SENP3 Exacerbates Spinal Cord Injury by Increasing H6PD deSUMOylation to Promote Glycolysis

Spinal cord injury (SCI) leads to persistent neurological deficits in patients, and effective clinical interventions remain limited. This study aims to elucidate the role and regulatory mechanisms of H6PD in SCI progression, thereby providing insights for developing novel therapeutic strategies. Functional recovery after SCI was assessed using BBB scores, inclined plane tests, and rotarod tests. Spinal cord pathology was evaluated through HE and Nissl staining. The ECAR and OCR were measured using the Seahorse XF96 analyzer. Intracellular ROS levels were detected with DCFH‐DA fluorescent probes. Lactate levels, NADPH/NADP + ratios, and the levels of MDA, GSH, and SOD were determined using commercial kits. Apoptosis was analyzed by flow cytometry. Protein interactions and SUMOylation levels were examined by Co‐IP. H6PD was compensatorily upregulated in SCI rats. H6PD knockdown aggravated neurological deficits and tissue damage. In H 2 O 2 ‐induced primary neurons, H6PD knockdown enhanced glycolysis, oxidative damage, and apoptosis. Mechanistically, SENP3 interacted with H6PD and promoted its deSUMOylation to inhibit its protein stability. Furthermore, SENP3 exacerbated H 2 O 2 ‐induced neuronal oxidative damage, apoptosis, and glycolytic abnormalities by downregulating H6PD and disrupting the SIRT1/HIF‐1α pathway. SENP3 aggravated neuronal injury and glycolytic dysfunction in SCI by promoting H6PD deSUMOylation and impairing the SIRT1/HIF‐1α pathway.