Ferroptosis and gastric cancer: from molecular mechanisms to clinical implications

Abstract

Gastric cancer, one of the leading causes of cancer-related mortality globally, faces challenges in treatment due to limitations in surgery, chemotherapy resistance, and high recurrence rates. Ferroptosis, an iron-dependent form of cell death, induces cell membrane rupture through dysregulated iron metabolism, lipid peroxidation, and the accumulation of reactive oxygen species (ROS), offering a promising therapeutic avenue for gastric cancer treatment. This article systematically explores the core mechanisms of ferroptosis, including iron overload catalyzing lipid peroxidation via the Fenton reaction, dysregulation of antioxidant systems (such as GPX4 and FSP1), and their associations with gastric cancer cell proliferation, metastasis, and resistance. Studies indicate that abnormalities in iron metabolism in gastric cancer cells, such as upregulation of TFR1 and dysregulated ferritin storage, significantly promote ferroptosis sensitivity, while ferroptosis inducers (such as Erastin and RSL3) can enhance chemotherapy sensitivity and reverse resistance by inhibiting GPX4 or system Xc-. Preclinical experiments confirm that targeting ferroptosis-related pathways (such as the USP7/SCD axis and ABCC2-mediated glutathione efflux) effectively inhibits tumor growth and metastasis. However, the dual-edged effect of ferroptosis warrants caution regarding its oxidative damage risk to normal tissues and potential pro-metastatic mechanisms. This article further proposes the potential of ferroptosis biomarkers (such as 4-HNE and GPX4) in early diagnosis and prognosis assessment of gastric cancer and emphasizes the need for precision medicine to optimize ferroptosis-targeted strategies, balancing efficacy and safety. Ferroptosis opens a new avenue for gastric cancer treatment, but its clinical translation still requires in-depth mechanistic exploration and personalized treatment plan design.

Keywords: GPx4; ferroptosis; gastric cancer; lipid peroxidation; treatment resistance.

Figure 1

This figure illustrates the core molecular mechanisms of ferroptosis, with a particular emphasis on the interactions among iron metabolism, glutathione metabolism, and lipid peroxidation. Ferroptosis is an iron-dependent form of programmed cell death, primarily characterized by lipid peroxidation of polyunsaturated fatty acids (PUFAs) within the cell membrane, ultimately leading to cell death. The left panel depicts the antioxidant defense mechanism: Cells utilize System Xc^- (a cystine/glutamate antiporter) to export extracellular glutamate while simultaneously importing cystine. System Xc^- is a heterodimer composed of SLC7A11 and SLC3A2, where SLC7A11 serves as the functional subunit mediating cystine uptake (23).The imported cystine is subsequently reduced to cysteine, which serves as a precursor for glutathione (GSH) synthesis catalyzed by glutathione synthetase. GSH, in cooperation with glutathione peroxidase 4 (GPX4), eliminates lipid hydroperoxides (PUFAs-OOH), thereby preventing the excessive accumulation of lipid reactive oxygen species (ROS) and inhibiting the onset of ferroptosis (24). GPX4 is the core enzyme responsible for reducing lipid hydroperoxides into non-toxic PUFAs-OH, and its inactivation directly triggers ferroptosis (25).The right panel illustrates the iron metabolism pathway: Iron uptake is mediated by transferrin receptor (TFR), which facilitates the internalization of Fe³⁺. Intracellular six-transmembrane epithelial antigen of prostate 3 (STEAP3) then reduces Fe³⁺ to Fe²⁺. Subsequently, divalent metal transporter 1 (DMT1) transports Fe²⁺ into the cytoplasm (26). Free ferrous iron (Fe²⁺) can participate in the Fenton reaction, generating hydroxyl radicals (•OH), which initiate and propagate lipid peroxidation chain reactions, thereby acting as one of the key triggers of ferroptosis (27). Cells store excess Fe²⁺ in ferritin, a cytosolic iron storage protein. Nuclear receptor coactivator 4 (NCOA4) mediates the selective autophagic degradation of ferritin, a process known as ferritinophagy, which releases Fe²⁺ and exacerbates intracellular iron overload (28). Iron-responsive element-binding protein 2 (IREB2) regulates the expression of iron metabolism-related genes, such as TFR, DMT1, and ferroportin (FPN). This regulation contributes to the maintenance of intracellular iron homeostasis at the systemic level. Meanwhile, FPN exports Fe²⁺ out of the cell, thereby preventing iron overload (29, 30). In summary, disruptions in iron uptake, storage, transport, and the antioxidant system can lead to the excessive accumulation of polyunsaturated fatty acid (PUFA) peroxides and elevated levels of lipid ROS, thereby initiating the process of ferroptosis.

Figure 2

This figure illustrates the different stages of GC progression. The various stages depicted reflect the extent of cancer spread. In Stage 1a, the tumor is confined to the inner layer of the stomach; in Stage 1b, the tumor begins to breach the inner layer and invades the supporting tissue; at Stage 2, the tumor continues to expand, reaching the muscular layer; by Stage 3, the tumor has invaded more lymph nodes and extended to surrounding tissues; and in Stage 4, GC has reached its advanced stage, with the tumor metastasizing to organs distant from the primary site.

Figure 3

This Figure illustrates how iron metabolism dynamically influences cell fate decisions. It depicts the distinct effects of Fe²⁺ at varying intracellular concentrations on cellular functions: Mild Fe²⁺ accumulation enhances metabolic activity, thereby promoting cell proliferation and survival (87). In contrast, excessive accumulation of Fe²⁺ induces lipid peroxidation and mitochondrial damage, ultimately triggering ferroptosis (88). At high intracellular concentrations, Fe²⁺ participates in the Fenton reaction, generating hydroxyl radicals (•OH) that initiate lipid peroxidation cascades. This lipid peroxidation primarily affects PUFAs within membrane phospholipids, leading to the accumulation of lipid hydroperoxides (PUFA-OOH), which are cytotoxic when not neutralized by antioxidant systems such as GPX4 (89). Importantly, ferroptosis itself can further release Fe²⁺, forming a positive feedback loop that exacerbates intracellular iron burden and oxidative stress (90). The entire illustration provides a visual representation of the delicate balance of iron metabolism between cell survival and death, particularly in tumor cells.

Figure 4

This figure illustrates the molecular mechanism by which GC cells regulate their survival and metastatic potential under hypoxic conditions through modulation of the ferroptosis pathway. In the hypoxic tumor microenvironment, hypoxia-inducible factor 1α (HIF-1α) is upregulated, activating the hypoxia response element (HRE) region of the promoter of PMAN, a hypoxia-associated long non-coding RNA, thereby promoting its transcription (97). Upregulated PMAN directly binds to and stabilizes ELAVL1 (HuR), an RNA-binding protein that functions as a post-transcriptional stabilizer, which recognizes and binds to the 3′-untranslated region (3′-UTR) of SLC7A11 mRNA, enhancing its stability and translational efficiency (98). SLC7A11 and SLC3A2 together form system Xc^-, which facilitates cystine uptake in tumor cells for the synthesis of GSH, thereby eliminating ROS and suppressing ferroptosis (14, 99). Activation of this pathway confers enhanced antioxidant capacity to tumor cells, enabling their survival in hostile microenvironments and promoting metastatic potential. In contrast, in certain cells where this antioxidant axis is insufficiently activated, Fe²⁺ and ROS accumulate, leading to mitochondrial destruction and elevated lipid peroxidation, ultimately inducing ferroptosis and exerting antitumor effects (100). This mechanism suggests that ferroptosis plays a dual role in GC—both tumor-suppressive and pro-metastatic: while functioning as a cell death pathway to limit tumor expansion, its adaptive escape mechanisms may conversely enhance metastatic potential.

Figure 5

This figure illustrates the dual role of ferroptosis in GC,underscoring the complexity of its regulatory mechanisms. On theone hand, ferroptosis, as an emerging form of cell death, exhibitsnotable therapeutic potential in GC. For example, ferroptosis canserve as a diagnostic biomarker for early cancer detection; it may alsoovercome drug resistance and provide new therapeutic strategies bytargeting tumor ferroptosis mechanisms. These positive effects opennew avenues for GC treatment. On the other hand, the figure alsopoints out the potential risks of ferroptosis, such as triggeringunnecessary inflammatory responses, causing off-target cytotoxicdamage, and possibly promoting cancer cell metastasis.

Figure 6

This figure illustrates the key translational pathway of ferroptosis from basic research to clinical application in the treatment of GC. The upper right quadrant represents the stage of target identification and drug screening, focusing on mechanistic exploration and clinical relevance validation. The lower right quadrant corresponds to the clinical exploration stage, encompassing resistance overcoming strategies, mechanism-driven approaches, and evaluation of survival benefits. The lower left quadrant presents the key tasks of the late-stage translational phase, such as drug approval, safety evaluation, and regulatory compliance. The upper left quadrant illustrates the clinical implementation stage, highlighting the potential application of ferroptosis inducers in combination with immunotherapy and nanotechnology in patients. At the center of the figure, a circular translational loop is constructed around GC cell biomarkers, forming a closed-loop path from "early diagnosis—clinical validation—combination therapy—precision therapy," which illustrates the multidimensional integrative mechanism of ferroptosis therapy from laboratory research to clinical practice.