Sacubitril/Valsartan Attenuates Inflammation and Fibrosis Associated With Decreased Integrin α8 and Inhibits Hepatocarcinogenesis in a Rat Model of Metabolic Dysfunction‐Associated Steatohepatitis

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.