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. 2025 Jul 28.
doi: 10.1007/s12072-025-10880-w. Online ahead of print.

USP13 promotes hepatic stellate cells activation and aggravates liver fibrosis through deubiquitinating SMAD3

Ao Wang #  1   2   3 , Hui Dong #  1   2 , Yaqian Cui  2 , Weiwei Zhu  1   2 , Jiaxi Ye  2 , Leiming Jin  2 , Yongqiang Xiong  1   2 , Qianhui Zhang  2   3 , Mengsha Lin  2 , Jibo Han  2 , Zimin Fang  2 , Xiang Hu  1 , Wu Luo  4   5 , Guang Liang  6   7   8
Affiliations

USP13 promotes hepatic stellate cells activation and aggravates liver fibrosis through deubiquitinating SMAD3

Ao Wang et al. Hepatol Int. .

Abstract

Background/aims: Activation of hepatic stellate cells (HSCs) is key to the development of liver fibrosis. Recent studies have highlighted the role of deubiquitinating enzymes (DUBs) in regulating protein stability and function, closely related to liver fibrosis. In this study, we screened out a key DUB, ubiquitin-specific peptidase 13 (USP13), in HSCs activation and explored its role and underlying mechanism.

Methods: Gene Expression Omnibus (GEO) public database were used to demonstrate the correlation of USP13 with HSC activation. Mice with adeno-associated virus (AAV)-mediated HSC-specific USP13 deficiency are proceeded to carbon tetrachloride (CCl4) or common bile duct ligation (BDL) models. Co-immunoprecipitation combined with mass spectrometry (Co-IP/MS) was used to identify the substrate for USP13.

Results: We first found that USP13 expression was upregulated in activated HSCs and in both CCl4- and BDL-induced liver fibrosis mice. HSC-specific knockdown of USP13 alleviates liver fibrosis and HSC activation in mice caused by CCl4 or BDL. Mechanistically, we identified SMAD3 as a potential substrate for USP13 by Co-IP/MS. USP13 binds to the MH2 domain of SMAD3 and deubiquitinates SMAD3. USP13 cysteine at position 345 (C345) promotes the stability of SMAD3 by removing the K48 ubiquitin chain from the lysine at position 13 (K13) of SMAD3, enhancing SMAD3 protein activity and inducing transcription of downstream profibrotic genes, which finally leads to HSCs activation and liver fibrosis.

Conclusions: This study illustrates an HSC-specific USP13-SMAD3 axis in regulating liver fibrosis and presents USP13 as a potential target for the treatment of liver fibrosis.

Keywords: Deubiquitinating enzyme; HSC; Liver fibrosis; SMAD3; USP13.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval and consent to participate: All animal care and experimental procedures were conducted in accordance with the guidelines approved by the Ethics Committee of the Animal Experiment Center at Wenzhou Medical University.

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References

    1. Devaraj E, Perumal E, Subramaniyan R, Mustapha N. Liver fibrosis: extracellular vesicles mediated intercellular communication in perisinusoidal space. Hepatology. 2022;76:275–285 - DOI - PubMed
    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–218 - DOI - PubMed - PMC
    1. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397–411 - DOI - PubMed
    1. Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56:1171–1180 - DOI - PubMed
    1. Senoo H, Kojima N, Sato M. Vitamin A-storing cells (stellate cells). Vitam Horm. 2007;75:131–159 - DOI - PubMed

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