Bridging protein quality control and epigenetic dysregulation: The HDAC6 paradox in neurological disorders and therapeutic targeting.

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics.