CARM1 as a therapeutic target: The future of disease-modifying therapies for epilepsy

Epilepsy is a chronic neurological condition characterised by persistent or recurrent spontaneous seizures caused by aberrant and hyper-synchronisation of neurons. It is one of the leading causes of neurological problems affecting over 50 million people all around the globe, and at present, disease-modifying therapeutic agents are not widely available. This intricate set of molecular processes, including the intrusion of excitatory glutamatergic and inhibitory GABA neurotransmission, maladaptive synaptic remodelling, neuroinflammation, long-term oxidative stress, and activity-induced transcriptional reprogramming, is the genesis of epilepsy. The findings highlight the role of epigenetic regulators in linking repeated neuronal activity to long-term changes in gene expression that stabilise the hyperexcitable neural system. Recently, coactivator-associated arginine methyltransferase-1, a type 1 protein arginine methyltransferase, has gained attention as a core activity-responsive epigenetic enzyme that integrates chromatin remodelling and neuronal signalling. CARM1 is a histone H3 and non-histone asymmetric dimethyltransferase that orchestrates transcriptional programs implicated in maintaining chromatin accessibility, synaptic plasticity, neuronal excitability, and inflammatory mediator expression. The dysregulated activity of CARM1 has been implicated in increased glutamatergic signalling, diminished GABAergic inhibition, persistent neuronal hyperexcitability, and heightened microglial and astrocytic inflammatory responses, all of which play key roles in epileptogenic remodelling of connectivity. The review provides an overall synthesis of current mechanistic understanding of CARM1's functions in epilepsy, with specific attention to the mechanisms by which CARM1 regulates the excitatory-inhibitory balance, neuroinflammatory signals, and activity-dependent transcriptional plasticity. The manuscript also discusses the preclinical evidence, translational challenges, and future experimental requirements for evaluating CARM1 as a potential therapeutic target in epilepsy.