FAF1 Blocks Ferroptosis by Inhibiting Peroxidation of Polyunsaturated Fatty Acids

Abstract

Iron-catalyzed peroxidation of polyunsaturated fatty acids (PUFAs) leads to ferroptosis. While scavenging reactions removing lipid peroxides such as that catalyzed by Gpx4 protect cells from ferroptosis, the mechanism through which cells prevent the initial physiological event in ferroptosis – the peroxidation of PUFAs, is not known. We previously identified Fas-associated factor 1 (FAF1) as a protein directly interacting with PUFAs through its UAS domain. Here we report that the UAS domain of FAF1 and PUFAs form a globular structure that sequesters PUFAs into a hydrophobic core. This sequestration prevents PUFA peroxidation by limiting their access to iron. In the absence of FAF1-mediated protection, cultured cells became sensitive to ferroptosis upon exposure to PUFAs, and mice developed hepatic injury upon consuming a diet enriched in arachidonic acid (AA), a PUFA. Our study suggests that the FAF1-mediated sequestration of PUFAs from iron-catalyzed peroxidation acts upstream of Gpx4 to protect cells from ferroptosis.