GLP-1 agonists reduce right ventricular mitochondrial dysfunction by inhibiting the GSK3β-Drp1 signalling in pulmonary hypertension

Right ventricular (RV) dysfunction is a critical complication of pulmonary hypertension (PH) with limited treatment strategies. This study evaluated the therapeutic efficacy of the GLP-1 agonist semaglutide on RV dysfunction in rodent PH models, focusing on mitochondrial dynamics and GSK3β-Drp1 signalling. Semaglutide significantly improved RV function, as evidenced by reduced right ventricular systolic pressure (RVSP), hypertrophy index (RV/LV + S), and improved echocardiographic parameters (RVEDA, RVFAC, TAPSE). Histological analysis revealed reduced RV hypertrophy and fibrosis, along with preserved mitochondrial ultrastructure in semaglutide-treated PH animals. Semaglutide restored GSK3β-Drp1 signalling, maintained mitochondrial membrane potential, and decreased mitochondrial fragmentation in primary cardiomyocytes via GLP-1R activation. Modulation of GSK3β expression further confirmed its role in GLP-1's protective effects. These findings collectively suggest that GLP-1 agonists, such as semaglutide, may represent a novel therapeutic strategy for RV dysfunction by targeting mitochondrial pathology and restoring critical signalling pathways like GSK3β-Drp1.