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Updated: Jul 12, 2026
Lipidomics and Transcriptomics in Neurological Diseases
Published on: March 18, 2022
Resveratrol alleviates epilepsy-induced brain damage via the P62-Keap1-Nrf2 Pathway: A multi-omics study integrating
Yuanying Jiang1, Ruijin Xie2, Yingsi Cao2
1Department of Internal Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Linping Campus, Hangzhou, China.
Insights
Pediatric epilepsy involves ferroptosis, a cell death pathway linked to brain damage. Resveratrol shows promise in reducing seizures and brain injury by targeting this pathway.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Pediatric epilepsy causes significant cognitive and neurodevelopmental impairments.
- Oxidative stress and metabolic dysfunction are implicated in seizure-induced brain injury.
- The role and regulation of ferroptosis in pediatric epilepsy remain unclear.
Purpose of the Study:
- To investigate ferroptosis and related pathways in pediatric epilepsy.
- To identify key regulators and potential therapeutic targets.
- To evaluate resveratrol as a therapeutic agent.
Main Methods:
- Analyzed a pediatric epilepsy cohort using metabolomics, neuroimaging, and gene expression.
- Employed integrated bioinformatics, Mendelian randomization, and single-cell RNA sequencing.
- Validated findings in a murine epilepsy model and neuronal cell cultures with resveratrol treatment.
Main Results:
- Pediatric epilepsy exhibits metabolic reprogramming, iron accumulation, lipid peroxidation, and inflammation.
- SQSTM1/P62 and NFE2L2/NRF2 were identified as key regulators linking autophagy and ferroptosis.
- Resveratrol treatment reduced seizure severity, neurobehavioral deficits, and neuronal injury in mice.
Conclusions:
- Pediatric epilepsy is characterized by ferroptosis-related neuronal injury and metabolic dysregulation.
- Resveratrol demonstrates neuroprotective effects by modulating P62-Keap1-Nrf2 signaling and suppressing ferroptosis.
- Resveratrol represents a potential therapeutic strategy for pediatric epilepsy.
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.
