Class of Disulfide Compounds that Suppress Ferroptosis by Stabilizing GPX4

作者全名："Liu, Jin-Pin; Cen, Si-Yu; Xue, Zian; Wang, Tian-Xiang; Gao, Yun; Zheng, Jia; Zhang, Cheng; Hu, Junchi; Nie, Shenyou; Xiong, Yue; Guan, Kun-Liang; Yuan, Hai-Xin"

作者地址："[Liu, Jin-Pin; Cen, Si-Yu; Xue, Zian; Wang, Tian-Xiang; Gao, Yun; Zhang, Cheng; Yuan, Hai-Xin] Fudan Univ, Peoples Hosp Shanghai 5, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China; [Liu, Jin-Pin; Cen, Si-Yu; Xue, Zian; Wang, Tian-Xiang; Gao, Yun; Yuan, Hai-Xin] Fudan Univ, Sch Pharm, Shanghai 200032, Peoples R China; [Hu, Junchi; Nie, Shenyou] Chongqing Med Univ, Inst Life Sci, Ctr Novel Targetand Therapeut Intervent, Chongqing 400016, Peoples R China; [Xiong, Yue] Cullgen Inc, San Diego, CA 92130 USA; [Guan, Kun-Liang] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA; [Guan, Kun-Liang] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA"

通信作者："Yuan, HX (通讯作者)，Fudan Univ, Peoples Hosp Shanghai 5, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200032, Peoples R China.; Yuan, HX (通讯作者)，Fudan Univ, Sch Pharm, Shanghai 200032, Peoples R China."

来源：ACS CHEMICAL BIOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000891470500001

JCR分区：Q2

影响因子：3.5

年份：2023

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文献类型：Article; Early Access

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摘要："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 erastininduced 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."

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