Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones Journal Article

Authors: Liang, D.; Feng, Y.; Zandkarimi, F.; Wang, H.; Zhang, Z.; Kim, J.; Cai, Y.; Gu, W.; Stockwell, B. R.; Jiang, X.
Article Title: 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. © 2023 Elsevier Inc.
Keywords: androgen receptor; estrogen receptor; ferroptosis; mboat1; mboat2; phospholipid remodeling; sex hormone signaling
Journal Title: Cell
Volume: 186
Issue: 13
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2023-06-22
Start Page: 2748
End Page: 2764.e22
Language: English
DOI: 10.1016/j.cell.2023.05.003
PUBMED: 37267948
PROVIDER: scopus
PMCID: PMC10330611
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Xuejun Jiang -- Source: Scopus
Citation Impact
MSK Authors
  1. Xuejun Jiang
    110 Jiang
  2. Zeda Zhang
    16 Zhang
  3. Yan   Feng
    6 Feng
  4. Yanyan Cai
    15 Cai
  5. Deguang Liang
    5 Liang
  6. Hua Wang
    7 Wang
  7. Jinnie Kim
    1 Kim