Sirtuin 6 as a therapeutic target: opportunities for drug discovery through modulation

Sirtuin 6 (SIRT6), a NAD⁺-dependent deacetylase, plays a crucial role in several biological processes essential to health and longevity, including DNA repair, chromatin maintenance, and metabolic regulation. Dysregulation of SIRT6 has been implicated in aging-related diseases, diabetes, neurodegenerative conditions, inflammatory disorders, and various cancers, underscoring its potential as a therapeutic target. Despite promising advances in the development of SIRT6 modulators, none have yet to be progressed to clinical approval. Further structural and mechanistic studies are required to fully understand how these modulators influence SIRT6’s enzymatic activities, including deacetylation, deacylation, and mono-ADP-ribosylation. Identifying and optimizing these compounds is critical not only for elucidating SIRT6’s biological functions but also for advancing therapeutic applications. This review aims to summarize recent advances in SIRT6 modulators with a focus on their chemical diversity, mechanisms of action, and pharmacological potential. Particular attention is given to the selectivity profiles of these modulators, which are vital for the development of precise and effective therapeutic agents. Overall, this work highlights the need for continued optimization of SIRT6 modulators to improve potency, specificity, and pharmacokinetic properties.