Wuhuang Zhizi Decoction promotes diabetic foot ulcer healing via SIRT1/Nrf2-dependent M2 polarization and gut-immune modulationOA

Background:Diabetic foot ulcer(DFU)is a severe diabetes complication driven by persistent inflammation,and effective pharmacotherapies remain limited.Although classical compound herbal formulas are used clinically,the efficacy and mechanisms of the modified Wuhuang Zhizi Decoction(WHZZ)delivered by enema are unclear.Methods:DFU was induced in Balb/c mice.WHZZ was administered to animals via retention enema,and wound closure,fasting blood glucose,and serum lipid levels(total cholesterol and triglycerides)were subsequently evaluated.Gut effects were evaluated by measuring short-chain fatty acids(SCFAs;butyric acid,acetate,and propionate)in serum and feces,as well as colonic tight junction proteins(ZO-1 and occludin).Systemic and local inflammation(IL-6,TNF-α,IL-10,TGF-β)and macrophage phenotypes were measured by immunoassays,immunofluorescence,and Western blot.In vitro,high-glucose–polarized macrophages were treated with WHZZ;EX-527 was used to inhibit SIRT1 for rescue experiments.Results:Rectal administration of WHZZ accelerated wound closure,lowered fasting glucose from week 4,and reduced total cholesterol and triglycerides by week 8.SCFAs increased in serum and feces,and colonic ZO-1/occludin were upregulated,indicating improved barrier integrity.WHZZ decreased IL-6 and TNF-αand increased IL-10 and TGF-βin serum and wounds,suppressed M1 features,promoted M2 polarization,and enhanced SIRT1/Nrf2 signaling.Sodium butyric acid reproduced part of the anti-inflammatory and pro-M2 effects but was inferior to WHZZ.EX-527 attenuated WHZZ-induced M2 polarization and partly restored pro-inflammatory cytokine production.Conclusion:WHZZ promotes DFU healing by enhancing SCFA availability and epithelial barrier function and by driving SIRT1/Nrf2-linked M2 macrophage polarization to resolve chronic inflammation.These data support a multi-component herbal intervention delivered via the rectal route as a feasible strategy for DFU and provide a mechanistic rationale for further translational studies.