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  • The precise mechanism by which

    2021-09-18

    The precise mechanism by which erastin inhibits SLC7A11-mediated cystine import it still unknown. The initially proposed mechanism, by which erastin binds a related transport protein, SLC7A5, and inhibits SLC7A11 in trans [25], was revised soon after, and it was suggested that erastin inhibits SLC7A11 perhaps directly [112]. An additional inhibitor of system Xc-, the FDA-approved multi-kinase inhibitor sorafenib (Nexavar), was shown to induce a GSH-depletion-mediated ferroptosis in cancer cell lines [112], [158], [159], [160] and enhance ROS accumulation in cancer patients [161]. Although the clinical benefit of sorafenib was in part caspase-independent [160], [161], this drug was shown to trigger classic apoptosis in some cells [162]. The specific contribution of ferroptotic cell death to the therapeutic effects of sorafenib in cancer patients is unknown [163]. A more potent inhibitor for system Xc-, imidazole ketone erastin (IKE), was designed by introducing a stable ketone to erastin [164]. In addition to the improved potency of IKE compared to erastin, IKE was shown to have improved metabolic stability placing this compound as a good candidate for in vivo studies of ferroptosis induction. Downstream of system Xc- is a central cellular guard against lipid ROS-induced ferroptotic death, GPX4. GPX4 acts as a guardian of cell membranes and converts potentially toxic lipid hydroperoxides (L-OOH) to non-toxic lipid alcohols (L-OH) [64]. Small molecule inhibition of GPX4 was first observed with the small molecule (1 S, 3 R)-RSL3, and resulted in uncontrolled polyunsaturated fatty Erastin phospholipid (PUFA-PL) oxidation and fatty acid radical generation, leading to ferroptotic cell death [114], [124]. Genetic or pharmacological inhibition of GPX4 leads to ferroptotic death, and hence is independent of cystine supply [114], [144]; deletion of GPX4 in mice is embryonically lethal [87]. Concomitantly, overexpression of GPX4 blocks RSL3-induced ferroptosis [114], and the lethality of GPX4-depleted mice could be rescued with ferroptosis inhibitors (e.g., ferrostatin-1) [87], [144]; further confirming that GPX4 activity is essential to prevent ferroptosis. The fact that elimination of this important cellular guard against lipid ROS is sufficient to induce ferroptotic death suggests that cells are continually exposed to the threat of radical-mediated lipid destruction. In addition to RSL3, other less potent small molecule inhibitors of GPX4 were identified (e.g., altretamine [165]), yet the mechanism of action of these inhibitors is not clear [138]. Although both cys-mediated GSH synthesis and GPX4 activity were shown to be essential for protecting cells against ferroptotic death, alternative antioxidant pathways maintain cell survival in the absence of GSH-GPX4. Indeed, the majority of commonly used ferroptosis inhibitors, including the original ferrostatin-1 and the more recently discovered liproxstatin-1 [144], are believed to function by trapping lipid radicals [122], [166]. Radical-trapping antioxidants are molecules that react with chain-carrying radicals and break the oxidation chain reaction [167]. Vitamin E, a lipophilic antioxidant, was discovered almost a century ago [168] and its beneficial antioxidant effect in human health was recognized since. The most biologically active form of vitamin E, α-tocopherol [169], was shown to inhibit ferroptotic death both in vitro and in vivo [170], [171], [172], [173], and vitamin E deficiency was linked to ferroptosis-mediated premature onset of neurodegeneration [174], [175]. In some cells, both in vitro and in vivo, high levels of SLC7A11-mediated cystine import, in conjugation with the GSH-independent thioredoxin (Txn) system, maintains endogenous α-tocopherol (vitamin E) in a reduced state and prevent lethal lipid-ROS accumulation [176], [177], [178], [179]. Additionally, it was recently suggested that in addition to the direct antioxidant activity of vitamin E in limiting lipid-ROS, it can also act as inhibitor of lipogeneses by competing for their substrate binding site, further inhibiting ferroptosis [26].