Role of Sirtuin 6 in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide and arises from systemic metabolic dysregulation and insulin resistance. Despite its increasing prevalence, effective pharmacological interventions remain limited. Recent evidence has identified sirtuin 6 (SIRT6), an NAD+-dependent epigenetic regulator, as an important modulator of hepatic metabolic and stress-responsive pathways. This review summarizes current knowledge regarding the role of SIRT6 in liver physiology and MASLD pathogenesis. Accumulating evidence indicates that SIRT6 suppresses lipogenic transcriptional programs while enhancing mitochondrial oxidative capacity and fatty acid oxidation, thereby maintaining metabolic homeostasis. Beyond lipid metabolism, SIRT6 is implicated in the regulation of endoplasmic reticulum stress responses, inflammatory signaling, and chromatin accessibility, which are the processes that collectively influence hepatocellular injury and disease progression. In addition, emerging data suggest that SIRT6 modulates hepatic stellate cell activation and fibrogenic signaling pathways, thereby linking epigenetic regulation to the development of liver fibrosis. A reduction in hepatic SIRT6 expression and activity has been reported in metabolic disorders, including MASLD. We further discuss the therapeutic potential of targeting SIRT6, including the development of selective small-molecule activators and naturally derived compounds aimed at restoring SIRT6 activity. Together, the available evidence positions SIRT6 as an important regulatory node in MASLD and a promising candidate for future therapeutic intervention.