Epilepsy is one of the most common neurological disorders in childhood. However, classical antiepileptic drugs are linked with drug toxicity and cognitive function impairment in children. Hence, it is essential to develop a novel therapy to solve this problem. Currently, studies indicate regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis pathway represents a potential advanced therapy for seizures. Hence, the present study aimed to explore whether quercetin, a natural polyphenol, could alleviate seizure-induced neuron death and preserve cognitive function by inhibiting Nrf2-mediated ferroptosis. Kainic acid-induced epileptic mice model, morris water maze (MWM) test, cell counting kit-8 (CCK-8) assays, western blotting analysis, enzyme-linked immunosorbent assay, flow cytometry, quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence staining, and RNA sequencing analysis were employed to explore the potential mechanisms by which quercetin exerts protective effects on seizure-induced neuron death in kainic acid-induced epileptic mice model and glutamate-induced HT22 neuronal cell death. Our findings suggested the association between the Nrf2-mediated ferroptosis pathway and seizures in a clinical setting. Quercetin pretreatment alleviates seizure-like behaviors and cognitive impairment in KA-induced epileptic mice. Additionally, in vitro, co-treatment with quercetin effectively exerts neuroprotective effects in glutamate-induced HT22 neuronal cell death. These protective effects were also closely linked to regulating the Nrf2-mediated ferroptosis pathway. Furthermore, bioinformatic profiling revealed that the SIRT1/Nrf2/SLC7A11/GPX4 pathway plays a crucial role in the Glu-induced HT22 cell death pretreated with quercetin. These findings indicated that quercetin effectively protects against seizure-induced neuron death in vivo and in vitro and alleviates cognitive function impairment via the SIRT1/Nrf2/SLC7A11/GPX4 pathway.

Microplastics are tiny plastic particles originating from both commercial product manufacturing and the degradation of larger plastic materials. These particles pose significant risks to environmental and animal health. A growing body of evidence highlights plastic packaging as a major source of microplastic exposure in children, who are particularly vulnerable to these contaminants compared to adults^[1]. Despite growing concern, research on the effects of microplastics on human health remains limited, particularly regarding the potential consequences of long-term microplastic exposure. The aim of this study was to investigate the possible association between the neurotoxic effects of prolonged polystyrene microplastic exposure and seizure symptoms, with a special emphasis on the interplay between inflammation and ferroptosis. We hypothesize that long-term ingestion of polystyrene microplastics may disrupt the gut microbiota and induce systemic inflammation, which could subsequently trigger ferroptosis in hippocampal neurons and exacerbate seizure symptoms. Our research contributes significantly to the existing body of knowledge in three key areas. Our investigation makes significant contributions in three key areas: Firstly, by integrating observational pilot cohort studies and interpretable machine learning techniques, we demonstrate that long-term environmental microplastic exposure exposure may affect the independent inflammation-related risk factors of seizures and thereby exacerbate seizure symptoms. Second, through human network toxicology and therapeutic molecular analyses, our results suggest that melatonin may serve as a potential therapeutic intervention, uncovering mechanistic links between inflammation and ferroptosis involved in microplastic-induced seizure exacerbation. Finally, utilizing mice behavioral assays, our results validate how microplastic exposure disrupts iron and lipid metabolism in the brain, triggering neuronal ferroptosis in the hippocampus. Our study not only deepens our understanding of the neurological impacts of microplastic exposure but also identifies viable pathways for therapeutic interventions.