Targeting histone deacetylase 1: Inhibition and activation as promising therapeutic strategies for diverse disorders

Epigenetic regulation plays a crucial role in several pathological conditions. Dysregulation of histone deacetylase (HDAC) enzymes has been implicated in the onset and progression of numerous diseases, including cancer, inflammatory disorders, and neurodegenerative conditions. Most known HDAC inhibitors (HDACi) are classified as “pan-inhibitors”, targeting multiple HDAC isoforms indiscriminately. However, the growing demand for isoform-selective ligands has emphasized the need for more targeted therapeutic strategies. Among HDAC isoforms, HDAC1 has emerged as a particularly promising target for pharmacological intervention. This review provides a comprehensive overview of current HDAC1-selective ligands, including inhibitors and activators, highlighting their potential as useful therapeutic tools. The most promising class I of HDACi currently in clinical trials is discussed.