{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T12:27:23Z","timestamp":1780576043721,"version":"3.54.1"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24fk03105149"],"award-info":[{"award-number":["JP24fk03105149"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25fk0310539"],"award-info":[{"award-number":["JP25fk0310539"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Netrin-1, a secreted laminin-related protein, is increasingly recognized for its role in viral pathogenesis, alongside its established functions in neural guidance and immune regulation. We previously identified endothelial lipase (LIPG) as a host factor that facilitates hepatitis B virus (HBV) attachment via heparan sulfate proteoglycans (HSPGs) and\/or the sodium taurocholate cotransporting polypeptide (NTCP). Through LIPG-based screening, we identified Netrin-1 as an LIPG-interacting protein, and synthetic peptides derived from Netrin-1 sequences exhibited potent anti-HBV activity. In primary human hepatocytes, Netrin-1 demonstrated antiviral activity against HBV, and in HepG2-NTCP-YFP cells, it inhibited viral attachment and internalization. Mechanistically, Netrin-1 binds to LIPG through heparin-binding motifs in its V and C domains, disrupting LIPG-HBV interactions and displacing LIPG from HSPGs. Furthermore, Netrin-1 binds to the extracellular domain of epidermal growth factor receptor (EGFR), abrogating NTCP-EGFR complex formation and inhibiting EGFR dimerization and phosphorylation, independently of HSPGs.\n                    <jats:italic>In vivo,<\/jats:italic>\n                    recombinant Netrin-1 suppressed the viral infection in humanized hepatocyte chimeric mice. These findings establish Netrin-1 as a multifunctional host factor that interferes with HBV entry, supporting the development of Netrin-1-based therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013776","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:33:02Z","timestamp":1765996382000},"page":"e1013776","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Netrin-1 inhibits the attachment and internalization of Hepatitis B virus for hepatocyte infection"],"prefix":"10.1371","volume":"21","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Murai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuya","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narumi","family":"Kawasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Kuroki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuga","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaro","family":"Miura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kureha","family":"Takara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianghao","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Shimakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouki","family":"Nio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Suemizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yanagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3050-5854","authenticated-orcid":true,"given":"Masao","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"issue":"6","key":"ppat.1013776.ref001","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1002\/hep.28025","article-title":"Present 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