Hepcidin (HAMP) is the master regulator of systemic iron homeostasis — a 25-aa peptide hormone secreted by hepatocytes that binds ferroportin (SLC40A1, the only known cellular iron exporter) on duodenal enterocytes, macrophages, and hepatocytes → triggers ferroportin internalization + degradation → blocks iron egress → ↓serum iron. Reciprocal regulation: BMP6 (sinusoidal endothelium) + iron-loaded transferrin via TfR2 + HFE → SMAD1/5/8 + BMP-receptor complex on hepatocytes → ↑HAMP transcription (the high-iron limb). IL-6 (inflammation) → STAT3 → ↑HAMP (the inflammation limb; explains anemia of chronic disease + functional iron deficiency). Erythroid demand: erythroferrone (ERFE, secreted by erythroblasts in response to EPO) → suppresses hepcidin → ↑iron availability for erythropoiesis (the bone-marrow demand limb). Tissue effects: ↑hepcidin → enterocyte ferroportin internalized → iron trapped in mucosa, lost in shed enterocyte → ↓absorption; macrophage ferroportin internalized → iron retained in RES (reticuloendothelial sequestration). Disease: hereditary hemochromatosis (HFE, HJV, TfR2, HAMP mutations — failed hepcidin response → unopposed iron absorption → tissue overload + cirrhosis, DM, cardiomyopathy); iron-refractory iron deficiency anemia (TMPRSS6 LOF — constitutively elevated hepcidin); anemia of chronic disease (IL-6 driven hepcidin → functional Fe deficiency); CKD-MBD anemia (multifactorial; hepcidin + EPO). Therapeutics: classical iron supplementation (ferrous sulfate, iron-bisglycinate, heme iron) overcomes mild deficiency; IV iron (sucrose, gluconate, carboxymaltose, derisomaltose) bypasses gut absorption block; iron chelators (deferoxamine SC/IV, deferasirox oral, deferiprone) for overload; hepcidin agonists (PTG-300/rusfertide for polycythemia vera) — clinical pipeline; hepcidin antagonists for hemochromatosis (in development); EPO/darbepoetin → ERFE → ↓hepcidin (functional). Cross-links: iron metabolism (transferrin, ferritin, cellular iron), heme biosynthesis (iron demand sink), ferroptosis gpx4 lipid peroxidation (Fe²⁺ toxicity downstream).
Organ Systems
immune-hematologic
digestive
endocrine
Pathway Steps
BMP6 (sinusoidal endothelium) + Tf-Fe via TfR2/HFE → hepatocyte SMAD1/5/8 + BMPR → HAMP transcription — via high-iron limb — physiological hepcidin upregulation. Hepcidin, the master iron hormone, is made by hepatocytes under the iron-sensing BMP/SMAD pathway: BMP6 from liver sinusoidal endothelium (rising with iron) plus transferrin-iron read through TfR2/HFE activate SMAD1/5/8 to transcribe HAMP. This is the circuit that mutations in HFE/TfR2/HJV break in hereditary hemochromatosis.
IL-6 (inflammation) → STAT3 → HAMP transcription — via inflammation limb — anemia of chronic disease mechanism. Inflammation overrides iron sensing: IL-6 activates STAT3 to induce hepcidin independently of iron stores. The resulting iron sequestration starves pathogens but, when chronic, produces the anemia of inflammation/chronic disease — a maladaptive consequence of an innate-immune defense.
EPO → erythroblast ERFE secretion → BMP6 antagonism → ↓HAMP — via erythroid-demand limb — high-demand suppresses hepcidin to free iron. Erythropoiesis suppresses hepcidin so iron can be mobilized for new red cells: EPO drives erythroblasts to secrete erythroferrone (ERFE), which antagonizes BMP signaling to lower HAMP. This “erythroid regulator” explains the low hepcidin and iron overload of β-thalassemia and other expanded-erythropoiesis states.
hepcidin → ferroportin binding + internalization — via ferroportin = only cellular iron exporter; endocytosis → lysosomal degradation. Hepcidin acts by binding ferroportin — the only known cellular iron exporter — triggering its internalization and degradation. So hepcidin controls iron not by entering cells but by closing the single gate through which iron leaves them; the hepcidin-ferroportin axis is the master switch of systemic iron flux.
enterocyte ferroportin down → ↓iron absorption (mucosal trap) — via apical DMT1 → cytoplasm → cannot exit basolaterally → lost when enterocyte sheds. When hepcidin lowers ferroportin on duodenal enterocytes, dietary iron taken up at the apical surface cannot be exported to blood and is lost as the cell is shed — the “mucosal block”. This is how hepcidin sets the rate of dietary iron absorption to match body needs.
macrophage ferroportin down → RES iron sequestration — via red-pulp macrophages cannot release recycled iron → functional iron deficiency in plasma. Hepcidin also closes ferroportin on macrophages, trapping the iron they recover from senescent red cells (the largest daily iron flux). In inflammation this reticuloendothelial sequestration withholds iron from plasma — protective against microbes but a key cause of the anemia of chronic disease.
Known Modulators
iron (substrate) — pool — ↑Tf saturation → hepcidin
iron bisglycinate (substrate) — chelated iron — better tolerance, similar net absorption