Abstract
Ferroptosis is a recently recognized regulated form of cell death characterized by accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides and loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). This iron-dependent form of cell death is morphologically, biochemically, and also genetically discrete from other regulated cell death processes, which include autophagy, apoptosis, necrosis, and necroptosis. Ferroptosis is defined by three hallmarks, defined as the loss of lipid peroxide repair capacity by GPX4, the bioavailability of redox-active iron, and oxidation of polyunsaturated fatty acid- (PUFA-) containing phospholipids. Experimentally, it can be induced by many compounds (e.g., erastin, Ras-selective lethal small-molecule 3, and buthionine sulfoximine) and also can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and deferoxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin and liproxstatin). The sensitivity of a cell towards ferroptotic cell death is tightly associated with the metabolism of amino acid, iron, and polyunsaturated fatty acid metabolism, and also with the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis sensitivity is also governed by many regulatory proteins, which also link ferroptosis to the function of key tumour suppressor pathways. In this review, we highlight the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its association with other cellular metabolic processes.
Highlights
Cell death is an indispensable biological process that critically governs the development of multicellular organisms
The deprivation of cystine was found to be equivalent to system xc− inhibition. These findings provided the evidence for a unique form of regulated cell death mechanism induced by amino acid starvation in the presence of an exogenous iron source is ferroptosis (Figure 1)
Beclin1 promotes lipid peroxidation in the process of regulating ferroptosis. These findings suggest that BECN1 promotes ferroptosis through regulation of lipid peroxidation [88]
Summary
Cell death is an indispensable biological process that critically governs the development of multicellular organisms It needs to be balanced with cell proliferation in order to maintain tissue homeostasis and to prevent the onset of neoplastic diseases. The regulated cell death processes are effectively controlled by pharmacological and biochemical interventions which could be modulated by molecular mechanisms. The term “ferroptosis” was coined by the lab of Dr Brent R Stockwell in 2012 which describes a regulated cell death process which differs morphologically, biochemically, and genetically from the other forms of cell death processes: apoptosis, autophagy, and necrosis. Ferroptosis is a nonapoptotic, peroxidation-driven form of regulated cell death process identified more recently using a pharmacological approach which is characterized by the elevation of intracellular iron and oxidative stress generation in response to different stress stimuli [3]. Inhibitors of lipid peroxidation, depletion of polyunsaturated fatty acids, and lipophilic antioxidants are found to work as effective suppressors of ferroptosis which have a direct correlation with the accumulation of lipid peroxidation markers
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