Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids 1,2. To date, ferroptosis has been believed to be restrained only by the phospholipid hydroperoxide (PLOOH)-reducing enzyme glutathione peroxidase 4 (GPX4) 3,4 and radicaltrapping antioxidants (RTAs) 5,6. The factors which underlie a given cell type's sensitivity to ferroptosis 7 is, however, critical to understand the pathophysiological role of ferroptosis and how it may be exploited for cancer treatment. Although metabolic constraints 8 and phospholipid composition 9,10 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 gene 11 , 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. Conclusively, FSP1/CoQ10/NAD(P)H exists as a standalone parallel system, which cooperates with GPX4 and glutathione (GSH) to suppress phospholipid peroxidation (pLPO) and ferroptosis. program NEUROPROTEKT (03VP04260), as well as the m4 Award provided by the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi) to M.C., the Cancer Research UK

Key Points Heme and iron induce macrophage phenotypic switching toward an M1 proinflammatory phenotype. By scavenging free heme, hemopexin reverts heme-induced proinflammatory activation of macrophages in a mouse model of sickle cell disease.