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The present study examined the preventive effect of lenvatinib on experimental liver fibrosis and sinusoidal capillarization as well as the in vitro phenotypes of hepatic stellate cells. LX\u20102, a human stellate cell line, was used for in vitro studies. In vivo liver fibrosis was induced in F344 rats using carbon tetrachloride by intraperitoneal injection for 8\u00a0weeks, and oral administration of lenvatinib was started two weeks after initial injection of carbon tetrachloride. Lenvatinib restrained proliferation and promoted apoptosis of LX\u20102 with suppressed phosphorylation of extracellular signal\u2010regulated kinase 1\/2 and AKT. It also down\u2010regulated <jats:italic>COL1A1<\/jats:italic>, <jats:italic>ACTA2<\/jats:italic> and <jats:italic>TGFB1<\/jats:italic> expressions by inhibiting the transforming growth factor\u2010\u03b21\/Smad2\/3 pathway. Treatment with lenvatinib also suppressed platelet\u2010derived growth factor\u2010BB\u2010stimulated proliferation, chemotaxis and vascular endothelial growth factor\u2010A production, as well as basic fibroblast growth factor\u2010induced LX\u20102 proliferation. In vivo study showed that lenvatinib attenuated liver fibrosis development with reduction in activated hepatic stellate cells and mRNA expression of profibrogenic markers. Intrahepatic neovascularization was ameliorated with reduced hepatic expressions of <jats:italic>Vegf1<\/jats:italic>, <jats:italic>Vegf2<\/jats:italic> and <jats:italic>Vegfa<\/jats:italic> in lenvatinib\u2010treated rats. Collectively, these results suggest the potential use of lenvatinib as a novel therapeutic strategy for liver fibrosis.<\/jats:p>","DOI":"10.1111\/jcmm.16363","type":"journal-article","created":{"date-parts":[[2021,2,21]],"date-time":"2021-02-21T03:49:00Z","timestamp":1613879340000},"page":"4001-4013","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lenvatinib prevents liver fibrosis by inhibiting hepatic stellate cell activation and sinusoidal capillarization in experimental liver fibrosis"],"prefix":"10.1111","volume":"25","author":[{"given":"Hiroyuki","family":"Ogawa","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Nara Medical University Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-6759","authenticated-orcid":false,"given":"Kosuke","family":"Kaji","sequence":"additional","affiliation":[{"name":"Department of 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