CD81 is a tetraspanin membrane protein that functions as a molecular facilitator, organizing cell surface receptors into tetraspanin-enriched microdomains 1. In hematopoiesis, CD81 expression on CD34+ cells helps define lymphohematopoietic stem cell populations and their differentiation pathways 2. CD81 plays critical roles in cellular communication through tunneling nanotubes, where it regulates vesicle transfer between cells 3. The protein exhibits complex roles in cancer, acting as a tumor suppressor in gastric cancer through p38 signaling inhibition and promotion of G1 arrest and apoptosis 4, while paradoxically facilitating growth and metastasis in osteosarcoma via Akt/ERK signaling 5. CD81 also serves as a host factor for pathogen invasion, specifically facilitating Salmonella entry into epithelial cells 1 and being required for Plasmodium falciparum hepatocyte infectivity. In extracellular vesicles, CD81 is an abundant marker protein but plays only a marginal role in determining overall vesicle protein composition 6. These diverse functions reflect CD81's role as a scaffolding protein that creates specialized membrane microdomains for various cellular processes.