Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
School of Life Sciences; Hangzhou, China.
Antioxid Redox Signal. 2023 Jul;39(1-3):59-78. doi: 10.1089/ars.2023.0278. Epub 2023 May 2.
Ferroptosis is featured by the accumulation of polyunsaturated-lipid peroxidation on cellular membranes in an iron-dependent manner. Ferroptosis has been implicated in various pathophysiological processes, including cancer, neurodegeneration, and ischemia-reperfusion tissue injury. However, our understanding about the dynamic and context-specific regulation of ferroptosis remains incomplete. As the major substrate for peroxidation, the cellular lipidome regulates ferroptosis sensitivity and execution by controlling the abundance and availability of polyunsaturated-lipids for peroxidative modifications. In turn, the cellular lipidome is regulated by a complex network of enzymes and transporters, as well as upstream layers of receptors, kinases, and transcription factors. A number of research has shed light on the link between lipid metabolism and ferroptosis. Here, we summarize our current knowledge on the role of the lipidome and associated protein regulators in various stages of ferroptosis, ranging from initiation, execution to cell death evasion by cells experiencing ferroptotic stress. This review provides an overview of the mechanisms underlying lipid peroxidation and ferroptosis by discussing the lipid species that directly contribute to lipid peroxidation and ferroptosis, how cells regulate the abundances of these pro-ferroptosis lipids, how lipid peroxidation causes cell death, and how cells prevent and repair membrane lipid damage under ferroptotic conditions. Cell fate regulation could be different from culture settings. We envision that a comprehensive and detailed understanding about these important questions in the dynamic regulation of ferroptosis will accelerate our development of ferroptosis-targeted therapies to improve human health.
铁死亡的特征是细胞膜上多不饱和脂质过氧化的积累，这种积累依赖于铁。铁死亡已被牵连到各种病理生理过程中，包括癌症、神经退行性变和缺血再灌注组织损伤。然而，我们对铁死亡的动态和特定环境调节的理解仍然不完整。作为过氧化的主要底物，细胞脂质组通过控制多不饱和脂质的丰度和可用于过氧化修饰的可用性来调节铁死亡的敏感性和执行。反过来，细胞脂质组受酶和转运蛋白的复杂网络以及受体、激酶和转录因子的上游层调节。许多研究揭示了脂质代谢与铁死亡之间的联系。在这里，我们总结了脂质组及其相关蛋白调节剂在铁死亡的各个阶段（从起始、执行到经历铁死亡应激的细胞逃避细胞死亡）中的作用的现有知识。通过讨论直接促进脂质过氧化和铁死亡的脂质种类、细胞如何调节这些促铁死亡脂质的丰度、脂质过氧化如何导致细胞死亡以及细胞如何在铁死亡条件下预防和修复膜脂质损伤，本文综述了脂质过氧化和铁死亡的机制。细胞命运的调控可能因培养条件而异。我们设想，对铁死亡动态调节中这些重要问题的全面和详细了解将加速我们开发针对铁死亡的治疗方法，以改善人类健康。
