Ginkgolide B inhibits ferroptosis in PC12 cells and ameliorates the oxidative stress in spinal cord injury through activating Nrf2 signaling pathway

Spinal cord injury (SCI) commonly leads to loss of motor and sensory function and results in huge socioeconomic burden, and it triggers numerous secondary pathological events, including oxidative stress and ferroptosis. This study investigates the therapeutic potential of Ginkgolide B (GB), a neuroprotective compound derived from Ginkgo biloba, in mitigating SCI by targeting on ferroptosis. By using Erastin-induced ferroptosis in PC12 cells and a rat contusion SCI model, the present study demonstrated that GB significantly improved locomotor recovery, reduced neuronal loss, and attenuated histopathological damage. Mechanistically, GB suppressed ferroptosis markers, including elevated iron content, lipid peroxidation, and ACSL4, while restoring the expression of GPX4 and xCT. Crucially, GB enhanced nuclear translocation of Nrf2, upregulating downstream antioxidants and ferroptosis-related genes (HO-1 and NQO1). Notably, the functions of GB were abolished after utilization of Nrf2 signaling inhibitor ML385 which revealed the role of GB on recovery of SCI was highly related to the activation of Nrf2 signaling. These findings reveal that GB alleviates SCI by inhibiting ferroptosis through Nrf2 activation, positioning it as a promising therapeutic agent. This study elucidates a novel mechanism linking Nrf2 signaling to ferroptosis suppression in SCI and provides a translational framework for repurposing GB in SCI treatment.