Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/MAPK Pathway of Hepatic Stellate Cells

  • Yoon, Young-Chan (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Fang, Zhenghuan (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Lee, Ji Eun (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Park, Jung Hee (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Ryu, Ji-Kan (Department of Urology, College of Medicine, Inha University) ;
  • Jung, Kyung Hee (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University) ;
  • Hong, Soon-Sun (Department of Biomedical Sciences, College of Medicine, and Program in Biomedical Science & Engineering, Inha University)
  • Received : 2020.02.05
  • Accepted : 2020.04.29
  • Published : 2020.11.01
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Abstract

Liver fibrosis constitutes a significant health problem worldwide due to its rapidly increasing prevalence and the absence of specific and effective treatments. Growing evidence suggests that apoptosis-signal regulating kinase 1 (ASK1) is activated in oxidative stress, which causes hepatic inflammation and apoptosis, leading to liver fibrogenesis through a mitogen-activated protein kinase (MAPK) downstream signals. In this study, we investigated whether selonsertib, a selective inhibitor of ASK1, shows therapeutic efficacy for liver fibrosis, and elucidated its mechanism of action in vivo and in vitro. As a result, selonsertib strongly suppressed the growth and proliferation of hepatic stellate cells (HSCs) and induced apoptosis by increasing Annexin V and TUNEL-positive cells. We also observed that selonsertib inhibited the ASK1/MAPK pathway, including p38 and c-Jun N-terminal kinase (JNK) in HSCs. Interestingly, dimethylnitrosamine (DMN)-induced liver fibrosis was significantly alleviated by selonsertib treatment in rats. Furthermore, selonsertib reduced collagen deposition and the expression of extracellular components such as α-smooth muscle actin (α-SMA), fibronectin, and collagen type I in vitro and in vivo. Taken together, selonsertib suppressed fibrotic response such as HSC proliferation and extracellular matrix components by blocking the ASK1/MAPK pathway. Therefore, we suggest that selonsertib may be an effective therapeutic drug for ameliorating liver fibrosis.

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References

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