This study was designed to study the effect and mechanism of dehydroepiandrosterone(DHEA)on diabetic wound healing in mice.High-fat feed combined with streptozotocin was utilized to induce diabetes and full-thickness incisional wounds were made on the back.The mice were randomly divided into normal wound group(NW),diabetic wound group(DW)and DHEA intervention group(DHEA).The wounds were photographed and the wound healing rates were calculated;RT-PCR was used to detect the expression of inflammatory factors in wound tissues and wound macrophages,and the expression of Dicer1 and pentose phosphate pathway(PPP)related factors in wound macrophages.Furthermore,wound macrophages phagocytosis of apoptotic Jurkat cells were measured by flow cytometry.Data showed that the wound healing rate,the expression of inflammatory factors and the phagocytosis rate were similar between the DHEA group and the NW group(P>0.05);compared with the DW group,the wound healing rate in the DHEA group was accelerated,the expression of TNF-α,IL-6 and IL-1β were decreased,the expression of IL-10 and TGF-β were increased,and the phagocytosis rate was increased(P<0.01);the expression of Dicer1 in wound macrophages of the DW group was lower than that in the NW group,and the expression of PPP-related factors G6pdx,Taldo1,Pfkl,H6pd,Pgd,Aldoc1 and Tkt were increased(P<0.01);the expression of Dicer1 between DW group and DHEA group was similar(P>0.05),and the expression of PPP-related factors G6pdx,Taldo1,Pfkl,H6pd,Pgd,Aldoc1 and Tkt were lower in the DHEA group(P<0.01).In conclusion,DHEA promotes diabetic wound healing by inhibiting macrophage pentose phosphate pathway activity.