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Regulation of Iron Metabolism by Hepcidin
Abstract
▪ Abstract Hepcidin, a peptide hormone made in the liver, is the principal regulator of systemic iron homeostasis. Hepcidin controls plasma iron concentration and tissue distribution of iron by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter. Synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia and hypoxia. Hepcidin is also elevated during infections and inflammation, causing a decrease in serum iron levels and contributing to the development of anemia of inflammation, probably as a host defense mechanism to limit the availability of iron to invading microorganisms. At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of hemochromatosis, either due to mutations in the hepcidin gene itself or due to mutations in the regulators of hepcidin synthesis. The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.
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“Once secreted, HAMP circulates and reaches the duodenum and spleen where it tags the iron exporter FPN1 for internalization from the cell membrane and subsequent degradation in the proteasome (Nemeth and Ganz, 2006).”
From Iron in infection and immunity (2020) · cites this paper as Nemeth and Ganz, 2006
In the citing paper
“The presence of Fpn1 in the absorptive epithelium is under negative control of hepcidin, which is mainly secreted by hepatocytes in response to high circulating and tissue amounts of iron or upon stimulation by inflammatory mediators [171, 229].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [171]
In the citing paper
“The key to systemic iron homeostasis lies with hepcidin (HAMP) regulation. 37”
From The battle for iron in enteric infections (2020) · cites this paper as [37]
Citations
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“Hepcidin, the primary regulator of systemic iron homeostasis, controls plasma iron concentration and the distribution of iron in tissues by inhibiting intestinal iron absorption, iron recycling in macrophages, and iron mobilization from hepatic stores (Nemeth and Ganz, 2006).”
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BackgroundAqueous humor hepcidin prohormone levels in patients with primary open angle glaucoma.
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Peters, A., Raidal, S. R., Blake, A., Atkinson, M., Atkinson, P., & Eggins, G. (2012) · Australian Veterinary Journal · doi:10.1111/j.1751-0813.2011.00867.x · Cited by 14
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“This condition is seen in anaemia of chronic disease, both in chronic inflammatory conditions and cancer, and is aggravated when erythropoietin treatment increases the demand for iron transport to the erythron (11, 12).”
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“present study also suggested that the hepcidn-FPN1 axis has an important role in Fe haemostasis regulation((33)).”
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“mechanisms involved in iron homeostasis have revealed that hepcidin is a master regulator of systemic iron availability [16, 17].”
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“to and inhibiting the iron-exporter protein ferroportin which is expressed on enterocytes, hepatocytes, and macrophages [50].”
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“Iron homeostasis is strictly controlled at the transcriptional level in the body and at posttranscriptional level in the cells [2,3].”
BackgroundChronic Administration of 2-Acetylaminofluorene Alters the Cellular Iron Metabolism in Rat Liver
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CD1 Mouse Retina Is Shielded From Iron Overload Caused by a High Iron Diet
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“Hepcidin (Hepc), a liver-synthesized peptide hormone, is expressed in the retina(20) and can limit cellular iron export by triggering Fpn degradation.(8,21) The transcription of Hepc is upregulated by bone morphogenic protein 6 (Bmp6).”
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“Hepcidin is responsible for lysosomal internalization and degradation of FPN, thus inhibiting FPN-mediated release of Fe from enterocytes, macrophages, and hepatocytes (43, 47).”
BackgroundLysosomal Storage Disorders and Iron
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New insights into the role of iron in the development of nonalcoholic fatty liver disease†‡
Sharp, P. (2010) · Hepatology · doi:10.1002/hep.23774 · Cited by 11
“Furthermore, induction of the UPR stimulates the production of hepcidin,(16,17) the major regulator of iron homeostasis.(18) Based on these recent advances, a hypothetical model for the development of NAFLD can be proposed, which encompasses the roles of both iron and cholesterol (Fig.”
BackgroundGnanagobal, H., Chakraborty, S., Vásquez, I., Chukwu-Osazuwa, J., Cao, T., Hossain, A., Dang, M., Valderrama, K., Kumar, S., Bindea, G., et al. (2024) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2024.105165 · Cited by 10
“…as a result of interleukin 6 (IL-6)-mediated hypoferric inflammatory response, which in turn inhibits iron exporters (i.e., ferro-portin) and lowers the iron in tissues to a level below which the pathogen cannot proliferate and cause disease (Gnanagobal and Santander, 2022; Nemeth and Ganz, 2006).”
BackgroundIron-regulatory gene expression during liver regeneration
Mollbrink, A., Holmström, P., Sjöström, M., Hultcrantz, R. W., Eriksson, L. C., & Stal, P. I. (2012) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2012.661761 · Cited by 9
“Hepcidin blocks iron transport in enterocytes and macrophages and leads to decreased serum iron levels [3,4].”
BackgroundIfeanyi, O. E., Felix, C. E., Ochiabuto, M. T. B., Ugwuja, M. C., Nchekwubedi, C. S., & Chinedum, O. K. (2021) · African Journal of Biological Sciences · doi:10.33472/afjbs.3.1.2021.146-156 · Cited by 10
“This results in sequestration of Fe in the stores and Fe-limited erythropoiesis, and eventually anemia of inflammation (Nemeth and Ganz, 2006).”
BackgroundAsperti, M., Brilli, E., Denardo, A., Gryzik, M., Pagani, F., Busti, F., Tarantino, G., Arosio, P., Girelli, D., & Poli, M. (2021) · American Journal of Hematology · doi:10.1002/ajh.26311 · Cited by 10
Role of Hepcidin in Anemia of Chronic Disease in Rheumatoid Arthritis
Nita, E., Bairaktari, E. T., Kolios, G. C., Migkos, M. P., Somarakis, G.-P., Markatseli, T. E., Archimandriti, D. T., Tsaousi, C., & Voulgari, P. V. (2021) · Journal of Laboratory Physicians · doi:10.1055/s-0041-1732827 · Cited by 10
Thankachan, P., Kalasuramath, S., Hill, A. L., Thomas, T. S., Bhat, K., & Kurpad, A. V. (2011) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2011.169 · Cited by 10
“Fe absorption is tightly regulated (Cook et al., 1974; Bezwoda et al., 1979; Taylor et al., 1988; Ganz 2005; Nemeth and Ganz 2006; Roe et al., 2009) by the Fe regulatory hormone hepcidin, which is feedback regulated by the plasma and liver Fe concentrations, and by the erythropoietic demand for Fe (Ganz 2005, 2011; Ga…”
BackgroundDesgagné, M., Désilets, A., Ferková, S., Lepage, M., Perreault, O., Joushomme, A., Lemieux, G., Guerrab, W., Froehlich, U., Comeau, C., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00922 · Cited by 9
“5 At the molecular level, regulation of the HAMP gene (coding for hepcidin) involves several proteins of the bone morphogenetic protein, suppressor of mothers against decapentaplegic (BMP-SMAD) pathway, including the BMP coreceptor hemojuvelin (HJV), which is required to fully activate the…”
An overview of the current evidences on the role of iron in colorectal cancer: a review
Yousefi, M. H., Masoudi, A., Rounkian, M. S., Mansouri, M., Hojat, B., Samani, M. K., Veisi, R., Bakeshloo, P. H., Nosratipour, R., Afkhami, H., et al. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1499094 · Cited by 9
“Iron export from macrophage and hepatocyte stores is also mainly carried out by ferroportin 1 (42).”
Tortuyaux, R., Avila‐Gutierrez, K., Oudart, M., Mazaré, N., Mailly, P., Deschemin, J., Vaulont, S., Escartin, C., & Cohen‐Salmon, M. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15747 · Cited by 10
“Hepcidin deletion upregulates ferritin mRNAs and increases the Fth1/Ftl1 ratio in hippocampal astrocytes Hepcidin, the iron regulatory hormone is mainly expressed by the liver and affects systemic iron availability by controlling ferroportin activity (Atanasiu et al., 2007; Nemeth & Ganz, 2006).”
BackgroundZhou, Q., Mao, M., Li, J., & Deng, F. (2023) · Renal Failure · doi:10.1080/0886022x.2023.2195011 · Cited by 12
“After hypoxia activates the HIF pathway, the expression of hepcidin in the liver will be significantly reduced [37,38], which helps to increase the synthesis of transferrin, enhance the intestinal absorption of iron [39,40], and also increase iron binding to promote the transport of iron to the bone marrow [41].”
Background[Effect of hepcidin on iron metabolism in athletes].
Domínguez, R., Garnacho‐Castaño, M. V., & Maté‐Muñoz, J. L. (2014) · PubMed · doi:10.3305/nh.2014.30.6.7440 · Cited by 11
Yapakç, E., Ecevit, A., Gökmen, Z., Tarcan, A., & Özbek, N. (2009) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e3181b91667 · Cited by 9
Chothe, P. P., Gnana‐Prakasam, J. P., Ananth, S., Martin, P. M., Kannan, R., Hinton, D. R., Smith, S. B., & Ganapathy, V. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.01.018 · Cited by 9
“Hepcidin is a peptide hormone whose primary physiological function is to regulate iron homeostasis [6,7].”
BackgroundEvaluation of iron and zinc levels in recurrent tonsillitis and tonsillar hypertrophy
Somuk, B. T., Sapmaz, E., Soyalıç, H., Yamanoğlu, M., Mendil, D., Arıcı, A., & Gürbüzler, L. (2015) · American Journal of Otolaryngology · doi:10.1016/j.amjoto.2015.11.002 · Cited by 9
Noguchi‐Sasaki, M., Sasaki, Y., Matsuo-Tezuka, Y., Yasuno, H., Kurasawa, M., Yorozu, K., & Shimonaka, Y. (2016) · International Journal of Hematology · doi:10.1007/s12185-015-1929-3 · Cited by 9
“Iron trafficking is negatively regulated by hepcidin, a 25-amino acid peptide hormone produced mainly in the liver, which regulates intestinal iron absorption and iron release from hepatic stores by causing degradation of the iron transporter ferroportin in enterocytes and reticuloendothelial macrophages [1, 4].”
BackgroundDorsey, A. F., & Thompson, A. L. (2020) · American Journal of Human Biology · doi:10.1002/ajhb.23538 · Cited by 9
“Immune activation also causes decreased iron absorption as well as a reduction in the amount of circulating iron in order to restrict pathogen growth and proliferation (Nemeth & Ganz, 2006).”
BackgroundElevated Iron Indices in Preterm Infants: Association with Male Gender
Molloy, E. J., EL-Khuffash, A. F., Bieda, A., Jelinek, M., & Baley, J. E. (2008) · American Journal of Perinatology · doi:10.1055/s-0028-1090588 · Cited by 9
“This may be associated with decreased iron absorption and a tendency to anemia in contrast to the low hepcidin levels seen in haemachromatosis.(24) Iron overload alters immune function.”
ResultObesity and iron deficiency anemia as risk factors for asymptomatic bacteriuria
Cuttitta, F., Torres, D., Vogiatzis, D., Buttà, C., Bellanca, M., Gueli, D., Lupo, U., Schimmenti, C., Virzì, G., Petrantoni, R., et al. (2014) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2014.01.018 · Cited by 8
Dostalikova‐Cimburova, M., Krátká, K., Balušíková, K., Chmelíková, J., Hejda, V., Hnaníček, J., Neubauerová, J., Vránová, J., Kovár̆, J., & Horák, J. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01458.x · Cited by 9
“Hepcidin appears to act by binding to and internalization of ferroportin and its subsequent degradation [12, 13] which results in reduced iron efflux from enterocytes.”
BackgroundMaruna, P., Lindner, J., Kunstýř, J., Kubzova, K., & Hubacek, J. A. (2009) · Physiological Research · doi:10.33549/physiolres.931678 · Cited by 9
In vivo assessment of iron bioavailability from fortified pearl millet based weaning food
Sihag, M. K., Sharma, V., Goyal, A., Arora, S., & Kapila, R. (2016) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.7651 · Cited by 9
Boumaiza, M., Carmona, F., Poli, M., Asperti, M., Gianoncelli, A., Bertuzzi, M., Ruzzenenti, P., Arosio, P., & Marzouki, M. N. (2016) · Protein Engineering Design and Selection · doi:10.1093/protein/gzw066 · Cited by 9
“Hepcidin binds and inhibits ferroportin1, the only cellular iron exporter (Ramey et al., 2010) and thus, high hepcidin reduces while low hepcidin increases systemic iron availability (Nemeth and Ganz, 2006).”
BackgroundIron Deficiency Treatment in Patients with Heart Failure
Jankowska, E. A., Drozd, M., & Ponikowski, P. P. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_30 · Cited by 9
Makubi, A. N., & Roberts, D. J. (2017) · British Journal of Haematology · doi:10.1111/bjh.14650 · Cited by 9
“The levels of hepcidin, the master regulator of iron, rise in inflammation (Nemeth & Ganz, 2006).”
BackgroundMazgaj, R., Lipiński, P., & Starzyński, R. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074106 · Cited by 13
Biological removal of iron content from water sources using iron-oxidizing bacteria: a review
Bahuguna, M., Joshi, N., Bhandari, G., Singh, P. K., Gupta, S. K., Rafatullah, M., Anggayasti, W. L., & Huda, N. (2025) · Environmental Pollutants and Bioavailability · doi:10.1080/26395940.2025.2556182 · Cited by 10
The efficiency and safety evaluation of hemoglobin hydrolysate as a non-heme iron fortifier
Xue, D., Jiang, S., Zhang, M., Shan, K., Lametsch, R., & Li, C. (2023) · Food Science and Human Wellness · doi:10.26599/fshw.2022.9250086 · Cited by 8
Mansion, F., Chiap, P., Houbart, V., Crommen, J., Servais, A., & Fillet, M. (2011) · Journal of Separation Science · doi:10.1002/jssc.201100244 · Cited by 8
Hepcidin induction limits mobilisation of splenic iron in a mouse model of secondary iron overload
Camberlein, E., Abgueguen, E., Fatih, N., Canonne‐Hergaux, F., Leroyer, P., Turlin, B., Ropert, M., Brissot, P., & Loréal, O. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.12.007 · Cited by 8
“Excessive hepcidin production has been associated with reductions in iron release from macrophages and intestinal epithelial cells [9].”
BackgroundThe acute phase response to parturition: a cross-sectional study in Zimbabwe.
Friis, H., Gomo, E., Mashange, W., Nyazema, N. Z., Kostel, P., Wieringa, F. T., & Krarup, H. B. (2009) · African Journal of Reproductive Health · Cited by 8
Metadata
- Authors
- Nemeth, E., & Ganz, T.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Annual Review of Nutrition
- Publisher
- Annual Reviews
- Published
- 2006-08-01
- Volume
- 26
- Issue
- 1
- Pages
- 323-342
- ISSN
- 0199-9885 (ISSN-L)
- 1545-4312
- OpenAlex
- W2153145418
- Cited by
- 756
- References
- 89
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 26 · 2023: 32 · 2022: 28 · 2021: 39 · 2020: 47 · 2019: 27 · 2018: 29 · 2017: 33 · 2016: 38 · 2015: 38 · 2014: 57 · 2013: 39 · 2012: 41
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK065029, R01DK065029)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hepcidin, iron metabolism, iron homeostasis, ferroportin, intestinal iron absorption, hepatic iron stores, anemia of chronic disease, iron deficiency anemia, hemochromatosis, hypoxia, infection, inflammation, iron efflux
- MeSH terms
- Hemochromatosis, Homeostasis, Humans, Inflammation, Iron, Iron Metabolism Disorders, Antimicrobial Cationic Peptides, Hepcidins
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