SIRT5: a potential target for discovering bioactive natural products

Silent information regulator 5 (SIRT5) is the fifth member of the sirtuin family, which is mainly expressed in mitochondrial matrix. SIRT5 plays a key role in metabolism and antioxidant responses, and is an important regulator for maintaining intracellular homeostasis. Given its involvement in multiple cellular processes, dysregulation of SIRT5 activity is associated with a variety of diseases. This review explores the structural characteristics of SIRT5 that influence its substrate specificity, highlights recent research advances, and summarizes its four key enzymatic activities along with their corresponding substrates in disease contexts. We also discuss the natural products that modulate SIRT5 activity and identify potential targets of SIRT5 through virtual docking, which may provide new therapeutic avenues. Although the mechanism of SIRT5 in diseases needs to be further elucidated and deglutathionylation activities are still at an early stage, targeting SIRT5 and its substrates holds significant promise for the development of novel therapeutics.