Panax notoginseng Saponins Accelerate Diabetic Wound Repair by Minimizing Mitochondrial Dysfunction and Inhibiting Pyroptosis of Macrophage via Regulating Ephx2/11,12-EET Axis

Impaired diabetic wound (DW) healing is mainly driven by excessive inflammatory response, while Panax notoginseng saponins (PNS), the core bioactive components of Panax notoginseng, show pro-healing potential in diabetic ulcers with unclear mechanisms. Here, we established a streptozotocin-induced DW mouse model, and combined untargeted metabolomics with in vitro and in vivo validations to decipher PNS's therapeutic mechanism and active ingredients. In vivo, PNS dose-dependently accelerated wound closure, enhanced collagen deposition, and improved glucose tolerance and insulin sensitivity in diabetic mice, without affecting body weight or random blood glucose. Mechanistically, PNS inhibited Ephx2 expression (at both mRNA and protein levels) in macrophages to upregulate 11,12-EET, thus mitigating wound inflammation, NLRP3 inflammasome-mediated pyroptosis, and mitochondrial dysfunction. In vitro, the protective effects of PNS on macrophage mitochondrial function and pyroptosis were not enhanced by Ephx2 inhibitor TPPU, but completely abolished by 11,12-EET antagonist 14,15-EEZE. Furthermore, five major saponins (R1, Rg1, Re, Rb1, Rd) from PNS were identified as active ingredients, all exerting pro-healing effects in DW mice. Conclusively, PNS accelerates DW healing via regulating the macrophage Ephx2/11,12-EET axis to preserve mitochondrial homeostasis and inhibit pyroptosis, supporting its therapeutic potential for diabetic foot ulcers.