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  • Following these discoveries the term


    Following these discoveries, the term ferroptosis was coined in 2012 [25], to describe this iron-dependent, non-apoptotic form cell death induced by erastin and RSL3. This discovery was accompanied by the development of the first small molecule ferroptosis inhibitor, termed ferrostatin-1, and the demonstration of glutamate-induced ferroptosis in organotypic rat brain slices, suggesting the potential function of ferroptosis in neurodegeneration. Elucidation of the RSL3 mechanism of action provided the next major insight in the regulation of the emerging mechanism of ferroptosis. Chemoproteomic studies using (1 S,3 R)-RSL3 (the active diastereomer out of the four possible RSL3 stereoisomers) as an affinity reagent identified the crucial role for the glutathione-dependent selenoprotein glutathione peroxidase 4 (GPX4) in the regulation of ferroptosis [114]. Subsequently, numerous other studies began identifying a similar ferroptotic process underlying diverse phenomena. In multiple cell types, amino TW-37 starvation was reported to induce cell death that is non-apoptotic and non-necroptotic, but only in the presence of serum [116], [117]. It was shown that deprivation of cystine was sufficient to induce the same serum-dependent cell death pathway, and that the serum component crucial for cell killing was transferrin, an iron carrier. Deprivation of cystine was thus equivalent to system Xc- inhibition. These findings led to the confirmation that the cell death mechanism induced by amino acid starvation in the presence of an exogenous iron source is ferroptosis. It was later found that not all ROS function equally in ferroptosis, and that lipid peroxidation is the main driver for ferroptotic death [118], supported by the previous identification of lipophilic antioxidants as suppressors of ferroptotic death induced by erastin and other compounds [111].
    Identification of positive regulators of ferroptosis Iron has an essential role in life on Earth dating back billions of years. However, emergence of iron-dependent oxygen utilization and polyunsaturated fatty acid metabolism to drive processes in living cells created a deadly paradox: while these processes of energy production, lipid metabolism, and signaling are valuable for the existence of complex life forms, they are also associated with generation of harmful and ultimately lethal species. The oxidation of organic substrates by iron (II) with hydrogen peroxide (H2O2) is referred to as Fenton chemistry (or the Fenton reaction) and was first described by Fenton in 1894 [119] (reviewed in [120]). This reaction partially explains the dependency of ferroptosis on iron, as redox-active iron pools are able to directly catalyze propagation of lipid peroxidation to form damaging species that lead to death. Early in the 1960s, iron was shown to contribute to lipid peroxidation-associated pathological changes in rats, that could be prevented by vitamin E [121]. As implied by the name ‘ferroptosis’, the existence of high levels of intracellular iron is a requirement for the execution of this type of cell death. An indication of this necessity is that ferroptotic death, whether induced by system Xc− inhibition, direct GPX4 inhibition, cystine deprivation, or extracellular glutamate, can be suppressed by iron chelators, knockdown of the iron transporter transferrin or its receptor, or the lack of iron in serum [25], [109], [114], [122], [123], as well as inhibition of iron availability to lipoxygenases [124], which drive ferroptosis through peroxidation of PUFA-PLs (see below). Moreover, addition of iron to the growth medium [25], as well as of iron-bound transferrin [117], were shown to accelerate erastin-induced ferroptosis, and administration of a bioavailable iron form enhances ferroptotic death in mouse models defective in system Xc- [125]. Mechanistically, intracellular redox-active iron promotes ferroptosis by catalyzing the formation of soluble lipid radicals that can initiate or propagate oxidative PUFA fragmentation, enzymatically and non-enzymatically [126]. Intracellular iron homeostasis is strictly regulated by the iron-binding and mRNA-regulatory proteins named iron-regulatory proteins 1 and 2 (IRP1 and IRP2), that can sense the cellular concentration of free iron and respond by altering the expression of proteins governing iron export, import, storage and release [127]. Ferroptotic death is often linked to the disruption of delicate iron homeostasis, which causes an undesired increase of free cellular iron concentration (Fe2+; also known as the ‘labile iron portion’ or ‘LIP’). This fine-tuning of iron levels is mostly attributed to an impaired activity of IRP2, coupled with increased expression of the iron carrier transferrin, and transferrin receptor [117].