 119 10.1186/s13046-023-02677-2 37170264 PMC10173527 Saha, A. et al. Cysteine depletion sensitizes prostate cancer cells to agents that enhance DNA damage and to immune checkpoint inhibition. J. Exp. Clin. Cancer Res. 42 , 119 (2023). 37170264 10.1186/s13046-023-02677-2 PMC10173527

443. Truong Hoang Q Piezoelectric Au-decorated ZnO nanorods: Ultrasound-triggered generation of ROS for piezocatalytic cancer therapy Chem. Eng. J. 2022 435 135039 10.1016/j.cej.2022.135039 Truong Hoang, Q. et al. Piezoelectric Au-decorated ZnO nanorods: Ultrasound-triggered generation of ROS for piezocatalytic cancer therapy. Chem. Eng. J. 435 , 135039 (2022).

444. Ma X Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy Nat. Commun. 2023 14 6187 10.1038/s41467-023-41782-w 37794000 PMC10550994 Ma, X. et al. Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy. Nat. Commun. 14 , 6187 (2023). 37794000 10.1038/s41467-023-41782-w PMC10550994

445. Wu Q Cancer cell membrane camouflaging mesoporous nanoplatform interfering with cellular redox homeostasis to amplify photodynamic therapy on oral carcinoma J. Drug Target. 2023 31 511 520 10.1080/1061186X.2023.2198172 37000919 Wu, Q. et al. Cancer cell membrane camouflaging mesoporous nanoplatform interfering with cellular redox homeostasis to amplify photodynamic therapy on oral carcinoma. J. Drug Target. 31 , 511–520 (2023). 37000919 10.1080/1061186X.2023.2198172

446. Yu H GPX4 inhibition synergistically boosts mitochondria targeting nanoartemisinin-induced apoptosis/ferroptosis combination cancer therapy Biomater. Sci. 2023 11 5831 5845 10.1039/D3BM00601H 37439624 Yu, H. et al. GPX4 inhibition synergistically boosts mitochondria targeting nanoartemisinin-induced apoptosis/ferroptosis combination cancer therapy. Biomater. Sci. 11 , 5831–5845 (2023). 37439624 10.1039/d3bm00601h

447. Monroy-Cárdenas M A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells Antioxidants 2023 12 1597 10.3390/antiox12081597 37627592 PMC10451541 Monroy-Cárdenas, M. et al. A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells. Antioxidants 12 , 1597 (2023). 37627592 10.3390/antiox12081597 PMC10451541

448. Kammire M Fannin E Ford JM Alli E Abstract 4846: Targeting BRCA1 -mutated cancer cells with elesclomol Cancer Res. 2018 78 4846 10.1158/1538-7445.AM2018-4846 Kammire, M., Fannin, E., Ford, J. M. & Alli, E. Abstract 4846: Targeting BRCA1 -mutated cancer cells with elesclomol. Cancer Res. 78 , 4846 (2018).

449. Wang W A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment ACS Nano 2023 17 11023 11038 10.1021/acsnano.3c03450 37257082 Wang, W. et al. A Native Drug-Free Macromolecular Therapeutic to Trigger Mutual Reinforcing of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction for Cancer Treatment. ACS Nano 17 , 11023–11038 (2023). 37257082 10.1021/acsnano.3c03450

450. Wang X IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy Int. J. Nanomed. 2023 18 6199 6212 10.2147/IJN.S431910 PMC10625775 37933299 Wang, X. et al. IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy. Int. J. Nanomed. 18 , 6199–6212 (2023). 10.2147/IJN.S431910 PMC10625775 37933299

451. O’Day S Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma J. Clin. Oncol. 2009 27 5452 5458 10.1200/JCO.2008.17.1579 19826135 O’Day, S. et al. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J. Clin. Oncol. 27 , 5452–5458 (2009). 19826135 10.1200/JCO.2008.17.1579

452. O’Day SJ Final results of phase III SYMMETRY study: Randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma J. Clin. Oncol. 2013 31 1211 1218 10.1200/JCO.2012.44.5585 23401447 O’Day, S. J. et al. Final results of phase III SYMMETRY study: Randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J. Clin. Oncol. 31 , 1211–1218 (2013). 23401447 10.1200/JCO.2012.44.5585

453. Modica-Napolitano JS The In Vitro Cytotoxic Effect of Elesclomol on Breast Adenocarcinoma Cells Is Enhanced by Concurrent Treatment with Glycolytic Inhibitors Cancers 2024 16 4054 10.3390/cancers16234054 39682240 PMC11639995 Modica-Napolitano, J. S. et al. The In Vitro Cytotoxic Effect of Elesclomol on Breast Adenocarcinoma Cells Is Enhanced by Concurrent Treatment with Glycolytic Inhibitors. Cancers 16 , 4054 (2024). 39682240 10.3390/cancers16234054 PMC11639995

454. Muller C The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors Cancer Cell. Int. 2024 24 132 10.1186/s12935-024-03319-z 38594745 PMC11005237 Muller, C. et al. The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors. Cancer Cell. Int. 24 , 132 (2024). 38594745 10.1186/s12935-024-03319-z PMC11005237

455. Hu X ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics Bioact. Mater. 2024 36 490 507 39055351 10.1016/j.bioactmat.2024.06.038 PMC11269796 Hu, X. et al. ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics. Bioact. Mater. 36 , 490–507 (2024). 39055351 10.1016/j.bioactmat.2024.06.038 PMC11269796

456. Li J You Z Zhai S Zhao J Lu K Mitochondria-Targeted Nanosystem Enhances Radio–Radiodynamic–Chemodynamic Therapy on Triple Negative Breast Cancer ACS Appl. Mater. Interfaces. 2023 15 21941 21952 10.1021/acsami.3c02361 37099714 Li, J., You, Z., Zhai, S., Zhao, J. & Lu, K. Mitochondria-Targeted Nanosystem Enhances Radio–Radiodynamic–Chemodynamic Therapy on Triple Negative Breast Cancer. ACS Appl. Mater. Interfaces. 15 , 21941–21952 (2023). 37099714 10.1021/acsami.3c02361

457. Wei X Boosting Energy Deprivation by Synchronous Interventions of Glycolysis and Oxidative Phosphorylation for Bioenergetic Therapy Synergetic with Chemodynamic/Photothermal Therapy Adv. Sci. 2024 11 2401738 10.1002/advs.202401738 PMC11187878 38489668 Wei, X. et al. Boosting Energy Deprivation by Synchronous Interventions of Glycolysis and Oxidative Phosphorylation for Bioenergetic Therapy Synergetic with Chemodynamic/Photothermal Therapy. Adv. Sci. 11 , 2401738 (2024). 10.1002/advs.202401738 PMC11187878 38489668

458. Song P Dual-pathway glycolysis inhibition for boosting bioenergetic therapy synergistic with chemodynamic/photothermal therapy Chem. Eng. J. 2024 483 149248 10.1016/j.cej.2024.149248 Song, P. et al. Dual-pathway glycolysis inhibition for boosting bioenergetic therapy synergistic with chemodynamic/photothermal therapy. Chem. Eng. J. 483 , 149248 (2024).

459. Luo Z Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy Nanoscale 2021 13 17737 17745 10.1039/D1NR06214J 34697618 Luo, Z. et al. Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy. Nanoscale 13 , 17737–17745 (2021). 34697618 10.1039/d1nr06214j

460. Guo B Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD-L1 for Enhanced Cancer Immunotherapy Adv. Mater. 2023 35 2212267 10.1002/adma.202212267 36916030 Guo, B. et al. Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD-L1 for Enhanced Cancer Immunotherapy. Adv. Mater. 35 , 2212267 (2023). 10.1002/adma.202212267 36916030

461. Nguyen Cao TG Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion Biomaterials 2023 301 122242 10.1016/j.biomaterials.2023.122242 37473534 Nguyen Cao, T. G. et al. Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion. Biomaterials 301 , 122242 (2023). 37473534 10.1016/j.biomaterials.2023.122242

462. Meric-Bernstam F CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study J. Clin. Oncol. 2019 37 549 10.1200/JCO.2019.37.7_suppl.549 Meric-Bernstam, F. et al. CB-839, a glutaminase inhibitor, in combination with cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC): Results of a phase I study. J. Clin. Oncol. 37 , 549 (2019).

463. Eads JR Phase I clinical trial of the glutaminase inhibitor CB-839 plus capecitabine in patients with advanced solid tumors J. Clin. Oncol. 2018 36 2562 10.1200/JCO.2018.36.15_suppl.2562 Eads, J. R. et al. Phase I clinical trial of the glutaminase inhibitor CB-839 plus capecitabine in patients with advanced solid tumors. J. Clin. Oncol. 36 , 2562 (2018).

464. Guerra V Interim results from a phase Ib/II clinical study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS) J. Clin. Oncol. 2019 37 7037 10.1200/JCO.2019.37.15_suppl.7037 Guerra, V. et al. Interim results from a phase Ib/II clinical study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS). J. Clin. Oncol. 37 , 7037 (2019).

465. Huang J Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency Adv. Sci. 2024 12 2411479 10.1002/advs.202411479 PMC11809341 39680480 Huang, J. et al. Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency. Adv. Sci. 12 , 2411479 (2024). 10.1002/advs.202411479 PMC11809341 39680480

466. Chakrabarti G Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone Cancer Metab 2015 3 12 10.1186/s40170-015-0137-1 26462257 PMC4601138 Chakrabarti, G. et al. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab 3 , 12 (2015). 26462257 10.1186/s40170-015-0137-1 PMC4601138

467. Mai Z Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy ACS Nano 2023 17 1583 1596 10.1021/acsnano.2c11037 36595443 Mai, Z. et al. Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy. ACS Nano 17 , 1583–1596 (2023). 10.1021/acsnano.2c11037 36595443

468. Hwang Y Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer Cell Death Dis. 2023 14 515 10.1038/s41419-023-06041-2 37573361 PMC10423221 Hwang, Y. et al. Co-inhibition of glutaminolysis and one-carbon metabolism promotes ROS accumulation leading to enhancement of chemotherapeutic efficacy in anaplastic thyroid cancer. Cell Death Dis. 14 , 515 (2023). 37573361 10.1038/s41419-023-06041-2 PMC10423221

469. Bénéteau M Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response Proc. Natl. Acad. Sci. 2012 109 20071 20076 10.1073/pnas.1206360109 23169636 PMC3523878 Bénéteau, M. et al. Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response. Proc. Natl. Acad. Sci. 109 , 20071–20076 (2012). 23169636 10.1073/pnas.1206360109 PMC3523878

470. Tang T Inhibition of thioredoxin-1 enhances the toxicity of glycolysis inhibitor 2-deoxyglucose by downregulating SLC1A5 expression in colorectal cancer cells Cell. Oncol. 2024 47 607 621 10.1007/s13402-023-00887-6 PMC12974035 37867183 Tang, T. et al. Inhibition of thioredoxin-1 enhances the toxicity of glycolysis inhibitor 2-deoxyglucose by downregulating SLC1A5 expression in colorectal cancer cells. Cell. Oncol. 47 , 607–621 (2024). 10.1007/s13402-023-00887-6 PMC12974035 37867183

471. Luo M Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling Cell Metab 2018 28 69 86 10.1016/j.cmet.2018.06.006 29972798 PMC6037414 Luo, M. et al. Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metab 28 , 69–86 (2018). 29972798 10.1016/j.cmet.2018.06.006 PMC6037414

472. Li Y Biodegradable Ferric Phosphate Nanocarriers with Tumor-Specific Activation and Glutathione Depletion for Tumor Self-Enhanced Ferroptosis and Chemotherapy Adv. Funct. Mater. 2024 34 2313540 10.1002/adfm.202313540 Li, Y. et al. Biodegradable Ferric Phosphate Nanocarriers with Tumor-Specific Activation and Glutathione Depletion for Tumor Self-Enhanced Ferroptosis and Chemotherapy. Adv. Funct. Mater. 34 , 2313540 (2024).

473. Su T Polymeric micelles amplify tumor oxidative stresses through combining PDT and glutathione depletion for synergistic cancer chemotherapy Chem. Eng. J. 2021 411 128561 10.1016/j.cej.2021.128561 37304676 PMC10254784 Su, T. et al. Polymeric micelles amplify tumor oxidative stresses through combining PDT and glutathione depletion for synergistic cancer chemotherapy. Chem. Eng. J. 411 , 128561 (2021). 37304676 10.1016/j.cej.2021.128561 PMC10254784

474. Liang, Y. et al. Exploiting metabolic vulnerabilities through synergistic ferroptosis and disulfidptosis for breast cancer therapy. J. Adv. Res . 79, 905–916 (2026). 10.1016/j.jare.2025.03.052 PMC12766248 40164329

475. Zhao Z Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis Nat. Commun. 2025 16 3605 10.1038/s41467-025-58992-z 40240371 PMC12003730 Zhao, Z. et al. Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis. Nat. Commun. 16 , 3605 (2025). 40240371 10.1038/s41467-025-58992-z PMC12003730

476. Sang J Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells Biochem. Pharmacol. 2024 223 116194 10.1016/j.bcp.2024.116194 38583812 Sang, J. et al. Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells. Biochem. Pharmacol. 223 , 116194 (2024). 38583812 10.1016/j.bcp.2024.116194

477. Chen L Combined photothermal and photodynamic therapy enhances ferroptosis to prevent cancer recurrence after surgery using nanoparticle-hydrogel composite Chem. Eng. J. 2023 468 143685 10.1016/j.cej.2023.143685 Chen, L. et al. Combined photothermal and photodynamic therapy enhances ferroptosis to prevent cancer recurrence after surgery using nanoparticle-hydrogel composite. Chem. Eng. J. 468 , 143685 (2023).

478. Li N Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence J. Ovarian. Res. 2024 17 49 10.1186/s13048-024-01366-8 38396022 PMC10885431 Li, N. et al. Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence. J. Ovarian. Res. 17 , 49 (2024). 38396022 10.1186/s13048-024-01366-8 PMC10885431

479. Wu S Liao K Chen J Li F Dual approach: micellar delivery of chlorambucil prodrug with concurrent glutathione depletion and GST inhibition for enhanced anticancer activity Nanotechnology 2024 35 345601 10.1088/1361-6528/ad501a 38788695 Wu, S., Liao, K., Chen, J. & Li, F. Dual approach: micellar delivery of chlorambucil prodrug with concurrent glutathione depletion and GST inhibition for enhanced anticancer activity. Nanotechnology 35 , 345601 (2024). 10.1088/1361-6528/ad501a 38788695

480. Tiburcio PDB Chen K Xu L Chen KS Suppressing proteasome activity enhances sensitivity to actinomycin D in diffuse anaplastic Wilms tumor Cell Rep. Med. 2025 6 5 10.1016/j.xcrm.2025.102133 PMC12147910 40347939 Tiburcio, P. D. B., Chen, K., Xu, L. & Chen, K. S. Suppressing proteasome activity enhances sensitivity to actinomycin D in diffuse anaplastic Wilms tumor. Cell Rep. Med. 6 , 5 (2025). 10.1016/j.xcrm.2025.102133 PMC12147910 40347939

481. Bu Z Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer Adv. Sci. 2023 10 2301638 10.1002/advs.202301638 PMC10427397 37303273 Bu, Z. et al. Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer. Adv. Sci. 10 , 2301638 (2023). 10.1002/advs.202301638 PMC10427397 37303273

482. Lee MS Carfilzomib in combination with bortezomib enhances apoptotic cell death in b16-f1 melanoma cells Biology 2021 10 1 26 10.3390/biology10020153 PMC7918982 33671902 Lee, M. S. et al. Carfilzomib in combination with bortezomib enhances apoptotic cell death in b16-f1 melanoma cells. Biology 10 , 1–26 (2021). 10.3390/biology10020153 PMC7918982 33671902

483. Prelowska MK Inhibition of the ʟ-glutamine transporter ASCT2 sensitizes plasma cell myeloma cells to proteasome inhibitors Cancer Lett. 2021 507 13 25 10.1016/j.canlet.2021.02.020 33713737 Prelowska, M. K. et al. Inhibition of the ʟ-glutamine transporter ASCT2 sensitizes plasma cell myeloma cells to proteasome inhibitors. Cancer Lett. 507 , 13–25 (2021). 33713737 10.1016/j.canlet.2021.02.020

484. Li N Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles J. Nanobiotechnology 2022 20 270 10.1186/s12951-022-01486-7 35690781 PMC9188091 Li, N. et al. Reciprocal regulation of NRF2 by autophagy and ubiquitin–proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles. J. Nanobiotechnology 20 , 270 (2022). 35690781 10.1186/s12951-022-01486-7 PMC9188091

485. Shao R Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties MedComm 2024 5 e562 10.1002/mco2.562 38737470 PMC11082532 Shao, R. et al. Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties. MedComm 5 , e562 (2024). 38737470 10.1002/mco2.562 PMC11082532

486. Lei K Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma J. Hematol. Oncol. 2020 13 141 10.1186/s13045-020-00979-y 33087132 PMC7579906 Lei, K. et al. Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma. J. Hematol. Oncol. 13 , 141 (2020). 33087132 10.1186/s13045-020-00979-y PMC7579906

487. Luo M Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling Cancer Res. 2024 84 4264 4282 10.1158/0008-5472.CAN-24-0800 39264695 PMC11647209 Luo, M. et al. Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling. Cancer Res. 84 , 4264–4282 (2024). 39264695 10.1158/0008-5472.CAN-24-0800 PMC11647209

488. Wang S Engineering Magnetic Extracellular Vesicles Mimetics for Enhanced Targeting Chemodynamic Therapy to Overcome Ovary Cancer ACS Appl. Mater. Interfaces. 2024 16 39021 39034 10.1021/acsami.4c06862 39033517 Wang, S. et al. Engineering Magnetic Extracellular Vesicles Mimetics for Enhanced Targeting Chemodynamic Therapy to Overcome Ovary Cancer. ACS Appl. Mater. Interfaces. 16 , 39021–39034 (2024). 39033517 10.1021/acsami.4c06862

489. Su X PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage Cancer Lett. 2021 519 304 314 10.1016/j.canlet.2021.07.040 34329742 PMC8403654 Su, X. et al. PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage. Cancer Lett. 519 , 304–314 (2021). 34329742 10.1016/j.canlet.2021.07.040 PMC8403654

490. Huang X Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors Cancer Cell 2016 30 940 952 10.1016/j.ccell.2016.11.006 27960087 PMC5161231 Huang, X. et al. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell 30 , 940–952 (2016). 27960087 10.1016/j.ccell.2016.11.006 PMC5161231

491. Xie Y Down-regulating Nrf2 by tangeretin reverses multiple drug resistance to both chemotherapy and EGFR tyrosine kinase inhibitors in lung cancer Pharmacol. Res. 2022 186 106514 10.1016/j.phrs.2022.106514 36252771 Xie, Y. et al. Down-regulating Nrf2 by tangeretin reverses multiple drug resistance to both chemotherapy and EGFR tyrosine kinase inhibitors in lung cancer. Pharmacol. Res. 186 , 106514 (2022). 36252771 10.1016/j.phrs.2022.106514

492. Tao W Enhanced ROS-Boosted Phototherapy against Pancreatic Cancer via Nrf2-Mediated Stress-Defense Pathway Suppression and Ferroptosis Induction ACS Appl. Mater. Interfaces 2022 14 6404 64166 10.1021/acsami.1c22861 35077153 Tao, W. et al. Enhanced ROS-Boosted Phototherapy against Pancreatic Cancer via Nrf2-Mediated Stress-Defense Pathway Suppression and Ferroptosis Induction. ACS Appl. Mater. Interfaces 14 , 6404–64166 (2022). 35077153 10.1021/acsami.1c22861

493. Hong T PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer Redox Biol. 2021 42 101928 10.1016/j.redox.2021.101928 33722571 PMC8113041 Hong, T. et al. PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer. Redox Biol. 42 , 101928 (2021). 33722571 10.1016/j.redox.2021.101928 PMC8113041

494. Tai Y MOF@COF Nanocapsules Enhance Soft Tissue Sarcoma Treatment: Synergistic Effects of Photodynamic Therapy and PARP Inhibition on Tumor Growth Suppression and Immune Response Activation Adv. Healthc. Mater. 2024 13 2303911 10.1002/adhm.202303911 38215731 Tai, Y. et al. MOF@COF Nanocapsules Enhance Soft Tissue Sarcoma Treatment: Synergistic Effects of Photodynamic Therapy and PARP Inhibition on Tumor Growth Suppression and Immune Response Activation. Adv. Healthc. Mater. 13 , 2303911 (2024). 10.1002/adhm.202303911 38215731

495. Amos A Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition BMC Cancer 2023 23 117 10.1186/s12885-022-10465-y 36737723 PMC9896811 Amos, A. et al. Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition. BMC Cancer 23 , 117 (2023). 36737723 10.1186/s12885-022-10465-y PMC9896811

496. Zhan Y Berbamine Hydrochloride inhibits lysosomal acidification by activating Nox2 to potentiate chemotherapy-induced apoptosis via the ROS-MAPK pathway in human lung carcinoma cells Cell Biol. Toxicol. 2023 39 1297 1317 10.1007/s10565-022-09756-8 36070022 Zhan, Y. et al. Berbamine Hydrochloride inhibits lysosomal acidification by activating Nox2 to potentiate chemotherapy-induced apoptosis via the ROS-MAPK pathway in human lung carcinoma cells. Cell Biol. Toxicol. 39 , 1297–1317 (2023). 36070022 10.1007/s10565-022-09756-8

497. Zuo W Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy Acta Biomater 2020 111 327 340 10.1016/j.actbio.2020.04.052 32434075 Zuo, W. et al. Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy. Acta Biomater 111 , 327–340 (2020). 32434075 10.1016/j.actbio.2020.04.052

498. Wu T Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer J. Ethnopharmacol. 2025 336 118754 10.1016/j.jep.2024.118754 39208999 Wu, T. et al. Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer. J. Ethnopharmacol. 336 , 118754 (2025). 39208999 10.1016/j.jep.2024.118754

499. Chen J Cell Membrane-Targeting Type I/II Photodynamic Therapy Combination with FSP1 Inhibition for Ferroptosis-Enhanced Photodynamic Immunotherapy Adv. Healthc. Mater. 2024 13 2304436 10.1002/adhm.202304436 38335308 Chen, J. et al. Cell Membrane-Targeting Type I/II Photodynamic Therapy Combination with FSP1 Inhibition for Ferroptosis-Enhanced Photodynamic Immunotherapy. Adv. Healthc. Mater. 13 , 2304436 (2024). 10.1002/adhm.202304436 38335308

500. Song J Cheng M Xie Y Li K Zang X Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug J. Nanobiotechnol. 2023 21 93 10.1186/s12951-023-01842-1 PMC10018933 36927803 Song, J., Cheng, M., Xie, Y., Li, K. & Zang, X. Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug. J. Nanobiotechnol. 21 , 93 (2023). 10.1186/s12951-023-01842-1 PMC10018933 36927803

501. Benbelkacem M Moulai N Chader H Ouahioune W Bourouba M Dichloroacetate and chloroquine in combination with arsenite suppress ROS-induced oral squamous cell carcinoma (OSCC) development and improve BALB/c mice survival Free Radic. Biol. Med. 2025 227 593 607 10.1016/j.freeradbiomed.2024.12.035 39694118 Benbelkacem, M., Moulai, N., Chader, H., Ouahioune, W. & Bourouba, M. Dichloroacetate and chloroquine in combination with arsenite suppress ROS-induced oral squamous cell carcinoma (OSCC) development and improve BALB/c mice survival. Free Radic. Biol. Med. 227 , 593–607 (2025). 39694118 10.1016/j.freeradbiomed.2024.12.035

502. Adeshakin AO Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy Cell. Immunol. 2021 362 104286 10.1016/j.cellimm.2021.104286 33524739 Adeshakin, A. O. et al. Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy. Cell. Immunol. 362 , 104286 (2021). 33524739 10.1016/j.cellimm.2021.104286

503. Saghatelyan T Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial Phytomedicine 2020 70 153218 10.1016/j.phymed.2020.153218 32335356 Saghatelyan, T. et al. Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine 70 , 153218 (2020). 32335356 10.1016/j.phymed.2020.153218

504. Lilly MB A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients Clin. Transl. Med. 2024 14 e1627 10.1002/ctm2.1627 38515274 PMC10958125 Lilly, M. B. et al. A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients. Clin. Transl. Med. 14 , e1627 (2024). 38515274 10.1002/ctm2.1627 PMC10958125

505. Rungratanawanich W Qu Y Wang X Essa MM Song BJ Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury Exp. Mol. Med. 2021 53 168 188 10.1038/s12276-021-00561-7 33568752 PMC8080618 Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M. & Song, B. J. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp. Mol. Med. 53 , 168–188 (2021). 33568752 10.1038/s12276-021-00561-7 PMC8080618

506. Kehm R Baldensperger T Raupbach J Höhn A Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases Redox Biol. 2021 42 101901 10.1016/j.redox.2021.101901 33744200 PMC8113053 Kehm, R., Baldensperger, T., Raupbach, J. & Höhn, A. Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases. Redox Biol. 42 , 101901 (2021). 33744200 10.1016/j.redox.2021.101901 PMC8113053

507. Shah D Mahajan N Sah S Nath SK Paudyal B Oxidative stress and its biomarkers in systemic lupus erythematosus J. Biomed. Sci. 2014 21 23 10.1186/1423-0127-21-23 24636579 PMC3995422 Shah, D., Mahajan, N., Sah, S., Nath, S. K. & Paudyal, B. Oxidative stress and its biomarkers in systemic lupus erythematosus. J. Biomed. Sci. 21 , 23 (2014). 24636579 10.1186/1423-0127-21-23 PMC3995422

508. Hahm JY Park J Jang ES Chi SW 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification Exp. Mol. Med. 2022 54 1626 1642 10.1038/s12276-022-00822-z 36266447 PMC9636213 Hahm, J. Y., Park, J., Jang, E. S. & Chi, S. W. 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification. Exp. Mol. Med. 54 , 1626–1642 (2022). 36266447 10.1038/s12276-022-00822-z PMC9636213

509. Giustarini D Santucci A Bartolini D Galli F Rossi R The age-dependent decline of the extracellular thiol-disulfide balance and its role in SARS-CoV-2 infection Redox Biol. 2021 41 101902 10.1016/j.redox.2021.101902 33662873 PMC7889000 Giustarini, D., Santucci, A., Bartolini, D., Galli, F. & Rossi, R. The age-dependent decline of the extracellular thiol-disulfide balance and its role in SARS-CoV-2 infection. Redox Biol. 41 , 101902 (2021). 33662873 10.1016/j.redox.2021.101902 PMC7889000

510. Sezgin B Thiol-disulfide status of patients with cervical cancer J. Obstet. Gynaecol. Res. 2020 46 2423 2429 10.1111/jog.14480 32909381 Sezgin, B. et al. Thiol-disulfide status of patients with cervical cancer. J. Obstet. Gynaecol. Res. 46 , 2423–2429 (2020). 32909381 10.1111/jog.14480

511. Ramazi S Daddzadi M Sahafnejad Z Allahverdi A Epigenetic regulation in lung cancer MedComm 2023 4 e401 10.1002/mco2.401 37901797 PMC10600507 Ramazi, S., Daddzadi, M., Sahafnejad, Z. & Allahverdi, A. Epigenetic regulation in lung cancer. MedComm 4 , e401 (2023). 37901797 10.1002/mco2.401 PMC10600507

512. Chen L-L Kim VN Small and long non-coding RNAs: past, present, and future Cell 2024 187 6451 6485 10.1016/j.cell.2024.10.024 39547208 Chen, L.-L. & Kim, V. N. Small and long non-coding RNAs: past, present, and future. Cell 187 , 6451–6485 (2024). 39547208 10.1016/j.cell.2024.10.024

513. Morin Coulombe A North American patterns of care in clinical stage I testicular cancer from SWOG S1823 J. Clin. Oncol. 2024 42 509 10.1200/JCO.2024.42.4_suppl.509 Morin Coulombe, A. et al. North American patterns of care in clinical stage I testicular cancer from SWOG S1823. J. Clin. Oncol. 42 , 509 (2024).

514. Kara G Calin GA Ozpolat B RNAi-based therapeutics and tumor targeted delivery in cancer Adv. Drug Deliv. Rev. 2022 182 114113 10.1016/j.addr.2022.114113 35063535 Kara, G., Calin, G. A. & Ozpolat, B. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv. Drug Deliv. Rev. 182 , 114113 (2022). 35063535 10.1016/j.addr.2022.114113

515. Liu L Zhang Y Lu J The roles of long noncoding RNAs in breast cancer metastasis Cell Death Dis. 2020 11 749 10.1038/s41419-020-02954-4 32929060 PMC7490374 Liu, L., Zhang, Y. & Lu, J. The roles of long noncoding RNAs in breast cancer metastasis. Cell Death Dis. 11 , 749 (2020). 32929060 10.1038/s41419-020-02954-4 PMC7490374

516. Dhawan MS Phase 1 study of ANDES-1537: A novel antisense oligonucleotide against non-coding mitochondrial DNA in advanced solid tumors J. Clin. Oncol. 2018 36 2557 2557 10.1200/JCO.2018.36.15_suppl.2557 Dhawan, M. S. et al. Phase 1 study of ANDES-1537: A novel antisense oligonucleotide against non-coding mitochondrial DNA in advanced solid tumors. J. Clin. Oncol. 36 , 2557–2557 (2018).29945518

517. Van Zandwijk N Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study Lancet Oncol. 2017 18 1386 1396 10.1016/S1470-2045(17)30621-6 28870611 Van Zandwijk, N. et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 18 , 1386–1396 (2017). 28870611 10.1016/S1470-2045(17)30621-6

518. Wang J Yi J Cancer cell killing via ROS: To increase or decrease, that is a question Cancer Biol. Ther. 2008 7 1875 1884 10.4161/cbt.7.12.7067 18981733 Wang, J. & Yi, J. Cancer cell killing via ROS: To increase or decrease, that is a question. Cancer Biol. Ther. 7 , 1875–1884 (2008). 18981733 10.4161/cbt.7.12.7067

519. Cipriano A NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors J. Med. Chem. 2023 66 11632 11655 10.1021/acs.jmedchem.3c00770 37650225 PMC10510401 Cipriano, A. et al. NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors. J. Med. Chem. 66 , 11632–11655 (2023). 37650225 10.1021/acs.jmedchem.3c00770 PMC10510401

520. Gong S Wang S Shao M NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy Front. Cell Dev. Biol. 2022 10 884412 10.3389/fcell.2022.884412 35646942 PMC9130727 Gong, S., Wang, S. & Shao, M. NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy. Front. Cell Dev. Biol. 10 , 884412 (2022). 35646942 10.3389/fcell.2022.884412 PMC9130727

521. Li J Tumor-Specific GPX4 Degradation Enhances Ferroptosis-Initiated Antitumor Immune Response in Mouse Models of Pancreatic Cancer Sci. Transl. Med. 2023 15 eadg3049 10.1126/scitranslmed.adg3049 37910602 Li, J. et al. Tumor-Specific GPX4 Degradation Enhances Ferroptosis-Initiated Antitumor Immune Response in Mouse Models of Pancreatic Cancer. Sci. Transl. Med. 15 , eadg3049 (2023). 37910602 10.1126/scitranslmed.adg3049

522. Larrauri-Rodríguez KA Leon-Chavez BA Vallejo-Ruiz V Peña LMP Maycotte P Interplay between reactive oxygen species and ERK activation in cervical cancer cells Front. Cell Dev. Biol. 2024 12 1465729 10.3389/fcell.2024.1465729 39629272 PMC11611811 Larrauri-Rodríguez, K. A., Leon-Chavez, B. A., Vallejo-Ruiz, V., Peña, L. M. P. & Maycotte, P. Interplay between reactive oxygen species and ERK activation in cervical cancer cells. Front. Cell Dev. Biol. 12 , 1465729 (2024). 39629272 10.3389/fcell.2024.1465729 PMC11611811

523. Luobin L Nanomedicine-induced programmed cell death in cancer therapy: mechanisms and perspectives Cell Death Discov. 2024 10 386 10.1038/s41420-024-02121-0 39209834 PMC11362291 Luobin, L. et al. Nanomedicine-induced programmed cell death in cancer therapy: mechanisms and perspectives. Cell Death Discov. 10 , 386 (2024). 39209834 10.1038/s41420-024-02121-0 PMC11362291

524. Mendoza EN Ciriolo MR Ciccarone F Hypoxia-Induced Reactive Oxygen Species: Their Role in Cancer Resistance and Emerging Therapies to Overcome It Antioxidants 2025 14 94 10.3390/antiox14010094 39857427 PMC11762716 Mendoza, E. N., Ciriolo, M. R. & Ciccarone, F. Hypoxia-Induced Reactive Oxygen Species: Their Role in Cancer Resistance and Emerging Therapies to Overcome It. Antioxidants 14 , 94 (2025). 39857427 10.3390/antiox14010094 PMC11762716

525. Griendling KK Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system Circ. Res. 2016 119 e39 e75 10.1161/RES.0000000000000110 27418630 PMC5446086 Griendling, K. K. et al. Measurement of reactive oxygen species, reactive nitrogen species, and redox-dependent signaling in the cardiovascular system. Circ. Res. 119 , e39–e75 (2016). 27418630 10.1161/RES.0000000000000110 PMC5446086

526. Sutton TR A robust and versatile mass spectrometry platform for comprehensive assessment of the thiol redox metabolome Redox Biol. 2018 16 359 380 10.1016/j.redox.2018.02.012 29627744 PMC5953223 Sutton, T. R. et al. A robust and versatile mass spectrometry platform for comprehensive assessment of the thiol redox metabolome. Redox Biol. 16 , 359–380 (2018). 29627744 10.1016/j.redox.2018.02.012 PMC5953223