• MEF2A is identified as a master transcriptional regulator of endothelial redox homeostasis, directly activating SIRT1 expression by binding to two cis-elements in its promoter.
• MEF2A silencing induces oxidative stress in endothelial cells, characterized by elevated ROS, reduced GSH/GSSG ratio, and mitochondrial membrane potential collapse, while overexpression restores redox balance.
• In vivo, endothelial-specific MEF2A knockdown in high-fat diet-fed mice increases vascular oxidative damage, evidenced by elevated 8-OHdG and ROS levels, and downregulates SIRT1/PGC-1α.
• Pharmacological activation of MEF2A represents a novel precision antioxidant strategy for treating oxidative cardiovascular disorders, addressing the limitations of current nonspecific antioxidant therapies.