Sirtuins as Endogenous Regulators of Cardiac Fibrosis: A Current Perspective

Cardiac fibrosis is a pathological condition marked by the excessive accumulation of extracellular matrix (ECM) components, which leads to impaired cardiac function and heart failure. Despite its significant contribution to cardiovascular morbidity and mortality, no effective therapeutic drugs specifically target the inhibition of cardiac fibrosis, largely due to the complex etiological heterogeneity and pathogenesis of this disease. Sirtuins (SIRTs), a family of NAD + -dependent deacetylases, play a critical role in cellular processes such as oxidative stress, inflammation, energy metabolism, mitochondrial function, epithelial-to-mesenchymal transition (EMT), and ECM homeostasis, all of which are implicated in cardiac fibrosis. Growing clinical and experimental evidence suggests that SIRTs regulate the cellular and molecular mechanisms of cardiomyocytes through various biological pathways. Emerging evidence indicates that sirtuin activators, including resveratrol and NAD + precursors, hold therapeutic potential in mitigating cardiac fibrosis. However, the complex and context-dependent roles of sirtuins necessitate further research to fully elucidate their mechanisms and translational applications. As the role of SIRTs in relation to cardiac fibrosis and its associated mechanisms is rarely discussed in the literature, this review comprehensively addresses the roles of the seven mammalian sirtuins (SIRT1-SIRT7) in the pathogenesis and progression of cardiac fibrosis. It highlights the key role of SIRTs as molecular targets for innovative anti-fibrotic therapies, offering new avenues for the treatment of cardiac fibrosis and associated cardiovascular diseases.