Hepcidin is the master regulator of iron homeostasis. In chronic inflammatory states (anemia of chronic disease), hepcidin levels are markedly elevated. The molecular mechanism by which elevated hepcidin causes hypoferremia is:

• A Binding to and inducing internalization and degradation of ferroportin on enterocytes and macrophages ✓
• B Inhibiting duodenal DMT1 expression, reducing dietary iron absorption
• C Blocking transferrin receptor 2 (TfR2) on erythroid precursors
• D Activating ceruloplasmin to oxidize Fe2+ to Fe3+ in circulation

Explanation

Hepcidin, a peptide hormone produced by hepatocytes, binds to ferroportin (FPN1/SLC40A1) — the sole iron export channel on enterocytes, macrophages, and hepatocytes. Hepcidin-ferroportin binding triggers ferroportin internalization and lysosomal degradation, trapping iron inside cells and preventing its efflux into plasma. In chronic inflammation, IL-6 upregulates hepcidin via JAK/STAT3 signaling, causing hypoferremia, reduced transferrin saturation, and impaired erythropoiesis. DMT1 mediates luminal iron uptake (Fe2+) — its regulation is by IRE/IRP system, not directly by hepcidin.

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

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Written and medically reviewed by the StethoPrep medical team.