Cyclic mechanical stretching enhances mitophagy and oxidative stress resistance in adipose-derived stem cells via the Piezo1/ATP axis to accelerate wound healing

Adipose-derived stem cells (ADSCs) hold significant potential in regenerative medicine, yet their therapeutic efficacy is often limited by low survival rates in the presence of oxidative stress. While mechanical cues regulate cytoskeletal dynamics, their roles in modulating cellular metabolism and mitochondrial adaptation remain unexplored. This study aimed to elucidate how physiological-range cyclic mechanical stretching (CMS) enhances ADSCs resistance to oxidative stress through the Piezo1/ATP signaling axis, thereby establishing an innovative strategy for developing antioxidant-functionalized stem cell therapies. <b>Methods:</b> To examine the impact of CMS on oxidative stress resistance, ADSCs were exposed to CMS (8% strain, 0.5 Hz, 24 h) using the Flexcell FX-6000 system. Oxidative stress models employed H₂O₂ (200 μM), with apoptosis, mitochondrial function, and metabolic flux analyzed <i>in vitro</i>. A murine full-thickness wound model was used to assess <i>in vivo</i> survival and regenerative outcomes. <b>Results:</b> CMS activated Piezo1 channels, resulting in enhanced ATP synthesis and remodeling of the tricarboxylic acid cycle. This improved the effectiveness of mitochondrial oxidative phosphorylation. Mechanically preconditioned ADSCs exhibited reduced apoptosis, ​enhanced oxidation resistance, stabilized mitochondrial membrane potential, and upregulated mitophagy. <i>In vivo</i>, these cells demonstrated superior healing capacity and accelerated wound closure. <b>Conclusion:</b> CMS orchestrated the Piezo1/ATP-driven metabolic-mitochondrial axis to enhance ADSCs oxidative stress resistance by coupling metabolic reprogramming with mitophagy activation. This mechanometabolic interaction identifies mechanical signaling as a direct regulator of cellular bioenergetics, offering a translatable strategy to engineer antioxidant-functionalized stem cells for regenerative therapies.