EPOR (erythropoietin receptor) is a 66 kDa transmembrane protein that functions as the primary receptor for erythropoietin (EPO) signaling 1. Its cardinal role is regulating erythropoiesis in bone marrow, where it promotes erythroblast survival, proliferation, and differentiation 2. EPOR signaling increases both the speed and number of erythroblast cell cycles while paradoxically increasing red cell size independent of iron regulation 3. Beyond hematopoiesis, EPOR is expressed in non-hematopoietic tissues including endothelium and adipose tissue, where it exerts cytoprotective functions and regulates metabolic homeostasis through the EPO-EPOR-RUNX1 axis 24. Pathogenic EPOR variants cause primary familial and congenital polycythemia, characterized by increased red cell mass and EPO hypersensitivity in erythroid progenitors 5. Additionally, CD163+EPOR+ tumor-associated macrophages in osteosarcoma metastases express high M2 markers and are associated with tumor aggressiveness and poor survival 6. The EPO-EPOR pathway also contributes to tumor angiogenesis and neovascularization 4. EPOR signaling involves multiple downstream pathways beyond classical survival mechanisms, including novel response factors and receptor trafficking regulation 7.