A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4.
A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4.
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一类二硫化合物通过稳定GPX 4抑制铁凋亡。
DOI：
10.1021/acschembio.2c00445
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发表时间：
2022-11
影响因子：
4
通讯作者：
Jin-Pin Liu;Siyu Cen;Zian Xue;Tian-Xiang Wang;Yun Gao;J. Zheng;Cheng Zhang;Junchi Hu;S. Nie;Y. Xiong;K. Guan;Hai‐Xin Yuan
中科院分区：
文献类型：
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作者：
Jin-Pin Liu;Siyu Cen;Zian Xue;Tian-Xiang Wang;Yun Gao;J. Zheng;Cheng Zhang;Junchi Hu;S. Nie;Y. Xiong;K. Guan;Hai‐Xin Yuan
铁凋亡是一种非凋亡形式的细胞死亡，其特征是铁依赖性脂质过氧化，并已涉及多种病理条件。谷胱甘肽过氧化物酶4（GPX 4）通过谷胱甘肽（GSH）作为还原剂清除脂质过氧化物，在抑制铁凋亡中起重要作用。在这项研究中，我们发现Ellman试剂DTNB和一系列二硫化物化合物，包括双硫仑（DSF），一种FDA批准的药物，可以保护细胞免受erastin诱导的铁凋亡。从机制上讲，DTNB或DSF与GPX4中的多个半胱氨酸残基缀合，并破坏GPX4与HSC 70（一种用于伴侣介导的自噬的衔接蛋白）的相互作用，从而防止由erastin诱导的GPX4降解。此外，DSF通过抑制小鼠模型中的铁凋亡来改善伴刀豆球蛋白A诱导的急性肝损伤。我们的工作揭示了GPX4蛋白稳定性控制的一种新的调节机制。我们还发现了二硫化合物作为一类新的铁凋亡抑制剂，并建议在治疗铁凋亡相关疾病的DSF的治疗再利用。
Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation and has been implicated in multiple pathological conditions. Glutathione peroxidase 4 (GPX4) plays an essential role in inhibiting ferroptosis by eliminating lipid peroxide using glutathione (GSH) as a reductant. In this study, we found Ellman's reagent DTNB and a series of disulfide compounds, including disulfiram (DSF), an FDA-approved drug, which protect cells from erastin-induced ferroptosis. Mechanistically, DTNB or DSF is conjugated to multiple cysteine residues in GPX4 and disrupts GPX4 interaction with HSC70, an adaptor protein for chaperone mediated autophagy, thus preventing GPX4 degradation induced by erastin. In addition, DSF ameliorates concanavalin A induced acute liver injury by suppressing ferroptosis in a mouse model. Our work reveals a novel regulatory mechanism for GPX4 protein stability control. We also discover disulfide compounds as a new class of ferroptosis inhibitors and suggest therapeutic repurposing of DSF in treating ferroptosis-related diseases.