α-酮戊二酸通过增强PINK1的O-GlcNAc修饰及线粒体自噬作用，减轻骶丛神经切断后脊髓运动神经元的铁死亡损伤。

Abstract

Sacral plexus transection (SPT), mostly caused by high‑energy trauma, induces secondary death of spinal motor neurons in the lumbosacral segments and contributes to poor clinical outcomes after nerve repair. This study aimed to investigate the protective effect of α‑ketoglutarate (AKG) against ferroptosis in spinal motor neurons following SPT and the underlying molecular mechanism. Our results showed that endogenous AKG levels were significantly decreased in the spinal cord of SPT rats and in oxidative stress‑injured motor neurons, accompanied by abnormal expression of core ferroptosis‑related proteins, including downregulated glutathione peroxidase 4 and solute carrier family 7 member 11, upregulated acyl-CoA synthetase long-chain family member 4, as well as Fe2+ overload, malondialdehyde accumulation, and glutathione depletion. Exogenous AKG supplementation markedly reversed these anomalies, suppressed ferroptosis, and improved neuronal survival. Mechanistically, AKG specifically enhanced O-GlcNAcylation at the Thr177 site of PTEN‑induced kinase 1 (PINK1) and suppressed its ubiquitin-mediated degradation, which in turn selectively activated PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and sustain mitochondrial homeostasis. Furthermore, downregulation of isocitrate dehydrogenase 1 (IDH1) after SPT was identified as a critical upstream event leading to endogenous AKG depletion. This study systematically elucidates the key role of the IDH1‑AKG‑PINK1 O‑GlcNAcylation ‑mitophagy axis in regulating SPT‑induced ferroptosis in spinal motor neurons, providing novel targets and experimental evidence for neuroprotective therapy of sacral plexus injury.