Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.

Abstract

Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.

• Authors: Deguang Liang, Yan Feng, Fereshteh Zandkarimi, Hua Wang, Zeda Zhang, Jinnie Kim, Yanyan Cai, Wei Gu, Brent R Stockwell, Xuejun Jiang
• Journal: Cell (Cell) Vol. 186 Issue 13 Pg. 2748-2764.e22 (06 22 2023) ISSN: 1097-4172 [Electronic] United States
• PMID: 37267948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Phospholipid Hydroperoxide Glutathione Peroxidase
• Peroxides
• Phospholipids

Topics

• Male
• Humans
• Phospholipid Hydroperoxide Glutathione Peroxidase
• Lipid Peroxidation
• Ferroptosis
• Peroxides
• Phospholipids