<scp>FKBP5</scp> Mediates Alveolar Fibroblast Necroptosis During Acute Respiratory Distress Syndrome
Dong Zhang, Wei Liu, Ting Sun, Yangyang Xiao, Qiuwen Chen, Xiaozhi Wang, Xiaozhi Wang, Qian Qi, Hao Wang, Tao Wang
Abstract
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 Fkbp5 flox/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.