Metformin-Induced Ferroptosis as a Novel Therapeutic Strategy for Cancer

Introduction: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising target in cancer therapy. Metformin, a widely used antidiabetic drug, has shown potential to induce ferroptosis, offering novel insights into its anticancer mechanisms. Methods: This review summarizes current literature on the molecular mechanisms of metformin-induced ferroptosis, focusing on its regulation of iron metabolism, redox homeostasis, lipid peroxidation, and relevant signaling pathways across different cancer types. Results: Metformin modulates key ferroptosis regulators, including SLC7A11, GPX4, AMPK, NRF2, and ACSL4, thereby promoting intracellular ROS accumulation, GSH depletion, and enhanced lipid peroxidation. Through these effects, metformin enhances ferroptotic sensitivity in multiple cancers and synergizes with ferroptosis inducers, chemotherapy, or radiotherapy to overcome resistance. Discussion: Although metformin shows promise in targeting ferroptosis, several challenges remain, including the heterogeneity of tumor ferroptosis sensitivity, optimal dosing strategies, and the need for reliable biomarkers. Furthermore, the dual roles of some ferroptosis regulators in cancer biology warrant cautious interpretation. Continued research is required to optimize therapeutic combinations and validate preclinical findings in clinical settings. Conclusion: Metformin-induced ferroptosis represents a promising anticancer strategy. Its integration into combination therapies could enhance treatment efficacy and overcome resistance, supporting its clinical repurposing in oncology.