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However, TRPC6 expression is decreased in patients with liver diseases. Here, we explored the role of TRPC6 in liver fibrosis and the underlying mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Bile duct ligation and thioacetamide gavage were used to model liver fibrosis in C57BL\/6J mice. Western blotting, immunolabelling and qPCR were employed for protein and mRNA expression. Liver injury\/fibrosis were assessed using serum alanine transaminase and aspartate transaminase assays, haematoxylin\u2013eosin, Masson and Sirius red staining. Adenoviruses were used to overexpress TRPC6 and CREB1<jats:sup>Y134F<\/jats:sup>. ChIP and dual\u2010luciferase reporter assays were performed to test the direct inhibition of <jats:italic>Acta2<\/jats:italic> transcription by CREB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>TRPC6 protein levels were decreased in fibrotic liver tissues from both patients and mice, with the decrease being more robust in fibrotic areas. In hepatic stellate cells (HSCs), TRPC6 ablation aggravated liver injury and fibrosis, which was alleviated by overexpressing TRPC6. In primary cultured HSCs, deletion of TRPC6 exacerbated self\u2010activation of HSCs, which was reversed by restoration of TRPC6 expression. Mechanistically, TRPC6 suppressed HSC activation through CaMK4\u2010mediated CREB phosphorylation. CREB directly interacted with the promoter region of <jats:italic>Acta2<\/jats:italic> to inhibit its transcription. Expression of a constitutively active form of CREB1 (CREB1<jats:sup>Y134F<\/jats:sup>) in HSCs attenuated BDL\u2010induced liver injury\/fibrosis in TRPC6 knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Deficiency of TRPC6 aggravates liver injury\/fibrosis through augmentation of HSC activation. Increasing TRPC6 expression\/function would be therapeutically beneficial for fibrotic liver diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17431","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T23:39:23Z","timestamp":1738193963000},"page":"5004-5022","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["TRPC6 suppresses liver fibrosis by inhibiting hepatic stellate cell activation via CaMK4\u2010CREB pathway"],"prefix":"10.1111","volume":"182","author":[{"given":"Shan","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy China 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