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We previously reported that the suppression of dedicator of cytokinesis 11 (DOCK11) decreases cccDNA and HBV-DNA levels and identified it as a new HBV therapeutic target. The DOCK11-associated gene, Wnt\/\u03b2-catenin signaling regulator tankyrase (TNKS), was identified using in vitro methods; however, its function in the HBV life cycle remains unknown. Here, we used various inhibitors, antagonists, and short-hairpin RNA treatments related to TNKS signaling in HBV-infected hepatocytes. The role of TNKS-related Wnt\/\u03b2-catenin signaling in the HBV life cycle was evaluated using immunoprecipitation assays with DOCK11 and bulk RNA sequencing methods. TNKS and Wnt\/\u03b2-catenin signaling inhibitors significantly repressed cccDNA and HBV-DNA levels. Conversely, certain Wnt\/\u03b2-catenin signaling agonists enhanced the HBV life cycle. DOCK11 directly binds to \u03b2-catenin to regulate HBV using its nuclear transport system. SKL2001, normally used as a Wnt\/\u03b2-catenin signaling agonist, strongly reduced cccDNA in HBV-infected hepatocytes and in combination with entecavir predominantly eradicated HBV without cytotoxicity. Therefore, DOCK11 and other Wnt\/\u03b2-catenin signaling molecules may be therapeutic targets to prevent persistent HBV infection.<\/jats:p>","DOI":"10.3390\/ijms26146942","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"6942","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Wnt\/\u03b2-Catenin Signaling Regulates Hepatitis B Virus cccDNA Levels"],"prefix":"10.3390","volume":"26","author":[{"given":"Atsuya","family":"Ishida","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-0942, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-3054","authenticated-orcid":false,"given":"Sadahiro","family":"Iwabuchi","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa 920-0934, Japan"},{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Murai","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-0942, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Shirasaki","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-0942, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Kuroki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Shimakami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-8313","authenticated-orcid":false,"given":"Koki","family":"Nio","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4927-1704","authenticated-orcid":false,"given":"Kazunori","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Imafuku","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Ito","sequence":"additional","affiliation":[{"name":"Purotech Bio Inc., Yokohama 230-0045, 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Biomedical Sciences, Tokyo University of Science, Noda 278-0022, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3050-5854","authenticated-orcid":false,"given":"Masao","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-0942, Japan"},{"name":"Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa 920-0934, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1223-2349","authenticated-orcid":false,"given":"Shinichi","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-0012, 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