Regulation of Nrf2/GPX4 Signaling Pathway by Hyperbaric Oxygen Protects Against Depressive Behavior and Cognitive Impairment in a Spinal Cord Injury Rat Model

ABSTRACT Aims Neuroinflammation, microglial activation, and oxidative stress contribute to neuropsychiatric deficits following spinal cord injury ( SCI ). Hyperbaric oxygen ( HBO ) therapy has demonstrated anti‐inflammatory, antioxidant, and neuroprotective properties. This study aimed to investigate the therapeutic effects and underlying mechanisms of HBO on depressive‐like behavior, cognitive impairment, and hippocampal pathology in a rat model of SCI . Methods We employed a battery of behavioral assessments, unbiased stereological analysis, immunofluorescence staining, and biochemical assays to evaluate neuroinflammation, oxidative stress, mitochondrial damage, and iron accumulation in the hippocampus. Untargeted proteomic analysis was conducted to identify potential molecular targets of HBO . Western blotting was used to assess the activation of the Nrf2/ GPX4 signaling pathway. ML385 , a selective Nrf2 inhibitor, was intrathecally administered 30 min prior to daily HBO treatment to validate pathway involvement. Results HBO treatment significantly alleviated depressive‐like behavior and cognitive deficits in SCI rats. It also suppressed M1 ‐type microglial activation and reduced hippocampal neuroinflammation. Additionally, HBO mitigated neuronal ferroptosis induced by SCI through activation of the Nrf2/ GPX4 signaling pathway. The protective effects of HBO were abolished by coadministration of ML385 , confirming the critical role of Nrf2 signaling in mediating its anti‐ferroptosis effects. Conclusion These findings highlight ferroptosis as a key pathological mechanism in SCI ‐induced hippocampal damage and suggest that HBO therapy alleviates depressive‐like behavior and cognitive impairment by targeting the Nrf2/ GPX4 pathway. This study provides new insights into the therapeutic potential of HBO in managing SCI ‐related neuropsychiatric dysfunction.