Targeting UBE2B-mediated U2AF1 degradation to alleviate endothelial dysfunction in renal ischemia-reperfusion injury: therapeutic potential of semaglutide.

BACKGROUND: Renal ischemia-reperfusion injury (RIRI) is a major cause of acute kidney injury, with endothelial dysfunction playing a central role in its pathophysiology. However, the molecular mechanisms underlying endothelial damage during RIRI remain incompletely understood. METHODS AND RESULTS: We investigated the role of ubiquitin-conjugating enzyme E2 B (UBE2B) in endothelial cell regulation during RIRI. Our data indicate that upregulation of UBE2B promotes endothelial apoptosis and inhibits proliferation by targeting U2 small nuclear RNA auxiliary factor 1 (U2AF1) for ubiquitination and degradation, thereby modulating the p53/p21 signaling pathway. Furthermore, treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, alleviated endothelial injury in our models, which was associated with reduced UBE2B expression, oxidative stress, and apoptosis. CONCLUSIONS: These findings suggest a previously unrecognized role of UBE2B in mediating endothelial dysfunction during RIRI and indicate that targeting this pathway may hold therapeutic potential. Moreover, semaglutide showed protective effects against endothelial damage under our experimental conditions, pointing to a possible strategy for RIRI management that warrants further validation in long-term and clinical studies.