Decoding the role of m6A RNA methylation regulators in psychiatric and substance use disorders

Abstract

N6-methyladenosine (m⁶A) is the most prevalent internal modification of eukaryotic mRNA and plays a crucial role in regulating gene expression. This dynamic and reversible epitranscriptomic mark responses to both environmental and internal cues and influences RNA stability, splicing, translation, and localization. In the central nervous system, m⁶A modifications are tightly regulated and critically involved in neural development, synaptic plasticity, learning, memory, and stress responses. These modifications are governed by a complex and responsive network of regulatory proteins, including writers (methyltransferases), erasers (demethylases), and readers (RNA-binding proteins). Emerging evidence indicates that dysregulation of m⁶A regulators contributes to the pathophysiology of various psychiatric disorders. Altered expression or function of m⁶A-related genes has been associated with neuroadaptive changes underlying conditions such as schizophrenia, depression, bipolar disorder, and substance use disorder. This review provides an overview of the molecular mechanisms of m⁶A modification, highlights the roles of m⁶A regulators in psychiatric disorders, summarizes recent findings, and discusses potential therapeutic strategies targeting m6A pathways. A better understanding of m⁶A-mediated mechanisms may advance the diagnosis and treatment of neuropsychiatric conditions.

Keywords: Epitranscriptomic modification; Gene expression regulation; Psychiatric disorders; Substance use disorder; m(6)A RNA methylation; m(6)A erasers; m(6)A readers; m(6)A writers.