YWHAZ-mediated metabolic reprogramming via HIF1A/LDHA signaling promotes pulmonary arterial remodelling

Hypoxia-related pulmonary arterial hypertension (PAH) remains poorly managed by current therapies. Metabolic dysregulation, particularly glycolysis, plays a key role in PAH pathogenesis. This study investigated YWHAZ’s role in PAH using hypoxia-induced pulmonary arterial endothelial cells (PAECs) and a hypoxia/SU5416-induced PAH rat model. Silencing YWHAZ inhibited PAEC proliferation, migration, and glycolysis, while improving right ventricular function and reducing pulmonary vascular remodeling. Mechanistically, YWHAZ stabilized HIF-1α, which transcriptionally activated LDHA, a critical glycolytic enzyme. HIF-1α agonist treatment reversed YWHAZ silencing effects, confirming the YWHAZ/HIF-1α/LDHA axis. These findings highlight YWHAZ as a potential therapeutic target for metabolic intervention in PAH.