Research progress on ferroptosis in drug resistance and therapy of gastric cancer

Abstract

Aim

The clinical management of gastric cancer (GC) is frequently challenged by the development of drug resistance, leading to poor patient outcomes. This review aims to explore the role of ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, in overcoming this therapeutic hurdle. Our objective is to provide a theoretical foundation for developing novel strategies to reverse drug resistance in GC by targeting the ferroptosis pathway.

Methods

This review systematically elucidates the core regulatory mechanisms of ferroptosis and analyzes its key role in mediating drug resistance in GC. We synthesize current literature to explore potential therapeutic strategies that leverage ferroptosis induction to sensitize cancer cells. Furthermore, we critically examine the complex interplay between ferroptosis and the tumor microenvironment (TME) and discuss the challenges associated with translating these findings into personalized treatment approaches, integrating insights from emerging technologies.

Results

Our analysis confirms that ferroptosis is governed by a precise regulatory network involving glutathione metabolism, lipid peroxidation, and iron homeostasis, which is frequently dysregulated in GC. We identify that key mechanisms of conventional drug resistance are linked to the evasion of ferroptosis. Consequently, several potential therapeutic strategies, including the use of ferroptosis inducers (FINs) and combination therapies, show promise in resensitizing resistant GC cells. The review also highlights the dual role of the TME, which can either suppress or promote ferroptosis, adding a layer of complexity. Finally, we identify significant challenges in patient stratification and the need for reliable biomarkers to achieve personalized ferroptosis-based therapies.

Conclusion

Targeting ferroptosis presents a promising and innovative research avenue for reversing drug resistance in gastric cancer. Strategies designed to induce ferroptosis effectively overcome common resistance mechanisms and hold significant therapeutic potential. Future research must focus on integrating multi-omics technologies and advanced drug delivery systems to decipher the complex regulatory networks of ferroptosis within the TME and to develop biomarkers for personalized treatment, thereby paving the way for improved clinical outcomes.

Introduction

GC is a common malignant tumor of the digestive system, ranking as the fifth most frequently diagnosed cancer worldwide ((Park et al. 2016) and the third leading cause of cancer-related deaths ((Smyth et al. 2020). Although current treatment strategies—including surgery, chemotherapy, and targeted therapy—have achieved certain clinical benefits, drug resistance remains a major obstacle that severely compromises therapeutic efficacy ((Che et al. 2024). In recent years, ferroptosis, a novel form of regulated cell death, has been increasingly recognized to be closely associated with tumorigenesis, progression, and drug resistance ((Zhu et al. 2023). It is an iron-dependent programmed cell death process characterized by the accumulation of lipid peroxides, primarily driven by intracellular iron overload, lipid peroxidation, and impaired antioxidant defense mechanisms ((Zhang et al. 2022).

Unlike apoptosis, necrosis, or autophagy, ferroptosis is initiated through the inhibition of the cystine/glutamate antiporter system (system Xc⁻) by oncogenic signals such as RAS or by small molecules like erastin (Dixon et al. 2012). This leads to depletion of glutathione (GSH), which in turn attenuates the reducing capacity of glutathione peroxidase 4 (GPX4), resulting in redox imbalance and massive accumulation of reactive oxygen species (ROS) (Li et al. 2024a, b, c). This process is often accompanied by mitochondrial dysfunction, which amplifies Fenton reaction-derived ROS, ultimately compromising membrane integrity (Zeng et al. 2023). Key regulatory pathways, including the inactivation of nuclear factor erythroid 2-related factor 2 (NRF2) or degradation of GPX4, further exacerbate this cascade of oxidative stress (Li et al. 2025).

In various pathological models—such as skin injury, liver fibrosis, and myocardial injury—the interplay between ferroptosis and oxidative stress has been extensively documented ((Ishikawa et al. 2024). Intervention strategies targeting GPX4, mitochondrial ROS (MtROS), or the NRF2 pathway have demonstrated potential therapeutic value ((Yang et al. 2024).Therefore, the essence of ferroptosis lies in the synergistic effect of oxidative stress and iron-dependent lipid peroxidation. Targeting its core mechanisms not only provides novel insights into tumor drug resistance but also points toward new directions for developing innovative anticancer therapies.

Fig.1.

Simplified Regulatory Network of Ferroptosis in Gastric Cancer Drug Resistance AUpstream Regulatory Network: Baicalin and Dioscin activate p53 to transcriptionally suppress SLC7A11 and promote GPX4 degradation. The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) upregulates SLC7A11 and GPX4. The metabolic enzyme AGPS reprograms lipid metabolism, reducing the levels of easily peroxidized PUFA-PL, thereby inhibiting ferroptosisB.Core Execution of Ferroptosis: The collapse of this axis leads to the irreversible accumulation of lipid hydroperoxides (L-OOH). The buildup of lethal lipid peroxides directly triggers oxidative damage to the cell membrane, resulting in ferroptotic cell death.(C).Functional Outcome: Inducing ferroptosis effectively reverses resistance to conventional therapies (such as chemotherapy and targeted therapy), offering a promising combination treatment strategy.Arrows (→) indicate activation or promotion; blunt-end lines (┴) indicate inhibition

The relationship between ferroptosis and GC

Regulatory mechanisms of ferroptosis in GC cells

The manifestation of ferroptosis in GC cells is primarily characterized by its regulation through multiple molecular mechanisms and its susceptibility to targeted induction, thereby inhibiting GC progression and reversing chemotherapy resistance. Core regulatory factors include the downregulation of GPX4 and solute carrier family 7 member 11 (SLC7A11) ((Chen et al. 2024).

For instance, levobupivacine upregulates the expression of miR-489-3p, which specifically recognizes and binds to the 3’ untranslated region (3’ UTR) of SLC7A11 mRNA, thereby inhibiting SLC7A11 expression. This disrupts cystine uptake and GSH synthesis within GC cells, ultimately interfering with cellular redox homeostasis and inhibiting tumor growth ((Mao et al. 2021). This reveals a novel target through which levobupivacine influences the ferroptosis pathway via miRNA-mediated gene silencing ((Mao et al. 2021). Diosgenin, on one hand, downregulates SLC7A11 expression, impeding cystine uptake and inhibiting GSH biosynthesis ((Xie et al. 2025); on the other hand, it directly inhibits GPX4 activity, leading to the collapse of the antioxidant capacity in GC cells ((Sugezawa et al. 2022). Under their synergistic action, intracellular ROS persistently accumulate and attack polyunsaturated fatty acids, triggering substantial deposition of lipid peroxides ((Lu et al. 2025).

Within the transcription factor network, overexpression of POLE2 degrades KEAP1 protein, relieving its inhibitory effect on NRF2. This promotes NRF2 nuclear translocation and activates its transcriptional activity ((Kobayashi et al. 2006), consequently specifically upregulating GPX4 gene expression. This accelerates the reductive clearance of intracellular lipid peroxides and effectively blocks the oxidative damage chain reaction of polyunsaturated fatty acids ((Jian et al. 2024). This mechanism establishes a crucial link between DNA damage repair and oxidative stress defense, offering a novel molecular target for addressing radio- and chemotherapy resistance in GC ((Du et al. 2012).

STAT3 enhances GPX4 activity, upregulates SLC7A11, and promotes FTH1 expression, synergistically blocking ferroptosis (Jiang et al. 2024). Its inhibitor, W1131, by inhibiting STAT3 Tyr705 phosphorylation and nuclear translocation, causes the collapse of this regulatory axis, thereby reversing chemotherapy resistance (Ouyang et al. 2022a, b).

Wild-type p53 directly binds to the OTUD5 gene promoter and inhibits its transcription, leading to a loss of OTUD5 protein expression. This subsequently removes the deubiquitinating protective effect of OTUD5 on GPX4 ((Zhang et al. 2025). Under OTUD5 depletion conditions, the E3 ubiquitin ligase TRIM25 specifically recognizes GPX4 and catalyzes its Lys48-linked ubiquitination modification, promoting GPX4 degradation via the 26 S proteasome pathway. This ultimately leads to the collapse of lipid peroxide clearance capacity, oxidative damage to mitochondrial membranes, and ferroptosis activation in GC cells ((Zhang et al. 2025).

Furthermore, ferroptosis in GC cells can be cooperatively induced through multiple pathways: deficiency of the mitochondrial regulatory protein STX1A causes dysfunction of mitochondrial respiratory chain complex I, leading to superoxide (O₂•⁻) accumulation and its conversion into cytotoxic hydroxyl radicals (•OH), directly triggering lipid peroxidation and ferroptosis ((Niu et al. 2025); Tanshinone I activates the histone demethylase KDM4D to remove the repressive H3K9me3 mark on the p53 promoter region, enhancing wild-type p53 transcriptional activity. This, in turn, dually downregulates GPX4 and SLC7A11, disrupting redox homeostasis ((Xia et al. 2023); Propofol upregulates miR-125b-5p to target and inhibit STAT3 mRNA translation, blocking the STAT3-GPX4/SLC7A11/FTH1 antioxidant axis ((Liu et al. 2021), significantly enhancing the sensitivity of GC cells to ferroptosis. These three mechanisms, involving organelle functional regulation, epigenetic reprogramming, and post-transcriptional silencing respectively, form a multi-cascade intervention network. They collectively promote lipid peroxidation burst and mitochondrial membrane collapse, providing a synergistic targeting strategy to overcome cisplatin resistance in GC.

In the clinical treatment of GC, resistance to apatinib is closely associated with alkylglycerol phosphate synthase (AGPS)-mediated ether phospholipid metabolic reprogramming ((Wang et al. 2025a, b): resistant tumor cells significantly downregulate AGPS expression, catalyzing the conversion of lysophosphatidic acid (LPA) into protective ether phospholipids. This leads to reduced synthesis of polyunsaturated fatty acid phospholipids (PUFA-PLs), thereby weakening the key substrate supply for lipid peroxidation. Concurrently, ether phospholipids form a dual defensive barrier by scavenging free radicals and enhancing membrane antioxidant stability, ultimately conferring ferroptosis tolerance upon tumor cells.

Fig.2.

Multi-layer Molecular Regulatory Mechanisms and Targeting Strategies of Ferroptosis in Gastric Cancer A Pharmacological Targeting of SLC7A11 and GPX4:Levobupivacaine upregulates miR-489-3p, which binds to the 3'UTR of the solute carrier SLC7A11 mRNA, leading to its silencing. This disrupts cystine uptake and GSH synthesis .Dioscin dually inhibits the expression of SLC7A11 and the activity of GPX4, resulting in the collapse of the cellular antioxidant defense system .BTranscriptional Regulation of Ferroptosis:a. NRF2 Activation Axis: Overexpression of DNA polymerase epsilon catalytic subunit POLE2 degrades KEAP1, releasing NRF2 to translocate into the nucleus. This transcriptionally upregulates GPX4, thereby antagonizing ferroptosis .STAT3 Signaling Axis: Overexpression of STAT3 promotes drug resistance by enhancing GPX4 activity and fostering SLC7A11 expression. Its specific inhibitor, W1131, inhibits STAT3 phosphorylation and nuclear translocation, leading to the collapse of this pathway and induction of ferroptosis .p53-Mediated GPX4 Degradation: Wild-type p53 transcriptionally suppresses OTUD5, which subsequently promotes the degradation of GPX4 via the proteasomal pathway

Expression alterations of Ferroptosis-Related genes in GC

The key ferroptosis-suppressing genes GPX4 and SLC7A11 are commonly overexpressed in gastric cancer samples (Sun et al. 2023), showing positive correlations with tumor progression and chemotherapy resistance, particularly in 5-FU-resistant cells (Zhang et al. 2025). For instance, the iron storage protein FTH1 is upregulated in chemotherapy-resistant models (Ouyang et al. 2022a, b); POLE2 expression is elevated in gastric cancer (Jian et al. 2024); while OTUD5 is upregulated in gastric cancers with p53 mutation or deletion (Zhang et al. 2025). In contrast, the pro-ferroptotic gene ACSL4 is upregulated under tanshinone I induction (Xia et al. 2023). The drug resistance-related gene AGPS shows significant downregulation in apatinib-resistant cells (Wang et al. 2025a, b). Additionally, suppressed expression of miR-489-3p and miR-125b-5p can promote the oncogenic effects of SLC7A11 and STAT3, respectively (Mao et al. 2021). These aberrant gene expression patterns collectively constitute the molecular basis of ferroptosis resistance in gastric cancer, holding potential as novel prognostic biomarkers and therapeutic targets.

Table 1.

Key regulators of ferroptosis, their expression patterns in gastric cancer, and their association with drug resistance

Gene name	Expression change	Functional role	Effect on ferroptosis	Association with drug resistance	References
GPX4	Upregulated in gastric cancer tissues	Suppressor	Inhibits	Positively correlated with resistance to chemotherapy (e.g., 5-FU)	[22], [27]
SLC7A11	Upregulated in gastric cancer tissues	Suppressor	Inhibits	Positively correlated with tumor progression and chemotherapy resistance	[27]
STAT3	Upregulated in drug-resistant cells	Suppressor	Inhibits	Promotes resistance to chemotherapy	[21]
FTH1	Upregulated in chemoresistance models	Suppressor	Inhibits	Contributes to negative regulation and promotes drug resistance	[21]
POLE2	Upregulated in gastric cancer tissues	Suppressor	Inhibits	Promotes drug resistance via activation of the NRF2-GPX4 axis	[18]
OTUD5	Upregulated in p53-mutated/deleted gastric cancer	Suppressor	Inhibits	Promotes drug resistance through stabilization of GPX4 protein	[22]
ACSL4	Upregulated upon tanshinone I induction	Promoter	Promotes	Increases sensitivity to ferroptosis	[24]
AGPS	Downregulated in apatinib-resistant cells	Resistance-related	Inhibits	Confers tolerance to ferroptosis	[26]
miR-489-3p	Downregulated	Promoter	Promotes	Low expression promotes SLC7A11-mediated drug resistance	[13]
miR-125b-5p	Downregulated	Promoter	Promotes	Low expression promotes STAT3-mediated drug resistance	[25]

The association between ferroptosis and GC cell proliferation

Ferroptosis, an iron-dependent form of regulated cell death triggered by the accumulation of lipid peroxidation leading to membrane damage, plays a complex regulatory role in GC (Wang et al. 2024a, b). Studies by Juan Sun et al. indicate that ferroptosis indirectly results in the loss of proliferative capacity by inducing cell death (Sun et al. 2024). In contrast, its inhibition of cell migration and invasion may involve direct pathway interventions independent of its lethal effects. For example, inhibiting the expression of GPX4 can enhance the sensitivity of GC cells to ferroptosis, thereby suppressing cell proliferation and migration (Zhang et al. 2025).

In GC, selenium is incorporated into the active center of GPX4 in the form of selenocysteine, making it an absolute prerequisite for the enzyme’s catalytic activity ((Zhang et al. 2020). Selenium availability and metabolism directly regulate the expression and function of GPX4: insufficient dietary selenium intake or impaired selenium metabolism leads to a decrease in the abundance of selenocysteine tRNA within cells, thereby specifically inhibiting the synthesis of GPX4 at the translational level ((Vinn et al. 2019). This not only reduces GPX4 protein levels but also abolishes its ability to scavenge lipid peroxides, significantly enhancing the sensitivity of GC cells to ferroptosis. Research shows that supplementing with selenium or selenium compounds (e.g., sodium selenite) can effectively upregulate and activate GPX4, strengthening cancer cell resistance to ferroptosis, which constitutes an intrinsic mechanism of chemotherapy resistance ((Weber et al. 2023). Therefore, assessing intratumoral selenium metabolism status and the selenation level of GPX4 is crucial for predicting the efficacy of ferroptosis inducers. Therapeutic strategies targeting the selenium-GPX4 axis, such as developing drugs that inhibit selenium incorporation or using highly specific GPX4 inhibitors, hold promise for overcoming resistance arising from this mechanism, offering new directions for combination therapy in GC.

The induction of ferroptosis is associated with increased intracellular ROS levels and elevated lipid peroxidation, which can lead to cell cycle arrest and apoptosis (Zhang et al. 2024). In GC, cancer cells inhibit ferroptosis by activating defensive mechanisms (Peng et al. 2024). For instance, Cystatin-SN (CST1) binds to both GPX4 and the deubiquitinase OTU Deubiquitinase 1 (OTUB1), enhancing GPX4 protein stability by inhibiting its ubiquitin-mediated degradation. This maintains GPX4-mediated reduction of lipid peroxides and blocks the onset of ferroptosis (Li et al. 2023a, b). Although this process promotes Epithelial-Mesenchymal Transition (EMT) and metastasis, silencing or overexpressing CST1 does not alter the proliferative capacity of GC cells (Liu et al. 2021). Furthermore, the intrinsic “iron addiction” phenomenon makes cancer cells more susceptible to ferroptosis. However, by highly expressing defensive proteins such as SLC7A11 and GPX4, which enhance glutathione synthesis capacity and antioxidant pathway activity, cancer cells can effectively evade ferroptosis (Stockwell et al. 2017). In GC, the activation of such defense mechanisms, while not directly driving proliferation, supports cancer cell survival in high-ROS environments and indirectly promotes GC progression table 2.

Table 2.

Mechanisms and cellular impacts of ferroptosis and its key regulatory elements in gastric cancer

Core element	Mechanism of action	Impact on gastric cancer cells	References
Ferroptosis	An iron-dependent form of regulated cell death triggered by accumulation of lipid peroxides, leading to membrane damage.	Primarily enhances cell migration and invasion capabilities without directly regulating proliferation.	[28], [29]
GPX4 Inhibition	Increases cellular susceptibility to ferroptosis.	Suppresses both cell proliferation and migration.	[22]
ROS & Lipid Peroxidation	Induction of ferroptosis elevates intracellular ROS levels and promotes lipid peroxidation.	lipid peroxidation.Induces cell cycle arrest and apoptosis.	[33]
CST1	Binds to GPX4 and deubiquitinase OTUB1, enhances GPX4 protein stability and inhibits its ubiquitin-mediated degradation, thereby blocking ferroptosis.	Promotes epithelial-mesenchymal transition (EMT) and metastasis, but does not alter proliferative capacity.	[35]
“Iron Addiction"	An intrinsic characteristic of cancer cells that increases their sensitivity to ferroptosis.	Provides a theoretical basis for therapeutically targeting ferroptosis.	[36]
SLC7A11/GPX4 Overexpression	Constitutes a core defense mechanism against ferroptosis; enhances glutathione synthesis and antioxidant pathway activity.	Facilitates evasion of ferroptosis, supports survival in high-ROS environments, and indirectly promotes tumor progression.	[36]

Current understanding of drug resistance mechanisms in GC

Major mechanisms of drug resistance in GC

The mechanisms of drug resistance in gastric cancer primarily involve enhanced drug efflux, activation of DNA damage repair, evasion of apoptosis, epigenetic regulation, and cancer stemness ((Khaleel et al. 2024). The overexpression of drug efflux systems such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) reduces intracellular concentrations of chemotherapeutic agents—including cisplatin and 5-fluorouracil—by ATP-dependent transmembrane transport ((Szakács et al. 2006).

Upregulation of DNA repair pathways represents another critical mechanism: overexpression of excision repair cross-complementation group 1 (ERCC1) enhances nucleotide excision repair capacity, directly counteracting platinum-induced DNA crosslink damage ((Gossage and Madhusudan 2007). Additionally, activation of anti-apoptotic pathways—such as upregulation of Bcl-2/Bcl-xL and mutation of p53—blocks therapy-induced cell death ((Li et al. 2018).

Recent studies have highlighted the significant role of epigenetic reprogramming in driving drug resistance. ALKBH5-mediated m⁶A demethylation upregulates the transcription factor FOXM1, which promotes expression of the homologous recombination repair (HRR) gene BRCA1 and accelerates the repair of cisplatin-induced DNA damage ((Hao et al. 2021).

The FOXO transcription factor family, particularly FOXO1, emerges as a pivotal regulator of ferroptosis, interfacing with core oxidative stress response pathways to determine cell fate. Recent evidence demonstrates that FOXO1 can transcriptionally upregulate heme oxygenase-1 (HO-1), thereby increasing labile iron pools and sensitizing gastric cancer cells to ferroptosis by amplifying iron-dependent lipid peroxidation ((Ebrahimnezhad et al. 2024). This pro-ferroptotic role is integrated within a broader network: FOXO1 engages in cross-talk with the p53 axis, where they can cooperatively repress the expression of cytoprotective genes like SLC7A11, and it antagonizes the NRF2-mediated antioxidant program, disrupting the NRF2-GPX4 axis to shift the cellular balance toward ferroptotic death. Elucidating this FOXO1-centric network not only refines the mechanistic understanding of ferroptotic regulation but also reveals a promising therapeutic avenue to overcome chemoresistance in gastric cancer by co-opting FOXO1 activation to synergize with conventional agents.

Furthermore, cancer stem cells (CSCs) are considered a key factor in gastric cancer resistance. Capable of self-renewal and multilineage differentiation, CSCs can survive chemotherapy and contribute to tumor recurrence (Li et al. 2024a, b, c). They drive therapeutic resistance through stemness maintenance, metabolic remodeling, and enhanced DNA repair (Otaegi-Ugartemendia et al. 2022). CSCs highly express stemness markers (e.g., CD44, ALDH1) and drug-resistance proteins such as ABCG2, which reduce intracellular drug accumulation (Ramović HamzagiĆ et al. 2024). Sustained activation of Notch and Hedgehog signaling pathways promotes CSC self-renewal and induces EMT, further facilitating metastasis and drug-resistant phenotypes (Martins-Neves et al. 2023). Metabolic reprogramming in CSCs enhances oxidative phosphorylation and autophagy activity, enabling clearance of chemotherapy-induced ROS and maintenance of glutathione homeostasis, thereby conferring resistance to platinum-based drugs (Wang et al. 2025a, b).

Fig.3.

Key Mechanisms of Drug Resistance in Gastric Cancer A Enhanced Drug Efflux:Overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), actively pumps chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil) out of cancer cells, reducing intracellular drug concentration.BActivation of DNA Damage Repair:Excision Repair Cross-Complementation Group 1 (ERCC1) efficiently reverses platinum drug-induced DNA crosslinks. The transcription factor Forkhead Box M1 (FOXM1) promotes the expression of the homologous recombination repair gene Breast Cancer Gene 1 (BRCA1), thereby accelerating DNA damage repair.C Apoptosis Evasion:This is achieved through the upregulation of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), coupled with the mutational inactivation of the tumor suppressor p53.D Epigenetic Regulation of Ferroptosis:Forkhead Box O1 (FOXO1) transcriptionally activates HO-1, promoting the release of free iron and sensitizing gastric cancer cells to ferroptosis.E CSCs and Metabolic Reprogramming:Stemness markers CD44 and Aldehyde Dehydrogenase 1 (ALDH1) are cornerstones of drug resistance. The resistant phenotype is driven by the activation of developmental pathways such as Notch and Hedgehog.

The potential role of ferroptosis in GC drug resistance mechanisms

The suppression of ferroptosis is a pivotal mechanism underlying tumor drug resistance, which primarily involves the inactivation of the GSH metabolic axis and the enhanced stability of GPX4 core machinery ((Chen et al. 2025). Drug-resistant cells achieve this by upregulating SLC7A11 expression, thereby increasing cystine uptake and promoting GSH synthesis. This subsequently enhances GPX4-mediated clearance of lipid peroxides, ultimately reducing sensitivity to chemotherapeutic drugs ((Hangauer et al. 2017). Specifically, the OTUB1 complex inhibits ferroptosis by stabilizing the GPX4 protein through its deubiquitinating activity, thereby blocking cisplatin-induced ferroptosis and promoting cell survival ((He et al. 2025). Concurrently, mechanisms such as the inhibition of ferritinophagy, downregulation of Transferrin Receptor (TFR) and disruption of Labile Iron Pool metabolism in resistant cells lead to depletion of the free iron pool. This inhibits the Fenton reaction-mediated generation of lipid free radicals, further enabling evasion of ferroptosis fig.4.

Fig.4.

Mechanisms of Ferroptosis Inhibition and Targeted Therapeutic Strategies in Drug-Resistant Gastric Cancer A Reinforcement of the Core Antioxidant Axis:Drug-resistant gastric cancer cells upregulate the cystine/glutamate transporter SLC7A11, enhancing GSH synthesis and boosting the reducing capacity of Glutathione Peroxidase 4 (GPX4) to clear lipid peroxides. The Cystatin-SN (CST1)–OTUB1 complex stabilizes the GPX4 protein via deubiquitination, further protecting cells from cisplatin-induced ferroptosis. Iron metabolism is remodeled through suppressed ferritinophagy and downregulation of the Transferrin Receptor (TFRC), thereby inhibiting Fenton reaction-mediated generation of lipid free radicals. B Transcriptional Regulatory Network:ELK1 promotes apatinib resistance by maintaining low expression of AGPS. As a key negative regulator, STAT3 binds to the promoters of GPX4, SLC7A11, and FTH1, forming a "STAT3-Mediated Ferroptosis Suppression Axis" that confers resistance to 5-fluorouracil (5-FU).

The mechanisms by which ferroptosis contributes to reversing drug resistance in GC involve a network of transcription factors (e.g., ELK1, STAT3, p53), metabolic enzymes (e.g., AGPS), and the influence of natural compounds, collectively forming a targeted network for overcoming GC drug resistance (Wang et al. 2025a, b). Mechanistically, the downregulation of AGPS can mediate tolerance to ferroptosis in GC cells. Its expression is regulated by the transcription factor ELK1. Co-downregulation of both AGPS and ELK1 results in cellular resistance to apatinib (Wang et al. 2025a, b). Furthermore, STAT3, a key negative regulator of ferroptosis, directly binds to the promoter regions of GPX4, SLC7A11, and FTH1, a critical negative regulator of ferroptosis, binds to the promoter regions of GPX4, SLC7A11, and FTH1, thereby forming a “STAT3-Mediated Ferroptosis Suppression Axis” (Ouyang et al. 2022a, b). Inhibition of STAT3 triggers lipid peroxidation and iron accumulation, thereby overcoming 5-FU resistance (Ouyang et al. 2022a, b). Additionally, the glycolytic enzyme 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3) inhibits ferroptosis through dephosphorylation of the S26 site on SLC7A11, leading to cisplatin resistance. Combining ferroptosis inducers with cisplatin can resensitive cells (He et al. 2025). Moreover, supplementation with selenium or selenium compounds effectively upregulates GPX4 activity and enhances ferroptosis resistance, constituting an intrinsic mechanism of chemotherapy resistance (Weber et al. 2023).

Natural active components, such as Baicalin, promote ferroptosis, enhance sensitivity to oxaliplatin (Shao et al. 2024), and inhibit GC progression (Nie et al. 2024). Furthermore, the combination of Baicalin and 5-FU can elevate intracellular ROS levels, augmenting chemotherapy efficacy through ferroptosis induction (Shao et al. 2024). Meanwhile, Pachymic acid induces ferroptosis by inhibiting the Platelet-Derived Growth Factor Receptor Beta (PDGFRB)-Phosphoinositide 3-Kinase (PI3K)/Akt pathway (Liu et al. 2021). Non-coding RNAs, including LINC01134 and DACT3-AS1, impact ferroptosis by modulating the NRF2-GPX4 axis or the miR-181a-5p/Sirtuin 1 (SIRT1) axis, thereby reversing oxaliplatin resistance (Ouyang et al. 2022a, b).

Therapeutic strategies targeting ferroptosis

As of 2025, significant progress has been made in the field of ferroptosis for GC treatment, although all conclusions are based on preclinical models and have not yet entered human trials, rendering their clinical translation uncertain.It should be noted that different preclinical models, such as cell-derived xenograft (CDX), patient-derived xenograft (PDX), and patient-derived organoid (PDO), each have distinct characteristics in simulating the human tumor microenvironment and predicting drug efficacy, making direct comparisons of their efficacy data (e.g., tumor inhibition rate vs. viability inhibition rate) subject to certain limitations.

In GC-specific models, the STAT3 inhibitor W1131, by inhibiting the STAT3-ferroptosis negative regulatory (FNR) axis (whose key downstream targets are GPX4, SLC7A11, and FTH1), significantly induced lipid peroxidation, thereby effectively suppressing tumor growth. This effect was validated in three models: In a CDX model, the tumor inhibition rate reached 65% (n = 8 mice/group, p < 0.001).In PDO models, the viability inhibition rate was 62% (n = 5 patient-derived organoids, p < 0.01).In a PDX model, the tumor inhibition rate was 70% (n = 6 mice/group, p < 0.001) (Ouyang et al. 2022a, b). Although PDX models preserve tumor heterogeneity and the microenvironment and have high clinical predictive value, they are costly and have unstable engraftment success rates.Targeting PFKFB3 in a mouse model of cisplatin-resistant GC cell lines, by blocking its dephosphorylation of the SLC7A11/xCT serine 26 site, combined with cisplatin, resulted in a 50% reduction in tumor volume in the animal model (He et al. 2025).In oxaliplatin-resistant GC cell lines (e.g., HGC27/L), the natural compound wogonin activated the p53 protein (Western blot showed a 2.3-fold increase in expression, n = 3, p < 0.05), which subsequently transcriptionally repressed its downstream targets SLC7A11 and GPX4 (down to 45% and 52% of control, respectively, n = 3, p < 0.05). This mechanism led to a significant increase in intracellular ROS levels (2.1-fold compared to control, n = 6, p < 0.01) and ultimately, by inducing ferroptosis, reduced the IC50 value of oxaliplatin for the resistant cells to 38.7% of monotherapy (n = 6, p < 0.001) (Yuan et al. 2023), thereby enhancing the sensitivity of GC cells to oxaliplatin chemotherapy.In in vitro experiments using GC cell lines (e.g., MKN-45), pachymic acid induced lipid peroxidation by inhibiting the PDGFRB-PI3K/Akt signaling axis, increasing the level of the lipid peroxidation product MDA to 3.2 times that of the control group (n = 3 independent experiments, p < 0.01). In a GC CDX mouse model (n = 8 mice/group), the tumor weight in the pachymic acid treatment group was reduced by 55.6% compared to the control group (p < 0.001) (Nie et al. 2024).In a cisplatin-resistant GC CDX mouse model (n = 10 mice/group), a sand lizard extract combined with cisplatin, by synergistically inhibiting the activation of the NF-κB/Snail and PI3K/AKT signaling pathways (Western blot showed p65 phosphorylation reduced to 42% of control, n = 3, p < 0.01), significantly prolonged mouse survival (median survival extended by 32.5% compared to the cisplatin monotherapy group, p < 0.001) (Cheng et al. 2024).

In combination strategies, the combination of Erastin and cisplatin, by synergistically targeting the SLC7A11 pathway, significantly enhanced the antitumor effect of cisplatin in a subcutaneous tumor mouse model, increasing the in vivo tumor inhibition rate to 81.4% ((He et al. 2025).

However, all these studies remain in the preclinical stage and have not yet entered human clinical trials. Bottlenecks in translation include the risk of systemic toxicity and unclear pharmacokinetic properties, as the targeted drugs may cause damage to normal epithelial tissues. The complex composition of natural products like wogonin and pachymic acid poses challenges for standardized production and quality control (Li et al. 2023a, b). The unique acidic conditions of the gastric TME significantly impact drug stability and delivery efficiency (Zhang et al. 2023). There is still a lack of highly specific inducers for key targets like SLC7A11 and AGPS, making it difficult to advance into clinical trial stages.Therefore, establishing a standardized efficacy reporting system in future research will help more accurately evaluate the therapeutic potential of ferroptosis inducers.

Future research directions

Interaction between ferroptosis and the tumor microenvironment

Close bidirectional interactions exist within the TME: On one hand, the TME regulates ferroptosis through metabolic reprogramming and immune factors—lactic acid accumulation in the microenvironment inhibits GSH synthesis and GPX4 activity, promoting ferroptosis resistance (Li et al. 2024a, b, c).Hypoxia upregulates TFRC and suppresses ferroportin, leading to iron accumulation and enhanced ferroptosis sensitivity (Li et al. 2024a, b, c) .Meanwhile, IL-6 secreted by TAMs upregulates FTH1 via the STAT3 signaling pathway, reducing free iron and inhibiting ferroptosis (Guo et al. 2025). On the other hand, ferroptosis remodels the immune function of the TME: ferroptosis-induced immunogenic cell death releases HMGB1 and calreticulin, promoting dendritic cell maturation and antigen presentation (Zhao et al. 2023) .Clinical data indicate that a high ferroptosis score correlates with an immune-activated phenotype—such as increased CD8⁺ T cell infiltration and reduced MDSCs and TAMs—improving the immunosuppressive microenvironment in nasopharyngeal carcinoma and head and neck squamous cell carcinoma (Zhao et al. 2023).However, lipid peroxides generated during ferroptosis may also impair CD8⁺ T cell function, leading to immune escape (Zhai et al. 2024).

Notably, ferroptosis-mediated modulation of TME plays a pivotal role in immunotherapy resistance in gastric cancer. According to Mohammad et al. ((Xia et al. 2022), ferroptosis directly influences the efficacy of immune checkpoint inhibitors (ICIs) by remodeling the immune microenvironment in gastric cancer. Specifically, inducing ferroptosis significantly reduces the infiltration of immunosuppressive cells (such as TAMs and MDSCs) while enhancing the activity and cytotoxicity of CD8⁺ T cells, thereby reversing ICI resistance. The study further demonstrated that combining targeted inhibition of key ferroptosis pathways (e.g., GPX4 or system Xc⁻) with anti-PD-1/PD-L1 therapy could effectively overcome immunotherapy resistance in gastric cancer through synergistic activation of antitumor immune responses.

This interaction holds significant clinical implications: tumors with low ferroptosis scores, such as bladder cancer, often exhibit Wnt/NF-κB pathway activation and Treg infiltration, resulting in resistance to PD-1 inhibitors ((Xia et al. 2022) .Combining the GPX4 inhibitor RSL3 with PD-L1 blockade can overcome this resistance by enhancing ferroptosis, with preclinical studies showing significantly improved immunotherapy efficacy ((Zhai et al. 2024). Mohammad et al. confirmed that targeting the SLC7A11-GPX4 axis to induce ferroptosis synergizes markedly with anti-PD-L1 therapy, effectively reversing immunotherapy resistance ((Ebrahimnezhad et al. 2025). This synergistic mechanism arises because ferroptosis not only directly kills tumor cells but also improves the immune microenvironment by eliminating immunosuppressive cells and restoring CD8⁺ T cell function. Therefore, combining GPX4 inhibitors or system Xc⁻ blockers with PD-1/PD-L1 blockade represents a forward-looking strategy for gastric cancer treatment. Future efforts should focus on developing combined strategies targeting iron metabolism—such as iron chelators combined with immunotherapy—and utilizing ferroptosis scoring models to precisely identify patient populations likely to benefit from treatment.

Insights from other cancers

Multiple studies on other solid tumors have revealed multidimensional insights into the interaction between ferroptosis and the TIME, offering potential hypotheses for therapeutic strategies in GC. In nasopharyngeal carcinoma (Liu et al. 2022), the FEP score, based on ferroptosis-related genes, significantly correlates with CD8⁺ T cell infiltration density and EBV infection status, suggesting its potential as a biomarker for predicting the efficacy of ICIs.Patients with high FEP scores showed an overall survival benefit rate of ≥ 35%. Research on bladder cancer highlights the therapeutic heterogeneity of the ferroptosis score (Xia et al. 2022): high-score tumors exhibit increased sensitivity to cisplatin, whereas low-score tumors, due to their immunosuppressive microenvironment, may be more suitable for PD-1 blockade therapy, with the objective response rate potentially increasing by 2.1-fold. In HNSCC models (Zhao et al. 2023), RSL3-induced ferroptosis led to a 2.3-fold increase in CD8⁺ T cell numbers, but lipid peroxides (e.g., 4-HNE) simultaneously impaired their cytotoxic function, underscoring the dual immunomodulatory role of ferroptosis in solid tumors. To address this, microenvironment intervention strategies from glioma (Wang et al. 2022) and lung cancer (Wang et al. 2024a, b) studies can be referenced—for example, targeting System Xc⁻ to deplete glutathione and reverse T cell function inhibition, or combining HIF-2α inhibitors with pH-responsive nanocarriers (which can reduce systemic toxicity by up to 50%) to overcome hypoxia-mediated treatment resistance. These cross-cancer findings provide important insights for GC research, but their clinical applicability requires further validation in GC-specific models.

Current status and potential directions of ferroptosis research in GC

EBV-positive GC can leverage the FEP score to predict PD-1 inhibitor resistance by quantifying immune microenvironment features, such as CD8⁺ T cell infiltration and EBV gene expression ((Lei et al. 2023). Low ferroptosis score tumors exhibit treatment resistance due to NF-κB pathway activation and an immunosuppressive microenvironment ((Liu et al. 2022). Chemosensitization mechanisms resemble those in bladder cancer studies: the ferroptosis inducer RSL3 enhances the efficacy of DNA-damaging agents like cisplatin by promoting lipid peroxidation, but caution is needed to avoid ferroptosis escape via FTH1 upregulation or IL-6/STAT3 pathway activation ((Xia et al. 2022). Additionally, immune microenvironment remodeling can draw from HNSCC strategies: combining GPX4 inhibitors with immunotherapy reverses MDSC/M2-TAM-mediated immunosuppression by releasing HMGB1 and calreticulin, but ferroptosis intensity must be controlled to prevent lipid peroxide-induced impairment of CD8⁺ T cell function ((Zhai et al. 2024). Future targeted therapies for GC should incorporate tumor-specific delivery systems, such as pH-responsive nanocarriers tailored to the gastric acidic microenvironment, and dynamic monitoring indicators, such as tracking GPX4 mutations in ctDNA combined with serum ferritin levels, to overcome resistance while balancing immune activation and cytotoxic risks.

Summary

Fully leveraging the clinical potential of ferroptosis-related markers requires advancing both serum indicators and tumor genetic characteristics. Regarding serum biomarkers, ferritin levels indirectly reflect systemic iron stores.Elevated levels are associated with poorer prognosis and may indicate greater ferroptosis susceptibility ((Thompson et al. 2020). Lipid peroxidation end products (e.g., MDA and 4-HNE) serve as direct kinetic indicators of ferroptosis occurrence, useful not only for prognosis but also as effective pharmacodynamic markers when dynamically elevated post-treatment ((Song et al. 2020). Concurrently, the GSH/GSSG ratio effectively represents the real-time stress on the antioxidant system ((Saithong et al. 2018), providing a reference for efficacy evaluation. At the tumor tissue molecular level, high expression of SLC7A11, a key component of system Xc⁻, is a strong predictor of tumor sensitivity to ferroptosis inducers; such tumors are often resistant to conventional chemotherapy ((Ji et al. 2022). Low or absent GPX4 expression suggests inherent tumor susceptibility to ferroptosis. Furthermore, high expression of the alternative pathway protein FSP1 may mediate resistance to GPX4-targeted therapies, making concurrent evaluation of GPX4 and FSP1 crucial for accurate prediction ((Doll et al. 2019). Loss-of-function mutations in key regulators like p53 or aberrant activation of the NRF2 signaling pathway significantly raise the ferroptosis threshold via upregulated antioxidant programs, leading to treatment resistance ((Sun et al. 2016). Integrating serum biomarkers with tumor molecular subtyping that reveals intrinsic mechanisms to construct multimodal predictive models holds promise for precisely stratifying GC patients based on ferroptosis sensitivity, thereby providing critical decision-making support for individualized precision medicine.

Current core limitations in ferroptosis research for GC include: (1) Insufficient targeting specificity: Ferroptosis inducers lack tumor selectivity, potentially damaging normal gastric mucosa while targeting tumor cells, especially in non-EBV-positive GC (Sha et al. 2025). (2) Dual immunomodulatory dilemma: While lipid peroxides can kill tumor cells, they simultaneously impair CD8⁺ T cell function, potentially undermining immunotherapy efficacy (Kłopotowska et al. 2025). (3) Adaptive resistance in the TME: The GC-specific high-lactate microenvironment inhibits GPX4 activity, reducing ferroptosis sensitivity, and current drugs struggle to penetrate the acidic tumor core (Ouyang et al. 2022a, b). (4) Systemic ferroptosis induction may cause unpredictable on-target toxicity to metabolically active normal organs like the liver and kidneys (Fan and Guo 2025). (5) Most ferroptosis inducers suffer from suboptimal pharmacokinetic properties, hindering the achievement and maintenance of effective therapeutic concentrations at the tumor site (Gu et al. 2025). (6) Tumor cells themselves can rapidly develop acquired resistance to ferroptosis inducers by upregulating alternative pathways like FSP1 and DHODH (Luo et al. 2023).

Addressing these challenges requires breaking through existing research frameworks and designing more forward-looking solutions. For precision delivery, learning from multi-cancer studies to design GC-specific solutions is key: develop precision delivery systems, drawing on pH-responsive nanocarrier technology from lung cancer research ((Guo et al. 2025), to create smart nanoparticles surface-modified with gastric acid-activated groups for targeted release of inducers like Erastin in GC. In treatment, establish individualized prediction models integrating EBV status, serum ferritin, and GPX4 ctDNA mutations to stratify and guide cisplatin sensitization and immunotherapy. Clinical application must avoid immune damage: refer to HNSCC protocols ((Zhao et al. 2023), dynamically monitor lipid peroxide markers and T cell exhaustion indicators, and co-administer low-dose antioxidants to protect CD8⁺ T cell function. Long-term, it is essential to systematically validate these strategies using GC patient-derived organoid platforms, integrate single-cell metabolomics technologies to deeply analyze resistance pathways within the TME, and actively promote drug development targeting emerging targets like FSP1 and ACSL4. Future research must adopt more systematic experimental designs to comprehensively evaluate the therapeutic window and potential toxicity, laying a solid foundation for the practical application of ferroptosis in GC treatment.

Author contributions

Yuexin Liu wrote the manuscript and prepared the figures and tables. Yanmei Li and Lizhou Jia provided revision suggestions for the article, while Zhang Ning and Liu Yang contributed to modifying the figures and tables.

Funding

Natural Science Foundation of Inner Mongolia Autonomous Region (2025ZD009). Yuexin Liu is the first author.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.