HDAC5 is a class IIa histone deacetylase that catalyzes lysine deacetylation on core histones, creating a repressive epigenetic mark essential for transcriptional regulation and cell fate decisions. During muscle differentiation, HDAC5 shuttles from nucleus to cytoplasm, allowing myocyte enhancer factor expression; it also acts as a corepressor of retinoic acid receptor alpha, regulating inflammatory responses via microRNA-10a repression. HDAC5 has emerged as a critical node in multiple disease contexts. In pancreatic ductal adenocarcinoma, HDAC5 loss mediates intrinsic resistance to KRASG12D inhibitors by preventing c-Myc degradation, stabilizing c-Myc transcriptional activity despite KRAS pathway inhibition 1. In triple-negative breast cancer, HDAC5 inhibition triggers asparagine synthetase downregulation via RXRA deacetylation, suppressing mTOR signaling 2, and promotes radiotherapy sensitivity by preventing MRE11 lactylation 3. HDAC5 overexpression drives hypertrophic scar formation through Smad7 silencing 4 and suppresses anti-tumor immunity in pancreatic cancer by deacetylating NF-κB p65 5. Multiple HDAC inhibitors targeting HDAC5—including belinostat, panobinostat, and romidepsin—are approved or in late-stage development. These agents show promise in hematologic malignancies and solid tumors, with HDAC5 inhibition alone or combined with immunotherapy and targeted kinase inhibitors representing emerging therapeutic strategies.