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USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice

Cell Death & Differentiation volume 32, pages 1112–1127 (2025) Cite this article

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Abstract

Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25’s protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα’s lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.

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Fig. 1: Hepatocyte USP25 is downregulated in human and mice with MASLD/MASH.
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Fig. 2: USP25 deficiency aggravates MASLD in HFD-induced mice.
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Fig. 3: USP25 overexpression in hepatocytes protects against HFD-induced MASLD in mice.
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Fig. 4: USP25 activity in liver is positively associated with PPARα level.
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Fig. 5: USP25 reduces lipid accumulation in hepatocytes via increasing PPARα.
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Fig. 6: USP25 interacts directly with PPARα and regulates its deubiquitylation.
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Fig. 7: USP25 deubiquitinates PPARα at the K429 site through its H608 site, thereby attenuating PPARα degradation.
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Fig. 8: PPARα deficiency diminished USP25-mediated protection against MASLD.
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Data availability

The corresponding authors made the data utilized in the present investigation accessible to interested individuals upon a reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81930108 to G.L., 82000793 to W.L.) and the China Postdoctoral Science Foundation (2024M752443 to W.Z). We thank Scientific Research Center of Wenzhou Medical University for consultation and instrument availability that supported this work.

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Author notes

  1. These authors contributed equally: Leiming Jin, Weiwei Zhu, Xiang Hu.

Authors and Affiliations

  1. Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Leiming Jin, Weiwei Zhu, Xiang Hu, Wu Luo & Guang Liang

  2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Leiming Jin, Weiwei Zhu, Lin Ye, Shuaijie Lou, Qianhui Zhang, Minxiu Wang, Bozhi Ye, Wu Luo & Guang Liang

  3. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China

    Bozhi Ye, Julian Min & Guang Liang

  4. The Affiliated Xiangshan Hospital, Wenzhou Medical University, Xiangshan, Zhejiang, 315799, China

    Yi Wang & Lijiang Huang

  5. School of Pharmaceutical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 310000, China

    Yi Wang

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Contributions

Guang Liang, Wu Luo, and Lijiang Huang contributed to the literature search and study design. Yi Wang, Xiang Hu, and Leiming Jin participated in the drafting of the article. Leiming Jin, Weiwei Zhu, Lin Ye, Shuaijie Lou, Qianhui Zhang, Minxiu Wang, and Bozhi Ye carried out the experiments. Guang Liang, Leiming Jin, and Julian Min revised the manuscript. Wu Luo and Lijiang Huang contributed to data collection and analysis.

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Correspondence to Lijiang Huang, Wu Luo or Guang Liang.

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The study about the human samples was approved by the First Affiliated Hospital of Wenzhou Medical University (the ethical approval No. 2019-032), following the guidelines of Declaration of Helsinki. All participants provided informed consent. All animal studies were approved by Wenzhou Medical University Animal Policy and Welfare Committee (Approval Document No. wydw2020-0068) and and performed according to institutional guidelines.

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Jin, L., Zhu, W., Hu, X. et al. USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice. Cell Death Differ 32, 1112–1127 (2025). https://doi.org/10.1038/s41418-025-01444-4

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