HDAC6 is a cytoplasmic class IIB histone deacetylase with multifaceted roles extending beyond nuclear histone modification. Primary function: HDAC6 regulates both histone and non-histone protein acetylation, including Hsp90, α-tubulin, and cortactin 1. Mechanistically, HDAC6 catalyzes α-tubulin lactylation in response to lactate availability, enhancing microtubule dynamics and neurite outgrowth 2. Additionally, HDAC6 acts as a valine sensor through its SE14 repeat domain; valine deprivation causes nuclear retention and deacetylation of TET2, promoting DNA damage 3. HDAC6 also regulates myofibril stiffness by deacetylating titin's PEVK element, controlling myocardial passive stiffness 4. Disease relevance: HDAC6 dysfunction contributes to heart failure with preserved ejection fraction (HFpEF), with HDAC6 inhibition reversing established HFpEF and restoring mitochondrial function 5. In triple-negative breast cancer, phosphorylated HDAC6 undergoes phase separation to form nuclear condensates that establish aberrant chrX architecture 6. In Alzheimer's disease, HDAC6 inhibition promotes amyloid-β phagocytosis, reduces phospho-tau, and regulates neuroinflammation 7. Clinical significance: HDAC6 inhibitors (ACY-1215, ACY-241) are in clinical trials 1, with emerging evidence supporting their use in cardiovascular, neurodegenerative, and oncological conditions.