Endothelial Cells at the Crossroad of Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Unifying Target for Dual Treatment.

Atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD) are 2 highly prevalent conditions that frequently coexist and amplify each other's clinical burden. MASLD not only increases cardiovascular disease incidence but also promotes atherosclerosis independently of traditional risk factors, including obesity, diabetes, and dyslipidemia. Despite this strong clinical association, the biological mechanisms linking these diseases remain incompletely understood. Emerging evidence identifies endothelial dysfunction as a unifying pathogenic axis underlying their crosstalk. In atherosclerosis, vascular endothelial dysfunction facilitates lipoprotein retention, leukocyte recruitment, and plaque formation. Similarly, in MASLD, liver sinusoidal endothelial cells lose their capacity to regulate lipid trafficking, immune tolerance, and hepatic homeostasis, thereby promoting steatosis, inflammation, and fibrosis. This review highlights endothelial dysfunction as a common denominator in both diseases, emphasizing shared molecular mechanisms such as impaired nitric oxide production, oxidative stress, and cytokine-driven inflammation. We further discuss how metabolic disturbances including insulin resistance and dyslipidemia exacerbate endothelial activation, lipid accumulation, and immune cell responses across vascular and hepatic beds. By examining the interplay between MASLD and atherosclerosis at the endothelial level, we propose endothelial cells as a promising therapeutic target for both conditions. Emerging strategies, such as targeted cell therapies and nanomedicine, offer the potential to simultaneously address endothelial dysfunction in the liver and vasculature. Future research should prioritize therapies that address this shared endothelial axis, with the potential to reduce the morbidity and mortality associated with these interconnected diseases.