IP6K1 rewires LKB1 signaling to mediate hyperglycemic endothelial senescence.

Diabetes is a major risk factor for cardiovascular disease, but the molecular mechanisms underlying diabetic vasculopathy have been elusive. Here we report that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by rewiring the liver kinase B1 (LKB1) signaling from activating the adenosine monophosphate-activated protein kinase (AMPK) pathway to the p53 pathway. We found that hyperglycemia upregulated IP6K1, which disrupts the Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein (CHIP)-mediated LKB1 degradation, leading to increased expression levels of LKB1. High glucose also strengthens the binding of IP6K1 to AMPK, suppressing the LKB1-mediated AMPK activation. Thus, the elevated LKB1 does not lead to the activation of the AMPK pathway. Instead, it binds more to p53, resulting in p53-dependent endothelial senescence. Endothelial-specific deletion of IP6K1 alleviates, whereas endothelial-specific overexpression of IP6K1 exaggerates the hyperglycemia-induced endothelial senescence. This study reveals a regulatory mechanism of IP6K1 in switching the LKB1/AMPK pathway to LKB1/p53 pathway. IP6K1 represents a potential therapeutic target for treating hyperglycemia-induced endothelial dysfunction.