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The regulatory role of vitamin D\u2013vitamin D receptor (VDR) signaling in epithelial coagulation responses remains incompletely defined. We investigated the role of vitamin D\u2013VDR signaling in regulating epithelial\u2010driven intra\u2010alveolar coagulation in sepsis\u2010associated lung injury using vitamin D\u2010deficient mice, LPS\u2010induced acute lung injury models, RLE\u20106TN alveolar epithelial cells, and clinical samples from patients with ARDS. Expression of VDR, NF\u2010\u03baB p65, tissue factor (TF), and plasminogen activator inhibitor\u20101 (PAI\u20101) was assessed using qRT\u2010PCR, Western blotting, ELISA, and immunohistochemistry. Functional experiments included 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    supplementation, VDR silencing, and NF\u2010\u03baB p65 gain\u2010 and loss\u2010of\u2010function approaches. Vitamin D deficiency significantly exacerbated LPS\u2010induced lung injury, pulmonary edema, and intra\u2010alveolar hypercoagulation, as reflected by increased TF and PAI\u20101 expression in lung tissue and bronchoalveolar lavage fluid. LPS challenge suppressed VDR expression and concurrently activated NF\u2010\u03baB signaling In\u00a0Vivo and in alveolar epithelial cells. Supplementation with 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    restored VDR expression and attenuated TF and PAI\u20101 induction. Conversely, VDR silencing enhanced NF\u2010\u03baB p65 activation and amplified epithelial procoagulant responses. Mechanistically, NF\u2010\u03baB p65 was required for TF and PAI\u20101 upregulation, and its overexpression abolished the inhibitory effects of vitamin D\u2013VDR signaling. Clinically, patients with ARDS exhibited reduced circulating 25(OH)D levels and decreased VDR expression compared with healthy controls. Vitamin D\u2013VDR signaling acts as an endogenous protective axis that restrains NF\u2010\u03baB\u2013driven epithelial procoagulant activation in sepsis\u2010associated ARDS. Disruption of this pathway promotes TF\u2010 and PAI\u20101\u2010mediated intra\u2010alveolar coagulation, suggesting that restoration of vitamin D\u2013VDR signaling may represent a potential adjunctive therapeutic strategy for ARDS.\n                  <\/jats:p>","DOI":"10.1096\/fj.202505034rr","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T11:31:33Z","timestamp":1781609493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Vitamin D\u2013\n                    <scp>VDR<\/scp>\n                    Signaling Modulates Epithelial\u2010Driven Intra\u2010Alveolar Coagulation via\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    in Sepsis\u2010Associated\n                    <scp>ARDS<\/scp>"],"prefix":"10.1096","volume":"40","author":[{"given":"Qi","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit The Affiliated Hospital of Guizhou Medical University  Guiyang Guizhou China"},{"name":"Guizhou Medical University  Guiyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit The Affiliated Hospital of Guizhou Medical University  Guiyang Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit The Affiliated Hospital of Guizhou Medical University  Guiyang Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit The Affiliated Hospital of Guizhou 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