Restoring Neural Homeostasis via Class II HDAC Modulation: Mechanistic Insights and Therapeutic Opportunities

Class II histone deacetylases (HDACs) comprise class IIa enzymes HDAC4, HDAC5, HDAC7, and HDAC9 and class IIb enzymes HDAC6 and HDAC10, which differ substantially in structure, catalytic activity, subcellular localization, and neural function. Class IIa HDACs exhibit weak intrinsic deacetylase activity and function predominantly as signal-responsive scaffolds that couple calcium and kinase signaling to transcription through nucleocytoplasmic shuttling, recruitment of HDAC3-containing NCoR/SMRT corepressor complexes, and interactions with MEF2, CREB, and FOXO. Conversely, HDAC6 is a predominantly cytoplasmic deacetylase that regulates α-tubulin acetylation, cytoskeletal dynamics, axonal transport, autophagy, and proteostasis. Dysregulated class II HDAC signaling contributes to neurodegenerative diseases through convergent mechanisms involving synaptic dysfunction, maladaptive transcriptional repression, mitochondrial impairment, oxidative stress, neuroinflammation, blood-brain barrier disruption, and defective clearance of pathological proteins. Disease-associated substrates include amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and TDP-43/SOD1 in amyotrophic lateral sclerosis. Emerging evidence additionally links aberrant HDAC4/5 signaling to neurodevelopmental disorders through altered synaptic maturation, excitation-inhibition balance, and circuit development. This review integrates the structural and mechanistic biology of class II HDACs with their disease-specific roles and evaluates therapeutic approaches to restore neural homeostasis. Particular emphasis is placed on selective HDAC6 inhibitors, modulation of class IIa protein-protein interactions and subcellular trafficking, natural compounds, and RNA-based strategies. Finally, we discuss major translational challenges, including isoform specificity, brain penetration, context-dependent functions, and the need to distinguish catalytic from non-enzymic mechanisms when developing disease-modifying interventions for neurological disorders while preserving normal essential HDAC functions and minimizing off-target toxicity.