Transferrin receptor 2 (TfR2), mutated in hereditary hemochromatosis, plays a critical but poorly understood role in iron homeostasis. This study investigates the function and intracellular trafficking of TfR2 in human hepatoma cells. TfR2 was shown to be stabilized by its ligand, diferric transferrin (Fe²Tf), which redirects the receptor from degradative to recycling endosomal pathways. Ligand binding and a tyrosine-based endocytic motif were essential for proper TfR2 regulation. These findings suggest that TfR2 trafficking enables hepatocytes to sense systemic iron levels and regulate hepcidin expression accordingly.
