SMO (Smoothened) is a G protein-coupled receptor that serves as a critical component of the Hedgehog signaling pathway, essential for embryonic development and tissue homeostasis 1. SMO functions by transducing Hedgehog protein signals when released from inhibition by the Patched protein, leading to activation of GLI transcription factors and downstream target gene expression 1. The protein requires cholesterol modification at residue Asp95 for proper function, as this covalent modification is necessary for SMO's ciliary localization and signaling activation 2. SMO plays crucial roles in metabolic homeostasis, particularly in hepatocytes where its activity controls insulin sensitivity and lipid metabolism through regulation of the mTORC1-SREBP1c axis 3. Loss of SMO function promotes hepatic steatosis, insulin resistance, and susceptibility to metabolic dysfunction-associated steatotic liver disease 43. SMO also exhibits noncanonical signaling functions independent of GLI-mediated transcription, affecting cellular processes such as migration, cytoskeletal dynamics, and neurite formation 5. Clinically, SMO mutations are associated with various cancers including basal cell carcinomas, medulloblastoma, and meningiomas, making it an important therapeutic target 167.