Qi Dong, Yumei Cheng, Jia Yuan, Chuan Xiao, Xianjun Chen, Junling Tao, Yue Wang, Jingni Wang, Junyuan Tian, Feng Shen
ABSTRACT Sepsis‐associated acute respiratory distress syndrome (ARDS) is characterized by excessive inflammation and dysregulated intra‐alveolar coagulation, leading to fibrin deposition and impaired alveolar function. The regulatory role of vitamin D–vitamin D receptor (VDR) signaling in epithelial coagulation responses remains incompletely defined. We investigated the role of vitamin D–VDR signaling in regulating epithelial‐driven intra‐alveolar coagulation in sepsis‐associated lung injury using vitamin D‐deficient mice, LPS‐induced acute lung injury models, RLE‐6TN alveolar epithelial cells, and clinical samples from patients with ARDS. Expression of VDR, NF‐κB p65, tissue factor (TF), and plasminogen activator inhibitor‐1 (PAI‐1) was assessed using qRT‐PCR, Western blotting, ELISA, and immunohistochemistry. Functional experiments included 1,25(OH) 2 D 3 supplementation, VDR silencing, and NF‐κB p65 gain‐ and loss‐of‐function approaches. Vitamin D deficiency significantly exacerbated LPS‐induced lung injury, pulmonary edema, and intra‐alveolar hypercoagulation, as reflected by increased TF and PAI‐1 expression in lung tissue and bronchoalveolar lavage fluid. LPS challenge suppressed VDR expression and concurrently activated NF‐κB signaling In Vivo and in alveolar epithelial cells. Supplementation with 1,25(OH) 2 D 3 restored VDR expression and attenuated TF and PAI‐1 induction. Conversely, VDR silencing enhanced NF‐κB p65 activation and amplified epithelial procoagulant responses. Mechanistically, NF‐κB p65 was required for TF and PAI‐1 upregulation, and its overexpression abolished the inhibitory effects of vitamin D–VDR signaling. Clinically, patients with ARDS exhibited reduced circulating 25(OH)D levels and decreased VDR expression compared with healthy controls. Vitamin D–VDR signaling acts as an endogenous protective axis that restrains NF‐κB–driven epithelial procoagulant activation in sepsis‐associated ARDS. Disruption of this pathway promotes TF‐ and PAI‐1‐mediated intra‐alveolar coagulation, suggesting that restoration of vitamin D–VDR signaling may represent a potential adjunctive therapeutic strategy for ARDS.