Open AccessSelonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells
Author(s) -
Young-Chan Yoon,
Zhenghuan Fang,
Ji Eun Lee,
Jung Hee Park,
JiKan Ryu,
Kyung Hee Jung,
SoonSun Hong
Publication year - 2020
Publication title -
biomolecules and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.977
H-Index - 36
eISSN - 2005-4483
pISSN - 1976-9148
DOI - 10.4062/biomolther.2020.016
Subject(s) - hepatic stellate cell , ask1 , apoptosis , microbiology and biotechnology , fibrosis , mapk/erk pathway , downregulation and upregulation , annexin , cancer research , p38 mitogen activated protein kinases , fibronectin , kinase , in vivo , extracellular matrix , chemistry , protein kinase a , biology , medicine , mitogen activated protein kinase kinase , endocrinology , biochemistry , gene
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.