Asiaticoside-nitric oxide synergistically accelerate diabetic wound healing by regulating key metabolites and SRC/STAT3 signaling.

Background: Diabetic wounds pose significant clinical challenges due to impaired healing processes, often resulting in chronic, nonhealing ulcers. Asiaticoside (AC), a natural triterpene derivative from Methods: Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was utilized to identify differential metabolites and dysregulated metabolic pathways associated with diabetic wounds. Molecular docking analyses were conducted to confirm the binding affinity of AC to key therapeutic targets. The effects of asiaticoside-nitric oxide hydrogel (ACNO) on gene and protein expression were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Results: Metabolomic profiling revealed that diabetic wounds in mice exhibited marked metabolic dysregulation, which was attenuated by ACNO treatment. Key metabolites modulated by ACNO included mandelic acid, lactic acid, and 3-hydroxyisovaleric acid. The primary metabolic pathways involved were methyl histidine metabolism and the malate-aspartate shuttle. Immunofluorescence staining confirmed that ACNO therapy enhanced angiogenesis, promoted cellular proliferation, and facilitated diabetic wound closure. RT-qPCR data demonstrated that ACNO regulated the transcription of critical genes ( Conclusions: These findings emphasize the therapeutic potential of ACNO hydrogel in diabetic wound healing through the modulation of metabolic pathways and the SRC/STAT3 signaling axis. By correlating altered metabolites with molecular targets, this study elucidates the pharmacodynamic foundation for ACNO's preclinical application and provides valuable insights into the development of targeted therapies for diabetic wound management.