The dual role of fibrinogen in vascular permeability and alveolar senescence reveals its potential as a pharmacological target for asthma

Fibrinogen (Fg), a critical mediator in vascular and inflammatory diseases, is poorly understood in asthma pathogenesis. Here, our data support a model in which Fg acts as a dual-function driver of asthma progression through distinct endothelial and epithelial mechanisms, and we further validate its potential as a therapeutic target. Clinical analyses revealed that elevated plasma Fg levels in asthma patients inversely correlate with pulmonary function and are associated with marked Fg deposition in lung tissues. Notably, these clinical findings indicate that Fg accumulation is characteristic of T2-high airway inflammation, negatively correlating with overall pulmonary function impairment. In murine asthma models, Fg induced endothelial barrier dysfunction via p-VE-cadherin Y731 and caveolin-1–mediated endocytosis, leading to increased vascular permeability and progressive decline in pulmonary function. Simultaneously, alveolar Fg accumulation promoted epithelial senescence, as indicated by elevated SA-β–gal–positive cells and senescence-associated secretory phenotype (SASP) markers, through the TLR4/NF-κB pathway activation. Further mechanistic analysis revealed that this Fg-induced senescence is primarily driven by the downstream activation of the DDR-p21 axis rather than the p16/Rb pathway. Additionally, targeting the fibrin(ogen) pathway with Gly-Pro-Arg-Pro (GPRP) significantly attenuated asthma progression, demonstrating protective effects against pulmonary inflammation and pathological changes. In summary, our findings highlight Fg as a contributing pathogenic mediator of asthma pathogenesis through an inferential link between vascular and epithelial mechanisms, underscoring its potential as a therapeutic target. The efficacy of GPRP in countering Fg-mediated pathology supports its further investigation as a promising therapeutic candidate for asthma.