Two decades of FFAR4 biology: From nutrient sensing to therapeutic targeting

Free fatty acid receptor 4 (FFAR4; also known as GPR120) serves as a key lipid-sensing G-protein-coupled receptor that mediates the physiological actions of long-chain fatty acids, particularly omega-3 polyunsaturated fatty acids. Over the past two decades, studies of FFAR4 have revealed its pivotal role in metabolic regulation, inflammation resolution, and energy balance. This review integrates recent advances from structural biology, physiology, and translational research to provide an updated framework of FFAR4 biology. In particular, we highlight new cryo-electron microscopy-based insights into receptor activation and ligand recognition; the expanding roles of FFAR4 in non-metabolic systems, such as the central nervous system and kidney; and recent progress in the clinical development of selective FFAR4 agonists. By bridging molecular mechanisms with therapeutic translation, this review offers a comprehensive perspective on FFAR4's functions in health and disease.