Hepcidin (HAMP)

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Hepcidin (HAMP)

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HAMP Gene (Hepcidin)

<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>HAMP</td></tr>
<tr><td><strong>Full Name</strong></td><td>Hepcidin Antimicrobial Peptide</td></tr>
<tr><td><strong>Protein</strong></td><td>[Hepcidin](/entities/hepcidin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>57817</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>P81172</td></tr>
<tr><td><strong>Aliases</strong></td><td>HEPC, HEPCIDIN, HFE2B, LEAP1, PLTR</td></tr>
</table>
</div>

Overview

[HAMP](/entities/hamp) encodes hepcidin, the master regulator of systemic iron homeostasis and a key antimicrobial peptide.[@ganz2003] Hepcidin controls iron absorption and distribution by binding to and inducing the internalization of ferroportin, the sole cellular iron exporter.[@nemeth2004] Dysregulation of the hepcidin-ferroportin axis contributes to brain iron accumulation in neurodegenerative diseases.[@ward2014]

Structure and Expression

The HAMP gene spans approximately 2.6 kb on chromosome 19q13.1 and contains 3 exons encoding an 84-amino acid prepropeptide that is processed to the mature 25-amino acid hepcidin peptide.[@pigeon2001] Hepcidin is predominantly expressed in:

Hepatocytes: Primary source of circulating hepcidin
Macrophages: Local regulation of iron export
Brain cells: [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes) produce hepcidin for local iron regulation[@zanninelli2002]

Normal Function

...

HAMP Gene (Hepcidin)

<div class="infobox">
<table>
<tr><td><strong>Symbol</strong></td><td>HAMP</td></tr>
<tr><td><strong>Full Name</strong></td><td>Hepcidin Antimicrobial Peptide</td></tr>
<tr><td><strong>Protein</strong></td><td>[Hepcidin](/entities/hepcidin-protein)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>19q13.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>57817</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>P81172</td></tr>
<tr><td><strong>Aliases</strong></td><td>HEPC, HEPCIDIN, HFE2B, LEAP1, PLTR</td></tr>
</table>
</div>

Overview

[HAMP](/entities/hamp) encodes hepcidin, the master regulator of systemic iron homeostasis and a key antimicrobial peptide.[@ganz2003] Hepcidin controls iron absorption and distribution by binding to and inducing the internalization of ferroportin, the sole cellular iron exporter.[@nemeth2004] Dysregulation of the hepcidin-ferroportin axis contributes to brain iron accumulation in neurodegenerative diseases.[@ward2014]

Structure and Expression

The HAMP gene spans approximately 2.6 kb on chromosome 19q13.1 and contains 3 exons encoding an 84-amino acid prepropeptide that is processed to the mature 25-amino acid hepcidin peptide.[@pigeon2001] Hepcidin is predominantly expressed in:

Hepatocytes: Primary source of circulating hepcidin
Macrophages: Local regulation of iron export
Brain cells: [Neurons](/entities/neurons) and [astrocytes](/entities/astrocytes) produce hepcidin for local iron regulation[@zanninelli2002]

Normal Function

Hepcidin serves as the systemic iron regulatory hormone with the following functions:

Iron Export Inhibition: Binds ferroportin and induces internalization and degradation

Iron Homeostasis: Maintains appropriate serum iron levels

Antimicrobial Activity: Sequesters iron from pathogens as part of innate immunity

Inflammatory Response: Upregulated by interleukin-6 (IL-6) during inflammation[@nemeth2004a]

Role in Neurodegeneration

Neuroinflammation and Iron Dysregulation

Chronic neuroinflammation in neurodegenerative diseases upregulates hepcidin expression via IL-6 signaling, leading to ferroportin suppression and neuronal iron retention.[@urrutia2013] This creates a vicious cycle where iron accumulation promotes oxidative stress, which further drives inflammation.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), elevated hepcidin expression has been observed in the substantia nigra.[@wang2007] This contributes to iron accumulation in dopaminergic neurons, promoting oxidative damage and [alpha-synuclein](/proteins/alpha-synuclein) aggregation. Hepcidin levels correlate with disease severity and may serve as a biomarker.

Alzheimer's Disease

[Alzheimer's disease](/diseases/alzheimers-disease) patients show altered cerebrospinal fluid hepcidin levels and increased brain hepcidin expression.[@raha2013] Hepcidin-mediated suppression of ferroportin may contribute to iron accumulation in amyloid plaques and neurofibrillary tangles.

Amyotrophic Lateral Sclerosis

In [ALS](/diseases/amyotrophic-lateral-sclerosis), elevated serum hepcidin correlates with disease progression rate and reduced survival.[@goodall2008] Iron accumulation in motor neurons may be driven by hepcidin upregulation secondary to systemic inflammation.

Molecular Mechanisms

Hepcidin-Ferroportin Interaction

Hepcidin binds to ferroportin at a specific extracellular loop, inducing ubiquitination, internalization via clathrin-coated pits, and lysosomal degradation.[@qiao2012] Each hepcidin molecule inactivates one ferroportin molecule, blocking iron export for 24-48 hours.

Ferroptosis

Hepcidin-mediated ferroportin suppression leads to intracellular iron accumulation, promoting [ferroptosis](/entities/ferroptosis)—an iron-dependent form of regulated cell death characterized by lipid peroxidation.[@stockwell2017] Ferroptosis has been implicated in neuronal death in PD, AD, and ALS.

Regulation by Iron and Inflammation

Hepcidin expression is regulated by:

Iron status: High serum iron increases hepcidin via BMP-SMAD signaling
Inflammation: IL-6 activates JAK-STAT signaling to induce hepcidin
Hypoxia: HIF suppresses hepcidin to increase iron availability
Erythropoiesis: Erythroferrone from developing red blood cells suppresses hepcidin[@kautz2014]

Therapeutic Implications

Hepcidin Antagonists: Antibodies or small molecules blocking hepcidin-ferroportin interaction

Anti-inflammatory Agents: Reducing IL-6-driven hepcidin upregulation

Iron Chelation: Deferiprone and deferoxamine reduce brain iron burden

Ferroptosis Inhibitors: Ferrostatin-1 and liproxstatin-1 prevent iron-dependent cell death[@devos2014]

Key Interactions

| Protein | Relationship | Function |
|---------|--------------|----------|
| [Ferroportin](/entities/fpn1) | Target | Hepcidin induces internalization |
| IL-6 | Inducer | Activates JAK-STAT signaling |
| BMP6 | Inducer | Activates SMAD signaling |
| HFE | Regulator | Mutations alter hepcidin expression |
| TfR2 | Regulator | Senses iron status |

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
[Allen Human Brain Atlas](https://brain-map.org/)

References

[Ganz T, Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation (2003)](https://pubmed.ncbi.nlm.nih.gov/14630868/)

[Nemeth E, Tuttle MS, Powelson J, et al, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004)](https://doi.org/10.1126/science.1104742)

[Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L, The role of iron in brain ageing and neurodegenerative disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/24789079/)

[Pigeon C, Ilyin G, Courselaud B, et al, A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload (2001)](https://pubmed.ncbi.nlm.nih.gov/11278534/)

[Zanninelli G, Loreal O, Brissot P, et al, The central role of the liver in iron homeostasis and hemochromatosis (2002)](https://pubmed.ncbi.nlm.nih.gov/11341865/)

[Nemeth E, Rivera S, Gabayan V, et al, IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004)](https://doi.org/10.1172/JCI20945)

[Urrutia P, Aguirre P, Esparza A, et al, Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells (2013)](https://pubmed.ncbi.nlm.nih.gov/23506787/)

[Wang J, Jiang H, Xie JX, Ferroportin1 and hepcidin expression in rat midbrain and the effect of iron on hepcidin expression (2007)](https://pubmed.ncbi.nlm.nih.gov/17724598/)

[Raha AA, Vaishnav RA, Friedland RP, et al, The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23860225/)

[Goodall EF, Haque MS, Morrison KE, Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients (2008)](https://pubmed.ncbi.nlm.nih.gov/18379194/)

[Qiao B, Sugianto P, Schmidt PJ, et al, Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination (2012)](https://doi.org/10.1007/s00109-011-0833-5)

[Stockwell BR, Friedmann Angeli JP, Bayir H, et al, Ferroptosis: A Regulated Cell Death Nexus Connecting Metabolism, Redox Biology, and Disease (2017)](https://doi.org/10.1016/j.cell.2017.09.021)

[Kautz L, Jung G, Valore EV, et al, Identification of erythroferrone as an erythroid regulator of iron metabolism (2014)](https://doi.org/10.1038/ng.2570)

[Devos D, Moreau C, Devedjian JC, et al, Targeting chelatable iron as a therapeutic modality in Parkinson's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24864761/)

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📊 Evidence Profile Foundational

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📗 Cite This Artifact

Hepcidin (HAMP)

HAMP Gene (Hepcidin)

Overview

Structure and Expression

Normal Function

HAMP Gene (Hepcidin)

Overview

Structure and Expression

Normal Function

Role in Neurodegeneration

Neuroinflammation and Iron Dysregulation

Parkinson's Disease

Alzheimer's Disease

Amyotrophic Lateral Sclerosis

Molecular Mechanisms

Hepcidin-Ferroportin Interaction

Ferroptosis

Regulation by Iron and Inflammation

Therapeutic Implications

Key Interactions

See Also

External Links

References

💬 Discussion