GPR146 is a G protein-coupled receptor that plays a central role in cholesterol homeostasis by coordinating intestinal cholesterol absorption with hepatic cholesterol synthesis 1. The receptor functions as the cognate receptor for Cholesin, a gut-derived hormone secreted in response to intestinal cholesterol absorption 1. Upon Cholesin binding, GPR146 exerts antagonistic effects by inhibiting PKA signaling and suppressing SREBP2-controlled cholesterol synthesis in the liver, thereby reducing circulating cholesterol levels 1. Mechanistically, GPR146 also activates the ERK signaling pathway to promote hepatic SREBP2 activity and VLDL secretion, influencing LDL cholesterol and triglyceride levels 2. Clinically, GPR146 deficiency substantially reduces plasma cholesterol and produces remarkable 90% and 70% reductions in atherosclerotic lesions in male and female LDLR-deficient mice, respectively 2. Human genetic studies demonstrate that rare GPR146 variants are associated with reduced plasma cholesterol levels 3. Beyond lipid metabolism, GPR146 expression is upregulated in pulmonary hypertension, where it promotes pyroptosis of pulmonary artery endothelial cells and proliferation of smooth muscle cells through NLRP3/caspase-1 and 5-lipoxygenase pathways, contributing to pulmonary vascular remodeling 45. These findings establish GPR146 inhibition as a promising therapeutic strategy for hypercholesterolemia, atherosclerosis, and potentially pulmonary hypertension.