C2CD5 (C2 calcium-dependent domain containing 5) is a phospholipid-binding protein essential for insulin-stimulated glucose transport in adipocytes. It mediates GLUT4 translocation from intracellular glucose storage vesicles to the plasma membrane through calcium-dependent phospholipid binding and promotion of membrane fusion 1. The protein localizes to cytoplasmic vesicles, the cell cortex, and plasma membrane, where it facilitates glucose transporter trafficking and D-glucose transmembrane transport. Beyond its canonical role in glucose homeostasis, C2CD5 has emerged as a pathological driver in acute myeloid leukemia (AML). The deubiquitinase USP5 stabilizes C2CD5 through deubiquitination, which activates the PI3K/AKT/mTOR/HIF-1α signaling axis to enhance glycolytic flux and promote AML progression 2. USP5 knockdown increases AML chemosensitivity, establishing the USP5-C2CD5 axis as a therapeutic target. Population genetics studies identified a convergent selective sweep at C2CD5 between European and East Asian populations, potentially explaining differences in insulin responses between these groups 1. Additionally, C2CD5 was identified as a protein associated with bile acid metabolism alterations in intrahepatic cholestasis of pregnancy 3, and as a prognostic biomarker in diffuse large B-cell lymphoma 4. These findings suggest C2CD5 has broader metabolic and oncologic roles beyond glucose transport.