Noncoding RNAs in epilepsy: from molecular mechanisms to clinical translation.

Epilepsy comprises a heterogeneous group of brain disorders in which recurrent seizures arise from dynamic interactions among neuronal hyperexcitability, glial activation, neuroinflammation, vascular dysfunction, and maladaptive circuit remodeling. Despite advances in genetics, neuroimaging, and molecular profiling, clinically useful biomarkers remain limited, and disease-modifying therapies are still lacking. Noncoding RNAs (ncRNAs) have emerged as an important regulatory layer in epilepsy biology. MicroRNAs, long noncoding RNAs, circular RNAs, transfer RNA fragments, and other ncRNA species influence epileptogenesis through post-transcriptional repression, chromatin-associated regulation, competing endogenous RNA networks, stress-responsive translational control, and extracellular vesicle-mediated intercellular communication. These mechanisms converge on central pathological processes, including neuroinflammation, synaptic and ion-channel remodeling, neuronal injury, aberrant neurogenesis, blood-brain barrier dysfunction, and antiseizure drug resistance. Beyond brain tissue, circulating ncRNAs detectable in plasma, serum, cerebrospinal fluid, and extracellular vesicles have attracted increasing interest as minimally invasive biomarkers. Their relative stability in biofluids and potential ability to reflect disease-relevant cell-to-cell signaling support their translational relevance. However, clinical translation remains limited by substantial interstudy heterogeneity related to epilepsy subtype, sampling window, biospecimen handling, RNA isolation method, profiling platform, and normalization strategy. Preclinical studies targeting selected ncRNAs, particularly microRNAs, further support the possibility of RNA-based disease modification, although major challenges remain in target prioritization, CNS-directed delivery, and long-term safety. This Review integrates current knowledge of ncRNA biology in epilepsy with emerging biomarker and therapeutic evidence and outlines key steps required for clinical translation.