BACKGROUND: The polarization of inflammatory macrophages is an important factor contributing to delay wound healing in diabetic foot ulcers (DFU). In this study, the role of ubiquitin-specific protease 7 (USP7) in regulating macrophage polarization during DFU progression was investigated. METHODS: Gene and protein expression levels were assessed using qRT-PCR and western blot. In vitro and in vivo diabetes mellitus (DM) models were established by HG treatment and STZ injection, respectively. HUVEC viability, migration, and angiogenesis were detected by CCK8 assay, wound healing assay, and tube formation assay, respectively. Flow cytometry was employed to analyze the levels of macrophage polarization markers. Co-IP assay was performed to analyze the interaction between USP7 and GATA3. RESULTS: Our results demonstrated that USP7 was overexpressed in ulcer margin tissues of DFU patients, wound tissues of DFU mice, and HG-treated macrophages. Functionally, USP7 deficiency inhibited macrophage M1 polarization and promoted wound healing in DFU mice. In vitro, USP7 knockdown promoted HUVEC proliferation, migration, and angiogenesis by inducing M2 macrophage polarization and inhibiting M1 macrophage polarization under HG condition. Mechanistically, USP7 could stabilize GATA3 protein in macrophages by deubiquitinating GATA3. Moreover, the effects of USP7 knockdown on HUVEC function and macrophage polarization under HG condition were partially reversed by GATA3 overexpression. CONCLUSION: USP7 silencing enhanced wound healing in DFU by inhibiting M1 macrophage polarization and promoting M2 macrophage polarization through mediating GATA3 deubiquitylation.