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Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC\u2010LX2 cells using real\u2010time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co\u2010immunoprecipitation and site\u2010directed mutagenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Wnt\/\u03b2\u2010catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo\u2010independent Gli1 nuclear translocation followed by LARG\u2010mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a\u2010induced Gli1 nuclear translocation. Wnt\/\u03b2\u2010catenin repressed transcription of Sufu dependent on \u03b2\u2010catenin\/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site\u2010directed mutagenesis identified the \u03b2\u2010catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short\u2010term liver\u2010targeting \u03b2\u2010catenin deficiency or acute treatment with \u03b2\u2010catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long\u2010term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Interaction between Wnt\/\u03b2\u2010catenin and Smo\u2010independent Gli1 pathways promoted HSC contraction via TCF4\u2010dependent transrepression of Sufu. HSC\u2010specific inhibition of \u03b2\u2010catenin may have therapeutic benefits for cirrhotic portal hypertension.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15289","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T19:25:28Z","timestamp":1603308328000},"page":"2246-2265","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt\/\u03b2\u2010catenin signalling via interaction with Gli1"],"prefix":"10.1111","volume":"178","author":[{"given":"Feng","family":"Zhang","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy Nanjing University of Chinese Medicine  Nanjing 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