Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.016
Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells
Young-Chan Yoon1, Zhenghuan Fang1, Ji Eun Lee1, Jung Hee Park1, Ji-Kan Ryu2, Kyung Hee Jung1,* and Soon-Sun Hong1,*
1Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22332,
2Department of Urology, College of Medicine, Inha University, Incheon 22332, Republic of Korea
E-mail: hongs@inha.ac.kr (Hong SS), jkh0909@inha.ac.kr (Jung KH)
Tel: +82-32-890-3683 (Hong SS), +82-32-890-2466 (Jung KH)
Fax: +82-32-890-2462 (Hong SS), +82-32-890-2462 (Jung KH)
Received: February 5, 2020; Revised: April 23, 2020; Accepted: April 29, 2020; Published online: May 26, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: Liver fibrosis, ASK1, Selonsertib, MAPK


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