TULP3 (TUB-like protein 3) is a ciliary adaptor protein with dual roles in signaling regulation and metabolic sensing. Primarily, TULP3 functions as a negative regulator of Hedgehog (Shh) signaling by recruiting GPR161 to primary cilia via association with the IFT-A complex, promoting PKA-dependent basal repression 1. TULP3 contains phosphoinositide-binding domains essential for ciliary G protein-coupled receptor trafficking 2, and serves as a critical carriage component of the IFT-A train for transporting diverse membrane proteins into cilia 3. Beyond ciliary transport, TULP3 acts as a receptor for lithocholic acid, binding this metabolite to allosterically activate sirtuins and trigger v-ATPase deacetylation, ultimately activating AMPK to promote longevity pathways 4. This LCA-TULP3-sirtuin-AMPK axis is conserved from invertebrates to mammals 4. Disease relevance is substantial: bi-allelic TULP3 mutations cause hepatorenocardiac degenerative fibrosis, characterized by progressive liver, kidney, and heart degeneration in children and adults 5. Pathogenesis involves disrupted ciliary cargo composition, increased DNA damage, and upregulation of profibrotic TGF-β and WNT pathways 5. Additionally, TULP3 is upregulated in gastric cancer where it promotes proliferation and migration via the PTEN/Akt/Snail pathway 6.