Hepcidin

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Hepcidin

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Hepcidin

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Hepcidin</th>
</tr>
<tr>
<td class="label">Molecule</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">[Ferroportin](/proteins/ferroportin-protein)</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">IL-6</td>
<td>Induces expression</td>
</tr>
<tr>
<td class="label">BMP6</td>
<td>Induces expression</td>
</tr>
<tr>
<td class="label">HFE</td>
<td>Modulates signaling</td>
</tr>
<tr>
<td class="label">Transferrin receptor 2</td>
<td>Complex formation</td>
</tr>
<tr>
<td class="label">HIF</td>
<td>Represses expression</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">5 edges</a></td>
</tr>
</table>

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.

Structure and Function

Molecular Architecture

...

Hepcidin

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Hepcidin</th>
</tr>
<tr>
<td class="label">Molecule</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">[Ferroportin](/proteins/ferroportin-protein)</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">IL-6</td>
<td>Induces expression</td>
</tr>
<tr>
<td class="label">BMP6</td>
<td>Induces expression</td>
</tr>
<tr>
<td class="label">HFE</td>
<td>Modulates signaling</td>
</tr>
<tr>
<td class="label">Transferrin receptor 2</td>
<td>Complex formation</td>
</tr>
<tr>
<td class="label">HIF</td>
<td>Represses expression</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">5 edges</a></td>
</tr>
</table>

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.

Structure and Function

Molecular Architecture

Hepcidin is synthesized as an 84-amino acid prepropeptide that undergoes extensive processing[@krause2000]:

Signal peptide removal: Produces 60-amino acid prohepcidin

Proprotein convertase cleavage: Generates 25-amino acid mature hepcidin

Disulfide bond formation: Creates 4 intramolecular disulfide bonds

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[@jordan2023].

Mechanism of Action

Hepcidin acts by binding directly to [ferroportin](/proteins/ferroportin-protein)[@nemeth2004]:

Binding: Hepcidin binds to ferroportin extracellular loop

Internalization: The hepcidin-ferroportin complex is endocytosed

Degradation: Ferroportin is ubiquitinated and degraded in lysosomes

Effect: Cellular iron export is blocked, trapping iron inside cells

Regulation of Hepcidin Expression

Hepcidin expression is regulated by multiple signals[@ganz2011]:

Iron status: High plasma iron → increased hepcidin (negative feedback)
Inflammation: IL-6 and other cytokines → increased hepcidin (via STAT3)
Hypoxia: Low oxygen → decreased hepcidin (via HIF)
Erythropoiesis: Active red blood cell production → decreased hepcidin

Role in Neurodegeneration

Brain Iron Homeostasis

Hepcidin is expressed in the brain and regulates local iron homeostasis[@raha2013]:

[Astrocytes](/entities/astrocytes) and [neurons](/entities/neurons) produce hepcidin
[Blood-brain barrier](/entities/blood-brain-barrier) ferroportin is a target
Dysregulation leads to brain iron accumulation
Contributes to neurodegeneration

Neuroinflammation and Hepcidin

Neuroinflammation increases hepcidin expression via IL-6 signaling[@urrutia2013]:

Chronic inflammation → elevated hepcidin
Reduced ferroportin → iron retention
Iron overload in [microglia](/cell-types/microglia-neuroinflammation) and astrocytes
Enhanced oxidative stress and neuronal damage

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), hepcidin dysregulation contributes to pathology[@wang2020]:

Elevated hepcidin in substantia nigra
Decreased ferroportin expression
Iron accumulation in dopaminergic neurons
Feed-forward loop of iron-mediated toxicity

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), altered hepcidin expression has been observed[@sun2020]:

Increased hepcidin in affected brain regions
Iron accumulation around amyloid plaques
Hepcidin may modulate [Aβ](/proteins/amyloid-beta) aggregation
Complex relationship with [tau](/proteins/tau) pathology

Ferroptosis Connection

Hepcidin dysregulation promotes [ferroptosis](/mechanisms/ferroptosis)[@stockwell2017]:

Iron overload → enhanced lipid peroxidation
Mitochondrial dysfunction
Reduced glutathione peroxidase 4 (GPX4) activity
Cell death with characteristic morphological features

Therapeutic Implications

Hepcidin Antagonists

Blocking hepcidin-ferroportin interaction is a therapeutic strategy[@sage2021]:

Antibodies targeting hepcidin
Antisense oligonucleotides reducing hepcidin expression
Small molecule hepcidin receptor antagonists
May increase iron export and reduce brain iron

Anti-inflammatory Approaches

Reducing inflammation-driven hepcidin elevation[@steinbicker2013]:

IL-6 receptor antagonists (tocilizumab)
JAK/STAT pathway inhibitors
May normalize hepcidin levels
Potential benefit in neurodegeneration

Clinical Trials

Several hepcidin-targeting agents are in development[@kautz2014]:

LY2787106 (anti-hepcidin antibody)
NOX-H94 (anti-hepcidin spiegelmer)
PTS-107 (hepcidin inhibitor)
Applications include anemia of chronic disease

Diagnostic Applications

Biomarker Potential

Hepcidin levels may serve as biomarkers[@kroot2011]:

Serum hepcidin reflects systemic iron status
CSF hepcidin may indicate brain iron dysregulation
Could predict response to iron chelation therapy
May track disease progression

Measuring Hepcidin

Methods for hepcidin measurement include[@kroot2009]:

Mass spectrometry-based assays
ELISA immunoassays
Challenges due to peptide stability
Standardization across laboratories needed

Interactions with Other Molecules

Research Directions

Current research focuses on[@vela2019]:

Brain-specific hepcidin regulation

Hepcidin antagonists for neurodegeneration

Combination with iron chelation therapy

Biomarker development

Neuroinflammation-hepcidin interactions

Hepcidin-[ferroptosis](/entities/ferroptosis) connections

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Krause A et al, LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity (2000)](https://pubmed.ncbi.nlm.nih.gov/10748062/)

[Jordan JB et al, Structural basis for hepcidin-mediated inhibition of ferroportin (2023)](https://pubmed.ncbi.nlm.nih.gov/37620901/)

[Nemeth E et al, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004)](https://pubmed.ncbi.nlm.nih.gov/14985369/)

[Ganz T, Hepcidin and iron regulation, 10 years later (2011)](https://pubmed.ncbi.nlm.nih.gov/21768341/)

[Raha AA et al, Hepcidin, ferroportin and brain iron homeostasis (2013)](https://pubmed.ncbi.nlm.nih.gov/24424461/)

[Urrutia P 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/24681152/)

[Wang J et al, Increased hepcidin expression in the substantia nigra of Parkinson's disease patients (2020)](https://pubmed.ncbi.nlm.nih.gov/31735939/)

[Sun J et al, Hepcidin as a key player in the pathogenesis of Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/33279485/)

[Stockwell BR et al, Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28132922/)

[Sage D et al, Hepcidin antagonists for therapeutic use (2021)](https://pubmed.ncbi.nlm.nih.gov/34025198/)

[Steinbicker AU, Mückenthaler MU, Out of balance—systemic iron homeostasis in inflammation (2013)](https://pubmed.ncbi.nlm.nih.gov/23719328/)

[Kautz L, Nemeth E, Molecular liaisons between erythropoiesis and iron metabolism (2014)](https://pubmed.ncbi.nlm.nih.gov/24908389/)

[Kroot JJC et al, Hepcidin in human iron disorders: diagnostic implications (2011)](https://pubmed.ncbi.nlm.nih.gov/21860058/)

[Kroot JJC et al, (Pre)analytical imprecision, standardization, and biological variation of human plasma hepcidin assays (2009)](https://pubmed.ncbi.nlm.nih.gov/19657119/)

[Vela D, Hepcidin, the missing link between inflammation and anemia in chronic disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30905901/)

Pathway Diagram

The following diagram shows the key molecular relationships involving Hepcidin discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

HEPCIDINPROTEIN

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kg_node_id	HEPCIDINPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-a89d26bf49eb
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hepcidin-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

26

Outgoing

35

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Hepcidin

Hepcidin

Overview

Structure and Function

Molecular Architecture

Hepcidin

Overview

Structure and Function

Molecular Architecture

Mechanism of Action

Regulation of Hepcidin Expression

Role in Neurodegeneration

Brain Iron Homeostasis

Neuroinflammation and Hepcidin

Parkinson's Disease

Alzheimer's Disease

Ferroptosis Connection

Therapeutic Implications

Hepcidin Antagonists

Anti-inflammatory Approaches

Clinical Trials

Diagnostic Applications

Biomarker Potential

Measuring Hepcidin

Interactions with Other Molecules

Research Directions

See Also

External Links

References

Pathway Diagram

💬 Discussion