Hepcidin

Overview

Hepcidin is a 25-amino-acid peptide hormone produced primarily by hepatocytes in the liver and is recognized as the master regulator of systemic iron homeostasis. First isolated in 2000 from human blood and urine (originally named LEAP-1, liver-expressed antimicrobial peptide), hepcidin controls dietary iron absorption in the duodenum and iron release from macrophages and hepatic stores. Its discovery reshaped the field of iron metabolism and provided a unifying explanation for conditions ranging from anemia of chronic disease to hereditary hemochromatosis.

Hepcidin is closely tied to inflammatory signaling, and its upregulation during infection or chronic inflammation represents an ancient host-defense mechanism to starve invading pathogens of iron. It is conceptually related to innate immune peptides like LL-37 and defensins, reflecting its dual role in metabolism and immunity.

Structure / Sequence

Mature human hepcidin consists of 25 residues with the sequence DTHFPICIFCCGCCHRSKCGMCCKT, stabilized by four intramolecular disulfide bonds. The peptide adopts a distorted beta-hairpin structure. Hepcidin is synthesized as an 84-amino-acid preprohepcidin, processed to prohepcidin, and finally cleaved by furin to the active 25-mer. Shorter 20- and 22-residue isoforms circulate but have reduced bioactivity.

Mechanism of Action

Hepcidin binds the cellular iron exporter ferroportin on enterocytes, macrophages, and hepatocytes, triggering ferroportin internalization and lysosomal degradation. This blocks iron efflux into plasma, reducing transferrin saturation and iron availability to developing erythroblasts. Expression is controlled by:

• BMP-SMAD signaling via hemojuvelin (main iron-sensing pathway)
• IL-6/STAT3 signaling during inflammation
• Erythroferrone (ERFE) suppression during active erythropoiesis
• Hypoxia signaling via HIF suppression

Dysregulation drives hereditary hemochromatosis (low hepcidin), iron-refractory iron-deficiency anemia (high hepcidin via TMPRSS6 mutation), and the anemia of inflammation commonly seen with chronic kidney disease or malignancy.

Research Summary

Pharmacokinetics

Native hepcidin has a very short plasma half-life (minutes) due to rapid renal clearance, which limits its therapeutic use. Circulating concentrations range 1 to 30 nM in healthy adults and rise dramatically with inflammation. Therapeutic analogs such as rusfertide (PTG-300) are PEGylated or lipidated to extend half-life to several days, permitting weekly subcutaneous dosing. Hepcidin is measured clinically by mass spectrometry or ELISA, though assay standardization remains a challenge.

Dosing Protocols

Native hepcidin is not used therapeutically. Investigational hepcidin mimetics are administered under clinical trial protocols only:

• Rusfertide: Typically 10 to 80 mg subcutaneously weekly in polycythemia vera trials
• LJPC-401: Prior trials used 20 to 40 mg subcutaneous injections

Hepcidin modulators are not available outside research or sponsored expanded-access programs.

Common Discussion Topics

• Hepcidin's role in explaining why iron supplementation often fails during active infection
• Relationship between ferritin, hepcidin, and the anemia of chronic disease
• Hepcidin suppression during endurance training and its link to "sports anemia"
• Potential of hepcidin antagonism in functional iron deficiency of CKD
• Interaction with erythropoietin-driven erythropoiesis via erythroferrone

Related Compounds

• LL-37 — cathelicidin antimicrobial peptide
• Defensins — innate immune peptides
• Lactoferricin — milk-derived iron-binding peptide
• Humanin — mitochondrial-derived peptide