Paeonol alleviates pulmonary arterial hypertension by activation of BRCC3.

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and right ventricular failure. Paeonol, a bioactive compound extracted from the root bark of Paeonia suffruticosa, exhibits anti-inflammatory, antioxidant, and anticancer effects. However, its efficacy on pulmonary vasculature in the context of PAH remains unknown. This study aims to evaluate the protective effects of paeonol in murine pulmonary hypertension (PH) model and identify its underlying molecular mechanism. A murine PH model was used to assess the effect of paeonol on hemodynamics, echocardiography and pathology. In vitro, pulmonary arterial smooth muscle cells (PASMCs) proliferation and apoptosis were evaluated. RNA sequencing and network pharmacology were analyzed for pathway changes. Molecular docking and surface plasmon resonance (SPR) were employed to identify paeonol targets, which were further validated by Western blotting and immunofluorescence. Paeonol administration significantly reduced right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling in PH mice. Echocardiography further demonstrated that paeonol preserved right ventricular structural and functional integrity. In vitro, paeonol inhibited PASMCs proliferation and promoted apoptosis. RNA sequencing and network pharmacology revealed that the drug effect was on the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) pathway. SPR analysis confirmed a high-affinity direct binding between paeonol and BRCA1/BRCA2-containing complex subunit 3 (BRCC3). Paeonol binding promotes the stability of BMP receptors and restores the BMP/TGF-β signaling balance. Paeonol attenuates PH by rebalancing the BMP/TGF-β signaling through interacting with BRCC3 activation, thereby inhibiting vascular remodeling. These findings suggest that paeonol is a promising therapeutic candidate for PAH.