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While sodium taurocholate co-transporting polypeptide (NTCP) is the primary receptor for HBV entry, the molecular mechanisms regulating NTCP-mediated viral entry remain incompletely understood. Here, we identified CD46 as a crucial regulatory factor for NTCP membrane expression. We found that CD46 interacted with NTCP in cis at the plasma membrane through proximity-based labeling screening. The depletion of CD46 significantly reduced cell-surface NTCP levels and HBV infection in hepatocytes. Anti-CD46 monoclonal antibodies, particularly clone E4.3, inhibited HBV infection by triggering NTCP internalization from the plasma membrane to intracellular vesicles. The antiviral effect of CD46 antibodies was also confirmed in primary human hepatocytes. Our study reveals a previously unknown mechanism regulating NTCP-mediated HBV entry and suggests CD46 as a potential therapeutic target for HBV infection.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf055","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T13:12:11Z","timestamp":1766495531000},"source":"Crossref","is-referenced-by-count":0,"title":["CD46 regulates hepatitis B virus entry by modulating cell-surface NTCP levels through\n                    <i>cis<\/i>\n                    -interaction"],"prefix":"10.1093","volume":"18","author":[{"given":"Kei","family":"Miyakawa","sequence":"first","affiliation":[{"name":"AIDS Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]},{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]},{"name":"Institute for Vaccine Research and Development, Hokkaido University , Hokkaido 001-0021 ,","place":["Japan"]},{"name":"Department of Microbiology, Yokohama City University School of Medicine , Kanagawa 236-0004 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nakai","sequence":"additional","affiliation":[{"name":"Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Kameya","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Integrative Omics, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]},{"name":"Life Science Laboratory, Technology and Development Division, Kanto Chemical Co., Inc. , Kanagawa 259-1146 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Nishitsuji","sequence":"additional","affiliation":[{"name":"Department of Virology, Fujita Health University School of Medicine , Aichi 470-1192 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-9966","authenticated-orcid":false,"given":"Koichi","family":"Watashi","sequence":"additional","affiliation":[{"name":"Department of Drug Development, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo , Tokyo 113-0033 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Seya","sequence":"additional","affiliation":[{"name":"Nebuta Research Institute for Life Sciences, Aomori University , Aomori 030-0943 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunitada","family":"Shimotohno","sequence":"additional","affiliation":[{"name":"Institute of Microbial Chemistry (BIKAKEN) , Tokyo 141-0021 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayoi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Advanced Medical Research Center, Yokohama City University , Kanagawa 236-0004 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihide","family":"Ryo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Yokohama City University School of Medicine , Kanagawa 236-0004 ,","place":["Japan"]},{"name":"Department of Bioinformatics and Integrative Omics, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"2026073104463619500_bib1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nmeth.4533","article-title":"Biotinylation by antibody recognition\u2014a method for proximity labeling","volume":"15","author":"Bar","year":"2018","journal-title":"Nat. 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