Exploring the Role of Peroxisome Proliferator-Activated Receptors and Endothelial Dysfunction in Metabolic Dysfunction-Associated Steatotic Liver Disease.

The endothelium is a well known regulator of vascular homeostasis. Several factors can influence the balance of the bioavailability of active substances. This imbalance can lead to inflammation and, consequently, endothelial dysfunction, which is an underlying pathology in cardiovascular disease that commonly coexists with metabolic and chronic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In MASLD, a reduction in nitric oxide availability is observed, and as a result, hepatic stellate cells and liver sinusoidal endothelial cells are activated. Considering the extensive research dedicated to finding several targets with diagnostic and therapeutic effects, nuclear hormone receptors such as peroxisome proliferator-activated receptors have been highlighted as being highly influential in the gut-liver-adipose axis and are considered potential regulators of metabolism and inflammation in several pathologies. Currently, PPAR agonists are widely explored in clinical trials and experimental studies. Agents such as lanifibranor, elafibranor, daidzein, and Icariin have shown promise in improving the metabolic, hepatic, and cardiovascular health of patients with MASLD. This review aims to provide a comprehensive overview of the role of peroxisome proliferator-activated receptors in endothelial dysfunction and MASLD, exploring their mechanisms in disease progression and potential pharmacological targeting.