Hepcidin is the master regulator of systemic iron homeostasis. In the setting of anaemia of chronic disease (ACD), serum hepcidin is elevated. The mechanism by which elevated hepcidin causes iron-restricted erythropoiesis is:

• A Hepcidin inhibits intestinal DMT-1, preventing dietary iron absorption while stimulating hepatic storage
• B Hepcidin activates hephaestin, converting Fe2+ to Fe3+, which cannot be transported across the basolateral membrane
• C Hepcidin binds and induces degradation of ferroportin (FPN1) on enterocytes and macrophages, trapping iron intracellularly and reducing serum iron ✓
• D Hepcidin inhibits transferrin receptor 2 (TfR2) on erythroid precursors, reducing iron uptake

Explanation

Hepcidin is a 25-amino acid peptide hormone produced by the liver in response to inflammation (IL-6 → STAT3), iron loading, and BMP6/SMAD signalling. Its molecular mechanism involves binding to ferroportin (FPN1, SLC40A1), the sole known iron exporter in mammals. Hepcidin binding causes ferroportin internalisation and lysosomal degradation. When ferroportin is degraded on intestinal enterocytes, absorbed iron is trapped inside and excreted when the cell is shed. When degraded on macrophages (which recycle iron from senescent RBCs), recycled iron cannot be released into plasma. Together, these effects reduce serum iron and transferrin saturation, limiting erythropoiesis. DMT-1 inhibition is not hepcidin's mechanism; it acts at the export step, not import.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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