Peripheral Blood Non-Coding RNAs in Epilepsy: Biomarker Potential and Clinical Implications

Purpose: Epilepsy is a common neurological disorder characterized by recurrent seizures, complex molecular mechanisms, and clinical heterogeneity. Despite significant advances in neuroimaging techniques and antiseizure therapies, the diagnosis and management of epilepsy still largely rely on clinical findings, electroencephalography, and neuroimaging. However, these conventional approaches remain insufficient for accurately predicting disease progression, treatment response, and drug resistance, emphasizing the need for reliable molecular biomarkers. This review aims to evaluate current evidence regarding peripheral blood-derived non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), with respect to their molecular functions, biomarker potential, and clinical applicability in epilepsy.Methods: Current evidence on peripheral blood-derived ncRNAs in epilepsy was reviewed, with particular emphasis on their roles in epilepsy-related molecular mechanisms, their potential as minimally invasive biomarkers, and the methodological and translational factors affecting their clinical application.Results: Increasing evidence indicates that dysregulated ncRNA expression is associated with key pathological processes involved in epilepsy, including neuroinflammation, oxidative stress, synaptic dysfunction, neuronal hyperexcitability, apoptosis, and blood-brain barrier impairment. Circulating ncRNAs detected in serum, plasma, and whole blood exhibit remarkable stability and may reflect pathological alterations occurring within the central nervous system, supporting their potential use as minimally invasive biomarkers and candidates for liquid biopsy approaches in epilepsy. However, small cohort sizes, variability in sample processing and normalization strategies, patient heterogeneity, antiseizure medication effects, and insufficient large-scale validation studies currently limit their clinical applicability.Conclusion: Peripheral blood-derived ncRNAs represent promising candidates for minimally invasive biomarker development in epilepsy. Nevertheless, standardized methodologies, well-characterized patient cohorts, and large-scale independent validation studies are required before ncRNA-based biomarkers can be translated into routine clinical practice.