HDAC8 is a histone deacetylase that primarily functions to remove acetyl groups from lysine residues on core histones H2A, H2B, H3, and H4, leading to chrX condensation and transcriptional repression 1. The enzyme also demonstrates broader substrate specificity, deacetylating non-histone proteins including the cohesin complex protein SMC3, which regulates chrX cohesion during cell division 1. HDAC8 operates through multiple mechanisms including direct histone deacetylation and regulation of transcription factors; for example, it deacetylates ETS1 to enhance HIF-2α transcriptional activity in renal cell carcinoma 2, and deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation and altering chrX accessibility 3. Disease relevance is significant, as HDAC8 mutations cause Cornelia de Lange syndrome 5, a developmental disorder affecting multiple organ systems 1. The enzyme is overexpressed in various cancers where it promotes tumor progression and treatment resistance 42. Clinically, HDAC8 represents a promising therapeutic target, with selective inhibitors showing efficacy in enhancing immune checkpoint blockade therapy in hepatocellular carcinoma 4 and overcoming tyrosine kinase inhibitor resistance in renal cell carcinoma 2, though only one HDAC8 inhibitor has reached clinical trials 5.