Cortistatin Antagonizes Piezo1-STING Axis and Facilitates Mitochondrial Homeostasis of Keratinocytes by Attenuating AGEs Accumulation in Diabetic Ulcers
Summary: Published March 13, 2026 in Cell Death & Differentiation (Nature Publishing Group; impact factor 13.7), this mechanistic study from Qilu Hospital of Shandong University — in collaboration with Yale School of Medicine and the University of South Australia — identifies a novel CST-Piezo1-STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetic ulcers (DUs). The study begins from the clinical observation that diabetic complications arise preferentially in mechanically stressed anatomical regions and asks how biomechanical forces link to metabolic dysfunction in keratinocytes. Piezo1, a mechanosensitive calcium-permeable ion channel activated by membrane tension, is shown in this study to mediate intracellular glucose overload and downstream advanced glycation end-product (AGE) accumulation when activated by mechanical stress in keratinocytes. The AGEs accumulation induced mitochondrial DNA (mtDNA) leakage into the cytosol, which activated the cGAS-STING innate immune signalling cascade — a pathway typically associated with antiviral defence but here repurposed as a driver of sterile inflammatory damage to the wound microenvironment. Keratinocyte-specific Piezo1 deletion markedly reduced AGE accumulation and preserved mitochondrial integrity; STING ablation produced similar downstream protective effects. The study’s most translational finding is the identification of cortistatin (CST), an endogenous neuropeptide with established anti-inflammatory and cytoprotective properties, as a previously unrecognised inhibitory ligand of Piezo1. CST binding to Piezo1 attenuated calcium influx and glucose accumulation under mechanical stress, conferring notable protection both in vitro (keratinocyte culture) and in diabetic ulcer mouse models. Raw sequencing data are deposited in GEO under accessions GSE311847 and GSE313483.
Key Highlights:
- Mechanistic cascade: mechanical stress → Piezo1 activation → calcium influx + intracellular glucose overload → AGE accumulation → mtDNA leakage → cGAS-STING pathway activation → keratinocyte mitochondrial dysfunction and inflammatory damage in DUs
- Keratinocyte-specific Piezo1 knockout: markedly reduced AGE accumulation and preserved mitochondrial integrity in diabetic ulcer models — confirms Piezo1 as the upstream driver of the metabolic cascade
- STING ablation: downstream protective effects similar to Piezo1 deletion — confirms cGAS-STING as the effector pathway mediating keratinocyte damage
- Cortistatin (CST): endogenous neuropeptide identified as a previously unrecognised Piezo1 inhibitory ligand — CST binding attenuates calcium influx and glucose accumulation under mechanical stress
- In vivo validation: CST confers notable protection in diabetic ulcer mouse models, consistent with its established anti-inflammatory role in osteoarthritis, intervertebral disc degeneration, and septic cardiomyopathy
- Translational implication: CST or Piezo1-targeted therapies may represent a novel pharmacological approach to diabetic wound care by addressing the mechanotransduction-metabolic axis; CST-loaded nanoparticles have already been shown to enhance diabetic wound healing via mitochondrial rescue in prior work
Keywords: Piezo1 diabetic wound healing, cortistatin wound care, AGE advanced glycation diabetic ulcer, cGAS STING wound healing, keratinocyte mitochondria diabetic wound, mechanosensitive channel wound healing
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