TBC1D1 is a Rab GTPase-activating protein that regulates glucose transport and metabolic processes in skeletal muscle. Functionally, TBC1D1 controls GLUT4-containing vesicle trafficking and translocation to the cell membrane, facilitating insulin-stimulated glucose uptake 1. The protein is phosphorylated at distinct sites in response to different stimuli: Akt-mediated phosphorylation occurs with insulin signaling, while AMPK-dependent phosphorylation at Ser237 is triggered by exercise 2. Phosphorylation enhances TBC1D1's binding capacity to 14-3-3 regulatory proteins, modulating its GTPase activity 2. Clinically, TBC1D1 dysfunction is associated with metabolic disease. Polymorphisms in TBC1D1, particularly p.R125W, are linked to increased BMI and obesity risk 3. In type 2 diabetes, impaired insulin-stimulated phosphorylation of TBC1D1 accompanies dysregulated glucose uptake in skeletal muscle 4. Beyond metabolism, elevated TBC1D1 expression in macrophages promotes an immunosuppressive tumor microenvironment and correlates with poor prognosis and immunotherapy resistance in gliomas 5. Recent evidence suggests TBC1D1 may serve as a hub gene linking erectile dysfunction and depression through shared mechanisms involving vascular and muscle cell biology 6. These findings position TBC1D1 as a therapeutic target for metabolic disease and cancer immunotherapy resistance.