A daily dose of sodium selenite, a bioavailable selenium supplement, significantly improved hindlimb locomotor recovery and preserved myelin in rats with contusive spinal cord injury, according to a new preclinical study published in Frontiers in Molecular Neuroscience. The researchers, led by teams at Southwest Hospital, Third Military Medical University in Chongqing, report that the protective effect depends on upregulation of glutathione peroxidase 4 (GPX4), a selenoprotein enzyme that serves as the body’s principal defense against the iron-driven form of cell death known as ferroptosis. When the animals also received actinomycin D, a transcriptional inhibitor, the benefits of sodium selenite were largely abolished, pointing to transcriptional control of GPX4 as the mechanism underlying the therapy.

Spinal cord injury typically unfolds in two phases. The primary injury is the immediate mechanical trauma that disrupts axons and myelin sheaths. What follows is a secondary injury cascade involving sustained neuroinflammation, iron overload, and excessive lipid peroxidation, which progressively degrade tissue through astrocyte activation and oligodendrocyte loss. Despite decades of work on secondary injury mechanisms, clinical translation of candidate therapies remains limited, and treatment efficacy in patients remains unsatisfactory. The new study targets one specific vulnerability within this cascade: the susceptibility of oligodendrocytes, the myelin-forming cells of white matter, to ferroptotic death.

Oligodendrocytes are unusually exposed to this threat because their lipid-rich membranes contain abundant polyunsaturated fatty acids, the preferred substrates for peroxidation. Ferroptosis itself is a regulated, non-apoptotic form of cell death characterized by iron-dependent accumulation of lipid peroxides and distinctive mitochondrial changes, including shrinkage, reduced cross-sectional area, and increased membrane density. Prior work by the same group showed that the iron chelator deferoxamine attenuates ferroptotic injury in rat spinal cord injury models, that the ferroptosis inhibitor ferrostatin-1 reduces iron and reactive oxygen species accumulation and inhibits oligodendrocyte ferroptosis, and that hepcidin, a regulator of iron metabolism, promotes oligodendrocyte survival by suppressing iron transport proteins. The central antioxidant defense against this process is the glutathione–GPX4 pathway, in which GPX4 catalyzes the reduction of lipid hydroperoxides to non-toxic lipid alcohols.

Selenium is essential to this defense because GPX4 is a selenoprotein containing selenocysteine at its catalytic center, making selenium availability a critical determinant of GPX4 expression and activity. Clinical observations have lent plausibility to the approach: spinal cord injury patients with higher serum selenium levels tend to achieve better neurological recovery. In a mouse model of intracerebral hemorrhage, selenium enhanced GPX4 expression through activation of the transcription factors AP-2 gamma and specificity protein 1, promoting resistance to oxidative damage. Whether selenium could protect white matter after spinal cord injury, and whether it did so through ferroptosis and GPX4 signaling, remained untested before the present work.

The experimental design was straightforward. Forty-five adult male Sprague-Dawley rats underwent surgery; after six animals were excluded because of unsuccessful injury induction or unexpected postoperative death, 39 rats entered the final analyses. Moderate contusion injuries were produced at the tenth thoracic vertebra by dropping a 20-gram weight from a height of 30 millimeters. The animals were divided into a sham group receiving saline (n = 6), an injured group receiving saline (n = 11), an injured group treated with sodium selenite at 0.2 milligrams per kilogram body weight by daily oral gavage (n = 11), and an injured group receiving both sodium selenite and intraperitoneal actinomycin D at 1 microgram per gram (n = 11). Actinomycin D was used specifically as a transcriptional inhibitor to block de novo GPX4 synthesis, thereby testing whether GPX4 upregulation is required for the protective effect. No signs of selenium-related toxicity were observed during the experiment.

Functional outcomes favored the selenium-treated animals. Using the 21-point Basso–Beattie–Bresnahan (BBB) locomotor rating scale, scored by two blinded observers at 1, 7, 14, 21, and 42 days after injury, the sodium selenite group showed significantly higher scores than untreated injured rats at 21 and 42 days post-injury. Immunohistochemistry for CC1, a marker of mature oligodendrocytes, revealed a marked loss of these cells at the lesion epicenter after injury; sodium selenite significantly increased CC1-positive cell numbers relative to the injured control group, and this increase was significantly attenuated by actinomycin D, indicating that oligodendrocyte preservation is transcriptionally regulated.

Structural measures told a consistent story. Luxol Fast Blue staining at 14 days post-injury showed substantial tissue loss and white matter disruption at the lesion epicenter in injured controls, whereas selenium-treated animals retained markedly better spinal cord architecture. Immunofluorescence and western blotting showed that myelin basic protein, a structural component of compact myelin, was significantly reduced after injury and significantly restored by sodium selenite, while degraded myelin basic protein, a marker of myelin breakdown, and SMI-32, a marker of axonal injury, were both significantly elevated after injury and significantly suppressed by treatment. Transmission electron microscopy confirmed that injury reduced myelin sheath thickness and that selenium preserved it. The authors note an interesting dissociation: at 14 days, white matter preservation differed between the selenium and selenium-plus-actinomycin-D groups even though their BBB scores did not, a gap they attribute to functional recovery lagging behind structural preservation and to the limited resolution of the ordinal BBB scale at intermediate recovery phases.

The ferroptosis evidence came from mitochondrial ultrastructure and iron metabolism. Electron micrographs of oligodendrocytes within the white matter of the lesion epicenter revealed a significant increase in shrunken mitochondria with condensed membrane density after injury, the characteristic morphological signature of ferroptosis, and sodium selenite markedly reduced the proportion of these abnormal mitochondria. Western blotting showed that iron regulatory protein 2 (IRP2), a post-transcriptional regulator that expands the labile iron pool by stabilizing transferrin receptor mRNA and repressing ferritin translation, was significantly elevated after injury and substantially reduced by selenium treatment. GPX4 protein, by contrast, was markedly downregulated after injury and restored by sodium selenite, an effect abolished by actinomycin D. Double immunofluorescence for CNPase and GPX4 showed that GPX4 was predominantly expressed in oligodendrocytes and that treatment increased the abundance of GPX4-positive oligodendrocytes in the injured cord.

The authors are candid about the limits of the mechanism work. Actinomycin D is not a classical ferroptosis inducer, but recent cancer cell studies show it can enhance ferroptosis sensitivity through several routes, including downregulation of the cystine/glutamate antiporter and inhibition of glutathione synthesis. Because the study included no actinomycin-D-alone group, potential direct effects of the drug on ferroptosis sensitivity cannot be entirely excluded. The specific transcription factors mediating selenium-induced GPX4 upregulation in the injured spinal cord were not directly examined; the AP-2 gamma and SP1 mechanism demonstrated in intracerebral hemorrhage remains a plausible but unvalidated hypothesis requiring chromatin immunoprecipitation, promoter activity assays, and targeted transcription factor manipulation.

Further limitations frame the clinical outlook. The findings come exclusively from a male rat contusion model, and validation in large-animal models, female subjects, and human cell systems will be needed. The study did not examine interactions between ferroptosis and other regulated cell death pathways, nor did it directly assess neuroinflammatory markers. Selenium also has a narrow therapeutic window, with excessive exposure associated with increased oxidative stress and systemic toxicity, so optimal dosing and delivery regimens remain to be defined; the authors suggest biomaterial-based sustained-release systems or nanoparticle carriers as possible routes to improve bioavailability while limiting toxicity. Whether the protective effects persist beyond the 42-day observation period, and whether sodium selenite could combine productively with anti-inflammatory or regeneration-promoting therapies, are open questions. Within those boundaries, the study offers preclinical evidence that supplementing the selenium–GPX4–ferroptosis axis can preserve oligodendrocytes, protect myelin, and improve locomotor recovery after contusive spinal cord injury in rats, and it identifies GPX4 upregulation as a mechanistic requirement for that protection.

Subject of Research: GPX4-mediated suppression of ferroptosis by sodium selenite in a rat model of spinal cord injury

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

Article References: Shi, J., Yuan, L., Su, H., Quan, W., Zhao, D., Wang, L., Li, L., Chen, H., Zhong, J., Yin, Y., & Hu, S. (2026). Sodium selenite mitigates white matter injury after spinal cord injury through GPX4-mediated suppression of ferroptosis. Frontiers in Molecular Neuroscience, 19, Article 1969679. https://doi.org/10.3389/fnmol.2026.1969679

Image Credits: AI Generated

DOI: 10.3389/fnmol.2026.1969679

Keywords: spinal cord injury, sodium selenite, ferroptosis, GPX4, oligodendrocytes, white matter injury, myelin, selenium, rat model, lipid peroxidation, actinomycin D, preclinical study