Resveratrol Alleviates Epilepsy-Induced Brain Damage via the P62-Keap1-Nrf2 Pathway: A Multi-Omics Study Integrating the Pilot Cohort, In Silico Analyses, and Experimental Validation.
TL;DR
Resveratrol protects against seizure-associated brain damage by activating P62-Keap1-Nrf2 signaling and suppressing ferroptosis, suggesting a potential therapeutic strategy for pediatric epilepsy.
Abstract
Background
Pediatric epilepsy is frequently associated with long-term cognitive, behavioral, and neurodevelopmental impairments. Although oxidative stress and metabolic dysfunction contribute to seizure-induced brain injury, how ferroptosis operates and is regulated within the context of pediatric epilepsy has yet to be fully elucidated.
Methods
A pediatric pilot cohort of 15 pediatric patients at first seizure onset alongside age-matched neurotypical peers was established. Untargeted metabolomics, neuroimaging, biochemical assays, and gene expression analyses were performed to evaluate metabolic dysregulation, iron accumulation, oxidative stress, and ferroptosis-related alterations. Integrated bioinformatics, Mendelian randomization, external transcriptomic validation, single-cell RNA sequencing, virtual perturbation analysis, and in silico drug screening were used to identify key regulatory pathways and candidate therapeutic compounds. The effects of resveratrol were further validated in a kainic acid-based murine epilepsy model and glutamate-challenged HT22 neuronal cells.
Results
Pediatric epilepsy was characterized by metabolic reprogramming, iron accumulation, lipid peroxidation, inflammation, and impaired antioxidant defense. Integrated bioinformatics identified SQSTM1/P62 and NFE2L2/NRF2 as key regulators linking autophagy and ferroptosis. External validation and single-cell transcriptomic analyses further confirmed ferroptosis- and autophagy-related dysregulation, particularly in neuronal populations. In silico screening identified resveratrol as a candidate therapeutic compound. In epileptic mice, resveratrol reduced seizure severity, epileptiform discharges, neurobehavioral deficits, iron accumulation, lipid peroxidation, inflammation, and hippocampal neuronal injury.
Conclusion
Pediatric epilepsy is associated with metabolic dysregulation, oxidative stress, iron accumulation, and ferroptosis-related neuronal injury. Resveratrol protects against seizure-associated brain damage by activating P62-Keap1-Nrf2 signaling and suppressing ferroptosis, suggesting a potential therapeutic strategy for pediatric epilepsy.