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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Guoli Ma,
  • Qinghao Yuan,
  • Yonggang Li,
  • Ben Liu,
  • Jingwei Bi,
  • Mengfei Lv,
  • Hang Li,
  • Tengxiao Huang,
  • Kaitian Yin,
  • Wenke Zhao,
  • Gaoxin Jin,
  • Chuanju Liu,
  • Krasimir Vasilev,
  • Xinyu Liu,
  • Yunpeng Zhao,
  • Zhijian Wei,
  • Weiwei Li

摘要

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.