Diabetes is a major risk factor for cardiovascular diseases. The mechanisms of hyperglycemia-induced endothelial dysfunction have been elusive. We found that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by switching liver kinase B1 (LKB1) activation of the AMPK pathway to activation of the p53 pathway. Hyperglycemia upregulates IP6K1, which stabilizes LKB1 by disrupting Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein-mediated LKB1 degradation but suppresses LKB1-dependent AMPK activation. Elevated LKB1 binds more to p53, resulting in p53-dependent endothelial senescence. Endothelial cell-specific deletion of IP6K1 attenuates, whereas endothelial cell-specific overexpression of IP6K1 exaggerates, hyperglycemia-induced endothelial senescence.
© 2025 by the American Diabetes Association.