Asiaticoside-nitric oxide hydrogel enhances diabetic wound healing through p53/p21-mediated cell cycle regulation in vivo and in vitro

Objective Diabetic wounds represent a formidable clinical challenge characterized by mortality rates exceeding 70% in patients with recurrent infections, underscoring the urgent need for mechanism-based therapeutics. Here, this study investigated the wound-healing efficacy and underlying mechanisms of asiaticoside (AC)—a bioactive component of Centella asiatica —combined with nitric oxide (NO) in a diabetic mouse model, aiming to explore its therapeutic potential. Methods In vivo, this study treated full-thickness excisional wounds in db/db mice with asiaticoside-nitric oxide hydrogel (ACNO) or a vehicle control. The wound healing efficacy was assessed via closure rates, histology, and immunohistochemistry. In vitro , this study utilized the spontaneously immortalized human keratinocyte cell line HaCaT, derived from adult healthy skin, to elucidate the molecular mechanisms driving ACNO’s effects, specifically focusing on the p53/p21/cyclin D1/E1 pathway and cell cycle regulation. Results ACNO treatment significantly accelerated wound closure, enhanced re-epithelialization, and promoted angiogenesis in diabetic mice compared to the vehicle control. In vitro , ACNO stimulated HaCaT cell proliferation, migration, and cell cycle progression by modulating the p53/p21/cyclin D1/E1 signaling pathway. Notably, ACNO counteracted the inhibitory effects of the p53 agonist Tenovin-1, confirming its p53-targeting mechanism. Conclusion The ACNO hydrogel effectively promotes diabetic wound healing by regulating the p53/p21/cyclin D1/E1 signaling pathway, positioning it as a promising therapeutic strategy for chronic diabetic wounds.