{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:31:31Z","timestamp":1791919891101,"version":"4.3.4"},"reference-count":60,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T00:00:00Z","timestamp":1724025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSFC","award":["82171807"],"award-info":[{"award-number":["82171807"]}]},{"name":"NSFC","award":["31870903"],"award-info":[{"award-number":["31870903"]}]},{"name":"NSFC","award":["22KJA310005"],"award-info":[{"award-number":["22KJA310005"]}]},{"name":"Major Project of Natural Science Research in Jiangsu Higher Education Institutions","award":["82171807"],"award-info":[{"award-number":["82171807"]}]},{"name":"Major Project of Natural Science Research in Jiangsu Higher Education Institutions","award":["31870903"],"award-info":[{"award-number":["31870903"]}]},{"name":"Major Project of Natural Science Research in Jiangsu Higher Education Institutions","award":["22KJA310005"],"award-info":[{"award-number":["22KJA310005"]}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["82171807"],"award-info":[{"award-number":["82171807"]}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["31870903"],"award-info":[{"award-number":["31870903"]}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["22KJA310005"],"award-info":[{"award-number":["22KJA310005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute pancreatitis (AP) is an inflammatory disease initiated by the death of exocrine acinar cells, but its pathogenesis remains unclear. Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates immunity and the inflammatory response. The protective role of STAT3 is reported in Coxsackievirus B3 (CVB3)-induced cardiac fibrosis, yet the exact role of STAT3 in modulating viral-induced STAT1 activation and type I interferon (IFN)-stimulated gene (ISG) transcription in the pancreas remains unclarified. In this study, we tested whether STAT3 regulated viral-induced STAT1 translocation. We found that CVB3, particularly capsid VP1 protein, markedly upregulated the phosphorylation and nuclear import of STAT3 (p-STAT3) while it significantly impeded the nuclear translocation of p-STAT1 in the pancreases and hearts of mice on day 3 postinfection (p.i.). Immunoblotting and an immunofluorescent assay demonstrated the increased expression and nuclear translocation of p-STAT3 but a blunted p-STAT1 nuclear translocation in CVB3-infected acinar 266-6 cells. STAT3 shRNA knockdown or STAT3 inhibitors reduced viral replication via the rescue of STAT1 nuclear translocation and increasing the ISRE activity and ISG transcription in vitro. The knockdown of STAT1 blocked the antiviral effect of the STAT3 inhibitor. STAT3 inhibits STAT1 activation by virally inducing a potent inhibitor of IFN signaling, the suppressor of cytokine signaling-3 ((SOCS)-3). Sustained pSTAT1 and the elevated expression of ISGs were induced in SOCS3 knockdown cells. The in vivo administration of HJC0152, a pharmaceutical STAT3 inhibitor, mitigated the viral-induced AP and myocarditis pathology via increasing the IFN\u03b2 as well as ISG expression on day 3 p.i. and reducing the viral load in multi-organs. These findings define STAT3 as a negative regulator of the type I IFN response via impeding the nuclear STAT1 translocation that otherwise triggers ISG induction in infected pancreases and hearts. Our findings identify STAT3 as an antagonizing factor of the IFN-STAT1 signaling pathway and provide a potential therapeutic target for viral-induced AP and myocarditis.<\/jats:p>","DOI":"10.3390\/ijms25169007","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T10:11:28Z","timestamp":1724062288000},"page":"9007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["STAT3 Increases CVB3 Replication and Acute Pancreatitis and Myocarditis Pathology via Impeding Nuclear Translocation of STAT1 and Interferon-Stimulated Gene Expression"],"prefix":"10.3390","volume":"25","author":[{"given":"Tianming","family":"Liang","sequence":"first","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxin","family":"Bai","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2652-8244","authenticated-orcid":false,"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S0140-6736(20)31310-6","article-title":"Acute pancreatitis","volume":"396","author":"Boxhoorn","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/MOG.0000000000000195","article-title":"Inflammation in acute and chronic pancreatitis","volume":"31","author":"Habtezion","year":"2015","journal-title":"Curr. 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