Muhammad Shahzaib Rasheed, Irsa Akbar, Usman Javed, Mubashir Shakeel, Midra Sajid, Azka Sabir, Marva Zafar, Warda Amjad
Background: Epileptogenesis is a dynamic process characterized by continuous molecular, cellular, and network-level changes that result in persistent hyperexcitable neuronal activity and recurring seizures. While well-known, classical mechanisms (such as neurotransmitter imbalance, synaptic remodelling, neuroinflammation, and ion channel dysfunction) are not as well studied as RNA-based epigenetic regulation as an integrated mechanism. Mechanisms: The roles of N6-methyladenosine (m6A) epitranscriptomic modifications and microRNA (miRNA) mediated posttranscriptional regulation have been thoroughly explored as independent processes, but a systematic overview of the crosstalk between different stages of epileptogenesis (acute insult, latency, and chronic epilepsy) has not been conducted. This is a novel review of an integrative m6A-miRNA regulatory mechanism in which the m6A writer, eraser, and reader proteins (METTL3, METTL14, FTO and ALKBH5) directly regulate the biogenesis and maturation of miRNAs, and miRNAs and, in turn, fine-tune the expression of m6A-containing enzymes, creating a self-reinforcing regulatory loop that contributes to neuroinflammation, synaptic remodelling, oxidative stress, and neuronal dysfunction. Implications: Based on this, we review and combine new dual-pathway therapeutic strategies, such as antiepileptic drugs, modulators of the mTOR pathway, anti-inflammatory compounds, and RNA-based therapies, such as miRNA mimics and antagomirs, which can affect pathways that were not previously synthesized in the epilepsy literature. The use of emerging exosome-based nanocarriers to enhance blood-brain barrier penetration for such RNA-based cargo is additionally highlighted. Conclusion: This review, which combines mechanistic and translational approaches, provides a new conceptual framework for the discovery of disease-modifying biomarkers and targets, and for the rethinking of epileptogenesis as a result of an interconnected epitranscriptomic network instead of a series of isolated molecular events.