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USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ

Cell Death & Differentiation (2025)Cite this article

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide, yet the molecular mechanisms underlying its pathogenesis are not fully understood. Here, we identify the deubiquitinating enzyme Ubiquitin-specific protease 2 (USP2) as a key regulator in hepatic lipid metabolism and MASLD progression. We show that USP2 expression is significantly upregulated in liver tissues from MASLD patients and high-fat diet (HFD)-induced mouse models. Usp2 knockout or pharmacological inhibition alleviates hepatic steatosis and improves systemic metabolic parameters both in vivo and in vitro. Strikingly, hepatocyte-targeted GalNAc-conjugated siRNA against Usp2 markedly attenuates MASLD in mouse models, highlighting therapeutic potential. Mechanistically, USP2 directly interacts with and stabilizes peroxisome proliferator-activated receptor γ (PPARγ) by removing K48-linked ubiquitin chains at lysine 161 within its DNA-binding domain, thereby preventing proteasomal degradation and enhancing its transcriptional activity. This USP2-PPARγ axis promotes hepatic lipid accumulation and drives MASLD progression. Our findings uncover a novel regulatory mechanism in MASLD pathogenesis and suggest that USP2 may represent a promising and druggable therapeutic target for metabolic liver disease.

Highlights

  • USP2 expression is significantly upregulated in liver tissues from both MASLD patients and HFD-induced mouse models.

  • Hepatocyte-specific knockout of Usp2 protects mice from hepatic steatosis and improves metabolic parameters.

  • USP2 stabilizes PPARγ by removing K48-linked ubiquitin chains at lysine 161, thereby promoting lipid accumulation.

  • GalNAc-siRNAs targeting hepatic Usp2 offer a promising treatment strategy for MASLD.

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Fig. 1: USP2 expression is upregulated in MASLD.
Fig. 2: Hepatocyte-specific Usp2 knockout ameliorates MASLD.
Fig. 3: USP2 activity in liver is positively associated with PPARγ level.
Fig. 4: USP2 promotes lipid accumulation through PPARγ.
Fig. 5: USP2 directly interacts with PPARγ.
Fig. 6: USP2 increases the stability of PPARγ.
Fig. 7: USP2 deubiquitinates PPARγ by regulating its K48-linked ubiquitin chains.
Fig. 8: GalNAc-siRNAs targeting hepatic Usp2 alleviate diet-induced MASLD in mice.

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Data availability

The raw RNA-sequencing data have been submitted to the National Center for Biotechnologyinformation (accession number: PRJNA1280771). All data are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82400092, 82470152), the Shandong Provincial Natural Science Foundation (ZR2024MH161), the Weifang Science and Technology Development Plan Project (Medical)(2025YX032), the China Postdoctoral Science Foundation (2023M742311, 2024M762019), and the Shanghai Jiao Tong University School of Medicine the 18th Training Program for Innovation and Entrepreneurship (1824010).

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  1. These authors contributed equally: Hao Luo, Chujiao Zhu, Yingying Wang, Yidong Dai.

Authors and Affiliations

  1. Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People’s Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hao Luo, Chujiao Zhu, Yingying Wang, Wenhui Bai, Zhenge Zhang, Youping Zhang, Yuanhui Zhai, Wenxuan Wu, Hu Lei, Hanzhang Xu, Ming He & Yingli Wu

  2. School of Basic Medical Sciences, Shandong Second Medical University, Weifang, China

    Hao Luo, Peng Hao & Jiale Wan

  3. Shanghai Ruijin Rehabilitation Hospital, Shanghai, China

    Yidong Dai & Yun Sun

  4. Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

    Haiyan Cai

  5. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK

    Ziwei Zhang & Yunzhao Wu

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Contributions

HL and YW contributed to the literature search and study design. HL, YW, PH, and ZZ participated in the drafting of the article. HL, CZ, YW, YD, WB, YZ, YS, YZ, and WW carried out the experiments. YW, MH, YW, ZZ, HL, and HX revised the manuscript. PH, HC, and JW contributed to data collection and analysis. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hao Luo or Yingli Wu.

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The authors declare no competing interests.

Ethics

The collection and use of human samples were approved by the Ethics Committee of Shandong Second Medical University (Approval Number: SDSMU2024YX297) and strictly adhered to the principles of the Declaration of Helsinki. All participants or their close relatives signed written informed consent forms. All animal experiments were conducted with the approval of the Animal Ethics Committee of Shanghai Jiao Tong University School of Medicine (Approval Number: JUMC2023-027-A). All animal experiments were strictly conducted in accordance with institutional guidelines.

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Luo, H., Zhu, C., Wang, Y. et al. USP2 promotes metabolic dysfunction-associated steatotic liver disease progression via stabilization of PPARγ. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01589-2

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