FSP1 is a glutathione-independent ferroptosis suppressor.Nature 2019Nat
Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants (RTAs)5,6. The factors which underlie a given cell type's sensitivity to ferroptosis7 are, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been yet been identified that account for ferroptosis resistance. We undertook an expression cloning approach to identify genes able to complement GPX4 loss. These efforts uncovered the flavoprotein "apoptosis inducing factor mitochondria-associated 2 (AIFM2)" as a previously unrecognized anti-ferroptotic gene. AIFM2, hereafter renamed "ferroptosis-suppressor-protein 1" (FSP1), initially described as a pro-apoptotic gene11, confers an unprecedented protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that ferroptosis suppression by FSP1 is mediated via ubiquinone (CoQ10): its reduced form ubiquinol traps lipid peroxyl radicals that mediate lipid peroxidation, while FSP1 catalyses its regeneration by using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, FSP1/CoQ10/NAD(P)H exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis.