Resveratrol inhibits ferroptosis via activating NRF2/GPX4 pathway in mice with spinal cord injury

Abstract Ferroptosis is a newly defined form of cell death involved in neurologic disease. Resveratrol is a non‐flavonoid polyphenolic compound with anti‐inflammatory and antioxidant properties, but its potential therapeutic mechanism in spinal cord injury (SCI) remains unknown. Therefore, this study evaluates the mechanism by which resveratrol promotes neurological and motor function recovery in mice with SCI. The motor function of mice was evaluated using the Basso Mouse Scale score and footprint test. The effect of resveratrol on the neuronal cell state was observed using NeuN, fluoro‐Jade C, and Nissl staining. The expression of iron content in injured segments was observed using Perls blue and Diaminobenzidine staining. The effect of resveratrol on the levels of malondialdehyde, glutathione, Fe 2+ , and glutathione peroxidase 4 enzyme activity was also investigated. The mitochondrial ultrastructures of injured segment cells were observed using transmission electron microscope, while the protein levels of ferroptosis‐related targets were detected using Western blot. Our findings show that resveratrol improves motor function after SCI and has certain neuroprotective effects; in ferroptosis‐related studies, resveratrol inhibited the expression of ferroptosis‐related proteins and ions. Resveratrol improved changes in mitochondrial morphology. Mechanistically, the Nrf2 inhibitor ML385 reversed the inhibitory effect of resveratrol on ferroptosis‐related genes, indicating that resveratrol inhibits ferroptosis through the Nrf2/GPX4 pathway. Our findings elucidate that resveratrol promotes functional recovery, inhibits ferroptosis post‐SCI, and provides an experimental basis for subsequent clinical translational research. Our study shows that resveratrol inhibits the production of lipid peroxide and the accumulation of iron by activating Nrf2/GPX4 signaling pathway, thereby inhibiting neuronal ferroptosis. At the same time, it can promote the recovery of motor function of mice.