A comprehensive review of histone deacetylases: implications for pathogenesis and targeted therapy in hepatocellular carcinoma

Abstract Histone deacetylases (HDACs) are a family of evolutionarily conserved enzymes that catalyze the removal of acetyl groups from both histone and non-histone proteins, thereby playing a pivotal role in the regulation of gene expression and diverse cellular processes. Growing evidence indicates that HDACs are frequently dysregulated in hepatocellular carcinoma (HCC), contributing significantly to its pathogenesis and progression. In this comprehensive review, we systematically outline the structural classification and molecular functions of HDACs, emphasizing their aberrant expression and the regulatory mechanisms underlying this dysregulation in HCC, including genomic alterations, transcriptional and post-transcriptional regulation, post-translational modifications, and protein–protein interactions. We further explore the multifaceted roles of HDACs in driving oncogenic phenotypes, including uncontrolled cell cycle progression, evasion of apoptosis, enhanced migration and invasion, dysregulated autophagy, maintenance of cancer stemness, metabolic reprogramming, and therapy resistance. By integrating current findings, this review highlights how specific HDAC isoforms modulate key signaling pathways and cellular behaviors in HCC. Finally, we discuss the translational potential of HDAC targeting, summarizing the application of HDAC inhibitors (HDACis) as monotherapies and in rational combination strategies for HCC management, along with the associated challenges. This work aims to provide mechanistic insight and a valuable foundation for developing novel HDAC-directed therapeutic interventions against HCC.