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Zheng, J. ; Zhang, W. ; Ito, J. ; Henkelmann, B. ; Xu, C. ; Mishima, E. ; Conrad, M.

N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.

Cell Chem. Bio. 32, 767-775.e5 (2025)
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N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fsp1 ; Gpx4 ; Gsh ; Nac ; Cysteine ; D-nac ; Ferroptosis ; System X(c)(−) ; Xct ; β-me; Separation
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2451-9448
e-ISSN 2451-9456
Journal Cell Chemical Biology
Quellenangaben Volume: 32, Issue: 5, Pages: 767-775.e5 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Massachusetts
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants
German Federal Ministry of Education and Research
European Research Council under the European Union
China Scholarship Council
Deutsche Forschungsgemeinschaft
DOI 10.1016/j.chembiol.2025.04.002
WOS ID 001501153300010
Scopus ID 105003916008
PubMed ID 40311609
Erfassungsdatum 2025-05-11
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