FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids

Shaojie Cui, Glenn Simmons, Goncalo Vale, Yaqin Deng, Jungyeon Kim, Hyeonwoo Kim, Ruihui Zhang, Jeffrey G. McDonald, Jin Ye

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs) leads to ferroptosis. While detoxification reactions removing lipid peroxides in phospholipids such as that catalyzed by glutathione peroxidase 4 (GPX4) protect cells from ferroptosis, the mechanism through which cells prevent PUFA peroxidation was not completely understood. We previously identified Fas-associated factor 1 (FAF1) as a protein directly interacting with free PUFAs through its UAS domain. Here we report that this interaction is crucial to protect cells from ferroptosis. In the absence of FAF1, cultured cells became sensitive to ferroptosis upon exposure to physiological levels of PUFAs, and mice developed hepatic injury upon consuming a diet enriched in PUFA. Mechanistically, we demonstrate that FAF1 assembles a globular structure that sequesters free PUFAs into a hydrophobic core, a reaction that prevents PUFA peroxidation by limiting its access to iron. Our study suggests that peroxidation of free PUFAs contributes to ferroptosis, and FAF1 acts upstream of GPX4 to prevents initiation of ferroptosis by limiting peroxidation of free PUFAs.

Original languageEnglish (US)
Article number2107189119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 26 2022


  • FAF1
  • ferroptosis
  • polyunsaturated fatty acids

ASJC Scopus subject areas

  • General


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