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Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous <jats:italic>in vitro<\/jats:italic> study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis\u2010related portal hypertension still requires clarification. In this study, gain\u2010 and loss\u2010of\u2010function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl<jats:sub>4<\/jats:sub>\u2010caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl<jats:sub>4<\/jats:sub>\u2010administrated rat HSC but an increase in that in DHA\u2010treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl<jats:sub>4<\/jats:sub>\u2010induced liver injury. DHA also reduced CCl<jats:sub>4<\/jats:sub>\u2010caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT\u2010747 but weakened by Z\u2010guggulsterone. Noteworthily, DHA, analogous to INT\u2010747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction <jats:italic>via<\/jats:italic> a FXR activation\u2010dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.<\/jats:p>","DOI":"10.1111\/febs.13956","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T15:49:20Z","timestamp":1478533760000},"page":"114-133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Dihydroartemisinin counteracts fibrotic portal hypertension <i>via<\/i> farnesoid X receptor\u2010dependent inhibition of hepatic stellate cell contraction"],"prefix":"10.1111","volume":"284","author":[{"given":"Wenxuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Nanjing University of Chinese Medicine China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunfeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Nanjing University of Chinese Medicine 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