Abstract

BACKGROUND Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, and Furin, a proprotein convertase critical for TGF-β1 activation, has shown promise as a novel therapeutic target for PH. However, its specific role in PH pathogenesis and potential inhibitors have remained unexplored. PURPOSE This study aimed to investigate the role of Furin in PH-associated vascular remodeling and evaluate the therapeutic potential of the newly discovered Furin inhibitor, Licochalcone B (LicoB), in PH. METHODS We assessed Furin expression levels in multiple PH animal models and evaluated its cellular localization using single-cell transcriptomics. Then the functional role of Furin was validated through overexpression and knockdown studies in vitro. The protective effect of Furin inhibitor, LicoB, was validated in pulmonary artery vascular cells, and finally its therapeutic effects and potential mechanisms were evaluated in PH animal models. RESULTS Elevated Furin expression was consistently observed across diverse PH animal models. Furin overexpression promoted cell viability and migration, while its knockdown mitigated pathological features. The Furin inhibitor, LicoB, effectively suppressed aberrant pulmonary artery cell proliferation and migration, and restored mitochondrial membrane potential in vitro. Critically, in both murine and rat PH models, LicoB administration significantly ameliorated symptoms, exerted robust cardiopulmonary protection, and attenuated pulmonary vascular remodeling. Mechanistically, LicoB acted by inhibiting the Furin/TGF-β1 signaling axis. CONCLUSION Our findings establish Furin as a key driver of PH development and demonstrate that LicoB suppresses vascular remodeling via the Furin/TGF-β1 pathway, positioning LicoB as a highly promising novel therapeutic candidate for PH by targeting Furin.