PDHA1 Hyperactivation Orchestrates Metabolic Reprogramming Promoting Endothelial Senescence

While recent studies have established links between metabolic reprogramming and inflammatory senescence, the specific metabolic drivers in vascular aging remain incompletely defined. Here, we systematically characterized senescent phenotypes and targeted metabolomic profiles in primary aging endothelial cells, identifying a pyruvate dehydrogenase E1 component subunit alpha (PDHA1)-dependent metabolic shift as a hallmark of cellular senescence. Using a D-galactose-induced senescence model, we demonstrated that endothelial-specific Pdha1 knockdown alleviated pulmonary vascular endothelial senescence and associated functional decline. Further investigation revealed that PDHA1 hyperactivation disrupts mitochondrial homeostasis, leading to excessive mitochondrial reactive oxygen species production, oxidative mitochondrial DNA damage, and subsequent cytosolic mitochondrial DNA release, thereby triggering cyclic GMP-AMP synthase-mediated senescence. Mechanistically, decreased lactylation of PDHA1 at lysine 336 potentiated its activity and promoted dephosphorylation at serine 293. This posttranslational cross talk enhanced PDHA1 activation and drove a prosenescent metabolic shift. Together, our results elucidate that a previously unrecognized PDHA1 hyperactivation promotes endothelial senescence.