<p>Macrophage homeostasis is disrupted in periodontitis, a condition often exacerbated by diabetes. AZGP1 is an inflammation-associated factor capable of modulating macrophage polarization. Hyperglycemia alters O-GlcNAcylation dynamics in pathological contexts. This study investigated the regulatory role of AZGP1 in macrophage polarization during diabetic periodontitis and explored whether O-GlcNAcylation mediated this effect. Raw264.7 cells were exposed to lipopolysaccharide (LPS) and high glucose (HG) to simulate the periodontitis and hyperglycemia microenvironment, respectively. Macrophage polarization was analyzed by quantifying M1 and M2 markers via qRT-PCR and immunofluorescence. O-GlcNAcylation of AZGP1 regulated by OGT was examined using immunoprecipitation, immunoblotting, and cycloheximide-chase assays. A hyperglycemic periodontitis mouse model was established, and bone-related parameters and macrophage polarization were assessed. Porphyromonas gingivalis LPS induced M1 polarization and suppressed M2 polarization in Raw264.7 cells, while HG further amplified LPS-driven polarization. Following LPS/HG treatment, AZGP1 expression increased; its knockdown inhibited M1 polarization and enhanced M2 polarization. OGT depletion reduced AZGP1 protein stability by blocking O-GlcNAcylation at the tryptophan (T205) residue. AZGP1 overexpression counteracted the M1/M2 polarization inhibition caused by OGT knockdown. In vivo, AZGP1 knockdown mitigated alveolar bone destruction in periodontitis mice with hyperglycemia by promoting M1 to M2 polarization. O-GlcNAcylation of AZGP1, mediated by OGT, enhances its stability, promoting M1 polarization and suppressing M2 polarization under hyperglycemic conditions, thereby exacerbating periodontitis progression under hyperglycemic conditions. These findings offer novel insights into the pathogenesis and therapeutic strategies for diabetic periodontitis.</p>