{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T17:21:13Z","timestamp":1786296073630,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T00:00:00Z","timestamp":1765065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T00:00:00Z","timestamp":1765065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100008886","name":"Princess Takamatsu Cancer Research Fund","doi-asserted-by":"publisher","award":["20\u201025225"],"award-info":[{"award-number":["20\u201025225"]}],"id":[{"id":"10.13039\/501100008886","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Metabolic dysfunction\u2010associated 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A connexin 32 dominant negative transgenic rat MASH model was induced using a high\u2010fat diet plus dimethylnitrosamine and treated with Val (5\u00a0mg\/kg\/day) or Sac\/Val (10\u00a0mg\/kg\/day) for 17\u00a0weeks. Histological evaluation, immunohistochemistry, RT\u2010PCR, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sac\/Val significantly reduced steatohepatitis and hepatic fibrosis histologically compared with Val alone, with fewer\n                      <jats:italic>\u03b1<\/jats:italic>\n                      \u2010smooth muscle actin (SMA)\u2010positive activated HSCs. Hepatic preneoplastic lesions were also reduced. Sac\/Val suppressed\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      , reactive oxygen species levels, and phosphorylated p38 mitogen\u2010activated protein kinase, and cleaved gasdermin D, mitigating oxidative stress and inflammasome signaling. RNA sequencing revealed integrin alpha 8 (\n                      <jats:italic>Itga8<\/jats:italic>\n                      ), 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)\u2010\u03b21\u2010induced HSC activation, proliferation, and collagen production, further supporting its direct antifibrotic effects. Conversely, stable\n                      <jats:italic>Itga8<\/jats:italic>\n                      overexpression in HSC enhanced proliferation and upregulated\n                      <jats:italic>Tgfb1<\/jats:italic>\n                      and\n                      <jats:italic>\u03b1<\/jats:italic>\n                      \u2010SMA, supporting the role of Itga8 in HSC activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/hepr.70086","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:21Z","timestamp":1765152021000},"page":"420-435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sacubitril\/Valsartan Attenuates Inflammation and Fibrosis Associated With Decreased Integrin \u03b18 and Inhibits Hepatocarcinogenesis in a Rat Model of Metabolic Dysfunction\u2010Associated Steatohepatitis"],"prefix":"10.1111","volume":"56","author":[{"given":"Hayato","family":"Kawamura","sequence":"first","affiliation":[{"name":"Department of Experimental Pathology and Tumor Biology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"},{"name":"Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences  Nagoya 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