{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:14:45Z","timestamp":1788221685302,"version":"build-2803163510"},"reference-count":99,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ph19071072","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"1072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Context-Dependent Modulation of Ferroptosis by Metformin: Mechanisms, Therapeutic Implications and Open Questions"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6174-915X","authenticated-orcid":false,"given":"Nail","family":"Besli","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul 34668, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0137-4963","authenticated-orcid":false,"given":"Nilufer","family":"Ercin","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Graduate School, Istanbul Medeniyet University, Istanbul 34700, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6379-8994","authenticated-orcid":false,"given":"Rabia","family":"Kalkan Cakmak","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul 34668, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulkan","family":"Celik","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Istanbul Atlas University, Istanbul 34408, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis Turns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic Applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_2","first-page":"233","article-title":"Broadening Horizons: The Role of Ferroptosis in Cancer","volume":"21","author":"Chen","year":"2024","journal-title":"Nat. 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