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  • A common feature of ferroptosis is the iron dependent


    A common feature of ferroptosis is the iron-dependent accumulation of lipid-ROS and the subsequent depletion of polyunsaturated fatty GW5074 phospholipids (PUFA-PLs) [118]. The PUFA chains of membrane lipids are more susceptible to both enzymatic and non-enzymatic oxidation, which results in PUFA fragmentation into a variety of products [126]. Indeed, several cell types that contain relatively high levels of PUFAs, such as cells of the retina and spermatozoa, were known for a few decades to be more sensitive to lethal oxidative stress that can be reduced by vitamin E or GPX4 [68], [142]. This is in line with earlier observations that inhibition of arachidonate 12-lipoxygenase (Alox12), an iron-containing lipid dioxygenase, inhibited oxidative glutamate toxicity and cell death in neurons, while treatment of cells with arachidonic acid (AA), a substrate of Alox12, further potentiated such death [143]. Arachidonic acid (AA) is now known to be the most frequently depleted PUFA in cells undergoing ferroptosis [144], [145]. One study showed that deletion of crucial enzymes involved in the insertion of AA into membrane phospholipids can prevent ferroptosis induction [146]. Acyl-CoA synthetase long-chain family member 4 (ACSL4), thus drives ferroptosis by contributing to the accumulation of oxidizable cellular membrane phospholipids [26], [147]. The currently suggested mechanism for the involvement of lipid metabolic pathways in ferroptosis induction is the following: ACSL4, which prefers AA as its main substrate, promotes ferroptosis by producing oxidized phosphatidylethanolamines (PE) in endoplasmic-reticulum-associated oxygenation centers. ACSL4 catalyzes the ligation of an arachidonyl (AA) or adrenoyl (AdA) to produce AA or AdA acyl Co-A derivatives. These derivatives are then esterified into PE to form AA-PE and AdA-PE by lysophosphatidylcholine acyltransferase 3 (LPCAT3), and subsequently oxidized by 15-lipoxygenase (15-LOX) to generate lipid hydroperoxides, which execute ferroptosis [26], [124], [147]. Although 15-LOX is thought to play a central role in catalyzing lipid peroxidation that leads to ferroptotic death, this role may be attributed to multiple LOXs, since deletion in 15-LOX fails to rescue the renal phenotype of GPX4 null mice [144]. The idea that lipid metabolism and membrane lipid composition affect susceptibility of cells to ferroptosis is further supported by molecular dynamics modeling of membrane lipid peroxidation [148]. Although the essential role for lipid peroxides in induction of ferroptotic death has been established, there is still no definitive evidence that this class of ROS is the most downstream factors that execute ferroptosis. Therefore, the question of what the ultimate molecular executioner of ferroptotic cell death is (e.g., as caspases for apoptosis), remains to be resolved.
    Identification of negative regulators of ferroptosis The first description of ferroptosis induction, by Dixon et al. in 2012, was in the context of cystine deprivation by inhibiting cystine (Cys2) import via the system Xc- antiporter with the small molecule erastin [25]. System Xc− is a plasma membrane cystine/glutamate antiporter composed of a twelve-pass transmembrane transporter protein, SLC7A11 (xCT), linked to the transmembrane regulatory protein, SLC3A2, by a disulfide bridge [149]. The lethal effect of erastin (and also of SAS, see above) can be reversed by β-mercaptoethanol (β-ME) [25], [112], which bypasses the need for system Xc- by forming mixed disulfides with Cys2 that can be imported into the cell by a different transporter [150]. Additionally, some cells can use the transsulfuration pathway to biosynthesize cysteine from methionine when system Xc- is inactivated. This pathway was recently shown to also be upregulated upon knockdown of cystenyl-tRNA synthetase (CARS). Cells that use the transsulfuration biosynthetic pathway were thus found to be resistant to ferroptosis induced by system Xc- inhibitors, but could still undergo ferroptosis through GPX4 inhibition [151]. Consistent with the need of cellular cystine to protect from ferroptotic death, according to a recent series of experiments, the redox-sensitive transcription factor Nrf2 [152], [153] can protect cells from ferroptotic death by upregulating system Xc- [132], [154], and was found to be commonly overactivated in various cancers [155], [156]. In contrast, induction of ferroptosis through inhibition of system Xc- was suggested to be a mechanism of tumor suppression by p53 [157].