The Sirtuin Network: Linking NAD + Metabolism, Mitochondrial Function, and Metabolic Homoeostasis

ABSTRACT Metabolic disorders such as obesity, type 2 diabetes mellitus, and fatty liver disease are associated with a disruption in the coordinated regulation of nutrient sensing, energy metabolism, and cellular homoeostasis. Increasing evidence indicates that sirtuins, a family of NAD + ‐dependent enzymes, play a central role in integrating metabolic and stress‐responsive pathways. By coupling the cellular redox state to transcriptional and post‐translational regulation, sirtuins coordinate key processes such as glucose and lipid metabolism, mitochondrial function, and inflammatory signalling. Sirtuins are functionally specialised according to their subcellular localisation. Nuclear sirtuins (SIRT1, SIRT6, and SIRT7) regulate transcriptional programs controlling metabolism and inflammation, whereas mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) directly modulate metabolic enzyme activity and redox homoeostasis. SIRT2 links cytosolic metabolic signalling to cytoskeletal dynamics and cell cycle regulation. Importantly, the activity of all sirtuins is tightly dependent on NAD + availability, positioning NAD + metabolism as a central regulator of the sirtuin network. In this review, we provide a systems‐level perspective on sirtuin biology, highlighting how NAD + metabolism, subcellular compartmentalisation, and specific functions converge to form an integrated regulatory network governing metabolic homoeostasis. We further discuss how disruption of this network contributes to the pathogenesis of metabolic disorders through impaired metabolic flexibility, mitochondrial dysfunction, and chronic inflammation. Overall, this network‐based framework provides a unified view of sirtuin function in metabolic regulation and helps to explain the complexity and tissue‐specific heterogeneity of metabolic diseases.