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SIRT6 downregulation in atherosclerotic vascular endothelial cells (ECs) is exacerbated under diabetic conditions, and EC-specific Sirt6 knockout aggravates diabetic atherosclerosis progression. EC-specific Sirt6 knockout aggravates atherosclerosis progression through vasculature hyperpermeability and monocyte/macrophage accumulation in vessels. SIRT6 directly interacts with transcription factor zinc finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, preserving ZEB1 at a low level for normal expression of tight junction protein claudin-1 in ECs to maintain endothelial barrier function for vascular homeostasis. Naringin, a natural flavonoid ZEB1 inhibitor, reverses the diabetes-exacerbated vascular endothelial dysfunction to attenuate atherosclerosis progression, offering a promising, novel therapeutic strategy for diabetic atherosclerotic cardiovascular diseases.