Sirtuin family (SIRT)

The Sirtuin family consists of seven evolutionarily conserved NAD+-dependent enzymes (SIRT1–7) that function as key regulators of cellular homeostasis, metabolism, and longevity in humans [1, 2]. These proteins primarily act as deacetylases, removing acetyl groups from lysine residues on histones and a wide array of non-histone proteins, including transcription factors like p53 and NF-κB [1, 12]. By sensing cellular NAD+ levels, sirtuins link the metabolic state of a cell to its transcriptional and post-translational responses, influencing processes such as DNA repair, mitochondrial biogenesis, and stress resistance [10, 13]. Their diverse subcellular localizations—ranging from the nucleus (SIRT1, 6, 7) to the cytoplasm (SIRT2) and mitochondria (SIRT3, 4, 5)—allow them to coordinate systemic physiological adaptations [5, 17]. Sirtuins are implicated in the pathogenesis of numerous age-related conditions, including type 2 diabetes, neurodegenerative diseases, and various cancers, where they can act as either tumor suppressors or oncogenes depending on the cellular context [1, 3, 16]. Consequently, they have become prominent therapeutic targets, with drug development focusing on sirtuin-activating compounds (STACs) like resveratrol and isoform-specific inhibitors to treat metabolic and proliferative disorders [4, 10].

Other names

Silent information regulator 2 homologsSIRTsClass III histone deacetylasesSir2-like proteinsNAD-dependent protein deacetylases

Sirtuin-targeting drugs primarily act as either allosteric activators (Sirtuin-activating compounds or STACs) or competitive inhibitors of the NAD+-dependent deacetylation process. Activators like resveratrol enhance the enzyme's affinity for acetylated substrates, while inhibitors block the catalytic core or compete with the NAD+ cofactor, thereby modulating the acetylation status of key regulatory proteins such as p53, NF-κB, and PGC-1α [1, 4, 10].