Celastrol Ameliorates Hypoxia‐Induced Pulmonary Hypertension by Regulation of the PDE5‐cGMP‐PKG Signaling Pathway

ABSTRACT Pulmonary hypertension (PH) is a severe pulmonary vascular disease characterized by poor clinical outcomes and limited therapeutic options. Celastrol (CEL), a natural product derived from Tripterygium wilfordii Hook F , has shown therapeutic potential in PH models, although its mechanisms are not fully understood. This study aims to investigate the role of CEL in PH and explore its potential underlying mechanisms. This study investigates the role of CEL in PH and explores its underlying mechanisms. We evaluated the effects of CEL in a chronic hypoxia‐induced PH rat model and hypoxia‐stimulated human pulmonary arterial smooth muscle cells (HPASMCs). Bioinformatics and network pharmacology were employed to identify potential targets and pathways, which were then validated through mechanistic and functional analyses. CEL significantly reduced right ventricular systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia‐induced PH rats. It also decreased proliferating cell nuclear antigen expression and promoted apoptosis in pulmonary arterioles. Our findings suggest that CEL's therapeutic effects are mediated through the modulation of phosphodiesterase 5 (PDE5) and the activation of the cGMP‐PKG signaling pathway. In HPASMCs, CEL treatment mirrored the in vivo results, and PDE5 overexpression negated CEL's antiproliferative, antimigratory, and pro‐apoptotic effects. CEL ameliorates pulmonary vascular remodeling and right ventricular dysfunction in PH, potentially through the PDE5‐cGMP‐PKG signaling pathway. These findings position CEL as a promising candidate for PH therapy.