Targeting ferroptosis to overcome drug resistance in gastrointestinal cancers.

Gastrointestinal cancers, broadly defined to include malignancies arising from the digestive system and associated organs, including gastric, colorectal, pancreatic, and hepatocellular carcinomas, remain among the leading causes of cancer-related mortality worldwide, while the efficacy of conventional therapies continues to be limited by systemic toxicity and acquired resistance. Ferroptosis is an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation and impaired glutathione peroxidase 4 (GPX4)-mediated antioxidant defense. In gastrointestinal cancers, ferroptosis is regulated by the solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-GPX4 axis, nuclear factor erythroid 2-related factor 2 (NRF2)-mediated stress adaptation, iron metabolism, and lipid metabolic reprogramming. However, the regulatory landscape and therapeutic potential of ferroptosis across gastrointestinal malignancies remain incompletely understood. In this review, we provide an updated overview of ferroptosis regulation in these cancers, focusing on disrupted iron metabolism, the SLC7A11-GSH-GPX4 antioxidant axis, NRF2-mediated stress adaptation, and lipid metabolic reprogramming. We further discuss emerging evidence regarding ferroptosis-mediated immune modulation, nanotechnology-based therapeutic strategies, and potential biomarkers for patient stratification. Despite encouraging preclinical findings, clinical translation remains hindered by off-target toxicity, insufficient predictive biomarkers, and tumor-context-dependent resistance mechanisms. We propose that ferroptosis-targeted therapies represent a promising adjunctive approach to current treatment modalities; however, successful clinical implementation will require rational combination strategies and biomarker-guided patient selection.