Background: Spinal cord injury (SCI) represents a severe neurological condition with limited effective treatments. Hyperbaric oxygen (HBO) therapy has demonstrated efficacy in alleviating SCI, yet its precise molecular mechanisms remain poorly elucidated. Previous genome-wide transcriptome analysis indicated that HBO downregulates mRNA expression of Heme oxygenase 1 (HMOX1) and Ferritin light chain 1 (FTL1), suggesting a potential link to ferroptosis, a novel form of iron-dependent regulated cell death. Notably, hypoxia-inducible factor-1alpha (HIF-1alpha), a key regulator of cellular response to hypoxia, is upregulated following SCI, and this upregulation is attenuated by HBO intervention. Given the involvement of the HIF-1alpha/HMOX1 axis in regulating ferroptosis, we hypothesized that the therapeutic effect of HBO in SCI may be mediated through modulation of this pathway.

Methods: An SCI-induced mouse model was established and treated with HBO for 7 days. Nissl staining and hematoxylin-eosin staining were performed for histopathological assessment. Real-time quantitative polymerase chain reaction and Western blotting were used to quantify HIF-1alpha/HMOX1 expression and ferroptosis-related proteins (Glutathione Peroxidase 4 (GPX4), Solute Carrier Family 7 Member 11 (SLC7A11)) in spinal cord tissues. Primary rat spinal neurons were treated with Erastin (ferroptosis inducer), HBO, or HIF-1alpha overexpression plasmid. Malondialdehyde (MDA) and Fe²⁺ levels were measured in vitro employing thiobarbituric acid reactive substances (TBARS) kit and colorimetric assay.

Results: HBO therapy increased Nissl bodies and reduced spinal cord edema and cavitation in SCI mice. It diminished HIF-1alpha/HMOX1 expression and elevated GPX4/SLC7A11 levels in the mouse model and in Erastin-induced neurons. HBO therapy also abrogated Erastin-induced upregulation of MDA and Fe²⁺. Notably, HIF-1alpha overexpression reversed the protective effects of HBO on ferroptosis.

Conclusion: HBO therapy shows ameliorative effects against SCI, which are associated with the downregulation of the HIF-1alpha/HMOX1 signaling axis and the consequent suppression of ferroptosis. These findings elucidate a novel and promising molecular mechanism underlying HBO's therapeutic effect, providing a potential target for future SCI treatment strategies.