Abstract: Objective To investigate the therapeutic effect of the natural flavonoid taxifolin in experimental pulmonary arterial hypertension (PAH), and to further explore its potential molecular mechanisms underlying the amelioration of PAH. Methods This study first employed network pharmacology to predict the potential targets of taxifolin in PAH. After establishing a PAH model with monocrotaline (MCT), rats were administered with taxifolin or vehicle. Hemodynamic parameters, right ventricular hypertrophy, and pulmonary vascular remodeling were evaluated. Transcriptomic sequencing and analysis were performed to investigate the underlying molecular mechanisms, with results validated through immunofluorescence staining. Results Network pharmacology indicated that taxifolin was closely associated with biological processes related to leukocyte chemotaxis and vascular regulation. In MCT-induced PAH rats, taxifolin significantly reduced right ventricular systolic pressure (P＜0.001), attenuated right ventricular hypertrophy (P＜0.05), and inhibited pulmonary arteriolar remodeling (the number of muscularized vessels was significantly reduced, P＜0.000 1, and the medial wall thickness of small vessels was significantly decreased, P＜0.000 1). Transcriptomic analysis revealed that taxifolin intervention selectively reversed the aberrant expression of PAH-related chemokine-binding genes and regulated the expression of atypical chemokine receptors such as Ackr1 and Ackr2, suggesting that it may exert pulmonary vascular protection through regulating chemokine signaling. Conclusions Taxifolin ameliorates experimental PAH, showing disease-modifying effects in attenuating pulmonary vascular remodeling, potentially through the modulation of leukocyte chemotaxis. These findings suggest the therapeutic potential of taxifolin and highlight the chemotaxis pathway as a tractable target.

Key words: pulmonary arterial hypertension, pulmonary vascular remodeling, taxifolin, chemotaxis, atypical chemokine receptors