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Galectin-9 (Gal-9) is an immunomodulatory lectin implicated in various viral infections, yet its role in EVs remains unexplored. Here, we identify Gal-9 as a novel host restriction factor against a broad spectrum of EVs, including EV-A71, EV-D68, and Coxsackievirus B2.\n                      <jats:italic toggle=\"yes\">LGALS9<\/jats:italic>\n                      deficiency increased viral replication in cells and pathogenicity in a mouse model of EV-A71 infection, while its overexpression inhibited viral replication. Mechanistically, Gal-9 specifically interacts with the viral VP2 protein, and mapping identified residues 179\u2013194 of Gal-9 as critical for this interaction. A Gal-9 \u0394179\u2013194 mutant lost VP2-binding capacity and antiviral activity. These findings reveal that Gal-9 is a key component of the host antiviral response against EVs, functioning through a direct interaction with the viral VP2 protein.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Enteroviruses (EVs) cause a wide spectrum of disease and present a persistent global health challenge, highlighted by the cyclical resurgence of strains like EV-D68 and EV-A71. However, due to a lack of sufficient understanding of their pathogenesis, no EV-specific antiviral drugs are available. This study demonstrates that galectin-9 (Gal-9) is a key host factor that broadly antagonizes EVs, including EV-A71, EV-D68, and Coxsackievirus B2. We show that Gal-9 deficiency enhances viral replication both in cell culture and in an animal model. By identifying Gal-9 as a crucial restriction factor against EVs, our study provides foundational insight for the future development of antiviral strategies.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00179-26","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T13:00:17Z","timestamp":1774616417000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Galectin-9 is a restrictor of infection with multiple enteroviruses"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3378-3311","authenticated-orcid":false,"given":"Zichun","family":"Xiang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Health and Multimorbidity, and Christophe M\u00e9drieux Laboratory, National Institute 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