The multi-dimensional regulatory mechanism of Sirt6 in heart health: From cell death pathways to targeted therapy for cardiovascular diseases

Sirtuin 6 (Sirt6) is a member of the Sirtuin family, exhibiting histone deacetylase and ADP-ribosyltransferase activity. This enzyme is involved in several pathways, such as epigenetic regulation and inflammation control. It is essential for preserving cardiac equilibrium and postponing the emergence of cardiovascular disorders. Recent findings reveal that Sirt6 affects glucose and lipid metabolism and regulates oxidative stress via the HIF-1α/NF-κB signaling pathway, thereby delaying cardiomyocyte senescence and diminishing DNA damage accumulation. Sirt6 mitigates oxidative damage in cardiomyocytes by deacetylation, suppresses cardiac fibrosis, and improves cardiomyocyte survival rates. Sirt6 exhibits anti-atherosclerotic properties by enhancing DNA repair in endothelial cells, reducing lipid accumulation in macrophages, and promoting cholesterol transport via ATP-Binding Cassette A1 (ABCA1). Sirt6 promotes the degradation of the critical autophagic component Charged Multivesicular Body Protein 2B (CHMP2B) through the FoxO1-Atrogin-1 pathway. This action supports the autophagic process and mitigates ischemia-reperfusion harm. The regulatory mechanisms of Sirt6 in ferroptosis remain controversial. This article explores the specific molecular mechanisms of Sirt6 in the heart and various cell death pathways, including apoptosis, autophagy, and pyroptosis, while also considering the potential for targeted therapeutic applications of Sirt6 in cardiovascular medicine.