BackgroundSestrins are a highly conserved family of proteins that have garnered significant attention for their critical roles in regulating cellular stress responses, antioxidative defense, energy metabolism, and cell survival. Endothelial dysfunction, a pivotal early event in the development of cardiovascular diseases (CVDs), is strongly associated with oxidative stress, inflammation, and disruption of vascular homeostasis.FindingsRecent studies have demonstrated that Sestrins contribute to maintaining endothelial cell integrity by mitigating oxidative stress, modulating inflammatory signaling, and promoting cellular adaptation through the regulation of key pathways such as AMPK/mTOR and autophagy. Experimental evidence from cardiovascular disease models suggests that upregulation of Sestrins can improve endothelial function and attenuate vascular damage, highlighting their involvement in vascular protection and disease modulation.ConclusionsSestrins emerge as promising therapeutic targets for the prevention and treatment of endothelial dysfunction and cardiovascular diseases. This review underscores the potential of Sestrins in vascular biology and advocates for further research to elucidate their mechanisms and clinical applicability in cardiovascular medicine.