Metabolic control of ferroptosis in cancer: lipid dependencies as therapeutic vulnerabilities.

Authors

Anna Di Dio, Gerardina Smaldone, Valeria Napolitano, Alessia Bertamino, Isabel M Gomez-Monterrey

Published in

Frontiers in oncology. Volume 16. Pages 1872103. Epub Jul 23, 2026.

Abstract

Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of peroxidized phospholipids in cellular membranes. In cancer, susceptibility to ferroptosis is not fixed but instead reflects a dynamic metabolic state shaped by lipid remodeling programs that determine membrane composition, oxidative liability, and the capacity to detoxify lipid peroxides. Tumor cells rewire fatty acid synthesis, desaturation, esterification, storage, sterol metabolism, and ether phospholipid remodeling to alter the abundance and distribution of oxidizable phospholipids and thereby shift their ferroptotic threshold. Polyunsaturated fatty acid-rich membrane phospholipids and di-polyunsaturated phospholipids promote lipid peroxidation and ferroptosis sensitivity, whereas monounsaturated fatty acids, lipid-droplet sequestration, 7-dehydrocholesterol, membrane-bound O-acyltransferase domain-containing 1 and 2, and antioxidant defense systems including glutathione peroxidase 4, ferroptosis suppressor protein 1, and the GTP cyclohydrolase 1-tetrahydrobiopterin pathway suppress ferroptotic death. Therapy-resistant, mesenchymal-like, and drug-tolerant persister states often display elevated oxidative stress together with increased dependence on lipid peroxide detoxification, whereas cancer stem cell-like states can remain either buffered or vulnerable depending on context. Here, we synthesize how lipid-state remodeling, tumor genotype, cell-state plasticity, and microenvironmental cues position tumors along a functional ferroptotic threshold, and we discuss how integrated lipidomic, transcriptional, and state-associated biomarkers may support biomarker-guided ferroptosis-based strategies in precision oncology.

PMID:
42564157
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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