Introduction
Cancer is a major global public health challenge.1,2 Digestive system tumors represent a substantial global cancer burden. Earlier diagnosis of symptomatic cancer is an important clinical goal.3 Although advances in endoscopic techniques have improved the detection and treatment of early gastrointestinal cancers, many patients are still diagnosed at advanced stages. For patients with advanced disease, systemic therapy is often a major treatment option, but treatment resistance may develop. Although multiple mechanisms contribute to treatment resistance, many remain incompletely understood. Recent studies have shown that ferroptosis plays a key role in tumor suppression and offers new perspectives for tumor treatment. Inducing ferroptosis may help overcome tumor treatment resistance,4–7 but the mechanisms by which ferroptosis influences treatment resistance remain unclear. This review aims to summarize current evidence on the relationship between ferroptosis and treatment resistance in digestive system tumors, with particular emphasis on ferroptosis-related pathways and tumor-specific mechanisms.
Ferroptosis and tumor treatment resistance
Ferroptosis is a unique form of cell death driven by iron-dependent phospholipid peroxidation. It is regulated by multiple cellular processes, including redox balance, iron metabolism, and lipid metabolism.8 The core process of ferroptosis involves the peroxidation of polyunsaturated fatty acid-containing phospholipids in cellular membranes under conditions of iron accumulation and oxidative stress.9,10 The accumulation of lipid peroxides in the cell membrane eventually disrupts membrane integrity, leading to cell death. The principal regulatory mechanisms include GPX4-dependent antioxidant defense, iron metabolism, and lipid peroxidation (Fig. 1).11
Tumor cells can significantly enhance their defense against oxidative stress by regulating ferroptosis, which leads to treatment resistance.12–14 Resistance may develop during or after many anticancer treatments and represents an important cause of treatment failure, tumor recurrence, and disease progression. Studies have found that tumor resistance is primarily related to the activation of endogenous stress relief pathways by oncogenic stressors (e.g., starvation, DNA damage, dietary toxins, infection, or cancer therapy).15,16 These pathways enable cells to better cope with stressors during development and renewal. Radiation therapy, chemotherapy, targeted therapy, and immunotherapy increase oncogenic stress, leading to further dependence of cancer cells on stress relief pathways. Cancer cells, as well as cells in the tumor microenvironment, rapidly adapt to relieve the stress caused by cancer treatments. These factors ultimately contribute to the resistance mechanisms of tumor treatment and provide new therapeutic targets,17 with ferroptosis playing a key role in therapeutic resistance.18 In tumor cell treatment resistance, persister cells (PCs) are particularly important.19 PCs are tumor cells that survive after several rounds of chemotherapy and represent a treatment-resistant state.20 The survival of PCs critically depends on GPX4, and the downregulation of GPX4 levels can selectively induce ferroptosis in PCs. Additionally, ferroptosis can selectively target the unique metabolic and signaling pathways of cancer stem cells (CSCs), playing an important role in treatment resistance.21,22 Erastin induces ferroptosis by inhibiting system Xc−, whose light-chain subunit xCT is encoded by SLC7A11.23 In gastric cancer cells, the ATF2/HSPH1 axis increases SLC7A11 protein stability, thereby suppressing sorafenib-induced ferroptosis and reducing sensitivity to sorafenib.24 Therefore, ferroptosis offers hope for overcoming treatment resistance by modulating PCs and CSCs. Numerous studies have found that ferroptosis is involved in the treatment resistance of gastrointestinal tumors (Table 1).24–31 Previous reviews have also discussed ferroptosis-related mechanisms and therapeutic strategies in gastrointestinal tumors and colorectal cancer.32,33 The following sections discuss ferroptosis and treatment resistance in gastric, colorectal, pancreatic, liver, and esophageal cancers, as well as cholangiocarcinoma.
Table 1Ferroptosis- and redox-related mechanisms of treatment resistance in digestive system tumors
| Tumor type | Ferroptosis- and redox-related pathway | Mechanism | Treatment type | Medicine | References |
|---|
| Gastric cancer | System Xc−-dependent antioxidant defense | ROS-activated GCN2–eIF2α–ATF4 signaling upregulates xCT and contributes to cisplatin resistance | Chemotherapy | Cisplatin | Wang et al., 2016 25 |
| Ferroptosis and lipid peroxidation | SIRT6 silencing promotes ferroptosis and enhances sorafenib sensitivity | Targeted therapy | Sorafenib | Cai et al., 2021 30 |
| SLC7A11-dependent antioxidant defense | ATF2/HSPH1 signaling increases SLC7A11 protein stability and suppresses sorafenib-induced ferroptosis | Targeted therapy | Sorafenib | Xu et al., 2023 24 |
| Colorectal cancer | GPX4-dependent antioxidant defense | KIF20A/NUAK1/NRF2/GPX4 signaling suppresses ferroptosis and contributes to oxaliplatin resistance | Chemotherapy | Oxaliplatin | Yang et al., 2021 31 |
| System Xc−-dependent antioxidant defense | FAM98A promotes xCT translation in stress granules, suppresses ferroptosis, and contributes to 5-fluorouracil resistance | Chemotherapy | 5-fluorouracil | He et al., 2022 27 |
| Liver cancer | Lipid peroxidation | MT-1G inhibits lipid peroxidation and ferroptosis, thereby contributing to sorafenib resistance | Targeted therapy | Sorafenib | Sun et al., 2016 26 |
| Lipid peroxidation and iron overload | miR-23a-3p suppresses ACSL4-mediated ferroptosis and contributes to sorafenib resistance | Targeted therapy | Sorafenib | Lu et al., 2022 29 |
| Pancreatic cancer | ROS generation | Gemcitabine induces p22-phox expression through NF-κB activation, leading to NADPH oxidase-derived ROS accumulation | Chemotherapy | Gemcitabine | Ju et al., 2015 28 |
| NRF2-mediated antioxidant defense | NRF2 nuclear translocation induces cytoprotective antioxidant genes involved in GSH production, thereby reducing ROS and contributing to intrinsic gemcitabine resistance | Chemotherapy | Gemcitabine | Ju et al., 2015 28 |
Ferroptosis and gastric cancer treatment resistance
Studies have suggested that inducing ferroptosis may be a potential strategy for overcoming treatment resistance in gastric cancer. Reactive oxygen species (ROS) disrupt cellular redox homeostasis and may contribute to cell death. Fu et al.34 found that cisplatin-resistant gastric cancer cells exhibited higher intracellular glutathione levels and reduced ferroptosis, while ATF3-mediated ferroptosis induction sensitized these cells to cisplatin by restraining NRF2/Keap1/xCT signaling. Another potential strategy is to block the ROS-activated GCN2–eIF2α–ATF4–xCT pathway, which is associated with mitochondrial dysfunction and contributes to cisplatin resistance in gastric cancer cells.25 In preclinical gastric cancer models, sorafenib has been investigated as an inducer of ferroptosis. ATF2, a member of the ATF/CREB transcription factor family, was activated during sorafenib-induced ferroptosis; ATF2 knockdown enhanced ferroptosis, whereas ATF2 overexpression had the opposite effect. Tumor xenograft experiments further showed that ATF2 knockdown enhanced the antitumor effect of sorafenib in vivo.24 HSPB1 overexpression inhibits erastin-mediated ferroptosis by reducing cellular iron uptake and lipid reactive oxygen species production.35 Chaperone-mediated autophagy participates in ferroptosis by promoting GPX4 degradation.36 In contrast, HSPA5 can negatively regulate ferroptosis by binding to GPX4 and protecting it from degradation.37 HSPH1 belongs to the HSP70 family, whose members function as molecular chaperones involved in maintaining protein homeostasis and preventing protein aggregation.38 In gastric cancer cells, HSPH1 acts downstream of ATF2 and increases SLC7A11 protein stability, thereby suppressing sorafenib-induced ferroptosis. HSPH1 knockdown partially reverses the inhibitory effect of ATF2 overexpression on sorafenib-induced ferroptosis.24 These findings identify ATF2/HSPH1/SLC7A11 signaling and GPX4-related protein homeostasis as potential mechanisms associated with sorafenib resistance in gastric cancer.
The role of ferroptosis in treatment resistance in colorectal cancer
The prognosis for patients with advanced colorectal cancer is poor due to resistance to anticancer drugs. Studies have found that interfering with the lipid metabolism involved in ferroptosis in colorectal cancer cells disrupts the metabolic balance of iron in these cells and enhances the chemosensitivity of drug-resistant cancer cells.39–41 Ferroptosis plays a crucial role in both chemotherapy and targeted therapy.
The role of ferroptosis in chemotherapy resistance in colorectal cancer
The KIF20A/NUAK1/NRF2/GPX4 signaling pathway inhibits ferroptosis in colorectal cancer cells and contributes to oxaliplatin resistance.31 FAM98A, a microtubule-associated protein involved in cell proliferation and migration, promotes xCT translation in stress granules, suppresses ferroptosis, and contributes to 5-fluorouracil resistance in colorectal cancer cells.27 Therefore, inducing ferroptosis through various mechanisms may represent a potential strategy for overcoming chemotherapy resistance in colorectal cancer.
The role of ferroptosis in resistance to targeted therapy in colorectal cancer
Resistance to epidermal growth factor receptor (EGFR)-targeted therapy limits its effectiveness in colorectal cancer. Cetuximab, a monoclonal antibody targeting EGFR, can promote RAS-selective lethal 3 (RSL3)-induced ferroptosis by inhibiting the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway in KRAS-mutant colorectal cancer cells.42,43 Additionally, β-elemene, a ferroptosis inducer (FIN), can induce ferroptosis and inhibit epithelial-to-mesenchymal transition when combined with cetuximab, thereby enhancing cetuximab sensitivity in KRAS-mutant colorectal cancer cells.44 Vitamin C, an antioxidant that can induce oxidative stress at pharmacological doses, disrupts iron homeostasis and further increases ROS levels, ultimately leading to ferroptosis. The combination of cetuximab and vitamin C can induce ferroptosis and reduce acquired resistance to anti-EGFR antibodies.45 Therefore, modulating ferroptosis may help overcome cetuximab resistance.
The role of ferroptosis in treatment resistance in pancreatic cancer
Pancreatic cancer is often accompanied by lymph node invasion or distant organ metastasis at an early stage, with less than 20% of patients being eligible for surgical treatment once diagnosed.46 For patients with unresectable pancreatic cancer, chemotherapy and radiotherapy are currently the main treatments. However, chemoresistance, particularly to gemcitabine, remains a major obstacle in pancreatic cancer treatment.47 Despite advances in treatment, currently available systemic therapies for advanced pancreatic cancer remain only modestly effective.48 Previous studies have shown that FINs can inhibit pancreatic cancer growth by inducing cellular ferroptosis and, when combined with chemotherapy drugs, can increase tumor cell sensitivity to these drugs.49
Gemcitabine treatment is associated with ROS-mediated cellular responses.50 In addition, knocking down GPX4 can increase lipid ROS production and induce ferroptosis.11 Gemcitabine has been reported to induce p22-phox expression and NADPH oxidase (NOX)-derived ROS accumulation in pancreatic ductal adenocarcinoma cells.28 However, ROS accumulation is not specific to ferroptosis, and further evidence is needed to determine whether this response represents ferroptotic cell death. NRF2 is a major regulator of cellular antioxidant defense. Its nuclear translocation promotes the expression of enzymes involved in glutathione production, thereby reducing ROS levels and potentially contributing to gemcitabine resistance.28 Targeting NRF2-dependent antioxidant defense may therefore increase the susceptibility of pancreatic cancer cells to ferroptosis, although this strategy remains preclinical. In summary, modulation of GPX4-dependent antioxidant defense, NRF2 signaling, and ROS metabolism may influence gemcitabine sensitivity in pancreatic cancer. Further studies are needed to establish whether these effects are specifically mediated by ferroptosis.
The role of ferroptosis in treatment resistance in cholangiocarcinoma
Cholangiocarcinoma (CCA) is the second most common primary liver tumor after hepatocellular carcinoma.51 Ferroptosis has been implicated in cancer and liver diseases generally,11,52,53 but its role in CCA treatment resistance remains insufficiently defined. Chaijaroenkul et al. demonstrated that artemisinin derivatives exerted cytotoxic activity against cholangiocarcinoma CL-6 cells.54 However, this study did not determine whether ferroptosis mediated the observed cytotoxicity. Further studies are needed to determine whether ferroptosis-targeted approaches can enhance sensitivity to established therapies.
The role of ferroptosis in treatment resistance in liver cancer
Sorafenib is a systemic therapy used for hepatocellular carcinoma (HCC), but resistance can limit its therapeutic efficacy.55 Strategies that enhance sorafenib-induced ferroptosis have been proposed to increase the sensitivity of HCC cells to sorafenib.56,57 Preclinical studies suggest that sorafenib-induced ferroptosis may contribute to its antitumor activity in HCC; however, the clinical relevance of this mechanism remains under investigation.26
Lu et al.29 found that miR-23a-3p negatively regulates sorafenib-induced ferroptosis by reducing iron overload and lipid peroxidation. Knockout or downregulation of miR-23a-3p significantly improved the responsiveness of orthotopic HCC tumors and HCC cells to sorafenib treatment. Sun et al.26 discovered that upregulating metallothione-1G (MT-1G) expression could protect HCC cells from the effects of sorafenib and promote cancer progression by inhibiting lipid peroxidation-mediated ferroptosis. This study suggests that regulating MT-1G expression is a potential therapeutic strategy to overcome the acquired resistance of HCC cells to sorafenib. These findings suggest that targeting ferroptosis-related pathways may represent a potential strategy for overcoming sorafenib resistance, although further preclinical and clinical validation is required.26,29
The role of ferroptosis in treatment resistance in esophageal cancer
Treatment resistance remains a major challenge in esophageal cancer. System Xc−/SLC7A11 has been proposed as a ferroptosis-related therapeutic target in cancer, but its role in esophageal cancer treatment resistance requires further validation.58 Experimental evidence from non-esophageal tumor models indicates that immunotherapy-activated CD8+ T cells can promote tumor-cell ferroptosis through interferon-γ-mediated suppression of system Xc−.59 In esophageal squamous cell carcinoma models, targeting stearoyl-CoA desaturase enhanced radiation-induced ferroptosis and immunogenic cell death.60 These findings support further investigation of ferroptosis in esophageal cancer, but its clinical role in overcoming treatment resistance remains to be established.
Future perspectives and limitations
Current research on ferroptosis has also extended to other tumor types, such as non-small cell lung cancer, breast cancer, and clear cell renal cell carcinoma.61–64 Ferroptosis-related research in these tumors has focused on mechanisms and pathways such as inhibition of the system Xc−-glutathione/GPX4 axis, modulation of the p62-Keap1-NRF2 pathway and NRF2 downstream antioxidant genes, and regulation of lysosomes, ferritin, transferrin, and ferritinophagy-related processes. These findings suggest that ferroptosis may contribute to tumor cell killing and growth inhibition and may represent a potential strategy for overcoming treatment resistance. However, the clinical relevance of ferroptosis regulation in digestive system tumors remains insufficiently defined. Further studies are needed to clarify tumor-specific ferroptosis mechanisms, identify reliable biomarkers of ferroptosis activity, and determine whether ferroptosis-targeted approaches can be safely and effectively translated into clinical treatment.
Ferroptosis has emerged as a potential therapeutic direction and has attracted increasing attention in cancer research. Despite the growing research on ferroptosis, several issues remain: (1) Further exploration is needed to understand the unknown and regulatory mechanisms of ferroptosis in tumor treatment resistance; (2) Different tissues exhibit varying sensitivities to ferroptosis, making the correct application of ferroptosis in tumor treatment an important research direction; (3) Anti-tumor drugs are often used in combination, but the antagonistic or synergistic effects of these combinations are not yet fully understood, and substantial theoretical research support is still required; (4) While some drugs and compounds can induce ferroptosis, and new drug delivery systems such as exosomes and nanotechnology are being explored, clinical application remains a challenge. Further mechanistic and translational studies are needed to address these challenges.
The detection and application of ferroptosis in tumor drug resistance are important for understanding and intervening in this process. For example, measuring specific lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, can help assess ferroptosis.65 Detecting the activity of ferroptosis-related enzymes, such as GPX4, may provide additional mechanistic evidence. Changes in mitochondrial membrane potential and mitochondrial iron accumulation have been examined in ferroptosis-related studies.66 Peroxynitrite has also been investigated as a fluorescence imaging marker during ferroptosis.67 However, these changes are not specific to ferroptosis and should be interpreted together with other ferroptosis-related markers. Techniques such as flow cytometry, fluorescence microscopy,68 and Western blotting are widely used to assess ferroptosis-related changes.69,70 Because no single marker is sufficient to confirm ferroptosis, multiple complementary biochemical, imaging, and molecular approaches should be combined. Future research may identify more reliable biomarkers and detection technologies, thereby improving the accuracy of ferroptosis assessment and its potential clinical application.
This review also has several limitations. First, most available evidence regarding ferroptosis and treatment resistance in digestive system tumors is derived from preclinical studies, and clinical validation remains limited. Second, the literature included in this review was not selected using a systematic search and formal evidence-assessment process, which may introduce potential selection bias. In addition, the mechanisms and therapeutic implications of ferroptosis vary among tumor types, and evidence from different digestive system tumors cannot always be directly generalized.
Conclusions
Ferroptosis is closely associated with treatment resistance in digestive system tumors through mechanisms involving GPX4-dependent antioxidant defense, lipid peroxidation, iron metabolism, NRF2/xCT signaling, and tumor-specific metabolic adaptation. Current evidence suggests that regulating ferroptosis may influence treatment sensitivity in several digestive system tumors, particularly in the context of chemotherapy, targeted therapy, and immunotherapy. However, most findings remain preclinical, and the safety, specificity, and clinical efficacy of ferroptosis-targeted strategies require further validation. Future studies should clarify tumor-specific mechanisms, identify reliable biomarkers, and evaluate ferroptosis-based approaches in well-designed translational and clinical studies.
Declarations
Funding
This work was supported by the Innovation Team of Xi’an Medical University (2021TD15).
Conflict of interest
The authors have no conflicts of interest related to this publication.
Authors’ contributions
Manuscript drafting (XQ), study conception and design (XQ, HW, MXZ), figures and tables preparation (XQ, MXZ), manuscript revision (HL), critical revision of the manuscript for important intellectual content (MXZ). All authors read and approved the final manuscript.