Mechanistic and functional integration of sirtuin deacylases: from substrate specificity to biological outcomes

Sirtuins, as classic NAD⁺-dependent class III histone deacetylases (HDACs), have been the focus of extensive research since their discovery, primarily centered on the mechanisms by which their deacetylase activity mediates the pathogenesis of various diseases and regulates key biological processes. With the rapid advancement of epigenetics, numerous novel acylation modifications, including lysine malonylation (Kma), lysine β-hydroxybutyrylation (Kbhb), lysine succinylation (Ksucc), and have been identified to date. Notably, the recently discovered lysine lactylation (Kla) modification has fundamentally revised long-held perception of lactic acid as a mere "metabolic waste". Importantly, SIRT1-3 have been shown to possess robust delactylase activity. To date, SIRT1-7 have been discovered to exert over ten distinct novel enzymatic functions. Herein, we summarized the functions of SIRT1-7 and their associated metabolic regulatory pathways in the context of post-translational modifications.