Treating neurological diseases through epigenetic inhibition: A neuroepigenetic therapy hypothesis.

Epigenetics encompasses a highly coordinated set of reversible mechanisms that regulate gene expression and function without altering the underlying DNA code. Emerging evidence indicates that dysregulation of epigenetic pathways contributes to the pathogenesis and progression of numerous central nervous system disorders. This review summarizes the major epigenetic mechanisms implicated in neurological diseases, including histone acetylation and deacetylation, DNA methylation, microRNA-mediated regulation, and bromodomain and extraterminal domain protein signaling, and highlights emerging therapeutic strategies targeting these pathways. Epigenetic modulators, including histone deacetylase inhibitors, DNA methyltransferase inhibitors, microRNA-based modulators, and bromodomain and extraterminal domain inhibitors, can broadly influence transcriptional processes involved in neuroinflammation, neuronal survival, synaptic plasticity, and tissue repair. Although many of these approaches remain in the early stages of development, preclinical studies have demonstrated considerable potential to regulate pathological immune and inflammatory responses, promote neuroprotection, and enhance functional recovery following central nervous system injury and disease. Consequently, epigenetic-based therapies have emerged as promising disease-modifying strategies for a wide range of neurological disorders, including traumatic brain injury, stroke, epilepsy, neurodegenerative diseases, and chronic pain. We propose a unifying "neuroepigenetic therapy hypothesis" whereby precision targeting of reversible maladaptive epigenetic states can restore transcriptional homeostasis and shift treatment of neurological disorders from symptomatic control toward disease prevention, repair, and disease modification. A deeper understanding of the complex interplay among multiple transcriptional regulatory pathways may pave the way for precision neuroepigenetic therapies capable of preventing or mitigating chronic neurological disorders with improved efficacy and safety. SIGNIFICANCE STATEMENT: Aberrant neuroepigenetic signaling is increasingly recognized as a key driver of neuroinflammation, neuronal dysfunction, and disease progression in many neurological disorders. By targeting nuclear mechanisms that regulate gene expression, epigenetic therapies have emerged as a promising class of neuroprotective and disease-modifying agents. This review highlights recent advances in epigenetic therapeutics and their potential to transform the treatment of central nervous system disorders.