Isoform selective targeting of histone deacetylases as a precision therapeutic strategy for neurodegenerative diseases

Abstract Histone deacetylases (HDACs) are epigenetic enzymes that eliminate acetyl groups from histone lysine residues, promoting chromatin compaction and transcriptional repression. Dysregulation of HDAC activity is increasingly recognized as a central contributor to the pathogenesis of major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), through mechanisms encompassing synaptic gene silencing, neuroinflammation, impaired proteostasis, mitochondrial dysfunction, and oxidative stress. This review critically evaluates isoform-selective HDAC targeting as a precision epigenetic strategy for neurodegenerative disease, rather than providing a broad survey of pan-HDAC pharmacology. Emerging evidence consistently supports a disease-stratified isoform model: HDAC2 drives nuclear synaptic gene repression in AD; HDAC6 governs cytoplasmic proteostasis and axonal transport in PD and ALS; HDAC1 and HDAC3 amplify transcriptional repression in HD via direct interaction with mutant huntingtin; and SIRT1, a Class III deacetylase, exerts broadly neuroprotective effects across all four conditions through mitochondrial biogenesis and oxidative stress attenuation. These isoform-specific distinctions expose a critical limitation of broad-spectrum pan-HDAC inhibitors, which simultaneously suppress both pathogenic and homeostatic deacetylase activities, and provide a mechanistic explanation for the consistent failure of pan-HDAC inhibitors in clinical trials for neurodegeneration. The review further discusses translational barriers including blood-brain barrier penetrance, pharmacokinetic limitations, and the absence of validated CNS biomarkers of target engagement. Future therapeutic progress will require the development of isoform-selective inhibitors, brain-targeted delivery systems, and biomarker-guided clinical trial design to bridge the longstanding gap between compelling preclinical findings and effective human therapies.