铁死亡是由失控和过度的脂质过氧化引起的一种细胞死亡类型。NADPH对于铁死亡的调控至关重要，因为它为抗氧化防御系统提供还原等效物，并促使活性氧物质的产生。此外，NADPH水平可作为细胞对铁死亡的敏感性的生物标志物。泛素-蛋白酶体系统管理着许多铁死亡效应物质的稳定性。最近的研究揭示了内质网泛素连接酶MARCHF6作为泛素系统中一种前所未有的NADPH传感器，是与导致肿瘤发生和胎儿发育有关的铁死亡的重要调节因子。本综述总结了当前对NADPH代谢和泛素-蛋白酶体系统在调控铁死亡方面的认识，并强调MARCHF6作为NADPH代谢和铁死亡之间重要连接器的新兴重要性。版权所有2023 Elsevier Ltd. all rights reserved.

Ferroptosis is the type of cell death arising from uncontrolled and excessive lipid peroxidation. NADPH is essential for ferroptosis regulation because it supplies reducing equivalents for antioxidant defense systems and contributes to the generation of reactive oxygen species. Moreover, NADPH level serves as a biomarker for predicting the sensitivity of cells to ferroptosis. The ubiquitin-proteasome system governs the stability of many ferroptosis effectors. Recent research has revealed MARCHF6, the endoplasmic reticulum ubiquitin ligase, as an unprecedented NADPH sensor in the ubiquitin system and a critical regulator of ferroptosis involved in tumorigenesis and fetal development. This review summarizes the current understanding of NADPH metabolism and the ubiquitin-proteasome system in regulating ferroptosis and highlights the emerging importance of MARCHF6 as a vital connector between NADPH metabolism and ferroptosis.Copyright © 2023 Elsevier Ltd. All rights reserved.