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The rapid mutation of the IAV RNA genome undermines the efficacy of vaccines and prevention strategies, while the emergence of drug\u2010resistant strains has further complicated control efforts\u2014underscoring an urgent need for novel, effective anti\u2010influenza therapeutics. Herein, we demonstrate that cepharanthine (CEP), a secondary metabolite isolated from Stephania spp., potently inhibits infection and replication of multiple IAV subtypes in vitro with its antiviral mechanism being independent of host innate immune response modulation. CEP treatment conferred significant protection to mice infected with a high dose of PR8. Further investigations revealed that CEP treatment during pre\u2010infection and viral adsorption phases significantly suppresses IAV replication, markedly attenuates IAV\u2010induced cytopathic effects, and enhances cell viability. Importantly, we identified for the first time that CEP strongly blocks IAV attachment to host cell membranes. Moreover, CEP administration significantly reduces disease severity in IAV\u2010infected mice. These findings indicate that CEP exhibits broad\u2010spectrum anti\u2010IAV activity, providing a critical foundation for the development of novel anti\u2010influenza pharmaceuticals.<\/jats:p>","DOI":"10.1002\/jmv.71062","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T07:57:29Z","timestamp":1784275049000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cepharanthine Inhibits Influenza A Virus Infection by Blocking Viral Attachment to Host Cells"],"prefix":"10.1002","volume":"98","author":[{"given":"Shan","family":"Chen","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Beijing University of Agriculture Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine China 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