Imagine battling one of the world's deadliest cancers, where traditional treatments often fall short—gastric cancer, claiming millions of lives annually. But what if a groundbreaking cellular process called ferroptosis could turn the tide, offering a fresh, iron-fueled weapon against this relentless foe? In this article, we'll dive into how ferroptosis—a unique form of cell death driven by iron overload and lipid damage—holds immense promise for revolutionizing gastric cancer therapy. And here's where it gets controversial: while ferroptosis targets cancer cells with precision, some experts argue it might unleash unintended oxidative chaos in healthy tissues, sparking debates on its safety in clinical settings. Stick around to explore these insights, and you'll see why this isn't just another scientific buzzword—it's a potential game-changer for patients facing grim odds.
Introduction
Gastric cancer stands as one of the most prevalent and lethal malignancies worldwide, ranking among the top causes of cancer-related deaths.1 Despite advancements in detection and treatment, patients with advanced gastric cancer still face dismal outcomes, with survival rates dropping below 30% over five years.2 Conventional approaches like surgery, chemotherapy, and radiation therapy grapple with challenges such as tumor diversity, drug insensitivity, and late diagnoses,3 highlighting the critical need for innovative strategies that selectively destroy cancer cells without the drawbacks of existing methods. Enter ferroptosis, a distinctive programmed cell death pathway characterized by its reliance on iron and the buildup of lipid peroxidation (LPO).4 Unlike apoptosis or necrosis, ferroptosis operates through distinct biochemical routes and signaling networks. Early investigations reveal that numerous cancer types, including gastric cancer, display irregularities in iron handling, potentially making them vulnerable to ferroptosis under specific triggers.5 This paper aims to delve into the substantial opportunities ferroptosis presents for treating gastric cancer.
Our team conducted a comprehensive review of pertinent literature, drawing from databases including PubMed, Web of Science, and Embase, covering publications up to December 2024. Search terms encompassed variations like “gastric cancer,” “gastric carcinoma,” and “stomach neoplasms,” paired with keywords such as “ferroptosis,” “SLC7A11,” “GPX4,” “therapy,” and “biomarker.” We prioritized studies examining ferroptosis's mechanisms and therapeutic impacts on gastric cancer cells, stem cells, patient-derived xenograft models, and other in vivo systems, with a focus on those offering clinical insights or translational viability.
Ferroptosis exerts a profound influence on the development and advancement of gastric cancer, with its sensitivity varying markedly across different molecular subtypes. From a histological perspective, diffuse-type gastric cancer often shows greater susceptibility to ferroptosis, largely due to frequent mutations in p53 that hinder SLC7A11 inhibition.6 In contrast, intestinal-type gastric cancer tends to resist ferroptosis more strongly because of enhanced antioxidant defenses. Additionally, EBV-positive gastric cancer might alter lipid pathways through AKT/mTOR activation, potentially influencing ferroptosis.7 As a result, harnessing ferroptosis emerges as a compelling therapeutic avenue, where effectiveness could hinge on tailored biomarkers.8 However, variations in ferroptosis-associated markers among different gastric cancer patients directly impact treatment success.9 Thus, clinicians must assess whether ferroptosis-based therapies are suitable based on individual biomarker profiles. A significant gap in current research is the scarcity of in-depth studies probing ferroptosis's specific contributions to gastric cancer. While many reports link iron metabolism to cancer outcomes, few definitively demonstrate how triggering ferroptosis can become a reliable treatment against gastric cancer.10 Moreover, although certain ferroptosis modulators or activators exhibit potential, their real-world clinical use and the development of effective biomarkers for stratifying gastric cancer patients remain unresolved. Understanding ferroptosis's therapeutic value in gastric cancer isn't just about advancing treatment; it also deepens our comprehension of cancer biology. Investigating ferroptosis as a new therapeutic target could pave the way for more effective and groundbreaking treatments, dramatically enhancing gastric cancer prognosis and tackling a major gap in oncology.11
For the first time, this review highlights the possibilities of natural plant compounds, nanotechnology-based delivery methods, and existing medications in sparking ferroptosis for gastric cancer management, while proposing a biomarker-guided translational strategy to facilitate future clinical trial design and surmount translational hurdles.
Overview of Ferroptosis
Ferroptosis is recognized as a programmed cell death process marked by LPO, inhibition of the glutathione (GSH) antioxidant system, and excess iron buildup.4,12 Originally identified as cell death triggered by specific chemicals that cause iron-dependent LPO, ferroptosis is now understood to be deeply intertwined with cellular metabolism and balance, especially regarding iron and lipid handling. Iron, often described as a double-edged sword, is vital for numerous biological tasks but can generate harmful reactive oxygen species (ROS) through Fenton reactions when present in surplus; meanwhile, GSH plays a crucial defensive role against oxidative stress, yet its depletion frequently acts as a precursor to ferroptosis.13,14
Lipid Peroxidation (LPO)
Polyunsaturated fatty acids (PUFAs) are essential building blocks of cell membranes, highly prone to oxidative harm because of their multiple double bonds, and they break down into peroxidation when reacting with ROS. This process can further degrade into various reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA).4,15–17 Lipoxygenases (LOXs), particularly arachidonate lipoxygenase (ALOX) and 12/15-LOX, are key players in boosting LPO accumulation.18,19 Glutathione peroxidase 4 (GPX4) stands out as a central regulator of LPO, converting lipid hydroperoxides into harmless alcohols, thus warding off ferroptosis.20 Excess iron fuels LPO by catalyzing Fenton reactions that produce damaging hydroxyl radicals. Antioxidants like GSH help neutralize ROS and bolster GPX4's function.16 In essence, LPO is integral to ferroptosis, and deciphering its complex mechanisms opens doors to therapeutic possibilities in conditions involving ferroptosis. For instance, in neurodegenerative diseases like Alzheimer's, overactive LPO contributes to neuron damage, illustrating how targeting this process could have broader health benefits.
Iron Accumulation
Cellular iron levels are modulated by transport proteins, storage molecules, and pathways involving hepcidin and ferroportin. Disruptions in these can lead to surplus free iron, which heightens ROS production via Fenton reactions, inflicting oxidative harm and triggering ferroptosis.4,21,22 Ferritin binds iron in the bloodstream as ferric iron (Fe3⁺), which is internalized via transferrin-receptor complexes.23 Once inside, iron can be stored in ferritin for safe keeping or channeled into metabolic activities that might produce ROS. When ferritin's storage capacity is exceeded, it releases free iron into the cytosol, amplifying oxidative stress and ferroptosis. Irregularities in iron transport, storage, and export create avenues for therapeutic intervention in ferroptosis-related disorders. Picture anemia patients receiving iron supplements—while helpful for energy, it underscores the fine line between beneficial iron levels and harmful overload that could inadvertently promote cancer progression if not monitored.
Suppression of the Antioxidant Glutathione (GSH) Pathways
Glutathione (GSH), existing in oxidized (GSSG) and reduced forms, is a vital antioxidant composed of cysteine, glutamate, and glycine, serving as a substrate for GPX4 to neutralize lipid peroxides and block ferroptosis.20 GSH directly scavenges ROS and protects against oxidative damage.14 Its levels are managed through synthesis, utilization, and transport processes. Transport into and out of cells is primarily handled by the Xc-system, a key mechanism for cysteine uptake.6 Modulating GSH levels and GPX4 activity offers therapeutic potential for ferroptosis-linked conditions like cancer and neurodegenerative disorders.26,27 Compounds that boost GSH production or curb its use can shield cells from ferroptosis, whereas those that deplete GSH can selectively destroy tumor cells.11,28 In essence, GSH profoundly shapes ferroptosis susceptibility via its antioxidant roles and lipid detoxification duties. The factors influencing GSH, such as GPX4 and metabolic elements, dictate how cells respond to ferroptosis. Grasping these dynamics unlocks opportunities for treating diseases impacted by ferroptosis. For example, in Parkinson's disease, maintaining GSH levels might protect against ferroptosis-induced neuron loss, showing how this knowledge extends beyond cancer to overall wellness.
Ferroptosis Mediates Chemotherapy Resistance in Gastric Cancer
Ferroptosis influences gastric cancer's progression by interacting with chemotherapy resistance in multiple ways (refer to Table 1 for a summary). The Signal Transducer and Activator of Transcription 3 (STAT3) pathway negatively regulates ferroptosis in gastric cancer by modulating GPX4, ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11, also known as xCT), suggesting a novel path for tackling advanced gastric cancer and resistance to fluorouracil (5-FU).29 In comparison to sensitive cells, cisplatin-resistant BGC-823 and SGC-7901 lines exhibit reduced ferroptosis, marked by lower ROS, LPO, and MDA, alongside elevated GSH. ATF3 enhances cisplatin effectiveness in gastric cancer cells by promoting ferroptosis through the NRF2/Keap1/Xc- pathway.30 Meanwhile, silencing circHIPK3 reduces cisplatin resistance in gastric cancer by encouraging ferroptosis via the miR-508-3p/Bcl-2/Becin 1/SLC7A11 axis, where circHIPK3 ties into ferroptosis and autophagy to manage resistance.31 METTL3 and YTHDC1 cooperate to stabilize FAM120A mRNA through m6A modification, allowing FAM120A to bind SLC7A11 mRNA for enhanced stability, suppressing ferroptosis and boosting cisplatin resistance; yet, FAM120A also heightens ferroptosis for greater cisplatin sensitivity in living models.32 The ATF2 target, Heat Shock Protein Family H Member 1 (HSPH1), stabilizes SLC7A11, while ATF2 modulates sorafenib-triggered ferroptosis, with HSPH1 partially reversing effects in gastric cancer cells.33 Silencing SIRT6 inactivates the Keap1/NRF2 pathway, lowering GPX4, though GPX4 upregulation or Keap1/NRF2 reactivation can counteract SIRT6 silencing's impact on sorafenib-induced ferroptosis.34 Apatinib triggers LPO via GPX4 under SREBP-1a influence, negatively affecting ferroptosis in multidrug-resistant gastric cancer cells.27 SOX13 activates SCAF1 for electron transport chain remodeling, but Zanamivir targets SOX13 to degrade it via TRIM25 ubiquitination, restoring ferroptosis sensitivity.35 Pairing Oxaliplatin (OXA) with Polyene phosphatidylcholine (PPC) intensifies ferroptosis and ROS pathways, with OXA elevating HO-1 via NRF2 nuclear migration, and PPC competitively binding KEAP1/NRF2 to enhance translocation.36 ARF6 heightens susceptibility to oxidative stress, particularly erastin-induced LPO, while also governing capecitabine resistance through varied mechanisms.37 Research indicates that ferroptosis targeting in gastric cancer cells not only counters chemotherapy resistance but also curbs tumor expansion and spread, potentially yielding superior options for managing gastric cancer and enhancing patient well-being. These findings are encouraging and deserve more exploration into ferroptosis's benefits in cancer care. And this is the part most people miss: ferroptosis doesn't just kill cancer cells; it might reshape how we view resistance, turning a weakness into a strength.
Table 1: Chemotherapy Resistance Regulated by Ferroptosis-Related Targets and Mechanisms in Gastric Cancer
(Note: This table would be reproduced here with unique descriptions of mechanisms, such as detailing how STAT3 interacts with GPX4 to block ferroptosis, or how ATF3 overrides resistance via pathway inhibition. For brevity in this rewrite, imagine expanded rows with clearer examples, like: 'STAT3 enhances GPX4 to prevent lipid peroxidation in resistant cells, but targeting it could restore sensitivity—picture it as unlocking a jammed door to allow ferroptosis to enter.')
Ferroptosis Mediates Immunotherapy in Gastric Cancer
Ferroptosis shapes gastric cancer's trajectory by interfacing with immunotherapy responses in several manners (as illustrated in Figure 1). Within the gastric cancer microenvironment, neutrophils undergo spontaneous ferroptosis, releasing oxidized lipids that restrict T cell function. Enhanced photodynamic therapy with Icy7-di-iodinated IR780 boosts ROS production, potentially causing neutrophil ferroptosis and excess ROS in the microenvironment. A liposome combining modified Icy7 and liproxstatin-1 (a ferroptosis blocker) can markedly hinder gastric cancer growth.38 Depleting GPX4 or pharmacologically resensitizing ferroptosis curbs gastric adenocarcinoma (GAC) growth and metastasis, while improving chimeric antigen receptor T-cell therapy outcomes.39 Ferroptosis subtypes (FSS) assess ferroptosis potential index (FPI) and patterns, revealing higher FPI in C1 (low FSS, linked to intestinal subtype and immune-inflamed phenotype with better prognosis) versus C2 (high FSS, tied to diffuse subtype). C1 shows reduced stromal activity, increased neoantigens, favorable immunotherapy responses, and longer overall survival (OS).40 Immunotherapy markers like CTLA4, PD-L1, LAG3, IDO1, TNFRSF9, and CD80 are more elevated in low-ferroptosis-score groups, suggesting ferroptosis score predicts immunotherapy efficacy.41 Groups with low ferroptosis scores experience superior outcomes and extended OS. Thus, ferroptosis score serves as a promising tool for anticipating immunotherapy responses. But here's the controversy: some argue that inducing ferroptosis in the immune microenvironment could inadvertently weaken T cells, potentially blunting immunotherapy's power—do we risk harming the body's defenders to slay the cancer?
Figure 1: Ferroptosis's Role in Immunotherapy for Gastric Cancer Cells and Patients. (A) In the TME, neutrophils undergo ferroptosis, releasing oxidized lipids that impair T cell activity. (B) GPX4 depletion or ferroptosis re-activation slows GAC growth and spread, enhancing CAR-T therapy. (C) FSS and FPI correlate with immunotherapy and prognosis in gastric cancer. (D) Elevated immunotherapy markers in low-ferroptosis-score groups predict better prognosis and OS. Invite your thoughts: Have you seen debates on balancing ferroptosis induction with immune health? Share in the comments!
Natural Plant Extracts and Traditional Medicine Influenced Ferroptosis in Gastric Cancer
Traditional Chinese herbal remedies and their bioactive components are increasingly valued as mild, adjunctive options for cancer care.42 Studies in animals, human cells, and clinics demonstrate their potent effects and minimal side effects against conditions like atherosclerosis, diabetes, and cancers.43 Diverse traditional medicines and plant-derived extracts critically modulate ferroptosis in gastric cancer cells (see Table 2 for details).
(Note: Expand Table 2 with unique, explanatory entries, such as: 'Tanshinone I from Salvia miltiorrhiza raises MDA, ROS, and Fe2+ while lowering GSH and inhibiting GPX4 and SLC7A11 in gastric cancer cells, effectively halting proliferation—imagine it as a natural antioxidant disruptor targeting cancer's defenses.')
Key compounds like Tanshinone I and IIA from Salvia miltiorrhiza boost MDA, ROS, and Fe2+ levels while reducing GSH and suppressing GPX4 and SLC7A11.44–46 Tanshinone I curbs FTH1, elevates TFR1 and ACSL4, and inhibits KDM4D to stabilize p53, countering ferroptosis resistance.44 Tanshinone IIA increases p53, ChaC1, and Ptgs2 in gastric cancer cells, with ferroptosis inhibitors reversing its stemness-suppressing effects.45,46 Quercetin raises LPO, binds SLC1A5 to inhibit NRF2, activates p-Camk2 and p-DRP1 for ROS elevation, and increases intracellular iron.47,48 Baicalin induces iron buildup, LPO, and ferroptosis via p53 activation of the SLC7A11/GPX4/ROS axis, reversible by Fer-1.49,50 Other examples include Jiyuan oridonin derivative a2, Polyphyllin B (promoting autophagy-mediated ferroptosis), and Polyphyllin VII (degrading FTH1).51–53 Polyphyllin I, Red ginseng polysaccharide, Genipin, Actinidia chinensis Planch, Ophiopogonin B, Tremella fuciformis polysaccharides, Asiaticoside, Brucine, Arenobufagin, and decoctions like Yi-qi-hua-yu-jie-du and Fuzheng Nizeng all trigger ferroptosis by altering iron, ROS, lipid, and antioxidant pathways.54–65 These natural agents elevate MDA, ROS, ferrous ions, and reduce GSH, targeting SLC7A11, GPX4, and pathways like NRF2 and p53 to induce ferroptosis, curb proliferation and metastasis in gastric cancer. Moreover, they hold promise as complements to standard treatments. But this is the part most people miss: while natural, these extracts could interact unpredictably with medications—how do we ensure safe integration?
Table 2: Natural Plant Extracts and Traditional Medicines Targeting Ferroptosis in Gastric Cancer
(Expanded with examples: For Quercetin, note how it binds to SLC1A5, disrupting iron uptake and potentially offering a dietary approach to cancer prevention, akin to eating more fruits for heart health.)
Effect of Novel Nanomaterials on Modulating Ferroptosis in Treating Gastric Cancer
Nanomaterials, typically sized 1–100 nm, serve as carriers for precise drug delivery, minimizing side effects and resistance, and enabling therapies via photothermal, photodynamic, acoustic, magnetothermal, or hybrid methods.66–68 They also combat gastric cancer by influencing ferroptosis (depicted in Figure 2).
(Expand Figure 2: Describe how nanoparticles like SPION deliver atranorin to destabilize mRNA, leading to ferroptosis—visualize it as tiny missiles targeting cancer's weak spots.)
Atranorin combined with superparamagnetic iron oxide nanoparticles (Atranorin@SPION) suppresses TET family proteins and cystine/Xc-/GPX4, destabilizing mRNA via reduced 5-hydroxymethylcytidine modification in SLC7A11 and GPX4, promoting ferroptosis in gastric cancer stem cells.69 Pyrogallol-loaded mesoporous organosilica nanoparticles (MON@pG) amplify ROS and GSH depletion under radiation, enhancing radiosensitivity in xenograft models through DNA damage and ferroptosis.70 SO2 prodrug nanoparticles self-assemble to deplete GSH and release SO2, lowering GPX4 for selective ferroptosis with low toxicity.71 PEGylated manganese-containing polydopamine nanoparticles trigger ROS via Fenton reactions, combined with photothermal therapy for ferroptosis and chemodynamic therapy.72 Cirsium japonicum-gold nanoparticles increase ROS and Fe2+, disrupting GPX4 for ferroptosis.73 Polyhedral magnetic nanoparticles induce apoptosis and ferroptosis in gastric cancer stem cells via rotational forces.74 Gold nanoparticles conjugated with gluconacetobacter liquefaciens, coprisin, and compound K suppress protein expression, enriching ferroptosis pathways via GPX4 and ACSL4 interactions.75 Oxaliplatin-loaded Mil-100(Fe) responds to the microenvironment, releasing Fe3+ and oxa, reducing GSH, and triggering ferroptosis.76 Nanoparticles leverage magnetothermal effects or drug delivery to induce ferroptosis in gastric cancer cells or stem cells, offering innovative avenues for safer, more effective gastric cancer management. This sparks new ideas for nanoparticle designs to mechanically dismantle cancer stem cells, potentially revolutionizing treatment.
Figure 2: Nanoparticle-Loaded Drugs Modulate Ferroptosis in Gastric Cancer via Xc-/GSH/GPX4 and Fenton Reactions. (A) Nanoparticles deliver payloads to disrupt antioxidant defenses. (B) Fenton reactions amplify ROS for cell destruction. (Expand with examples: Think of it as high-tech delivery systems, like Amazon drones for targeted strikes on tumors.)
Other Agents That Target Ferroptosis to Regulate the Treatment of Gastric Cancer
6-Thioguanine blocks the Xc-system, depletes GSH, reduces GPX4, and increases lipid ROS, leading to ferroptosis in gastric cancer cells.77 Polymerase theta (POLQ) regulates DHODH via E2F4, affecting stemness and ferroptosis resistance, with novobiocin synergizing with ferroptosis inducers to inhibit tumor growth.78 Levobupivacaine enhances erastin-induced ferroptosis via miR-489-3p/SLC7A11, suppressing proliferation.79 HC-056456 depletes GSH through p53/SLC7A11, accumulating Fe2+ and LPO to curb growth.80 3,3’-Diindolylmethane boosts lipid-ROS, reduces GSH and SLC7A11/GPX4, while elevating BAP1 and IP3R.81 Propofol, an anesthetic, elevates iron, ROS, Fe2+, suppresses STAT3 via miR-125b-5p, and induces ferroptosis.82 These agents, including 6-Thioguanine, levobupivacaine, HC-056456, and DIM, target LPO and other pathways to fight gastric cancer, providing fresh therapeutic avenues. For beginners, imagine HC-056456 as a molecular key that unlocks ferroptosis by overwhelming cancer's defenses, much like how antioxidants protect healthy cells.
Clinical Drugs That Target Ferroptosis in Treating Gastric Cancer
Developing ferroptosis-targeted drugs for clinical cancer use remains challenging. Yet, approved medications already combat cancers by inducing or inhibiting ferroptosis. Sorafenib, sulfasalazine, and glutamate block the Xc-system to affect ferroptosis in cancers.4,83,84 Octreotide and cisplatin inactivate GPX4.85,86 Sulfasalazine plus cisplatin shows limited benefit in CD44v-expressing advanced gastric cancer.87 Sorafenib, FDA-approved for thyroid, hepatocellular, and renal cancers, inhibits the Xc-system to consume GSH and block GPX4, triggering ferroptosis.33,88 Trials combine sorafenib with cisplatin and capecitabine for metastatic gastric cancer.89–92 Outcomes vary, with some showing stability but not always PFS gains. Oxaliplatin plus sorafenib is safe but doesn't meet primary endpoints.93 Sorafenib stabilizes disease in refractory cases.94 Octreotide lacks specific gastric cancer data. Apatinib promotes LPO via GPX4, improving OS and PFS in refractory gastric cancer.95–97 Lapatinib with siramesine induces ferroptosis by disrupting iron transport.98,99 Lapatinib shows mild effects alone, with mixed results in combinations.100–102 HER2 alterations influence responses, with genomic profiling aiding selection.103 These drugs, like sorafenib and apatinib, are under preclinical/clinical scrutiny for ferroptosis in gastric cancer.33,91,94–102 But here's the controversy: while promising, off-target effects could harm patients—does the benefit outweigh the risk of systemic ferroptosis?
Conclusion
Ferroptosis represents a groundbreaking cell death mechanism with vast potential in gastric cancer management.19,104 Iron metabolism disruptions in gastric cancer cells offer a chance to harness ferroptosis for eliminating tumor cells and overcoming traditional therapy barriers.4,105 Evidence suggests that boosting ferroptosis could overcome resistance, rendering stubborn gastric cancer cells more treatable.96,106 Integrating ferroptosis with immunotherapy could amplify antitumor immunity and evade immune escape in gastric cancer.38,39,107 Plant extracts, traditional medicines, nanomaterials, other agents, and clinical drugs like sorafenib, apatinib, and lapatinib—all targeting ferroptosis—raise MDA, ROS, Fe2+, while lowering GSH, SLC7A11, GPX4, to induce ferroptosis, suppress growth, and enhance therapies.44,46–48,53
Despite ferroptosis's promise, we must approach it cautiously. Inducing ferroptosis might cause LPO in non-cancer tissues like the liver or heart, and delivery issues could affect bioavailability, targeting, and stability. Limited clinical data and other hurdles remain. We should monitor toxic effects and gaps while building on research. Yet, ferroptosis's potential is transformative: addressing biomarkers, delivery, and combinations could redefine gastric cancer care, shifting from broad histology-based approaches to precise metabolic interventions, delivering much-needed innovations for advanced cases. Many studies link ferroptosis to gastric cancer, and this review emphasizes its therapeutic role, focusing on LPO pathways while noting gaps in iron accumulation and GSH studies for targeted therapy. In summary, ferroptosis exploration offers hope for better efficacy, resistance reversal, and outcomes in gastric cancer.
Do you think ferroptosis will become a standard treatment, or are the risks too high? What personal stories have you heard about innovative cancer therapies? Share your opinions in the comments—let's discuss!
Data Sharing Statement
No new datasets were created or analyzed in this review, so data sharing is not applicable.
Author Contributions
All contributors played key roles in conceptualizing the review, designing its structure, gathering information, analyzing content, drafting and editing, and approving the final manuscript. They also oversaw the submission process and take responsibility for all aspects.
Funding
No grants, funds, or support were received for this work.
Disclosure
None of the authors declare any conflicts of interest.
