FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids

Significance The current study reveals the functions of FAF1 in protecting cells from ferroptosis, a novel cell death pathway triggered by PUFA peroxidation. In the absence of FAF1, cultured cells and mice are extremely sensitive to ferroptosis when exposed to physiological levels of PUFAs. Mechanistically, FAF1 sequesters PUFAs into the hydrophobic core of a global structure that limits their access to positively charged Fe2+ , which catalyzes the peroxidation reaction. These observations suggest that FAF1-mediated protection of PUFA peroxidation plays a critical role in preventing initiation of ferroptosis.