脂质过氧化在铁死亡中的基本位点鉴定。
Identification of essential sites of lipid peroxidation in ferroptosis.
发表日期：2023 Feb 06
作者：
A Nikolai von Krusenstiern, Ryan N Robson, Naixin Qian, Baiyu Qiu, Fanghao Hu, Eduard Reznik, Nailah Smith, Fereshteh Zandkarimi, Verna M Estes, Marcel Dupont, Tal Hirschhorn, Mikhail S Shchepinov, Wei Min, K A Woerpel, Brent R Stockwell
来源：
Nature Chemical Biology
摘要：
铁死亡是一种依赖于铁和脂质过氧化的细胞死亡形式，为药物耐受性癌症的潜在治疗途径提供了可能，并可能在一些退行性疾病的病理过程中起作用。确定对于铁死亡必不可少的亚细胞膜和它们的过氧化序列将阐明药物发现策略和与铁死亡相关的疾病机制。在本研究中，我们使用荧光和受激拉曼散射成像来检查调节铁死亡的化合物的结构活性分布关系。我们发现，虽然各种亚细胞膜中的脂质过氧化可以诱导铁死亡，但内质网（ER）膜是脂质过氧化的关键部位。我们的结果表明，在铁死亡期间，膜过氧化的有序进展模型首先在ER膜中积累，随后在质膜中积累。因此，设计针对ER的铁死亡抑制剂和诱导剂可以用于在经历铁死亡的细胞中最佳地控制脂质过氧化动态。© 2023. 作者，独家许可Springer Nature America，Inc.
Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure-activity-distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.