IFITM3-mediated neuroinflammation in epilepsy regulated by the let-7g-5p/STAT2 axis.

Epilepsy is a complex neurological disorder, ranking as a leading global contributor to disability and death. This study aimed to elucidate the molecular mechanisms underlying microglia-mediated inflammation, apoptosis, and pyroptosis in epilepsy using both cell and animal models. Public datasets (GSE73878 and GSE18740) were analyzed to determine differentially expressed genes. Transcription factors and microRNAs were predicted using UCSC, JASPAR, and TargetScan. BV2 microglial cells underwent lipopolysaccharide stimulation to establish an in vitro inflammation model of epilepsy. Chronic epilepsy was induced in mice using pentylenetetrazole kindling. Flow cytometry, reverse transcription quantitative real-time PCR, ELISA, western blotting, and immunofluorescence staining were employed to delineate the underlying molecular mechanisms. Seizure severity was assessed by electroencephalogram recordings and the Racine scale. In epilepsy models, interferon-induced transmembrane protein 3 (IFITM3) was significantly upregulated and associated with increased levels of cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α), apoptosis, and pyroptosis-related markers. Signal transducer and activator of transcription 2 (STAT2) directly regulated IFITM3 transcription, whereas let-7g-5p post-transcriptionally suppressed STAT2, leading to indirect downregulation of IFITM3 and thereby mitigating neuroinflammation in epilepsy. The let-7g-5p/STAT2/IFITM3 pathway offers a novel vantage point for formulating new therapeutic modalities against epilepsy.