Thiorphan improves motor function after spinal cord injury by inhibiting neuronal ferroptosis in female mice

Spinal cord injury (SCI) causes severe motor dysfunction, yet effective pharmacological treatments remain scarce, underscoring the urgent need for novel therapeutic agents. Thiorphan has shown therapeutic potential in central nervous system disorders due to its ability to modulate oxidative stress and neuroinflammation; however, its role in SCI remains largely unknown. Therefore, we selected Thiorphan and investigated whether it improves motor recovery after SCI. Our study found Thiorphan treatment significantly enhanced motor function, as evidenced by increased BMS scores (increased from 2.2 ± 0.8 to 4.9 ± 0.6), improved performance in the Oblique Board Test (improved by approximately 1.7-fold) and footprint assay, and prolonged latency of fall. Histological and biochemical analyses revealed that Thiorphan ameliorated SCI-induced pathological changes, reduced iron accumulation (about 2.8-fold), MDA and 4-HNE levels (all exceeded 2-fold), and restored GPX4 expression (improved by approximately 3.2-fold). Mechanistically, Thiorphan reversed the SCI-induced downregulation of Nrf2 in neurons. Moreover, neuron-specific Nrf2 deletion abolished the protective effects of Thiorphan, including the improvements in survival, motor function, and neuronal viability. Collectively, these results demonstrate that Thiorphan improves motor function after SCI by inhibiting neuronal ferroptosis through the reversal of Nrf2 reduction, highlighting its potential as a therapeutic agent for SCI.