Abstract
Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is crucial for mitochondrial function and biogenesis. However, whether and how PGC-1α can regulate hepatocyte ferroptosis during the pathogenic process of metabolic dysfunction-associated steatohepatitis (MASH) has not been clarified. Hepatocyte ferroptosis was assessed in the liver of MASH patients and in vivo and in vitro MASH models. The mechanisms by which PGC-1α regulated hepatocyte ferroptosis during the process of MASH were examined by Western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, luciferase reporter, and co-immunoprecipitation assays. Hepatocyte ferroptosis, down-regulated Tim23 and up-regulated ACSL4 expression were observed in the livers of MASH patients, and in vivo and in vitro MASH models. PGC-1α deficiency exacerbated hepatocyte ferroptosis in mouse models of MASH induced by high-fat diet and methionine- and choline-deficient diet, and primary mouse hepatocytes that had been treated with palmitic acid. Conversely, PGC-1α over-expression mitigated hepatocyte ferroptosis in these models. Mechanistically, PGC-1α promoted the binding of nuclear respiratory factor (Nrf)1 to the Tim23 promoter, reducing Drp1 transcription and ACSL4 mitochondrial translocation, inhibiting hepatocyte ferroptosis and MASH. These findings indicated that PGC-1α inhibited hepatocyte ferroptosis and attenuated MASH by upregulating Tim23 and inhibiting the Drp1-ACSL4 axis.
Data availability
All data are available in the main text or the supplementary materials.
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This work was supported by National Natural Science Foundation of Beijing Award number 7222003.
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YMZ, LZZ, and YTZ performed the experiments; YMZ, LZZ, BRL, YTZ, MHL and TL analyzed data and drafted the paper; XYZ and SBN designed, supervised study and wrote the paper.
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All methods were performed in accordance with the relevant guidelines and regulations. The study involving human participants was reviewed and approved by the Air Force Medical Center of Chinese People’s Liberation Army (approval number: 2024-78-PJ01) and was conducted in accordance with the Declaration of Helsinki. The requirement for written informed consent from participants was waived. The animal experiments were approved by Capital Medical University.
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Zhao, Y., Zhang, L., Li, B. et al. PGC-1α protects against MASH via Tim23-dependent inhibition of DRP1-mediated ferroptosis. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08493-8
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DOI: https://doi.org/10.1038/s41419-026-08493-8
