Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers

Diabetic complications frequently arise in mechanically stressed regions, yet the molecular links between biomechanical forces and metabolic dysfunction remain unclear. Here, we demonstrate that mechanical stress induces glucose accumulation and downstream metabolic stress in keratinocytes, leading to mitochondrial injury and inflammation. Mechanistically, Piezo1 activation led to intracellular glucose overload and excessive advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cGAS–STINGsignaling cascade. Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, while Stimulator of interferon genes (STING) ablation reproduced similar downstream protective effects. Keratinocyte-specific deletion of the mechanosensor Piezo1 reduces advanced glycation end-products (AGEs) accumulation, preserves mitochondrial integrity, and dampens inflammatory signaling. Further, we show that this injury cascade involves cytosolic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS–STING pathway. Stimulator of interferon genes (STING) ablation recapitulates the protective phenotype, confirming its downstream role. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium intake and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcer (DUs) models. These findings uncover a CST–Piezo1–STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.