Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells

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.

Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

“…Our work showed Ser could significantly block the activation of ASK1/P38/JNK and NFκB signal pathways induced by IL-1β in rat chondrocytes. The observations partly mimic results of Yoon et al study, which demonstrated that selonsertib alleviates liver fibrosis via blocking ASK1/MAPK pathway in hepatic stellate cells ( Yoon et al, 2020 ). Collectively, the two pathways were involved in the protective roles of Ser in OA.…”

“…However, the detailed role of Ser in OA treatment remains to explore. Previous study reported that Ser could block ASK1/MAPK pathway in hepatic stellate cells and down-regulate ASK1-JNK-DRP1 pathway in macrophage, suggesting the possible mechanism of its action ( Yoon et al, 2020 ; Lou et al, 2021 ). In this study, we aim to elucidate the therapeutic effects and molecular mechanisms of Ser in OA.…”

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

“…In this direction, selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, was proposed. In fact, selonsertib demonstrated potent antifibrotic activity in rodent models (64,65). However, two large phase 3 trials in NASH patients with either advanced fibrosis or cirrhosis failed, as selonsertib did not improve liver fibrosis after 48 weeks of therapy compared to placebo (66).…”

Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy

“…ASK1, which is activated by a variety of pro-fibrotic factors, activates MAPK signal pathway, and participates in hepatocyte apoptosis, inflammation and fibrosis. Selonsertib (GS-4997), a selective ASK1 inhibitor, inhibited HSCs proliferation and ECM production by blocking the ASK1/MAPK pathway, and significantly alleviated DMN-induced liver fibrosis in rats ( Yoon et al, 2020 ). Selonsertib was used to treat 74 NASH patients with F2–F3 fibrosis for 24 weeks with dose of 6 mg/d or 18 mg/d in a multicenter phase II clinical trial.…”