Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis

It is well established that Ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of Lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in Ferroptosis, it remains unclear whether and how SFA participates in the process of Ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated Ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent Ferroptosis. Furthermore, FAR1-mediated Ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced Ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent Ferroptosis pathway and suggests TMEM189 as a promising druggable target for Anticancer therapy.