Phosphocreatine-mediated enhancement of mitochondrial function for accelerated healing of diabetic foot ulcers through the PGC-1α-NRF-1 signaling pathway

Diabetic foot ulcers (DFUs) pose a significant clinical challenge due to their slow healing and high risk of complications, which severely affect patient quality of life. Central to the delayed healing observed in DFUs is mitochondrial dysfunction, a critical factor impairing cellular repair processes. Phosphocreatine (PCr), a vital molecule involved in cellular energy buffering and ATP regeneration, has recently emerged as a promising therapeutic candidate for ameliorating mitochondrial dysfunction and enhancing tissue repair. This study explores the novel therapeutic potential of PCr in restoring mitochondrial function and accelerating wound healing in DFUs through both in vitro and in vivo models. Using hyperglycemic human umbilical vein endothelial cells (HUVECs) as an in vitro model and a streptozotocin (STZ)-induced diabetic rat model as an in vivo, we evaluated the impact of PCr treatment on mitochondrial activity and wound repair. PCr treatment notably upregulated key mitochondrial biogenesis markers, including peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1 alpha) and nuclear respiratory factor 1 (NRF-1), indicating a restoration of mitochondrial function. In vivo, PCr-treated diabetic rats demonstrated significantly accelerated wound closure, enhanced granulation tissue formation, and reduced inflammatory cell infiltration. These findings underscore PCr's potential to address mitochondrial dysfunction and expedite wound healing in DFUs. This study offers promising new insights into PCr as a targeted therapeutic intervention, paving the way for improved patient outcomes in managing diabetic foot ulcers.