SUFU is a critical negative regulator of hedgehog/smoothened signaling that suppresses GLI transcription factor activity through multiple mechanisms 1. SUFU down-regulates GLI1 and GLI2-mediated transactivation of target genes and may link GLI1 to proteasomal degradation via BTRC 1. A key mechanism involves cytoplasmic sequestration of GLI proteins (GLI1, GLI2, GLI3), which is overcome when STK36 binds to both SUFU and GLI proteins 1. In the absence of hedgehog signaling, SUFU-GLI3 complexes are recruited to cilia, promoting processing of full-length GLI3 into the repressor form (GLI3R) 1. Upon hedgehog activation, SUFU dissociates from GLI3, allowing nuclear translocation and conversion to the activator form (GLI3A) 1. SUFU dysfunction is implicated in multiple human diseases. Loss-of-function SUFU mutations cause basal cell nevus syndrome and Joubert syndrome, while aberrant hedgehog pathway activation through SUFU dysregulation is associated with medulloblastoma and other cancers 2 3. The pathway can be activated in cancer through ligand-independent mechanisms that bypass upstream signaling components 1. Understanding SUFU's regulatory role is essential for developing targeted therapies against hedgehog-driven malignancies.