Peptide Angio‐3 Attenuates Pulmonary Fibrosis Via Modulation of the Coagulation Factor Xa—Protease‐Activated Receptor‐1 Signaling Axis

Pulmonary fibrosis (PF) is a chronic, progressive, and often fatal interstitial lung disease characterized by interstitial remodeling, fibroblastic foci formation, and excessive extracellular matrix (ECM) deposition. Current therapeutic options remain limited and are associated with unfavorable prognoses. Growing evidence indicates that dysregulated coagulation and fibrinolytic pathways are intimately involved in its pathology, suggesting that modulating this axis may offer novel therapeutic opportunities. In this study, we characterize Angio-3, a plasminogen kringle 3-derived decapeptide, as a potential antifibrotic agent targeting the coagulation cascade. We aimed to investigate the therapeutic efficacy of Angio-3 and elucidate its underlying mechanism. Our results show that Angio-3 significantly alleviates PF by inhibiting fibroblast invasion and migration and functions as a protease-activated receptor-1 (PAR-1) antagonist that disrupts the coagulation factor Xa (FXa)-PAR-1 signaling axis. Toxicological evaluations revealed a favorable safety profile, with no adverse effects observed at 0.5 mg/kg/day and only mild hepatomegaly at a supratherapeutic dose. These findings identify Angio-3 as a promising therapeutic candidate with dual advantages-combining antifibrotic efficacy with low toxicity-and offer a novel strategy for treating PF through targeting coagulation-mediated fibrotic signaling.