基于语境的铁死亡敏感性调控。
Context-dependent regulation of ferroptosis sensitivity.
机构信息
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Chem Biol. 2022 Sep 15;29(9):1409-1418.e6. doi: 10.1016/j.chembiol.2022.06.004. Epub 2022 Jul 8.
Ferroptosis is an important mediator of pathophysiological cell death and an emerging target for cancer therapy. Whether ferroptosis sensitivity is governed by a single regulatory mechanism is unclear. Here, based on the integration of 24 published chemical genetic screens combined with targeted follow-up experimentation, we find that the genetic regulation of ferroptosis sensitivity is highly variable and context-dependent. For example, the lipid metabolic gene acyl-coenzyme A (CoA) synthetase long chain family member 4 (ACSL4) appears far more essential for ferroptosis triggered by direct inhibition of the lipid hydroperoxidase glutathione peroxidase 4 (GPX4) than by cystine deprivation. Despite this, distinct pro-ferroptotic stimuli converge upon a common lethal effector mechanism: accumulation of lipid peroxides at the plasma membrane. These results indicate that distinct genetic mechanisms regulate ferroptosis sensitivity, with implications for the initiation and analysis of this process in vivo.
铁死亡是一种重要的病理生理细胞死亡的介体，也是癌症治疗的一个新兴靶点。铁死亡敏感性是否由单一的调控机制控制尚不清楚。在这里，基于整合 24 个已发表的化学遗传学筛选结果，并结合靶向后续实验，我们发现铁死亡敏感性的遗传调控具有高度的可变性和上下文依赖性。例如，脂质代谢基因酰基辅酶 A（CoA）合成酶长链家族成员 4（ACSL4）在由直接抑制脂质过氧化物谷胱甘肽过氧化物酶 4（GPX4）引起的铁死亡中比在胱氨酸缺乏时显得更为关键。尽管如此，不同的促铁死亡刺激因素汇聚到一个共同的致死效应机制上：质膜上脂质过氧化物的积累。这些结果表明，不同的遗传机制调节铁死亡敏感性，这对体内该过程的启动和分析具有重要意义。
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