Metrnl: A Novel Therapeutic Target in Atherosclerosis

ABSTRACT Atherosclerosis is a chronic inflammatory vascular disease and the main pathological basis of cardiovascular and cerebrovascular events. Exploration of endogenous protective factors in the disease is beneficial for the establishment of new therapeutic strategies. Metrnl is a secreted protein mainly derived from endothelial cells and widely expressed in multiple tissues. Animal studies show that Metrnl exerts atheroprotective effects by protecting endothelial cell function, maintaining endothelial cell mitochondrial homeostasis, and inhibiting the transformation of smooth muscle cells into foam cells. Beyond its direct vascular protective effects, skeletal muscle‐derived Metrnl serves as a critical mediator through which chronic aerobic exercise ameliorates atherosclerotic lesions. Serum Metrnl levels are closely associated with the progression of atherosclerosis in humans. Metrnl, particularly in the endothelium, may serve as a novel therapeutic target against atherosclerosis. Furthermore, existing research has verified that Metrnl acts as a high‐affinity ligand for the stem cell factor receptor KIT (KIT receptor tyrosine kinase). Apart from KIT, Metrnl may bind to other unknown receptors, and novel technologies such as AI‐driven structural prediction (AlphaFold2) with molecular docking can help identify these candidate receptors in future investigations. This review mainly summarizes the mechanisms of atherosclerosis and further elucidates the roles of Metrnl in different cell types involved in the disease.