Cited by 353Iron Metabolism and DisordersErythropoietin and Anemia TreatmentFerroptosis and cancer prognosis

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Molecular Control of Iron Transport

Ganz, Tomas·2007·Journal of the American Society of Nephrology

DOI 10.1681/asn.2006070802

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Abstract

The iron-regulatory hormone hepcidin is a 25-amino acid peptide that is synthesized in hepatocytes. Hepcidin binds to the cellular iron export channel ferroportin and causes its internalization and degradation and thereby decreases iron efflux from iron exporting tissues into plasma. By this mechanism, hepcidin inhibits dietary iron absorption, the efflux of recycled iron from splenic and hepatic macrophages, and the release of iron from storage in hepatocytes. Hepcidin synthesis is stimulated by plasma iron and iron stores and is inhibited by erythropoietic activity, ensuring that extracellular plasma iron concentrations and iron stores remain stable and the erythropoietic demand for iron is met. During inflammation, increased hepcidin concentrations cause iron sequestration in macrophages, resulting in hypoferremia and eventually anemia of inflammation. Hepcidin deficiency plays a central role in most iron overload disorders. The role of hepcidin abnormalities in anemias that are associated with renal disease and in resistance to erythropoietic therapies remains to be elucidated.

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Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
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IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
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“Although the acute hypoferremic response and hepcidin induction both are impaired in IL-6–deficient mice (21), chronic inflammatory stimulation elicits hepcidin even in IL-6–deficient mice (31).”
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Hepcidin, a urinary antimicrobial peptide synthesized in the liver
Park, C. H., Valore, E. V., Waring, A. J., & Ganz, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008922200 · Cited by 2,168
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A New Mouse Liver-specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload
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Background
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Background
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“Hepcidin-25 is filtered and reabsorbed in the proximal tubule, making urinary hepcidin an attractive biomarker of renal function.(17) It is important to point out that there is a tremendous variation among different hepcidin assays and the authors would urge caution when interpreting the findings.”
Background
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Background
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Background
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“Additionally, HIF-2α could directly upregulates ferroportin expression, the only known iron exporter to increase iron availability from stores in macrophages [52,53].”
Background
Modifying factors of theHFEhemochromatosis phenotype
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“Hepcidin is thought to be the major regulator of dietary iron absorption and cellular iron release, and it exerts its regulatory function by counteracting the function of ferroportin, the major cellular iron exporter in the various cells membrane [19].”
Background
Identification of a two-marker-haplotype on Bos taurus autosome 18 associated with somatic cell score in German Holstein cattle
Brand, B., Baes, C. F., Mayer, M., Reinsch, N., & Kühn, C. (2009) · BMC Genetics · doi:10.1186/1471-2156-10-50 · Cited by 16
“HAMP was selected as an immunological candidate gene because of its antifungal and antibacterial activity [16], the toll-like receptor-4 dependent induction by bacterial pathogens in myeloid cells [17] and to a lesser extent due to its function as a key regulator of iron metabolism [18].”
Background
Potential contribution of the hepcidin-macrophage axis to plaque vulnerability in acute myocardial infarction in human
Sasai, M., Iso, Y., Mizukami, T., Tomosugi, N., Sambe, T., Miyazaki, A., & Suzuki, H. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.11.147 · Cited by 16
Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome
Sousa, R. A. L. D., Yehia, A., & Abulseoud, O. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1237153 · Cited by 16
“The ferroxidase enzyme oxidizes ferrous iron into ferric iron (Nemeth et al., 2004; Ganz, 2005, 2006, 2007; Drakesmith et al., 2015).”
Background
Serum hepcidin-25 level linked with high mortality in patients with non-Hodgkin lymphoma
Hara, M., Ando, M., Tsuchiya, K., & Nitta, K. (2014) · Annals of Hematology · doi:10.1007/s00277-014-2255-1 · Cited by 14
Obesity and iron deficiency in chronic kidney disease: the putative role of hepcidin
Sarafidis, P. A., Rumjon, A., MacLaughlin, H. L., & Macdougall, I. C. (2011) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfr686 · Cited by 15
“Hepcidin was originally shown to have a weak selective antimicrobial activity against certain bacteria; thus, its name reflected the site of major tissue expression (‘hep’ for hepatocyte) and its antimicrobial properties (‘cidin’) [1, 2].”
BackgroundInfluential
Requirement of Integrin β3 for Iron Transportation during Enamel Formation
Yoshida, T., Kumashiro, Y., Iwata, T., Ishihara, J., Umemoto, T., Shiratsuchi, Y., Kawashima, N., Sugiyama, T., Yamato, M., & Okano, T. (2012) · Journal of Dental Research · doi:10.1177/0022034512462722 · Cited by 15
“All of these genes have been reported to be involved in iron transportation in several tissues, including airway and intestinal epithelium (Ganz, 2007; Reid et al., 2008).”
Background
The function of Eriocheir sinensis transferrin and iron in Spiroplasma eriocheiris infection
Xu, X., Liu, Y., Tang, M., Yan, Y., Gu, W., Wang, W., & Meng, Q. (2018) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2018.05.019 · Cited by 15
A hepcidina como parâmetro bioquímico na avaliação da anemia por deficiência de ferro
Lemos, A., Ismael, L. A. S., Boato, C. C. M., Borges, M. T. F., & Rondó, P. H. D. C. (2010) · Revista da Associação Médica Brasileira · doi:10.1590/s0104-42302010000500024 · Cited by 15
Antiviral peptides from aquatic organisms: Functionality and potential inhibitory effect on SARS-CoV-2
Sumon, T. A., Hussain, M. A., Hasan, M., Rashid, A., Abualreesh, M. H., Jang, W. J., Sharifuzzaman, S. M., Brown, C. L., Lee, E., & Hasan, M. T. (2021) · Aquaculture · doi:10.1016/j.aquaculture.2021.736783 · Cited by 15
“Incidentally, human ferroportin protein expressed in the duodenal enterocytes and macrophages can govern iron release, and human hepcidins underregulate this ferroportin leading to iron deficiency and compromised viral replication (Ganz, 2007; Liu et al., 2016).”
Iron‐encapsulated cold‐set whey protein isolate gel powder – Part 1: Optimisation of preparation conditions and in vitro evaluation
Bağcı, P. O., & Gunasekaran, S. (2016) · International Journal of Dairy Technology · doi:10.1111/1471-0307.12317 · Cited by 14
Erythropoiesis
Singh, A. K. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-803247-3.00012-x · Cited by 14
Ferrous and ferric differentially deteriorate proliferation and differentiation of osteoblast-like UMR-106 cells
Lertsuwan, K., Nammultriputtar, K., Nanthawuttiphan, S., Phoaubon, S., Lertsuwan, J., Thongbunchoo, J., Wongdee, K., & Charoenphandhu, N. (2018) · BioMetals · doi:10.1007/s10534-018-0130-6 · Cited by 14
The effect of nonsurgical periodontal therapy on hepcidin and on inflammatory and iron marker levels
Leite, S. A. M., Casanovas, R. C., Rodrigues, V. P., Pereira, A. D. F. V., Ferreira, T. C. A., do Nascimento, F. R. F., do Nascimento, J. R., Gomes‐Filho, I. S., Bastos, M. G., & Pereira, A. L. A. (2019) · Brazilian Oral Research · doi:10.1590/1807-3107bor-2019.vol33.0055 · Cited by 14
Evaluation of the relationship between splenic iron overload and liver, heart and muscle features evident on T2*-weighted magnetic resonance imaging
Çetinçakmak, M. G., Hattapoğlu, S., Söker, M., Ekici, F., Yılmaz, K., Göya, C., & Hamidi, C. (2020) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/116758 · Cited by 14
Cellular Iron Physiology
Muckenthaler, M. U., & Lill, R. (2011) · Humana Press eBooks · doi:10.1007/978-1-60327-485-2_2 · Cited by 13
“Conversely, increased hepcidin expression in response to infl ammatory mediators decreases FPN1 cell surface expression [ 60 ] .”
Background
Circulating fibroblast growth factor 23 (FGF23) levels are associated with metabolic disturbances and fat distribution but not cardiovascular risk in HIV-infected patients
Domingo, P., Lamarca, K., Gallego-Escuredo, J. M., Torres, F., Domingo, J. C., Villarroya, J., Gutierrez, M. D. M., Mateo, G. M., Vidal, F., Villarroya, F., et al. (2015) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv027 · Cited by 13
Effects of extracts from Gynura bicolor (Roxb. & Willd.) DC. on iron bioavailability in rats
Wu, C., Chang, W.-L., Lu, C.-H., Chang, Y.-P., Wang, J., & Hsieh, S. (2015) · Journal of Food and Drug Analysis · doi:10.1016/j.jfda.2014.11.001 · Cited by 13
“A previous study showed that hepcidin can bind to FPNs located on the basolateral side of intestinal cells and induce FPN phosphorylation and degradation, thereby increasing iron storage by intestinal epithelial cells, macrophages, and hepatocytes [3].”
Background
Iron and malaria: a dangerous liaison?
Moya‐Alvarez, V., Bodeau‐Livinec, F., & Cot, M. (2016) · Nutrition Reviews · doi:10.1093/nutrit/nuw021 · Cited by 13
Efficacy and Tolerability of Accelerated-Dose Low-Molecular-Weight Iron Dextran (Cosmofer) in Patients with Chronic Kidney Disease
Cooke, M., Lamplugh, A., Naudeer, S., Edey, M. M., & Bhandari, S. (2011) · American Journal of Nephrology · doi:10.1159/000334877 · Cited by 13
Overexpression of Leap2 impairs Xenopus embryonic development and modulates FGF and activin signals
Thiébaud, P., Garbay, B., Auguste, P., Sénéchal, C. L., Maciejewska, Z., Fédou, S., Gauthereau, X., Costaglioli, P., & Thézé, N. (2016) · Peptides · doi:10.1016/j.peptides.2016.06.008 · Cited by 12
Prolyl-hydroxylase inhibitors for the treatment of anemia in chronic kidney disease
McMahon, G. M., & Singh, A. K. (2019) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000554 · Cited by 12
The Synergistic Effect of Ruthenium Complex Δ-Ru1 and Doxorubicin in a Mouse Breast Cancer Model
Tang, X., Lin, K., Guo, S., Rong, Y., Chen, D., Chen, Z., Ping, F., & Wang, J. (2022) · Recent Patents on Anti-Cancer Drug Discovery · doi:10.2174/1574892817666220629105543 · Cited by 12
The beneficial role of Hepcidin peptide inhibitor in improved the symptoms of COVID-19 in diabetics: anti-inflammatory and potential therapeutic effects
Zeinivand, M., Jamali-Raeufy, N., & Zavvari, F. (2022) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-022-01053-9 · Cited by 10
Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide ( PTG ‐300), a hepcidin mimetic, in healthy volunteers: A double‐blind first‐in‐human study
Modi, N. B., Shames, R. S., Lickliter, J. D., & Gupta, S. (2024) · European Journal Of Haematology · doi:10.1111/ejh.14243 · Cited by 12
Hepcidin/Ferritin Ratios Differ Among Non‐Dialyzed Chronic Kidney Disease Patients, and Patients on Hemodialysis and Peritoneal Dialysis
Niikura, T., Maruyama, Y., Nakashima, S., Matsuo, N., Tanno, Y., Ohkido, I., Yokoyama, K., Yamamoto, H., & Yokoo, T. (2018) · Therapeutic Apheresis and Dialysis · doi:10.1111/1744-9987.12773 · Cited by 11
“iron retention in iron-storage cells such as hepatocytes, enterocytes, and macrophages (7), inhibiting”
Background
Intravenous Iron Dextran as a Component of Anemia Management in Chronic Kidney Disease: A Report of Safety and Efficacy
Yessayan, L., Sandhu, A., Besarab, A., Yessayan, A., Frinak, S., Zasuwa, G., & Yee, J. (2013) · International Journal of Nephrology · doi:10.1155/2013/703038 · Cited by 11
“Hindawi Publishing Corporation International Journal of Nephrology Volume 2013, Article ID 703038, 9 pages http://dx.doi.org/10.1155/2013/703038 Clinical Study Intravenous Iron Dextran as a Component of Anemia Management in Chronic Kidney Disease:”
BackgroundInfluential
Tip60/Kat5 may be a novel candidate histone acetyltransferase for the regulation of liver iron localization via acetylation
Baltacı, N. G., Toraman, E., Akyüz, M., Kalın, Ş. N., & Budak, H. (2022) · BioMetals · doi:10.1007/s10534-022-00435-z · Cited by 11
“Thus, iron metabolism is strictly regulated in mammalian cells (Ganz, 2004, 2007; Tandara & Salamunic, 2012; Stockwell et al., 2020; Vogt et al., 2021).”
Background
Serum prohepcidin is associated with soluble transferrin receptor-1 but not ferritin in healthy post-menopausal women
Huang, X., Fung, E. T., Yip, C., & Zeleniuch‐Jacquotte, A. (2008) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2008.06.009 · Cited by 11
In Vivo Analysis of Staphylococcus aureus-Infected Mice Reveals Differential Temporal and Spatial Expression Patterns of fhuD2
Bacconi, M., Haag, A. F., Chiarot, E., Donato, P., Bagnoli, F., Delany, I., & Bensi, G. (2017) · Infection and Immunity · doi:10.1128/iai.00270-17 · Cited by 12
“The liver is considered to be one of the major iron storage sites within vertebrates (35, 36), and increased initial availability of iron in this organ could explain the delayed induction of S.”
Background
Phenotypic Alterations in Erythroid Nucleated Cells of Spleen and Bone Marrow in Acute Hypoxia
Вячеславович, Н. К., Perik-Zavodskii, R., Perik-Zavodskaia, O., Alrhmoun, S., Volynets, M., Shevchenko, J. A., & Sennikov, S. V. (2023) · Cells · doi:10.3390/cells12242810 · Cited by 11
Study of anemia in nondialysis dependent chronic kidney disease with special reference to serum hepcidin
Goyal, H., Mohanty, S., Sharma, M., & Rani, A. A. (2017) · Indian Journal of Nephrology · doi:10.4103/0971-4065.179301 · Cited by 10
“[9] Hence, increased hepcidin production leads to decrease in plasma iron concentration and to iron-restricted erythropoiesis.[10] Hepcidin expression is upregulated by inflammation[11] and iron loading[12] and downregulated by erythropoietic activity.”
Background
Impact of anemia on the cardiovascular status in children with chronic kidney disease: A pilot study
Bhagat, N., Dawman, L., Naganur, S., Tiewsoh, K., Kumar, B., Pratyusha, K., Sharawat, I. K., & Gupta, K. L. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.11.031 · Cited by 10
Serum Vitamin D Concentrations, Time to Pregnancy, and Pregnancy Outcomes among Preconception Couples: A Cohort Study in Shanghai, China
Zhang, Y., Jukic, A. M. Z., Song, H., Zhang, L., Yang, F., Wu, S., Yin, D., & Jiang, H. (2022) · Nutrients · doi:10.3390/nu14153058 · Cited by 10
“Vitamin D deficiency may upregulate hepcidin—an iron-regulating peptide hormone made in the liver [53], which decreases hemoglobin concentrations and may contribute to anemia [54].”
Background
Hyperferritinémies non hémochromatosiques
Deugnier, Y., Bardou‐Jacquet, E., Lan, C. L., & Brissot, P. (2009) · Gastroentérologie Clinique et Biologique · doi:10.1016/j.gcb.2009.02.009 · Cited by 12
Low preoperative hepcidin concentration as a risk factor for mortality after cardiac surgery: A pilot study
Haase‐Fielitz, A., Plaß, M., Kuppe, H., Hetzer, R., Ostland, V. E., Westphal, S., Hoffmann, J., Prowle, J. R., Mertens, P. R., Westerman, M. E., et al. (2012) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2012.09.003 · Cited by 10
Hepcidin‐25/erythroferrone ratio predicts improvement of anaemia in haemodialysis patients treated with ferric citrate hydrate
Hara, M., Nakamura, Y., Suzuki, H., Asao, R., Nakamura, M., Nishida, K., Kenmotsu, S., Inagaki, M., Tsuji, M., Kiuchi, Y., et al. (2018) · Nephrology · doi:10.1111/nep.13495 · Cited by 10
“Moreover, patients with malignant breast cancer had © 2018 Asian Pacific Society of Nephrology 825 significantly higher levels of serum HEP-25 compared to patients with benign breast disease, although there was no significant difference in serum ERFE levels between each group of patients.18 These reports are inconsist…”
BackgroundResultInfluential
Sex-specific relationships among iron status biomarkers, athletic performance, maturity, and dietary intakes in pre-adolescent and adolescent athletes
Shoemaker, M. E., Gillen, Z. M., McKay, B. D., Bohannon, N. A., Gibson, S. M., Koehler, K., & Cramer, J. T. (2019) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-019-0306-7 · Cited by 10
Beyond efficacy and safety--the need for convenient and cost-effective iron therapy in health care
Bhandari, S. (2011) · Clinical Kidney Journal · doi:10.1093/ndtplus/sfr044 · Cited by 9
“Hepcidin acts as a regulator of iron metabolism with effects on absorption, transportation and storage [15].”
Background
Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies
Kulminski, A. M., Culminskaya, I. V., Arbeev, K. G., Arbeeva, L. S., Ukraintseva, S. V., Stallard, E., Wu, D., & Yashin, A. I. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136319 · Cited by 9
“The hemochromatosis (HFE) (rs1800562) gene controls iron absorption [18].”
Background
Anaemia and Related Nutritional Deficiencies in Chinese Patients with Obesity, 12 Months Following Laparoscopic Sleeve Gastrectomy
Zhang, C., Chen, X., Li, J., Liu, Z., Liu, W., Zhang, J., & Zhou, Z. (2021) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s303320 · Cited by 10
“Furthermore, IL-6 upregulates hepcidin, a peptide that decreases the iron absorption and releases iron from stores.(36) Thus, the improvement in serum iron found in our study might imply an improvement in iron bioavailability through decreased inflammation.”
Background
Microcytic and Malarial Anaemia Prevalence in Urban Children ≤15 Years in the Mount Cameroon Area: A Cross-Sectional Study on Risk Factors
Sama, S. O., Chiamo, S. N., Taïwé, G. S., Njume, G. E., & Sumbele, I. U. N. (2021) · Anemia · doi:10.1155/2021/5712309 · Cited by 9
“+e parasites feed on host haemoglobin, and to stop them from acquiring host iron, the recycling of iron by reticuloendothelial (RE) macrophages is impeded [14, 15].”
Background
Toddlers with anasarca and severe anemia
Salstrom, J. L., Kent, M. W., Liang, X., & Wang, M. (2011) · Current Opinion in Pediatrics · doi:10.1097/mop.0b013e32834dfc92 · Cited by 9
Ferroportin-encapsulated nanoparticles reduce infection and improve immunity in mice infected with Leishmania major
Rafiee, A., Riazi‐Rad, F., Darabi, H., Khaze, V., Javadian, S., Ajdary, S., Bahrami, F., & Alimohammadian, M. H. (2014) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2014.03.039 · Cited by 9

Authors: Ganz, T.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Ganz, Tomas
ORCID: Ganz, Tomas
Venue: Journal of the American Society of Nephrology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2007-02
Volume: 18
Issue: 2
Pages: 394-400
ISSN: 1046-6673 (ISSN-L)
DOI: 10.1681/asn.2006070802
OpenAlex: W2120359196
Cited by: 353
References: 58
Citations by year: 2026: 1 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 15 · 2021: 30 · 2020: 13 · 2019: 17 · 2018: 17 · 2017: 12 · 2016: 19 · 2015: 22 · 2014: 17 · 2013: 22 · 2012: 18
FWCI: 23.00
Type: journal article
Language: en
Open access: closed
Locations: Journal of the American Society of Nephrology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (R01HL046809, HL46809)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Keywords: hepcidin, iron transport, ferroportin, iron homeostasis, dietary iron absorption, iron storage, erythropoiesis, inflammation, anemia of chronic disease, iron overload, anemia of chronic kidney disease
MeSH terms: Ferroportin, Anemia, Biological Transport, Bone and Bones, Homeostasis, Humans, Inflammation, Intestinal Absorption, Iron, Kidney Diseases, Kinetics, Liver, Iron Overload, Antimicrobial Cationic Peptides, Cation Transport Proteins, Hepcidins

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