Asthmatic Pulmonary Fibroblasts Aggravate Airway Inflammation Through FKBP5-Dependent Necroptosis

Airway inflammation is a hallmark pathological feature of bronchial asthma and is closely associated with airway hyperresponsiveness. Pulmonary fibroblasts are key contributors to asthmatic inflammation, yet the underlying mechanisms remain insufficiently defined. In this study, FK506 binding protein 51 (FKBP5) was significantly upregulated in fibroblasts from individuals with asthma, and its expression was positively correlated with disease severity. Genetic knockout of Fkbp5 reduced HDM-induced airway barrier disruption and inflammatory injury. Single-cell RNA sequencing showed that Fkbp5 knockout suppressed the expression of eosinophil-attracting chemokines and inflammatory cytokines in fibroblasts of asthmatic mice. Fibroblast-specific Fkbp5 knockout further confirmed its essential role in promoting airway inflammation. Mechanistically, FKBP5 facilitated MLKL-dependent necroptosis in fibroblasts, which enhanced the production of proinflammatory cytokines and eosinophil chemokines, disrupted immune homeostasis, and exacerbated airway inflammation. These findings identify FKBP5 in fibroblasts as a potential therapeutic target for asthma prevention and treatment.