TFR2 (transferrin receptor 2) is a cell surface receptor that mediates the uptake of transferrin-bound iron into cells, functioning as a component of the body's iron-sensing machinery 1. Expressed predominantly in hepatocytes and erythroid precursors, TFR2 forms a complex with the hemochromatosis protein HFE and facilitates iron sensing in liver cells 1. In erythroid cells, TFR2 associates with the erythropoietin receptor to regulate erythropoiesis and additionally facilitates iron transport from lysosomes to mitochondria in erythroblasts 1. TFR2 plays a critical role in regulating hepcidin expression; defects in TFR2 impair this iron-sensing function, leading to inappropriately low hepcidin production and subsequent systemic iron overload 1. Mutations in TFR2 cause hemochromatosis type 3, a rare non-HFE form characterized by excessive iron accumulation in hepatocytes, pancreatic cells, and cardiomyocytes 2. TFR2 mutations can present with intermediate to severe phenotypes overlapping juvenile hemochromatosis, requiring aggressive clinical intervention 3. Beyond iron metabolism, TFR2 regulates ferroptosis in glioma cells, with TFR2 overexpression promoting reactive oxygen species production and enhancing temozolomide chemosensitivity 4.