Pterostilbene Promotes Spinal Cord Injury Recovery by Inhibiting Ferroptosis via Keap1/Nrf2/SLC7A11/GPX4 Axis Activation

Background: Spinal cord injury (SCI) represents a form of traumatic damage to the central nervous system, and oligodendrocytes play a central role in SCI recovery. Ferroptosis is a major factor in the pathophysiological development of SCI symptoms. Pterostilbene (Pte) has antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to investigate the potential role of Pte in SCI. Methods: A SCI model of rats was constructed. The BBB score assessment, the footprint test, EC staining, immunofluorescence (IF), and Western blot (WB) were conducted to observe the neuroprotective effects of Pte. The factors of ferroptosis, such as Glutathione (GSH), Malondialdehyde (MDA), Fe2+, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), were assessed. Then, transcriptomic data, network pharmacology, molecular docking analysis, and the erastin-induced ferroptosis model of OLN-93 cell lines were used to investigate the mechanism of inhibiting ferroptosis by Pte. Results: Pte treatment restored motor function and spinal cord tissue in SCI rats. Furthermore, Pte dramatically decreased oligodendrocyte ferroptosis. Finally, we discovered that Pte can repair SCI by blocking ferroptosis via the Keap1/Nrf2/SLC7A11/GPX4 axis. Conclusions: Pte reduces lipid peroxidation via the Keap1/Nrf2/SLC7A11/GPX4 axis, which reduces the development of ferroptosis in oligodendrocytes and improves locomotor function in rats with SCI.