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Diabetic foot ulcers (DFU) present a severe clinical challenge, marked by poor healing, chronic inflammation, and elevated amputation risk. The M2 macrophage is known to support the wound healing of DFU, and syndecan-4 (SDC4) contributes to this process. However, the upstream regulatory mechanisms involving post-translational modifications and transcriptional networks remain unclear. The related molecule levels were measured by RT-qPCR and Western blot. The M2 macrophage biomarkers (IL-10, Arg-1) were detected by ELISA kits, while the number of F4/80 + CD206 + cells was quantified via flow cytometry. The interaction between SP1 and SDC4 was checked by ChIP and dual-luciferase reporter assays. Furthermore, SUMOylation of SP1 was verified through Ni 2⁺ pull-down and Co-IP experiments. CCK-8, Transwell assay, and EdU staining were applied to determine the viability, migration, and proliferation of human dermal fibroblasts (HDF). Furthermore, in the wound tissues of diabetic mice, through HE staining, Masson staining, immunohistochemistry and immunofluorescence detection, the relevant molecular mechanisms in the body were verified. SUMO2, SP1, and SDC4 were upregulated in M2 macrophages. SP1 interacted with the promoter region of SDC4 to transcriptionally activate SDC4. Both SDC4 and SP1 overexpression facilitated HDF proliferation and migration by strengthening the polarization of M2 macrophages. However, subsequent knockdown of SDC4 could reverse the promoting effects induced by SP1 overexpression. SUMO2 mediated the SUMOylation of SP1 at the K16 site and increased its protein stability. The inhibition of SP1 SUMOylation impeded M2 phenotype polarization, thereby decreasing HDF viability and suppressing their proliferative and migratory capability under high-glucose conditions. In vivo, topical application of ginkgolic acid (GA) to diabetic mouse wounds significantly decreased the wound healing rate. SUMO2 stabilizes SP1 protein by mediating its SUMOylation at K16, an