HDAC11-Driven STAT3 Activation Modulates Epigenetic Regulation, Promoting Pro-Inflammatory Cytokine Production and Endothelial Dysfunction in Diabetes

Abstract Diabetes mellitus is marked by chronic low-grade inflammation, increasing the risk of infections and vascular complications. In this study, we uncover a novel link between bacterial infection and epigenetic regulation in diabetes. We found that infection with Escherichia coli strongly induces the expression of histone deacetylase 11 (HDAC11) in endothelial cell-derived induced pluripotent stem cells (iPS-ECs) from diabetic donors. This upregulation of HDAC11 correlated with a surge in pro-inflammatory cytokine production and marked endothelial dysfunction. Strikingly, treatment with an HDAC11-specific inhibitor significantly dampened inflammatory signaling and restored endothelial function, pointing to a potential therapeutic strategy. Further mechanistic insights revealed a direct interaction between HDAC11 and STAT3, a key regulator of inflammatory gene expression. These findings position HDAC11 as a critical mediator of infection-induced vascular inflammation in diabetes and highlight it as a promising epigenetic target to combat endothelial damage and improve vascular health in diabetic patients.