GPR137B (G protein-coupled receptor 137B, also known as TM7SF1) is a lysosomal membrane-localized GPCR-like protein that functions as a critical regulator of cell growth signaling and macrophage function. Mechanistically, GPR137B interacts with Rag small GTPases at lysosomes to regulate their localization and activity, thereby controlling mTORC1 translocation and signaling 1. The protein can recruit and activate mTORC1 independently of amino acids, and regulates the dissociation of activated Rag from lysosomes, creating a cycle of Rag activation and deactivation 1. In the context of atherosclerosis, a pseudogene variant (Gpr137b-ps) impairs autophagy by interfering with HSC70-G3BP interaction, blocking TSC complex recruitment to lysosomes and leading to sustained mTORC1 activation 2. GPR137B deficiency enhances macrophage autophagy and reduces atherosclerotic lesion progression 2. Beyond metabolic regulation, GPR137B appears involved in immune cell function, with emerging evidence linking it to macrophage polarization and disease pathogenesis in ulcerative colitis 3. GPR137B-knockout cells exhibit defective autophagy and expanded lysosomal compartments 1, establishing this protein as a crucial hub integrating lysosomal positioning, mTORC1 signaling, and autophagy—processes fundamental to cellular homeostasis and disease prevention.