Abstract
The inflammatory storm is a hallmark of acute respiratory distress syndrome (ARDS), yet effective therapies remain unavailable. FK506-binding protein 51 (FKBP5) has emerged as a regulator of inflammatory responses. In this study, FKBP5 expression was markedly increased in patients with sepsis and correlated with both cytokine levels and disease severity. Using sepsis-induced ARDS models in Fkbp5-/- and bone marrow chimeric mice, this study demonstrated that non-haematopoietic FKBP5 mitigates inflammatory injury. Single-cell transcriptomic analysis identified fibroblasts and epithelial cells as the primary sources of non-haematopoietic FKBP5 in the lung injury. Conditional deletion of FKBP5 in fibroblasts (Col1a2-iCre Fkbp5flox/flox) confirmed the essential role of fibroblast FKBP5 in the inflammatory response during ARDS. Mechanistically, FKBP5-mediated necroptosis of alveolar fibroblasts triggered NF-κB activation, proinflammatory cytokine release, neutrophil recruitment, and the establishment of an inflammatory microenvironment in alveolar epithelial tissue. These findings suggest a potential therapeutic strategy targeting fibroblast FKBP5 and provide a foundation for future clinical investigation in ARDS management.