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

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

  • Cell Chem Biol. 2025 May 15;32(5):767-775.e5. doi: 10.1016/j.chembiol.2025.04.002.
Jiashuo Zheng 1,  Weijia Zhang 1,  Junya Ito 2,  Bernhard Henkelmann 1,  Chenxi Xu 1,  Eikan Mishima 3,  Marcus Conrad 4
Affiliations

Affiliations

  • 1 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, 85764 Neuherberg, Germany.
  • 2 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, 85764 Neuherberg, Germany; Laboratory of Food Function Analysis, Tohoku University Graduate School of Agricultural Science, Sendai, Miyagi 980-8572, Japan.
  • 3 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, 85764 Neuherberg, Germany; Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
  • 4 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, 85764 Neuherberg, Germany; Translational Redox Biology, Technical University of Munich (TUM), TUM Natural School of Sciences, 85748 Garching, Germany. Electronic address: marcus.conrad@helmholtz-munich.de.
PMID: 40311609 DOI: 10.1016/j.chembiol.2025.04.002
Abstract

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.

Keywords

FSP1; GPX4; GSH; NAC; cysteine; d-NAC; ferroptosis; system x(c)(−); xCT; β-ME.

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