Ferroptosis: A Mechanism for Programmed Cell Death

Ferroptosis is defined as a non-apoptotic mechanism of regulated cell death, characterized by iron dependent accumulation of lipid hydroperoxides. Since its discovery, ferroptosis has grown as a fundamental biological process implicated in several pathological conditions including neurodegeneration, ischemia-reperfusion injury, inflammatory disorders and cancer. There are two major pathways for ferroptosis-the canonical and the non- canonical pathway. The canonical pathway involves the iron dependent accumulation of lipid hydroperoxides and is regulated by three major systems (1) the glutathione peroxidase 4 (GPx4)–glutathione system which serves as the major antioxidant defense against ferroptosis, (2) the Xc−  transporter system that provides raw material for fueling the GPx4 antioxidant system and (3) iron metabolism pathways that provide the catalytic substrate for lipid peroxidation via Haber -Wieiss and Fenton chemistry. The non- canonical pathways or the GPx4 independent pathways include the ferroptosis suppressor protein 1 (FSP1)–ubiquinol system, the GTP cyclohydrolase 1 (GCH1)–tetrahydrobiopterin system, and the DHODH mitochondrial defense. Thus, ferroptosis can be regarded as a multi-layered network affecting biology and progression of diseases. Ferroptosis is also regulated by transcriptional factors like the p53 tumor suppressor and Nrf2, heat shock proteins, and epigenetic modulators in a cell-type and context-dependent manner. The present review comprehensively delineates the molecular pathways of ferroptosis regulation, with emphasis on both traditional and emerging pathways, and discusses how this mechanistic understanding is being translated into therapeutic strategies for cancer sensitization and neuroprotection.

programmed cell death, iron metabolism, lipid peroxidation, glutathione peroxidase 4, therapeutic implication.

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