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Tytuł:
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A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4.
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Autorzy:
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Liu JP; 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.
Cen SY; 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.
Xue Z; 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.
Wang TX; 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.
Gao Y; 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.
Zheng J; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing400016, China.
Zhang C; 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.
Hu J; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing400016, China.
Nie S; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing400016, China.
Xiong Y; Cullgen Inc., 12671 High Bluff Drive, San Diego, California92130, United States.
Guan KL; Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California92093, United States.
Yuan HX; 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.; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing400016, China.
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Źródło:
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ACS chemical biology [ACS Chem Biol] 2022 Dec 16; Vol. 17 (12), pp. 3389-3406. Date of Electronic Publication: 2022 Nov 29.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Washington, D.C. : American Chemical Society, c2006-
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MeSH Terms:
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Disulfides*/pharmacology
Ferroptosis*/drug effects
Phospholipid Hydroperoxide Glutathione Peroxidase*/drug effects
Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism
Animals ; Mice ; Dithionitrobenzoic Acid ; Glutathione/metabolism ; Lipid Peroxidation/physiology ; Sulfides ; Disulfiram/pharmacology
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Substance Nomenclature:
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0 (Disulfides)
9BZQ3U62JX (Dithionitrobenzoic Acid)
GAN16C9B8O (Glutathione)
EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
0 (Sulfides)
EC 1.11.1.9 (glutathione peroxidase 4, mouse)
TR3MLJ1UAI (Disulfiram)
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Entry Date(s):
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Date Created: 20221129 Date Completed: 20221227 Latest Revision: 20230119
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Update Code:
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20240105
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DOI:
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10.1021/acschembio.2c00445
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PMID:
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36446024
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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.
