Garcinol promotes wound healing in diabetic mice by regulating inflammation and NLRP3 inflammasome-mediated pyroptosis via the PI3K/Akt/NF-κB pathway

Abstract

Diabetic wounds, characterized by chronic inflammation and impaired angiogenesis, often lead to severe complications such as persistent infections and an elevated risk of amputation, significantly affecting a patient's quality of life. Garcinol, a polyisoprenylated benzophenone derived from the rind of Garcinia indica, exhibits potent anti-inflammatory, angiogenic, and antioxidant effects in various disease models. However, its potential to enhance diabetic wound healing remains unclear. In this research, we firstly used network pharmacology analysis to identify the potential targets of Garcinol in treating diabetic wounds. Cellular study results revealed that Garcinol therapy alleviated high glucose-induced cellular dysfunction and increased the angiogenic potential of human umbilical vein endothelial cells (HUVECs). Additionally, Garcinol substantially downregulated the levels of inflammatory cytokines secreted by macrophages through inhibiting the PI3K/Akt/NF-κB signaling pathway, which was further validated using the PI3K/Akt agonist 740 YP. Furthermore, inhibiting PI3K signaling also resulted in a marked reduction of NLRP3 inflammasome-mediated pyroptosis in macrophages compared to control. In vivo study using a full-thickness diabetic wound model confirmed that Garcinol treatment promoted diabetic wound healing by improving angiogenesis, inhibiting inflammation and pyroptosis, whereas the addition of 740 YP reduced the beneficial effects of Garcinol. Overall, our findings suggested that Garcinol enhanced diabetic wound healing via its anti-inflammatory ability, suppression of pyroptosis, and enhancement of angiogenesis. These results highlight the potential of Garcinol as a therapeutic agent for diabetic wounds.