GPR176 is an orphan Class A G protein-coupled receptor with pleiotropic functions extending beyond its established role in circadian rhythm regulation. While GPR176 couples to Gz-alpha proteins with agonist-independent basal activity to inhibit cAMP production 1, recent evidence reveals significant pathological roles in multiple diseases. In fibrosis, GPR176 expression correlates with myofibroblast markers and profibrotic factors across lung, kidney, liver, and heart tissues. GPR176 knockdown reduces TGFβ1-induced myofibroblast differentiation and collagen deposition, suggesting GPR176 regulates fibroblast activation through Smad2 phosphorylation 2. In cancer, GPR176 is upregulated in ovarian, gastric, and colorectal cancers, where it promotes proliferation, migration, invasion, and anti-apoptosis 345. GPR176 drives tumor progression through Wnt/β-catenin pathway activation and M2 macrophage polarization, creating an immunosuppressive microenvironment that reduces CD8+ T cell infiltration and impairs immunotherapy response 56. In colorectal cancer liver metastasis, GPR176 interacts with GNAS to upregulate CXCR1/CXCR2, promoting angiogenesis and vascular permeability required for pre-metastatic niche formation 7. High GPR176 expression consistently predicts poor prognosis across malignancies. Recent identification of endogenous brain ligands 1 supports therapeutic targeting through inverse agonists or allosteric modulators for both fibrotic and neoplastic diseases.