Sirtuin 3 as a promising target in disease therapy: Model action and drug discovery

Sirtuin 3 (SIRT3) belongs to the Class III histone deacetylase (HDACIII) family and is an enzyme of significant importance in epigenetic regulation. Many studies have demonstrated that the aberrant expression of SIRT3 is closely associated with a variety of diseases, including inflammation, cancer, cardiovascular diseases, and disorders of the central nervous system disorders. SIRT3 is involved in the regulation of multiple intracellular processes, such as cell migration and apoptosis, and thus, has emerged in recent years as a promising therapeutic target for disease treatment. This review first summarizes the structure of SIRT3 and its pharmacological actions, followed by an analysis of the cocrystal structures of representative SIRT3 inhibitors/activators. Subsequently, we focus on the development of SIRT3 modulators (including inhibitors and activators) from a drug-design perspective in recent years. Finally, we present challenges encountered in the discovery of small-molecule modulators targeting SIRT3 and potential future developments.