CGREF1 (Cell Growth Regulator with EF-hand domain 1) is a secreted protein that functions as a multifaceted regulator with both metabolic and oncogenic properties. As a hepatokine, CGREF1 is regulated by transcription factor CREB-H and primarily targets epididymal white adipose tissue, where it suppresses insulin signaling and glucose uptake, potentially contributing to insulin resistance and metabolic dysfunction-associated steatotic liver disease 1. In cancer contexts, CGREF1 demonstrates oncogenic properties across multiple malignancies. In osteosarcoma, CGREF1 promotes cell proliferation by modulating the cell cycle through activation of the Wnt/β-catenin signaling pathway via GSK3/β-catenin regulation 2. Similarly, in hepatocellular carcinoma, CGREF1 facilitates proliferation, migration, and invasion through the EIF3H/Wnt/β-catenin signaling axis 3. In colorectal cancer, CGREF1 specifically promotes cell migration and invasion without affecting proliferation, correlating with aggressive tumor characteristics and poor prognosis 4. The protein has also been implicated in cisplatin resistance in osteosarcoma 5 and associated with schizophrenia susceptibility through rare coding variants 6. Additionally, CGREF1 shows associations with brain glymphatic system function 7.