APLNR (apelin receptor) is a G-protein-coupled receptor that functions as a broad regulator of cardiovascular and metabolic physiology 1. The receptor mediates signaling through G-protein and β-arrestin pathways, with G-protein bias conferring cardioprotective effects 23. Activation of APLNR by its endogenous ligand apelin promotes endothelium-dependent vasodilatation, enhances cardiac inotropy, lowers blood pressure, and facilitates angiogenesis 1. APLNR also protects against arrhythmias and thrombosis through anti-inflammatory and anti-fibrotic mechanisms 1. Beyond cardiovascular function, APLNR signaling enhances skeletal muscle function during aging by triggering mitochondriogenesis, autophagy, and anti-inflammatory pathways in myofibers 4. In immune contexts, APLNR is essential for CD8+ T-cell effector function; loss-of-function mutations in APLNR correlate with immunotherapy resistance in cancer patients 5, while apelin treatment reduces neuroinflammation in experimental autoimmune encephalomyelitis by modulating leukocyte recruitment 6. APLNR also participates in tumor immune regulation through PI3K-Akt and ERK-MAPK signaling pathways 7. Therapeutically, G-protein-biased APLNR agonists show promise for treating heart failure with preserved ejection fraction and cardiac hypertrophy while minimizing adverse effects 23.