Hepcidin is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Hepcidin is the master regulator of systemic iron homeostasis and a key hormone that controls iron absorption, recycling, and distribution throughout the body. This 25-amino acid peptide hormone directly binds to ferroportin, the sole cellular iron exporter, causing its internalization and degradation.
Hepcidin is synthesized as an 84-amino acid prepropeptide that undergoes extensive processing[1]:
The mature peptide adopts a compact hairpin structure stabilized by disulfide bridges between cysteine residues at positions 7-23, 10-13, 11-19, and 14-22[2].
Hepcidin acts by binding directly to ferroportin[3]:
Hepcidin expression is regulated by multiple signals[4]:
Hepcidin is expressed in the brain and regulates local iron homeostasis[5]:
Neuroinflammation increases hepcidin expression via IL-6 signaling[6]:
In Parkinson's disease, hepcidin dysregulation contributes to pathology[7]:
In Alzheimer's disease, altered hepcidin expression has been observed[8]:
Hepcidin dysregulation promotes ferroptosis[9]:
Blocking hepcidin-ferroportin interaction is a therapeutic strategy[10]:
Reducing inflammation-driven hepcidin elevation[11]:
Several hepcidin-targeting agents are in development[12]:
Hepcidin levels may serve as biomarkers[13]:
Methods for hepcidin measurement include[14]:
| Molecule | Interaction | Effect |
|---|---|---|
| Ferroportin | Direct binding | Induces degradation |
| IL-6 | Induces expression | Inflammatory response |
| BMP6 | Induces expression | Iron sensing |
| HFE | Modulates signaling | Iron homeostasis |
| Transferrin receptor 2 | Complex formation | Iron sensing |
| HIF | Represses expression | Hypoxia response |
Current research focuses on[15]:
Krause A et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Letters. 2000. ↩︎
Jordan JB et al. Structural basis for hepcidin-mediated inhibition of ferroportin. Nature Structural & Molecular Biology. 2023. ↩︎
Nemeth E et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004. ↩︎
Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011. ↩︎
Raha AA et al. Hepcidin, ferroportin and brain iron homeostasis. Neurobiology of Disease. 2013. ↩︎
Urrutia P et al. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. Journal of Neurochemistry. 2013. ↩︎
Wang J et al. Increased hepcidin expression in the substantia nigra of Parkinson's disease patients. Brain Research. 2020. ↩︎
Sun J et al. Hepcidin as a key player in the pathogenesis of Alzheimer's disease. Neurobiology of Disease. 2020. ↩︎
Stockwell BR et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017. ↩︎
Sage D et al. Hepcidin antagonists for therapeutic use. American Journal of Hematology. 2021. ↩︎
Steinbicker AU, Mückenthaler MU. Out of balance—systemic iron homeostasis in inflammation. Current Opinion in Neurobiology. 2013. ↩︎
Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood. 2014. ↩︎
Kroot JJC et al. Hepcidin in human iron disorders: diagnostic implications. Clinical Chemistry. 2011. ↩︎
Kroot JJC et al. (Pre)analytical imprecision, standardization, and biological variation of human plasma hepcidin assays. Clinical Chemistry. 2009. ↩︎
Vela D. Hepcidin, the missing link between inflammation and anemia in chronic disease. Journal of Inflammation Research. 2019. ↩︎