2. Academic Validation
  3. USP13 promotes hepatic stellate cells activation and aggravates liver fibrosis through deubiquitinating SMAD3

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

  • Hepatol Int. 2025 Jul 28. doi: 10.1007/s12072-025-10880-w.
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

Affiliations

  • 1 Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 3 School of Pharmacy, Yanbian University, Yanbian, Jilin, China.
  • 4 Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. wuluo@wmu.edu.cn.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. wuluo@wmu.edu.cn.
  • 6 Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. wzmcliangguang@163.com.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. wzmcliangguang@163.com.
  • 8 Department of Pharmacy and School of Pharmaceutical Sciences, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China. wzmcliangguang@163.com.
  • # Contributed equally.
PMID: 40719972 DOI: 10.1007/s12072-025-10880-w
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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