美国纪念斯隆-凯特琳癌症中心姜学军团队发现受性激素的差异调节但不依赖GPX4的铁死亡监控。该研究于2023年6月1日在线发表于国际一流学术期刊《细胞》。

通过全基因组CRISPR激活筛选，然后进行机理研究，研究人员发现磷脂修饰酶MBOAT1和MBOAT2是铁死亡的抑制因子。MBOAT1/2通过重塑细胞磷脂结构来抑制铁死亡，而且引人注目的是，它们的铁死亡监视功能与谷胱甘肽过氧化物酶4（GPX4）或FSP1无关。MBOAT1和MBOAT2分别受性激素受体，即雌激素受体（ER）和雄激素受体（AR）的转录上调。ER或AR拮抗剂与铁死亡诱导相结合，可显著抑制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抵抗力。

据介绍，铁死亡是一个由铁依赖性磷脂过氧化驱动的细胞死亡过程，已被牵涉到各种疾病中。抑制铁死亡有两个主要的监控机制：一个是由GPX4介导，催化还原磷脂过氧化物；另一个是由酶介导，如FSP1，产生具有自由基捕获抗氧化活性的代谢物。

附：英文原文

Title: Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones

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

Issue&Volume: 2023-06-01

Abstract: Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation,has been implicated in various diseases. There are two major surveillance mechanismsto suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzesthe reduction of phospholipid peroxides and the other mediated by enzymes, such asFSP1, that produce metabolites with free radical-trapping antioxidant activity. Inthis study, through a whole-genome CRISPR activation screen, followed by mechanisticinvestigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosissuppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipidprofile, and strikingly, their ferroptosis surveillance function is independent ofGPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors,i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combinationof ER or AR antagonist with ferroptosis induction significantly inhibited the growthof ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.

DOI: 10.1016/j.cell.2023.05.003

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00522-6