Orphan GPCRs regulate the metabolic liver diseases through mediating the crosstalk between the liver and immune cells: Mechanisms and therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver condition with increasing prevalence and few therapeutic options. Inflammatory pathways elicited by intrahepatic cell-autonomous ways or infiltration of immune cells are tightly coordinated to drive the progression of MASLD. Besides the extensively studied intrahepatic inflammatory pathways, the novel genes that mediate immune cell-liver crosstalk greatly impact the severity of MASLD and liver fibrosis by migration of immune cells into the liver. Among the genes are orphan G protein-coupled receptors (GPCRs), which are previously understudied transmembrane receptors without validated ligands. Here we critically discuss the emerging dual functions of GPR65, GPR18 and GPR84 expressed in bone marrow-derived immune cells in the progression of MASLD. They orchestrate the immune cell-liver crosstalk and regulate certain stages in the progression of MASLD. Our analyses indicate that GPR65, GPR18 and GPR84 are validated new targets for treating MASLD. GPR65 antagonists, GPR18 and GPR84 agonists are promising lead compounds for ameliorating MASLD and liver fibrosis through biasedly regulating the GPCR-coupled downstream signaling. The mechanisms, advantages and limitation of the agonists and antagonists have been critically discussed. The emerging critical function of orphan GPCRs in regulating the immune cell-liver crosstalk deepens our understanding of the pathogenesis of MASLD and liver fibrosis. Moreover, the concepts of biased agonists and pepducins that mimic the intracellular loops of GPCRs provide new approaches to address the challenges in the selectivity of targeting orphan GPCR-mediated immune cell-liver crosstalk and the treatment of MASLD.