Hepatology research : the official journal of the Japan Society of Hepatology · 2025
Sacubitril/Valsartan Attenuates Inflammation and Fibrosis Associated With Decreased Integrin α8 and Inhibits Hepatocarcinogenesis in a Rat Model of Metabolic Dysfunction-Associated Steatohepatitis.
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Kawamura Hayato, Naiki-Ito Aya, Kuang Xiaochen, Murakami Akihiro, Komura Masayuki, Suzuki Takanori, Kato Hiroyuki, Nagayasu Yuko, Matsuura Kentaro, Fujiwara Kei, Kataoka Hiromi, Takahashi Satoru
Аннотация
AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation and fibrosis. We aimed to elucidate the antifibrotic advantage of Sacubitril/Valsartan (Sac/Val) and molecular mechanisms using a rat MASH model and cells.
METHODS: A connexin 32 dominant negative transgenic rat MASH model was induced using a high-fat diet plus dimethylnitrosamine and treated with Val (5 mg/kg/day) or Sac/Val (10 mg/kg/day) for 17 weeks. Histological evaluation, immunohistochemistry, RT-PCR, western blot, and RNA sequencing were performed to assess steatohepatitis, fibrosis, hepatocarcinogenesis, and signaling pathways. Direct modulatory effects were analyzed using a rat hepatic stellate cell (HSC) line.
RESULTS: Sac/Val significantly reduced steatohepatitis and hepatic fibrosis histologically compared with Val alone, with fewer α-smooth muscle actin (SMA)-positive activated HSCs. Hepatic preneoplastic lesions were also reduced. Sac/Val suppressed Nlrp3, reactive oxygen species levels, and phosphorylated p38 mitogen-activated protein kinase, and cleaved gasdermin D, mitigating oxidative stress and inflammasome signaling. RNA sequencing revealed integrin alpha 8 (Itga8), a key regulator of HSC activation, was downregulated by Sac/Val compared with Val, correlating with HSC activation and fibrosis. Immunohistochemistry revealed decreased Itga8 protein expression in fibrotic regions with Sac/Val treatment. Sac/Val inhibited transforming growth factor (TGF)-β1-induced HSC activation, proliferation, and collagen production, further supporting its direct antifibrotic effects. Conversely, stable Itga8 overexpression in HSC enhanced proliferation and upregulated Tgfb1 and α-SMA, supporting the role of Itga8 in HSC activation.
CONCLUSIONS: Sac/Val attenuated fibrosis and inflammation in MASH, potentially through suppression of Itga8 expression, oxidative stress, and inflammasome signaling, highlighting Sac/Val as a promising MASH therapy.
METHODS: A connexin 32 dominant negative transgenic rat MASH model was induced using a high-fat diet plus dimethylnitrosamine and treated with Val (5 mg/kg/day) or Sac/Val (10 mg/kg/day) for 17 weeks. Histological evaluation, immunohistochemistry, RT-PCR, western blot, and RNA sequencing were performed to assess steatohepatitis, fibrosis, hepatocarcinogenesis, and signaling pathways. Direct modulatory effects were analyzed using a rat hepatic stellate cell (HSC) line.
RESULTS: Sac/Val significantly reduced steatohepatitis and hepatic fibrosis histologically compared with Val alone, with fewer α-smooth muscle actin (SMA)-positive activated HSCs. Hepatic preneoplastic lesions were also reduced. Sac/Val suppressed Nlrp3, reactive oxygen species levels, and phosphorylated p38 mitogen-activated protein kinase, and cleaved gasdermin D, mitigating oxidative stress and inflammasome signaling. RNA sequencing revealed integrin alpha 8 (Itga8), a key regulator of HSC activation, was downregulated by Sac/Val compared with Val, correlating with HSC activation and fibrosis. Immunohistochemistry revealed decreased Itga8 protein expression in fibrotic regions with Sac/Val treatment. Sac/Val inhibited transforming growth factor (TGF)-β1-induced HSC activation, proliferation, and collagen production, further supporting its direct antifibrotic effects. Conversely, stable Itga8 overexpression in HSC enhanced proliferation and upregulated Tgfb1 and α-SMA, supporting the role of Itga8 in HSC activation.
CONCLUSIONS: Sac/Val attenuated fibrosis and inflammation in MASH, potentially through suppression of Itga8 expression, oxidative stress, and inflammasome signaling, highlighting Sac/Val as a promising MASH therapy.