SIRT6 in health and diseases: From molecular mechanisms to therapeutic prospects

Sirtuins (SIRTs), particularly SIRT6, are nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases that play a critical role in regulating various metabolic pathways across different organisms. SIRT6 is involved in numerous biological processes through the modulation of multiple signaling pathways, influencing aging, proliferation, apoptosis, DNA repair, and cellular metabolism. Increasing evidence indicates that SIRT6 plays a significant role in both health and disease states. This review summarizes the pivotal functions of SIRT6 in the pathogenesis and progression of human diseases such as cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders, elucidating the underlying signaling mechanisms. Additionally, we discuss recent advances in the development of small-molecule SIRT6 modulators, including both activators and inhibitors, and highlight their pharmacological properties and potential therapeutic applications in SIRT6-mediated diseases.