SIRT1: Protean roles at the nexus of health, disease, and therapeutics.

Silent mating type information regulators (sirtuins and SIRTs) have emerged as central nodes linking cellular metabolism to stress adaptation and diseases. SIRT1 stands out as a ubiquitously expressed, NAD⁺-dependent deacetylase with remarkably broad and sometimes paradoxical functions. Beyond its canonical roles in chromatin regulation and DNA repair, SIRT1 regulates key pathways controlling metabolism, inflammation, circadian rhythms, mitochondrial biogenesis, mitophagy, immune response, and cellular survival. Growing evidence, including several studies published in JCCS, positions SIRT1 at the intersection of cardiovascular, metabolic, neurovascular, and oncogenic processes, highlighting both its biological complexity and therapeutic potential. Mechanistically, SIRT1 modulates through deacetylation, a diverse network of substrates including histones H3/H4, tubulin, BMAL1, p53, NF-κB, FOXO, PGC-1α, and eNOS, yet, its functional outcomes are highly context dependent. Although SIRT1 activation is often protective in metabolic and cardiovascular and neurovascular settings, its role in cancer remains dualistic, acting as both tumor suppressor and promoter. Similarly, its contribution to longevity remains unresolved, with conflicting results across experimental models. Pharmacological targeting of SIRT1, through compounds such as resveratrol and synthetic modulators, has generated considerable enthusiasm, but challenges related to specificity, bioavailability, and off-target effects persist. Here, I discuss SIRT1 not simply as a therapeutic target but as a molecular "shapeshifter," whose context-dependent actions demand more precise biomarker-guided strategies for clinical translation.