HDAC3 in neurodevelopmental disorders: Molecular mechanisms and targeted intervention

Autosomal dominant neurodevelopmental disorders are increasingly linked to genetic mutations that interfere with brain development and function. Among the genes implicated, HDAC3 plays a central role as an epigenetic regulator, maintaining chromatin structure and controlling gene expression. Mutations in HDAC3 have been associated with developmental delays, intellectual disabilities, and autism spectrum disorder. This narrative review explores recent genetic, molecular, and clinical research on HDAC3 and its involvement in autosomal dominant neurodevelopmental disorders. A comprehensive and detailed literature search was done, mainly focusing on studies that examine the gene's molecular functions, pathogenic variants, and clinical outcomes. Beyond its role in gene silencing and chromatin remodeling, HDAC3 is also critical for neural differentiation and synaptic plasticity. HDAC3 interacts with nuclear receptor co-repressors such as NCoR and SMRT, which are important for transcriptional repression during brain development. Recent studies have demonstrated that HDAC3 dysfunction can lead to abnormalities in cortical layering and neuron subtype specification. Moreover, HDAC3 is involved in regulating oxidative stress and neuroinflammation, processes that are critical for sustaining neural health. Experimental HDAC3 inhibitors are being explored as potential therapeutic agents to reverse epigenetic abnormalities and improve neurological outcomes in model systems. The review discusses emerging therapeutic strategies, including pharmacological targeting and gene-editing approaches. Continued research is essential to better understand HDAC3 mutations, expand genetic screening, and develop targeted treatments for individuals affected by these rare but impactful disorders.