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Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV reverse transcriptase, they cannot lead to negative conversion of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg). In this study, we revealed that the antifilarial drug ivermectin suppresses HBV production by a different mechanism from the nucleic acid analog entecavir or Na+ taurocholate co-transporting polypeptide-mediated entry inhibitor cyclosporin A. Ivermectin reduced the levels of several HBV markers, including HBsAg, in HBV-infected human hepatocellular carcinoma cells (HepG2-hNTCP-C4 cells) and humanized mouse hepatocytes (PXB hepatocytes). In addition, ivermectin significantly decreased the expression of HBV core protein and the nuclear transporter karyopherin \u03b12 (KPNA2) in the nuclei of HepG2-hNTCP-C4 cells. Furthermore, depletion of KPNA1\u20136 suppressed the production of cccDNA. These results suggest that KPNA1\u20136 is involved in the nuclear import of HBV and that ivermectin suppresses the nuclear import of HBV by inhibiting KPNA2. This study demonstrates the potential of ivermectin as a novel treatment for hepatitis B.<\/jats:p>","DOI":"10.3390\/v14112468","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T10:55:32Z","timestamp":1667904932000},"page":"2468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2"],"prefix":"10.3390","volume":"14","author":[{"given":"Anna","family":"Nakanishi","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-145X","authenticated-orcid":false,"given":"Tadahiro","family":"Hashita","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"},{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakina","family":"Kamimura","sequence":"additional","affiliation":[{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9164-9152","authenticated-orcid":false,"given":"Sanae","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"},{"name":"Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-2712","authenticated-orcid":false,"given":"Shuko","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Iwao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"},{"name":"Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari","family":"Ikeda","sequence":"additional","affiliation":[{"name":"\u014cmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyasu","family":"Hirose","sequence":"additional","affiliation":[{"name":"\u014cmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Sunazuka","sequence":"additional","affiliation":[{"name":"\u014cmura Satoshi Memorial Institute, Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8641, 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