SUFU is a negative regulator of hedgehog signaling that functions through multiple mechanisms to restrain pathway activation. It suppresses transcription by binding to GLI family transcription factors (GLI1, GLI2, and GLI3), promoting their proteasomal degradation through interaction with BTRC and sequestering them in the cytoplasm 1. In the absence of hedgehog signaling, SUFU maintains GLI3 in a complex at the ciliary tip, enabling its processing into the transcriptional repressor form GLI3R; when hedgehog signaling is initiated, SUFU dissociates from GLI3, allowing it to translocate to the nucleus and adopt an activator form. Dysregulation of hedgehog signaling through SUFU loss is implicated in multiple cancers, including medulloblastoma, basal cell carcinoma, and pancreatic cancer 2. SUFU mutations in humans are associated with childhood brain tumors and increased cancer susceptibility, and RNAi-mediated suppression of SUFU activates hedgehog signaling in cultured cells 3. Therapeutic inhibitors targeting the hedgehog pathway—including vismodegib and sonidegib—have been developed for treatment of refractory or advanced hedgehog-driven cancers, reflecting SUFU's central role in controlling this developmentally critical signaling cascade 2.