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Caerulein (CRE)\u2010induced AP mice represented significant pancreatic and lung pathological injury, with high Nr4a3 expression in lung tissues. Nr4a3 expression in lung tissues of AP mice inhibited CD31 expression, suggesting lung microvascular injury. In\u00a0vitro and in\u00a0vivo experiments were performed to investigate the effect of Nr4a3 inhibition in mitigating SAP\u2010associated ALI. Nr4a3 downregulation reduced permeability, increased trans\u2010endothelial electrical resistance (TEER) and VE\u2010cadherin expression in TNF\u2010\u03b1\u2010induced human pulmonary microvascular endothelial cells (hPMVECs), suggesting recovered endothelial barrier function. Nr4a3 knockdown attenuated lung injury in AP mice, as reflected by restored lung edema and endothelial barrier function. Reduced inflammatory cell counts and mediators indicated that Nr4a3 knockdown mitigated lung inflammation in AP mice. The up\u2010regulation of Nr4a3 in TNF\u2010\u03b1\u2010induced hPMVECs was further elevated after Sirt1 (a deacetylase) inhibition. Mechanistically, Sirt1 deficiency increased the enrichment of CREB at the Nr4a3 promoter through acetylating H3K27, thereby promoting Nr4a3 expression. Rescue experiments in\u00a0vivo demonstrated that Nr4a3 knockdown attenuated lung injury aggravated by Sirt1 inhibition. These results suggested that Sirt1 might prevent CREB enrichment by inhibiting histone acetylation in the Nr4a3 promoter, thereby suppressing Nr4a3 expression and ultimately attenuating ALI.<\/jats:p>","DOI":"10.1096\/fj.202501210r","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T16:12:31Z","timestamp":1753287151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sirt1\u2010Mediated Transcriptional Inhibition of Nr4a3 Alleviates Severe Acute Pancreatitis\u2010Associated Acute Lung Injury"],"prefix":"10.1096","volume":"39","author":[{"given":"Xiaolin","family":"Dou","sequence":"first","affiliation":[{"name":"Department of General Surgery Xiangya Hospital of Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongcheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Xiangya 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