Hepcidin

Also known as: Liver-expressed antimicrobial peptide 1, Putative liver tumor regressor, HAMP, P81172

**Mechanism of Action** Hepcidin, encoded by the *HAMP* gene, is a 25-amino-acid peptide hormone primarily synthesized in the liver. It functions as the master regulator of systemic iron homeostasis by binding to the iron exporter ferroportin on enterocytes, macrophages, and hepatocytes. This binding induces ferroportin internalization and degradation, thereby reducing dietary iron absorption from the duodenum and limiting iron release from storage sites (e.g., splenic macrophages) into the plasma. Hepcidin expression is upregulated by iron overload and inflammation (via IL-6/STAT3 signaling) and suppressed by hypoxia, erythropoietic demand, and iron deficiency (via the BMP/SMAD and HFE/TfR2 pathways). **Key Research Findings** Preclinical and clinical studies have established hepcidin dysregulation as central to multiple iron disorders. In hereditary hemochromatosis, *HAMP* mutations or defective upstream regulators (e.g., *HFE*, *TFR2*, *HJV*) cause hepcidin deficiency, leading to uncontrolled iron absorption and parenchymal iron overload. Conversely, hepcidin excess is implicated in anemia of chronic disease (ACD), where inflammatory cytokines drive sustained hepcidin elevation, causing functional iron deficiency and hypoferremia. Experimental models demonstrate that hepcidin agonists (e.g., minihepcidins) can correct iron overload in hemochromatosis, while antagonists (e.g., anti-hepcidin antibodies, LDN-193189) improve iron availability in ACD. Over 6,400 PubMed-indexed studies support these mechanisms, though no hepcidin-based therapies have yet received regulatory approval. **Clinical Relevance** Hepcidin is a validated biomarker for diagnosing iron disorders (e.g., distinguishing iron-deficiency anemia from ACD) and a therapeutic target for conditions such as hemochromatosis, β-thalassemia, and myelodysplastic syndromes. Clinical trials are evaluating hepcidin analogs (e.g., LJPC-401) for iron overload and hepcidin inhibitors (e.g., LY2787106) for anemia. However, challenges remain, including off-target effects on infection susceptibility (due to ferroportin’s role in macrophage iron retention) and the need for precise dosing to avoid iatrogenic iron deficiency or overload. For research purposes only — not medical advice.

Key data

Mechanism of action

Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. Acts by promoting endocytosis and degradation of ferroportin/SLC40A1, leading to the retention of iron in iron-exporting cells and decreased flow of iron into plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342). Controls the major flows of iron into plasma: absorption of dietary iron in the intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes (PubMed:22306005)

Research & studies

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