GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

Abstract Succinate receptor GPR91 is one of G protein‐coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3‐dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate‐GPR91‐G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91‐ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic‐associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age‐related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate‐GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.