Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones

By Deguang Liang, Yan Feng, Fereshteh Zandkarimi, Hua Wang, Zeda Zhang, Jinnie Kim, Yanyan Cai, Wei Gu, Brent R. Stockwell, Xuejun Jiang. Cell, 2023

615 citations recorded by the source corpus.

Summary 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 estrogen receptor (ER) and androgen receptor (AR), respectively. 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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/0433abed4da15a19faa604d0a19781bc10f81e97

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. D. Ofengeim
2. Junying Yuan

In Molecular Biology

1. D. Ofengeim
2. Junying Yuan
3. R. Kaufman

In Pulmonary and Respiratory Medicine

1. D. Ofengeim
2. Furong Zeng
3. Yu Meng
4. Yihuang Liu
5. Guangtong Deng
6. Xiang Chen
7. Yuming Sun
8. Jiayuan Le

Citations in the corpus

• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “59,197”
• The cell biology of ferroptosis (2024, neutral): “For example, fatty acid desaturase 1 (FADS1) and FADS2, which introduce carbon–carbon double bonds into fatty acids, can enhance or reduce ferroptosis sensitivity, respectively, by synthesizing specific PUFAs or MUFAs 102,103 .”
• A guide to cell death pathways (2023, positive): “In addition, induction of the phospholipid-modifying enzymes MBOAT1 and MBOAT2 by sex hormone receptors, such as oestrogen receptor and androgen receptor, can also modulate lipid peroxidation 183 .”