Regulated protein-protein interactions among HFE, TfR2, HJV (proteins mutated in HH), BMP receptors, and BMP ligands play a critical role in the “sensing” of transferrin-bound Fe to control hepcidin expression in hepatocytes. HFE binds to BMP receptor type I (Alk3) to prevent its ubiquitination and proteasomal degradation. As a result, expression of ALK3 is increased on the cell surface, activating BMP/SMAD signaling and hepcidin transcription. Professional illustration by Tom Webster, Lineworks, Inc.