HDAC5 is a class IIa histone deacetylase that catalyzes lysine deacetylation on core histones (H2A, H2B, H3, H4), enabling epigenetic repression and regulating transcription, cell cycle progression, and developmental events 1. Beyond its canonical histone-targeting function, HDAC5 exhibits critical nonhistone substrate specificity and subcellular localization dynamics. During muscle differentiation, HDAC5 shuttles to the cytoplasm, allowing myocyte enhancer factor (MEF2) expression; conversely, it represses MEF2C transcription during muscle maturation [UniProt annotation]. In the LKB1-SIK3 signaling pathway, phosphorylation of HDAC5 modulates sleep duration and depth via transcriptional regulation in posterior hypothalamus 2. HDAC5 deacetylates the nonhistone protein ACTN4 at K417 during skin reepithelialization, facilitating nuclear translocation of ACTN4 and YBX1-mediated transcription of wound-healing genes 3. In pathological contexts, HDAC5 contributes to multiple diseases. In diabetic kidney disease, HDAC5 upregulation, controlled by PI3K/Akt signaling, promotes epithelial-mesenchymal transition and fibrosis 4. HDAC5 overexpression in hypertrophic scars represses Smad7 via MEF2A, enhancing TGF-β signaling and fibroblast activation 5. In pancreatic cancer, HDAC5 deacetylates NF-κB p65, suppressing PD-L1 expression and promoting immune evasion; HDAC5 inhibition sensitizes tumors to immunotherapy 6. In polycystic ovary syndrome, elevated HDAC5 suppresses histone H3K14 and H3K56 acetylation, downregulating folliculogenesis genes 7. HDAC5 mutations confer androgen receptor-targeted therapy resistance in prostate cancer 8. These findings establish HDAC5 as a versatile epigenetic regulator with therapeutic targeting potential across multiple diseases.