2. Academic Validation
  3. A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4

A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4

  • ACS Chem Biol. 2022 Dec 16;17(12):3389-3406. doi: 10.1021/acschembio.2c00445.
Jin-Pin Liu 1,  Si-Yu Cen 1,  Zian Xue 1,  Tian-Xiang Wang 1,  Yun Gao 1,  Jia Zheng 2,  Cheng Zhang 1,  Junchi Hu 2,  Shenyou Nie 2,  Yue Xiong 3,  Kun-Liang Guan 4,  Hai-Xin Yuan 1 2
Affiliations

Affiliations

  • 1 The Fifth People's Hospital of Shanghai, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences and the School of Pharmacy, Fudan University, Shanghai200032, China.
  • 2 Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing400016, China.
  • 3 Cullgen Inc., 12671 High Bluff Drive, San Diego, California92130, United States.
  • 4 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California92093, United States.
PMID: 36446024 DOI: 10.1021/acschembio.2c00445
Abstract

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.

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