The histone deacetylase family in health and disease

Zinc-dependent classical histone deacetylases, including Classes I, II, and IV, are ubiquitously present in mammals and play vital roles in numerous biological processes. To date, eleven histone deacetylase members have been identified, namely, histone deacetylase 1 through histone deacetylase 11. A growing body of evidence underscores the crucial roles of these histone deacetylase members in both physiological and pathological conditions. Notably, these histone deacetylase members are involved in various cellular processes, including inflammation, metabolism, apoptosis, and oxidative stress. Consequently, histone deacetylases have emerged as promising therapeutic targets for a range of pathological conditions, including tumors, cardiovascular diseases, and neurological disorders. Moreover, the development of histone deacetylase modulators, which can regulate their activity, has shown significant therapeutic potential across various conditions. Several histone deacetylase inhibitors have been approved by the U.S. Food and Drug Administration for the treatment of multiple tumors and Duchenne muscular dystrophy, while many others are being developed for oncology and other therapeutic applications. In this review, we introduce the research history and structural characteristics of histone deacetylases. We then summarize the molecular mechanisms and biological functions of the eleven histone deacetylase family members. Moreover, we elucidate the critical regulatory roles of histone deacetylases in various human diseases. Furthermore, we provide an overview of histone deacetylase modulators, their current clinical applications, and potential benefits, offering insight into the regulation of histone deacetylases for the treatment of related diseases.