Targeting ferroptosis in major digestive system malignancies: regulatory networks and therapeutic opportunities

Ferroptosis is an iron-dependent form of regulated cell death that is associated with the accumulation of lipid peroxides, particularly in polyunsaturated fatty acids (PUFAs)-containing cellular membranes. Ferroptosis is initiated by aberrant iron metabolism, intense reactive oxygen species (ROS) production, oxidative damage to membrane structures and disruption of the cystine/glutamate antiporter system (System Xc − )–glutathione (GSH)–glutathione peroxidase 4 (GPX4) antioxidant pathway. Emerging evidence increasingly recognizes ferroptosis as a crucial mediator of tumor progression and response to therapy in digestive system malignancies. Aberrant iron homeostasis, lipid metabolic reprogramming, redox imbalance and remodeling of the tumor microenvironment (TME) are common events found in digestive system malignancies. This structured narrative review primarily focuses on colorectal cancer (CRC), hepatocellular carcinoma (HCC), gastric cancer (GC), and pancreatic ductal adenocarcinoma (PDAC) because ferroptosis regulatory mechanisms have been best defined for these cancers with respect to tumor-intrinsic regulation, metabolic vulnerability, antioxidant dependency, TME interactions and therapeutic responses. Additional evidence assessing whether the regulatory principles of ferroptosis extend to additional digestive system malignancies such as esophageal squamous-cell carcinoma and extrahepatic cholangiocarcinoma is also presented. Collectively, these modifications contribute to ferroptosis sensitivity as well as tumor growth, treatment resistance and immune evasion. Ferroptosis is not simply regulated by a single linear pathway, but rather orchestrated through multilayered regulatory networks involving transcriptional and epigenetic control, metabolic rewiring, immune modulation, exosome-mediated communication and extensive crosstalk between numerous signaling pathways. The application of ferroptosis inducers, nano-platform delivery systems, TME-responsive methodology and multimodal combination schemes indicates emerging therapeutic approaches with potential translational implications for digestive system malignancies. Nonetheless, clinical translation is limited by mechanistic complexity, tumor heterogeneity, incompletely defined resistance mechanisms, uncertainty of reliable predictive biomarkers and unaddressed biosafety issues with nanoplatforms. Thus, this Review frames current evidence within a three-tier mechanistic-to-translational framework that connects a common iron–lipid–redox vulnerability axis possessing tumor-type-specific resistance programs and biomarker-directed therapeutic prioritization to delineate context-dependent ferroptosis vulnerabilities and priorities for future clinical evaluation.