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  3. Proteomics and Phosphoproteomics Revealed Dysregulated Kinases and Potential Therapy for Liver Fibrosis

Proteomics and Phosphoproteomics Revealed Dysregulated Kinases and Potential Therapy for Liver Fibrosis

  • Mol Cell Proteomics. 2025 Jun;24(6):100991. doi: 10.1016/j.mcpro.2025.100991.
Xinyu Cheng 1,  Li Kang 2,  Jinfang Liu 3,  Qingye Wang 4,  Zhenpeng Zhang 4,  Li Zhang 1,  Yuping Xie 4,  Lei Chang 4,  Daobing Zeng 5,  Lantian Tian 6,  Lingqiang Zhang 7,  Ping Xu 8,  Yanchang Li 9
Affiliations

Affiliations

  • 1 Anhui Medical University School of Basic Medicine, Anhui, PR China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 2 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; School of Public Health, China Medical University, Shenyang, China.
  • 3 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; TaiKang Medical School (School of Basic Medical Sciences), Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, PR China.
  • 4 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 5 General Surgery Department, Beijing Youan Hospital, Capital Medical University, Beijing, China.
  • 6 Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, PR China.
  • 7 Anhui Medical University School of Basic Medicine, Anhui, PR China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. Electronic address: zhanglq@bmi.ac.cn.
  • 8 Anhui Medical University School of Basic Medicine, Anhui, PR China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; School of Public Health, China Medical University, Shenyang, China; College of Life Sciences, Hebei University, Baoding, China; TaiKang Medical School (School of Basic Medical Sciences), Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, PR China. Electronic address: xuping_bprc@126.com.
  • 9 Anhui Medical University School of Basic Medicine, Anhui, PR China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China; College of Life Sciences, Hebei University, Baoding, China. Electronic address: liyanchang1017@163.com.
PMID: 40368138 DOI: 10.1016/j.mcpro.2025.100991
Abstract

Liver fibrosis is the initial stage of most liver diseases, and it is also a pathological process involving the liver in the late stages of many metabolic diseases. Therefore, it is important to systematically understand the pathological mechanism of liver fibrosis and seek therapeutic approaches for intervention and treatment of liver fibrosis. Disordered proteins and their post-translational modifications, such as phosphorylation, play vital roles in the occurrence and development of liver fibrosis. However, the regulatory mechanisms that govern this process remain poorly understood. In this study, we analyzed and quantified the liver proteome and phosphoproteome of carbon tetrachloride-induced early liver fibrosis model in mice. Proteomic analysis revealed that the pathways involved in extracellular matrix recombination, Collagen formation, metabolism and Other related disorders, and protein phosphorylation modification pathways were also significantly enriched. In addition, Western blotting and phosphoproteomics demonstrated that phosphorylation levels were elevated in the context of liver fibrosis. A total of 13,152 phosphosites were identified, with 952 sites increased, whereas only 156 sites decreased. Furthermore, the upregulated phosphorylation sites, which exhibited no change at the proteome level, mainly shared a common [xxxSPxxx] motif. Consequently, the kinase-substrate analysis ascertained the overactive kinases of these upregulated substrates, which ultimately led to the identification of 13 significantly altered kinases within this dataset. These kinases were mainly cataloged into the STE, CMGC, and CaMK kinase families. Among them, STK4 (serine/threonine-protein kinase 4), GSK3α (glycogen synthase kinase 3α), and CDK11B (cyclin-dependent kinase 11B) were subsequently validated though cellular and animal experiments, and the results demonstrated that their inhibitors could effectively reduce the activation of hepatic stellate cells and extracellular matrix production. These kinases may represent potential therapeutic targets for liver fibrosis, and their inhibitors may serve as promising antihepatic fibrosis drugs.

Keywords

inhibitors; kinases; liver fibrosis; phosphoproteomics; proteomics.

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