Adipose-derived mesenchymal stem cell exosomes protect keratinocytes from high-glucose injury by modulating KEAP1/NRF2/HO-1 axis

Hyperglycemia exacerbates diabetic chronic wounds by inducing oxidative damage and epithelial-mesenchymal transition (EMT), impairing re-epithelialization. This study investigated the protective role of adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) against high glucose (HG)-induced keratinocyte injury and diabetic wound healing impairment. ADSC-Exos were isolated via density gradient ultracentrifugation, characterized using NTA, TEM, and immunoblotting, and applied to HG-treated HaCaT cells and diabetic mouse wounds. In vitro, ADSC-Exos significantly mitigated HG-induced oxidative stress by reducing reactive oxygen species (ROS), DNA damage (8-OHdG), and lipid peroxidation (MDA), while enhancing antioxidant enzymes (SOD, CAT). Mechanistically, ADSC-Exos suppressed KEAP1, activated the NRF2/HO-1 pathway, and attenuated pathological EMT-like changes by restoring E-cadherin and suppressing N-cadherin, α-SMA, and Vimentin. In diabetic mice, ADSC-Exos accelerated wound closure, improved collagen deposition, and reduced inflammatory cytokines (IL-1β, IL-6, TNF-α). These findings demonstrate that ADSC-Exos promote diabetic wound healing by alleviating oxidative stress and pathological EMT-like changes via KEAP1/NRF2/HO-1 signaling, supporting their potential as a therapeutic strategy for diabetic chronic wounds.