Role of the miR-340-5p/IRF1/USP18 Axis in Neuroinflammation Associated with Epilepsy

Epilepsy is a prevalent neurological disorder, in which maladaptive neuroinflammation critically contributes to epileptogenesis. In this study, we identified a previously unrecognized signaling axis that regulates inflammatory responses and inflammatory cell death in experimental epilepsy. Integrated bioinformatic analyses of the GSE73878 and GSE18740 datasets, together with transcription factor and microRNA prediction databases, highlighted USP18 and its upstream regulators as key candidates. Functional and mechanistic validations were performed using lipopolysaccharide-stimulated BV2 microglia and pentylenetetrazole-induced mouse seizure models. Seizure severity and epileptic phenotypes were confirmed using the Racine scale assessments and EEG recordings. USP18 was markedly upregulated under epileptic conditions accompanied by increased pro-inflammatory cytokine release, apoptosis, and pyroptosis. Silencing USP18 attenuated neuroinflammation and reduced seizure severity. Mechanistically, interferon regulatory factor 1 (IRF1) was identified as a direct transcriptional activator of USP18, whereas miR-340-5p suppressed USP18 expression by targeting IRF1, thereby mitigating inflammatory signaling and neuronal injury. Collectively, these findings reveal a novel regulatory pathway linking microRNA-mediated control, interferon-responsive transcription, and inflammatory effector mechanisms in epilepsy, and suggest that targeting the miR-340-5p/IRF1/USP18 axis may represent a promising disease-modifying therapeutic strategy.