PIWI-piRNA Axis in Epilepsy: Bridging Epigenetic Regulation, Neuroinflammation, and Neuronal Excitability

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, neuroinflammation, and epigenetic instability, with around one-third of patients experiencing drug-resistant epilepsy. While ion channels and neurotransmitter imbalances have been thoroughly examined in relation to epilepsy, the significance of piRNAs and their interaction with PIWI proteins in gene regulation, transposon silencing, and inflammatory signaling inside the epileptic brain is gaining recognition. This summary encapsulates the existing understanding of piRNA synthesis, the epigenetic control through PIWI-piRNA interactions, and their novel roles in epileptogenesis. PIWI-piRNA complexes target highly expressed genomic areas, such as LINE-1 retrotransposons, and mute them by recruiting chromatin modifiers such DNMT3A and H3K9 methyltransferase complexes, therefore influencing genome stability and neuronal excitability. Additionally, piRNAs initiate pathways associated with neuroinflammation, including the activation of the Toll-like receptor-4/NF-kB signaling pathway and the NLRP3 inflammasome, and indirectly influence GABAergic homeostasis through interactions with the extensive noncoding RNA regulatory network. Targeted modulation of kainic acid, pilocarpine, and hereditary epilepsy models has been documented to provide decreases in seizure load; however, the extent of this effect varies among the models and modulation techniques employed. The review critically evaluates emerging therapeutic strategies, including AAV9 vectors, lipid nanoparticles, exosome-based delivery systems, and antisense oligonucleotides, along with their associated challenges such as blood-brain barrier penetration, off-target effects, immune activation, and long-term safety. In conclusion, the PIWI-piRNA axis represents a potential yet nascent domain for biomarker creation and disease modulation in epilepsy.