title: Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events.
abstract: Ferroptosis is a recently discovered form of regulated necrosis that involves iron-dependent lipid peroxidation. How cells die once ferroptosis is triggered remains unclear. Ferroptosis is hypothesized to require three critical events: (1) accumulation of redox-active iron, (2) glutathione depletion, and (3) lipid peroxidation. It is proposed that these three events must unfold simultaneously because stopping any critical event also stops ferroptosis. These events are hypothesized to amplify in severity through positive feedback loops. The cause of death in ferroptosis is therefore the synergistic combination of antioxidant depletion, iron toxicity, and membrane denaturation. The relevance of these feedback loops for cancer and neurodegenerative therapies is discussed.
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg R3T 2N2, Canada. Electronic address: Robert.Bertrand@umanitoba.ca.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D015227:Lipid Peroxidation; D008055:Lipids / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D009369:Neoplasms / Q000628:therapy; D019636:Neurodegenerative Diseases / Q000628:therapy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D008055:Lipids; D017382:Reactive Oxygen Species; D007501:Iron; D005978:Glutathione
keywords: Cell death; Ferroptosis; Free radicals; Glutathione depletion; Iron toxicity; Oxidative stress