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Persistent inflammation, defective angiogenesis, and metabolic dysfunction impede diabetic wound repair. Although Zilian ointment (ZLO) is clinically applied to wounds, its activity in diabetic wounds and the associated molecular basis remain incompletely understood. We therefore assessed the reparative effects of ZLO and examined the signaling events potentially involved.

UHPLC-MS was used to characterize the chemical profile of ZLO, and network pharmacology was integrated to identify potential molecular targets and pathways. A diabetic wound model was applied to assess the reparative effects of ZLO on wound closure and tissue regeneration. Histological and immunohistochemical approaches were used to evaluate angiogenesis, macrophage polarization, and the expression of hypoxia/glycolysis-associated proteins, including HIF-1α, GLUT1, LDHA, PKM2, and VEGFA. AKT/HIF-1α pathway activation was further examined by western blotting.

ZLO-treated db/db mice displayed a smaller residual wound area and more complete histological repair, including greater epithelial coverage, granulation tissue formation, and collagen accumulation. Treatment was accompanied by stronger CD31 and VEGFA signals, together with a macrophage profile characterized by more F4/80⁺CD206⁺ cells and fewer F4/80⁺iNOS⁺ cells. KEGG enrichment and PPI network analyses highlighted HIF-1 signaling and AKT1, respectively. In wound sections, ZLO increased the expression of HIF-1α, GLUT1, PKM2, and VEGFA. Immunoblotting further revealed an elevated p-AKT/AKT ratio and recovery of HIF-1α and VEGFA protein levels.

ZLO facilitates diabetic wound repair, with its therapeutic effects potentially associated with AKT/HIF-1α-linked metabolic regulation and enhanced angiogenic responses.