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Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones
Cell ( IF 45.5 ) Pub Date : 2023-06-01 , DOI: 10.1016/j.cell.2023.05.003
Deguang Liang 1 , Yan Feng 1 , Fereshteh Zandkarimi 2 , Hua Wang 1 , Zeda Zhang 3 , Jinnie Kim 1 , Yanyan Cai 4 , Wei Gu 5 , Brent R Stockwell 2 , Xuejun Jiang 1
Affiliation  

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.



中文翻译:


铁死亡监测独立于 GPX4 并受性激素的差异调节



铁死亡是一种由铁依赖性磷脂过氧化驱动的细胞死亡过程,与多种疾病有关。有两种主要的抑制铁死亡的监视机制:一种由谷胱甘肽过氧化物酶 4 (GPX4) 介导,催化磷脂过氧化物的还原,另一种由酶(如 FSP1)介导,产生具有捕获自由基的抗氧化活性的代谢物。在这项研究中,通过全基因组 CRISPR 激活筛选,随后进行机制研究,我们确定了磷脂修饰酶 MBOAT1 和 MBOAT2 作为铁死亡抑制剂。 MBOAT1/2 通过重塑细胞磷脂谱来抑制铁死亡,引人注目的是,它们的铁死亡监视功能独立于 GPX4 或 FSP1。 MBOAT1和MBOAT2分别通过性激素受体即雌激素受体(ER)和雄激素受体(AR)进行转录上调。 ER或AR拮抗剂与铁死亡诱导的组合显着抑制ER +乳腺癌和AR +前列腺癌的生长,即使肿瘤对单药激素疗法有抗性。

更新日期:2023-06-01
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