<p>Spinal cord injury (SCI) is a serious complication of spinal fractures and/or dislocations, characterized by sensory and motor dysfunction in the trunk and limbs. The pathogenesis of SCI is highly complex and remains poorly understood. The role of O-GlcNAc modification and FOXD3 in SCI was studied in this study. The cell and animal models of SCI were established by H₂O₂ stimulation and heavy object impact method, respectively. HE and Nissl staining were used to analyze pathological changes and neuronal loss in the spinal cord tissues. The motor ability of rats was assessed by BBB score, ladder climbing, and grid climbing tests. Cell viability and apoptosis were assessed by CCK8, flow cytometry, and TUNEL staining, respectively. Co-IP assay detected O-GlcNAc modification level of FOXD3 protein. The interaction between FOXD3 and STUB1 promoter was analyzed by dual luciferase reporter gene and ChIP assays. O-GlcNAc modification level was significantly elevated in the cell and animal models of SCI. O-GlcNAc modification increased both the protein stability and expression of FOXD3. O-GlcNAc modification inhibition or FOXD3 knockdown reduced oxidative stress damage and apoptosis in H₂O₂-treated PC12 cells. Moreover, FOXD3 mediated transcriptional inhibition of STUB1, and STUB1 induced HMGB1 ubiquitination and degradation in PC12 cells. STUB1 knockdown or HMGB1 overexpression negated the protective effects of FOXD3 knockdown on H₂O₂-mediated oxidative stress damage and apoptosis in PC12 cells. Inhibiting the O-GlcNAc modification of FOXD3 alleviated oxidative stress damage and apoptosis in nerve cells to mitigate SCI by enhancing STUB1-induced HMGB1 ubiquitination degradation.</p>