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. Mechanistically, Piezo1 activation led to intracellular glucose overload and advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling cascade (cGAS-STING pathway). Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, and STING ablation exhibited similar downstream protective effects. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium influx and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcers (DUs) models. These findings uncover a CST-Piezo1-STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.
© 2026. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.