The mechanistic role of non-coding RNAs in febrile seizures in children: their potential as biomarkers and therapeutic targets-a systematic review.

Background: Febrile seizures (FSs) are the most common seizure disorder in children aged 6 months to 5 years, influencing approximately 2-5% of the global population, with a higher prevalence in men and those with a family history. Their complex pathogenesis involves fever-induced neuroinflammation, imbalances in neuronal excitation and inhibition, and genetic predispositions. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are key regulators of gene expression and have been implicated in various neurological disorders. However, their specific roles in FSs remain underexplored. This systematic review aimed to summarize the epidemiology and pathophysiological mechanisms of FSs, elucidate the emerging roles of ncRNAs, and evaluate their potential as biomarkers and therapeutic targets. Methods: A systematic literature search was conducted following the PRISMA guidelines. Electronic databases, including PubMed, Web of Science, and Embase, were searched using keyword combinations related to "Febrile Seizures" and "non-coding RNA". The screening process involved initial title/abstract review, full-text assessment, and final inclusion based on predefined criteria, with exclusions documented at each stage to ensure comprehensive coverage and minimize bias. Results: The review highlighted that FS pathophysiology could be influenced by developmental characteristics of the nervous system (e.g., heightened neuronal excitability), immune responses (e.g., pro-inflammatory cytokines regulated by ncRNAs, such as miR-146a and miR-155), and genetic factors (e.g., ion channel genes post-transcriptionally controlled by ncRNAs, such as miR-134). Key ncRNAs, including miR-134 (associated with neuronal hyperexcitability), miR-146a (modulating neuroinflammation), and circHIPK2 (involving astrocyte activation), were identified as critical in seizure mechanisms based on animal models and mechanistic studies. NcRNAs demonstrate promise as biomarkers due to their stability in biological fluids, while challenges in sensitivity and specificity should be addressed. Therapeutically, targeting ncRNAs through strategies, such as antisense oligonucleotides for miR-134 or mimics for miR-146a shows promise in preclinical models. However, efficient delivery to the central nervous system remains a significant challenge. Conclusions: NcRNAs serve as dynamic regulators in the pathogenesis of FSs, providing valuable insights for diagnosis and treatment. They hold remarkable potential as non-invasive biomarkers and therapeutic targets. However, future research should prioritize validating the findings in clinical cohorts, elucidating causal mechanisms, and addressing translational challenges, such as standardization and delivery systems, to advance personalized medicine for pediatric FSs.