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We assessed the anti\u2010MSRV activity of milbemycin A4 (A4), a macrolide derived from\n                    <jats:italic>Streptomyces bingchenggensis<\/jats:italic>\n                    in both cell\u2010based and animal models. Cytotoxicity assays revealed that A4 was not toxic to EPC cells at concentrations up to 6.4\u2009mg\/L. It significantly reduced viral N gene expression by approximately 90.25%. A4 also suppressed MSRV\u2010induced apoptosis, decreasing the apoptotic cell population by about 21.88%, and preserved mitochondrial membrane potential. Investigations of the viral life cycle demonstrated that A4 directly targets virions, impairing their binding and internalization, and additionally inhibits early post\u2010entry replication events. In\u00a0vivo analyses further revealed that A4 treatment led to significant induction of antiviral\u2010related genes (\n                    <jats:italic>IRF3<\/jats:italic>\n                    ,\n                    <jats:italic>IRF7<\/jats:italic>\n                    and\n                    <jats:italic>IFN\u2010\u03b3<\/jats:italic>\n                    ), which was accompanied by enhanced survival of infected fish (54%), along with reduced viral accumulation in the liver and spleen and alleviated histopathological damage. These findings suggest that A4 exhibits strong anti\u2010MSRV activity by targeting early infection stages, protecting mitochondrial integrity and enhancing host innate immunity, highlighting its potential for application in aquaculture disease control.\n                  <\/jats:p>","DOI":"10.1111\/jfd.70220","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:19:08Z","timestamp":1782400748000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Milbemycin\n                    <scp>A<\/scp>\n                    4, Derived From\n                    <i>Streptomyces bingchenggensis<\/i>\n                    Exhibits Antiviral Activity Against\n                    <scp>MSRV<\/scp>\n                    In\u00a0Vitro and In\u00a0Vivo"],"prefix":"10.1111","volume":"49","author":[{"given":"Qianhao","family":"Shao","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key 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