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However, its role in Zika virus (ZIKV) infection remains unclear. This study aims to investigate the effect of OPTN on ZIKV replication and to elucidate the underlying molecular mechanisms. Differential expressions of OPTN during ZIKV infection were analyzed in both A549 and U251\u2010MG cells. OPTN was overexpressed using an EGFP\u2010OPTN plasmid, with an empty EGFP\u2010N1 vector as a control. ZIKV NS5 mRNA and NS1 protein levels were quantified in A549 cells following ZIKV infection by qRT\u2013PCR and Western blotting, respectively, while ZIKV capsid protein expression in U251\u2010MG cells was assessed by immunofluorescence. The expression of type I interferons (IFNs), components of the JAK\/STAT signaling pathway, and downstream interferon\u2010stimulated genes (ISGs) were examined following OPTN overexpression during ZIKV infection. Interferon\u2010stimulated response element (ISRE) activity was evaluated using a dual\u2010luciferase reporter assay. And P\u2010STAT1 was assessed by Western blotting. OPTN mRNA expression was significantly upregulated in both A549 and U251\u2010MG cells in a dose\u2010dependent manner following ZIKV infection. Overexpression of OPTN markedly inhibited ZIKV replication in both cell lines. Mechanistically, OPTN enhanced antiviral activity by inducing type I IFN expression, promoting STAT1 phosphorylation, and increasing ISRE activity. In addition, OPTN upregulated several antiviral ISGs, including MxA, IFIT1, and viperin. These findings identify OPTN as a critical host restricting factor to suppress ZIKV replication by promoting type I IFN\u2010mediated JAK\/STAT signaling pathway.<\/jats:p>","DOI":"10.1002\/jmv.71152","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:42:13Z","timestamp":1789562533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optineurin Restricts ZIKV Replication Through Promoting IFN\u2010Mediated JAK\/STAT Signaling Pathway"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6850-493X","authenticated-orcid":false,"given":"Yike","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Sichuan Clinical Research Center for Laboratory Medicine Chengdu China"},{"name":"Center for Transfusion\u2010transmitted 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