Sodium selenite mitigates white matter injury after spinal cord injury through GPX4-mediated suppression of ferroptosis

Introduction Spinal cord injury (SCI) often results in permanent neurological impairments, and preserving residual white matter bundles is critical for sustaining post-injury locomotor function. Oligodendrocytes, the myelinating cells of white matter, are highly susceptible to ferroptosis due to their abundant polyunsaturated fatty acids; however, the role of glutathione peroxidase 4 (GPX4)-mediated ferroptosis regulation in selenium-induced neuroprotection remains unclear. This study aimed to investigate whether sodium selenite (SS) mitigates white matter injury (WMI) and promotes functional recovery via GPX4 upregulation in a rat SCI model. Methods In vivo , a rat model of SCI was established. Rats were treated with SS alone or in combination with actinomycin D, a classic transcriptional inhibitor known to suppress GPX4 expression. GPX4 expression at the lesion epicenter, oligodendrocyte viability, ferroptosis status, white matter integrity, and locomotor functional recovery were systematically evaluated. Results In vivo , SS treatment significantly upregulated GPX4 expression at the SCI lesion epicenter ( p < 0.01). Endogenous GPX4 in oligodendrocytes played a critical role in promoting cell survival and inhibiting ferroptosis in the injured spinal cord. SS administration markedly attenuated WMI and significantly improved locomotor functional recovery in SCI rats ( p < 0.01). Notably, co-administration of actinomycin D substantially abolished the therapeutic benefits of SS, indicating that GPX4 upregulation is required for SS-mediated neuroprotection. Conclusion These findings demonstrate that SS enhances oligodendrocyte survival and mitigates WMI after SCI via GPX4 upregulation, thereby facilitating functional recovery and suggesting SS as a potential therapeutic strategy for SCI-associated neurological dysfunction.