Groundbreaking Insights Into SIRT1 / NRF2 ‐Mediated Ferroptosis Inhibition by Resveratrol in Parkinson's Disease Models

ABSTRACT Background Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the degeneration of dopamine (DA) neurons in the substantia nigra (SN) of the midbrain. Recent studies have highlighted the role of ferroptosis in neuronal death, with elevated peroxide levels being a hallmark of this process. Resveratrol (RSV), a natural compound, has shown promise as a neuroprotective agent. This study explores the potential of RSV in mitigating ferroptosis in PD and elucidates its mechanisms. Methods Network pharmacology was employed to predict the interactions between RSV, ferroptosis, and PD‐related targets. Cytoscape protein‐protein interaction (PPI) analysis identified key potential targets, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses provided insights into the probable mechanisms linking RSV, ferroptosis, and PD. Subsequently, in vitro experiments were conducted to validate these findings, followed by in vivo studies to confirm the therapeutic efficacy of RSV in PD. Results Network pharmacology results indicated that RSV, PD and ferroptosis interact at multiple biological levels. Compared to the PD group, RSV upregulated the expression of SIRT1 and NRF2 and alleviated MPTP‐induced motor deficits in mice. Furthermore, RSV reduced levels of MDA, ROS, lipid peroxidation, and cellular iron, while upregulating ferroptosis‐negative regulators such as GPX4 and FTH1, as well as pathway indicators like SIRT1 and NRF2. Inhibition of SIRT1 and NRF2 resulted in a decrease in the expression of GPX4/FTH1 and the SIRT1/NRF2 signaling pathway. Conclusions Our findings demonstrate that RSV alleviates motor dysfunction in PD by inhibiting ferroptosis through SIRT1/NRF2 activation, providing novel mechanistic insights into its therapeutic potential for neurodegenerative diseases.