ReviewPharmaceuticals (Basel, Switzerland)2026
Context-Dependent Modulation of Ferroptosis by Metformin: Mechanisms, Therapeutic Implications and Open Questions.
Review in Pharmaceuticals (Basel, Switzerland), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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4 authors.
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Abstract
Ferroptosis is an iron-dependent regulated form of cell death characterized by lethal lipid peroxidation and is increasingly implicated in cancer, neurodegenerative diseases, cardiovascular injury, and metabolic disorders. Metformin, a widely prescribed antidiabetic biguanide, exerts pleiotropic effects beyond glucose lowering and has emerged as a context-dependent regulator of ferroptosis. In malignant cells, metformin may enhance ferroptotic susceptibility through activation of AMP-activated protein kinase (AMPK), suppression of mechanistic target of rapamycin (mTOR) signaling and SLC7A11, induction of ferritinophagy, mitochondrial complex I stress, and promotion of lipid peroxidation. Conversely, in normal or stressed non-malignant tissues, metformin may limit ferroptotic injury by activating nuclear factor erythroid 2-related factor 2 (NRF2), supporting glutathione peroxidase 4 (GPX4) and SLC7A11-dependent antioxidant defenses, improving mitochondrial quality control, and stabilizing iron homeostasis. This review synthesizes the molecular basis of this duality, evaluates therapeutic opportunities in oncology and cytoprotection, and outlines biomarker-driven and clinical trial strategies required for translation. Overall, metformin should not be regarded as a universal ferroptosis inducer or inhibitor, but rather as a context-dependent metabolic regulator whose effects are shaped by cell type, dose, exposure duration, transporter expression, iron status, and antioxidant capacity.
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