Deferoxamine mitigates neuronal loss following spinal cord injury via ferroptosis inhibition and Nrf2/HO‑1 pathway activation

Spinal cord injury (SCI) is a debilitating condition associated with significant morbidity and permanent disability. The neuroprotective potential of deferoxamine (DFO) in SCI by targeting ferroptosis has been highlighted; however, the underlying molecular mechanisms remain elusive. The present study aimed to investigate the role of the Nrf2/heme oxygenase‑1 (HO‑1) signaling pathway in mediating the inhibitory effects of DFO on neuronal ferroptosis following SCI. The study commenced with a bioinformatics analysis of the SCI microarray dataset, GSE162610. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significant activation of ferroptosis following SCI, while Gene Ontology analysis revealed that oxidative stress, inflammatory response and glutathione peroxidase activity were key biological processes associated with ferroptosis post‑SCI. The Nrf2, glutathione peroxidase 4 (GPX4), HO‑1 (encoded by Hmox1) and xCT (encoded by Slc7a11) genes were selected for further investigation. Subsequent experiments employed the Nrf2‑specific inhibitor ML385 to evaluate the regulatory role of the Nrf2/HO‑1 pathway. <i>In vitro</i>, an erastin‑induced neuronal ferroptosis model was established using ventral spinal cord 4.1 cells, while in vivo, a spinal cord contusion model was constructed using C57BL/6J mice for behavioral, histopathological and immunological assessments. The results demonstrated that, compared with the SCI group, DFO treatment significantly upregulated the expression of Nrf2, HO‑1, xCT and GPX4 both in vitro and in vivo as well as attenuated neuronal loss and tissue damage and promoted motor functional recovery in mice. Conversely, the administration of ML385 largely reversed these molecular and functional effects of DFO, thereby diminishing its neuroprotective efficacy. These findings indicated that DFO alleviated neuronal ferroptosis and promoted functional recovery after SCI, at least in part, through activation of the Nrf2/HO‑1 signaling pathway and enhancement of the xCT/GPX4 antioxidant system. Therefore, the present study elucidated the involvement of the Nrf2/HO‑1 signaling pathway in mediating the neuroprotective effects of DFO in SCI, highlighting the therapeutic potential of DFO and providing a theoretical foundation for future targeted strategies against ferroptosis in SCI management.