Non-coding RNA dysregulation in autism spectrum disorder: Mechanisms, biomarkers, and therapeutic perspectives

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, impaired eye contact, restricted interests, and deficits in communication. For many years, the identification and diagnosis of ASD have relied primarily on behavioral assessments, while no definitive molecular biomarker has yet been established. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and Piwi-interacting RNAs (piRNAs), directly and indirectly regulate gene expression and contribute to the pathophysiology of various diseases and disorders. Recent studies have highlighted the crucial role of ncRNAs in neuronal development and function, suggesting that aberrant ncRNA (Non-Coding RNA) expression may lead to neuronal dysregulation and neurodevelopmental disorders. In ASD, several miRNAs and lncRNAs have been reported to be dysregulated in cell lines, brain tissues, and peripheral blood samples derived from patients. Through competitive endogenous RNA network interactions between miRNAs, lncRNAs, and messenger RNAs (mRNAs), complex regulatory networks are formed that may influence ASD pathophysiology. Dysregulation of miRNAs and lncRNAs may also affect key neuronal receptors such as N-methyl-D-aspartate receptors (NMDARs), which play essential roles in synaptic plasticity, calcium permeability, and voltage-dependent signaling. Several miRNAs have been reported to regulate ASD-associated genes such as SHANK3, SYNGAP1, and CHD8 in experimental systems, suggesting their potential involvement in molecular pathways relevant to ASD. Although these ncRNAs show promise as potential biomarkers, their clinical utility will depend on replication across larger, multi-center cohorts and the establishment of standardized methodologies.