HDAC3 is a histone deacetylase that catalyzes deacetylation of lysine residues on core histones (H2A, H2B, H3, H4) and non-histone substrates, playing crucial roles in transcriptional repression, cell cycle progression, and development 1. HDAC3 functions within large multiprotein complexes, notably the N-CoR repressor complex, which enhances its enzymatic activity 1. Beyond classical deacetylation, HDAC3 exhibits broader deacylase activities, removing crotonyl, lactyl, and other acyl groups from lysine residues 2. Mechanistically, HDAC3 participates in BCL6-mediated transcriptional repression by deacetylating H3K27 on enhancer elements 1 and regulates circadian clock genes through deacetylase activity-independent mechanisms involving BMAL1 and CRY proteins [UniProt source]. In disease contexts, HDAC3 dysregulation contributes to multiple pathologies. In atherosclerosis, TRAP1-mediated lactate accumulation promotes histone H4K12 lactylation by downregulating HDAC3, activating senescence-associated secretory phenotype genes in vascular smooth muscle cells 3. HDAC3 deletion in intestinal epithelial cells restricts tuft cell differentiation and impairs type 2 immunity, with microbiota-derived butyrate suppressing HDAC3 activity 4. In osteoarthritis, ECM stiffening downregulates HDAC3, increasing Parkin acetylation and excessive mitophagy in chondrocytes 5. Conversely, HDAC3 shows neuroprotective properties in neurodegenerative diseases 6. Clinically, HDAC3 represents a therapeutic target for metabolic diseases, immune disorders, and cancer-related conditions, with potential interventions including HDAC3 activation through microbiota-derived metabolites 7 or inhibition in specific disease contexts.