| Symbol | HAMP |
| Full Name | Hepcidin Antimicrobial Peptide |
| Protein | [Hepcidin](/entities/hepcidin-protein) |
| Chromosome | 19q13.1 |
| NCBI Gene ID | 57817 |
| UniProt ID | P81172 |
| Aliases | HEPC, HEPCIDIN, HFE2B, LEAP1, PLTR |
HAMP encodes hepcidin, the master regulator of systemic iron homeostasis and a key antimicrobial peptide.[1] Hepcidin controls iron absorption and distribution by binding to and inducing the internalization of ferroportin, the sole cellular iron exporter.[2] Dysregulation of the hepcidin-ferroportin axis contributes to brain iron accumulation in neurodegenerative diseases.[3]
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.[4] Hepcidin is predominantly expressed in:
Hepcidin serves as the systemic iron regulatory hormone with the following functions:
Chronic neuroinflammation in neurodegenerative diseases upregulates hepcidin expression via IL-6 signaling, leading to ferroportin suppression and neuronal iron retention.[7] This creates a vicious cycle where iron accumulation promotes oxidative stress, which further drives inflammation.
In Parkinson's disease, elevated hepcidin expression has been observed in the substantia nigra.[8] This contributes to iron accumulation in dopaminergic neurons, promoting oxidative damage and alpha-synuclein aggregation. Hepcidin levels correlate with disease severity and may serve as a biomarker.
Alzheimer's disease patients show altered cerebrospinal fluid hepcidin levels and increased brain hepcidin expression.[9] Hepcidin-mediated suppression of ferroportin may contribute to iron accumulation in amyloid plaques and neurofibrillary tangles.
In ALS, elevated serum hepcidin correlates with disease progression rate and reduced survival.[10] Iron accumulation in motor neurons may be driven by hepcidin upregulation secondary to systemic inflammation.
Hepcidin binds to ferroportin at a specific extracellular loop, inducing ubiquitination, internalization via clathrin-coated pits, and lysosomal degradation.[11] Each hepcidin molecule inactivates one ferroportin molecule, blocking iron export for 24-48 hours.
Hepcidin-mediated ferroportin suppression leads to intracellular iron accumulation, promoting ferroptosis—an iron-dependent form of regulated cell death characterized by lipid peroxidation.[12] Ferroptosis has been implicated in neuronal death in PD, AD, and ALS.
Hepcidin expression is regulated by:
| Protein | Relationship | Function |
|---|---|---|
| Ferroportin | 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 |
Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003. ↩︎
Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004. ↩︎
Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurology. 2014. ↩︎
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. Journal of Biological Chemistry. 2001. ↩︎
Zanninelli G, Loreal O, Brissot P, et al. The central role of the liver in iron homeostasis and hemochromatosis. Advances in Experimental Medicine and Biology. 2002. ↩︎
Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation. 2004. ↩︎
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. Journal of Neurochemistry. 2013. ↩︎
Wang J, Jiang H, Xie JX. Ferroportin1 and hepcidin expression in rat midbrain and the effect of iron on hepcidin expression. Chinese Medical Journal. 2007. ↩︎
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. Acta Neuropathologica Communications. 2013. ↩︎
Goodall EF, Haque MS, Morrison KE. Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients. PLoS One. 2008. ↩︎
Qiao B, Sugianto P, Schmidt PJ, et al. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metabolism. 2012. ↩︎
Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Connecting Metabolism, Redox Biology, and Disease. Cell. 2017. ↩︎
Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nature Genetics. 2014. ↩︎
Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxidants & Redox Signaling. 2014. ↩︎