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Hepcidin

Hepcidin is a 25-amino-acid peptide hormone primarily produced by hepatocytes in the liver, serving as the master regulator of systemic iron homeostasis in vertebrates.^[1] It functions by binding to ferroportin, the only known cellular iron exporter, on the surface of enterocytes, macrophages, and hepatocytes, thereby inducing ferroportin endocytosis and lysosomal degradation, which inhibits dietary iron absorption in the duodenum and sequesters iron within recycling macrophages and hepatic stores.^[2] This mechanism maintains plasma iron levels within a narrow physiological range, preventing both iron deficiency and overload.^[3] The structure of mature hepcidin consists of a disulfide-rich β-hairpin motif stabilized by eight cysteine residues forming four disulfide bonds, which is essential for its antimicrobial activity and interaction with ferroportin.^[4] Hepcidin expression is tightly regulated by multiple pathways: iron loading via the BMP-SMAD signaling cascade increases hepcidin transcription to limit iron uptake, while inflammation induced by cytokines like IL-6 activates the JAK-STAT3 pathway to upregulate hepcidin and contribute to anemia of chronic disease; conversely, erythropoietic drive, hypoxia, and elevated erythroferrone suppress hepcidin to enhance iron availability for hemoglobin synthesis.^[5] Genetic variations in hepcidin or its regulators, such as mutations in HFE, hemojuvelin, or matriptase-2, underlie hereditary iron overload disorders like hemochromatosis, whereas inappropriately low hepcidin levels in iron deficiency or thalassemia promote excessive iron absorption.^[6] In clinical contexts, hepcidin measurement in serum or urine has emerged as a biomarker for diagnosing and monitoring iron-related disorders, with elevated levels indicating functional iron deficiency in inflammatory states and reduced levels signaling hereditary or acquired iron overload.^[7] Therapeutic strategies targeting hepcidin-ferroportin axis, including hepcidin mimetics like mini-hepcidins and ferroportin inhibitors, are under development to treat conditions such as β-thalassemia and non-transfusion-dependent anemias by modulating iron distribution.^[8] Beyond iron regulation, hepcidin exhibits antimicrobial properties due to its cationic structure, potentially contributing to innate immunity by sequestering iron from pathogens.^[4]

Structure and Biosynthesis

Molecular Structure

Hepcidin is synthesized as an 84-amino acid preprohormone, known as preprohepcidin, which undergoes posttranslational processing to yield mature peptide forms.^[3] The primary bioactive form is the 25-amino acid peptide (hepcidin-25), though shorter variants of 20 or 22 amino acids can also be produced through differential cleavage of the prohormone intermediate.^[3] These mature forms retain the conserved C-terminal region essential for structural integrity.^[9] The three-dimensional structure of human hepcidin-25 features a compact, hairpin-like β-sheet conformation with approximately 32% β-sheet content, forming a distorted antiparallel β-sheet linked by a turn.^[10] This fold is rigidly stabilized by four intramolecular disulfide bonds connecting eight cysteine residues, creating a cystine-knot motif that enhances stability and resistance to proteolysis.^[10] The cystine knot consists of an embedded ring formed by two disulfide bonds and the intervening backbone, through which a third disulfide bond penetrates, with the fourth bond further constraining the structure.^[11] The solution structure of hepcidin-25 was elucidated using two-dimensional ¹H NMR spectroscopy, revealing 20 low-energy conformers with a root-mean-square deviation of 0.4 Å for backbone atoms.^[10] This NMR-derived model is available in the Protein Data Bank under entry 1M4F.^[12] Complementary X-ray crystallographic analysis of a hepcidin-antibody Fab co-crystal at 2.2 Å resolution confirmed a similar β-hairpin and cystine-knot architecture, with minor conformational adjustments due to crystal packing.^[13] Structural variations exist across species, reflecting evolutionary adaptations. In humans, hepcidin is encoded by a single HAMP gene, producing a 25-amino acid peptide with the sequence DTHFPICIFCCGCCHRSKCGMCCKT. In contrast, rodents like mice possess two orthologous genes, Hamp1 and Hamp2; Hamp1 yields a peptide highly similar to human hepcidin (76% identity in the mature form), maintaining the cystine-knot fold, while Hamp2 is more divergent (about 56% identity) with a comparable but slightly altered β-sheet structure, influencing species-specific functional emphases.

Gene and Synthesis

The human HAMP gene, which encodes hepcidin, is located on the long arm of chromosome 19 at position 19q13.12 and consists of three exons that span approximately 2.7 kilobases.^[14] This gene produces a preprohepcidin precursor protein of 84 amino acids, initially synthesized as an inactive prohormone.^[15] The HAMP gene structure was first characterized in studies identifying hepcidin as a key regulator of iron homeostasis, with the mature peptide encoded primarily within the third exon.^[16] Hepcidin expression is predominantly restricted to hepatocytes in the liver, where it accounts for the majority of circulating levels, though lower levels of mRNA and protein have been detected in other tissues including the kidney, heart, and macrophages.^[17] This tissue-specific pattern underscores the liver's central role in systemic iron regulation, with extrahepatic expression potentially contributing to local iron control in macrophages and cardiac tissue under specific conditions.^[18] The biosynthetic pathway of hepcidin begins with transcription of the HAMP gene in hepatocytes, followed by translation into preprohepcidin on the rough endoplasmic reticulum.^[9] The 24-amino-acid N-terminal signal peptide is rapidly cleaved during translocation into the secretory pathway, yielding prohepcidin of 60 amino acids.^[9] Subsequent processing occurs in the trans-Golgi network, where proprotein convertases such as furin and PCSK7 cleave prohepcidin at the multibasic site (Arg59) to generate the mature 25-amino-acid hepcidin peptide, along with shorter isoforms of 22 and 20 residues.^[19] Mature hepcidin is then secreted into the bloodstream, where it exerts its regulatory effects.^[9]

Function

Role in Iron Homeostasis

Hepcidin serves as the central regulator of systemic iron homeostasis by controlling the export of iron from cells into the bloodstream. It achieves this primarily through its interaction with ferroportin (SLC40A1), the sole known iron exporter in mammals, which is expressed on the surface of iron-exporting cells. By binding to ferroportin, hepcidin induces a conformational change that promotes the protein's phosphorylation, ubiquitination, internalization via clathrin-coated pits, and subsequent degradation in lysosomes, thereby blocking iron efflux and reducing circulating iron levels.^[20]^[21] This mechanism exerts specific effects on key cell types involved in iron handling. In duodenal enterocytes, hepcidin inhibits the absorption of dietary iron by degrading basolateral ferroportin, limiting the transfer of iron from the intestinal lumen to the plasma and preventing excessive uptake during iron-replete states. In macrophages of the reticuloendothelial system, which recycle iron from senescent erythrocytes, hepcidin promotes iron sequestration by downregulating ferroportin, retaining iron within these cells and reducing its availability for erythropoiesis. Hepatocytes, while primarily responsible for hepcidin production, also express ferroportin and respond to hepcidin by limiting their own iron release, further contributing to systemic control.^[21]^[20] Through these actions, hepcidin maintains iron balance by dynamically adjusting export rates to match bodily needs, averting both iron deficiency and overload. During iron excess, elevated hepcidin levels suppress export to store iron safely in cells; conversely, low hepcidin allows increased export to support hemoglobin synthesis and prevent anemia. Circulating hepcidin concentrations in healthy humans typically range from 1 to 30 ng/mL, with levels showing an inverse correlation to serum iron and transferrin saturation, reflecting the hormone's responsiveness to iron status.^[21]^[22]^[23]

Antimicrobial Properties

Hepcidin was originally identified as LEAP-1 (liver-expressed antimicrobial peptide), a novel human peptide isolated from human blood ultrafiltrate and liver, exhibiting potent antimicrobial activity against a range of pathogens.^[24] This discovery highlighted its evolutionary role as a defense molecule, with homologs present in fish and amphibians where hepcidin primarily functions as an antimicrobial peptide rather than an iron regulator, suggesting it evolved from an innate immune effector to a multifunctional hormone in higher vertebrates.^[25] In addition to its hormonal functions, hepcidin demonstrates direct antimicrobial activity by disrupting microbial membranes through permeabilization, leading to rapid cell lysis, particularly effective at acidic pH levels such as those in phagosomes or infected tissues. It targets Gram-positive bacteria like Staphylococcus aureus and Staphylococcus epidermidis, as well as some Gram-negative species including Escherichia coli and Pseudomonas aeruginosa, with minimum inhibitory concentrations (MICs) typically ranging from 3.25 to 50 μg/mL in vitro against bacterial strains.^[26] Against fungi, hepcidin-20 shows fungicidal effects on yeasts such as Candida glabrata and Candida albicans, with minimum fungicidal concentrations (MFCs) of 25–100 μM, enhanced in acidic environments and effective even against fluconazole-resistant isolates.^[27] In vitro studies confirm these activities through assays measuring membrane blebbing and growth inhibition, while in vivo evidence includes upregulated hepcidin expression in inflamed liver and other tissues during bacterial or fungal infections, correlating with reduced pathogen burdens in animal models. Hepcidin also contributes indirectly to antimicrobial defense by sequestering iron from extracellular spaces, starving iron-dependent pathogens during infection and enhancing overall host immunity.^[28] This nutritional immunity mechanism is supported by in vivo studies in hepcidin-deficient mice, which exhibit increased susceptibility to extracellular bacteria like Vibrio vulnificus due to higher serum iron levels and bacterial dissemination, whereas hepcidin administration restores protection by inducing hypoferremia. Such iron withholding complements hepcidin's direct effects, with expression often overlapping with inflammatory responses to pathogens.^[28]

Regulation

Iron-Sensing Pathways

Hepcidin expression in hepatocytes is primarily regulated by systemic iron levels through the bone morphogenetic protein 6 (BMP6)/SMAD signaling pathway, which senses circulating iron and adjusts hepcidin to maintain homeostasis.^[29] High serum iron, in the form of diferric transferrin, binds to transferrin receptor 2 (TFR2) on the hepatocyte surface, stabilizing TFR2 and enabling its interaction with the hereditary hemochromatosis protein HFE.00035-7) This HFE-TFR2 complex facilitates BMP6 binding to type I (ALK2/ALK3) and type II (BMPR2) receptors, recruiting hemojuvelin (HJV) as a co-receptor and leading to phosphorylation of SMAD1, SMAD5, and SMAD8.^[29] The activated SMAD complex, together with SMAD4, translocates to the nucleus to drive transcription of the HAMP gene, thereby increasing hepcidin production.^[30] In contrast, low systemic iron suppresses hepcidin via the transmembrane serine protease matriptase-2 (encoded by TMPRSS6), which is upregulated under iron deficiency. Matriptase-2 proteolytically cleaves membrane-bound HJV, preventing its role as a BMP co-receptor and thereby inhibiting BMP/SMAD signaling to reduce HAMP transcription.00319-7) This cleavage disrupts the pathway's ability to sense iron effectively, ensuring hepcidin levels decrease when iron is scarce.^[31] The iron-sensing mechanisms establish a negative feedback loop wherein elevated hepcidin binds ferroportin on enterocytes and macrophages, inducing its internalization and degradation to limit iron absorption and release, which lowers serum iron and subsequently dampens BMP/SMAD activity to reduce hepcidin.^[32] Disruptions in this pathway due to genetic variants lead to impaired iron sensing and inappropriately low hepcidin. Common mutations in HFE (e.g., C282Y), TFR2, or HJV result in defective BMP/SMAD activation, causing iron overload as seen in hereditary hemochromatosis.^[33]^[32]

Inflammatory and Other Regulators

Hepcidin expression is significantly upregulated during inflammation as part of the acute phase response, primarily through the interleukin-6 (IL-6)/JAK/STAT3 signaling pathway. Pro-inflammatory cytokines such as IL-6 bind to the IL-6 receptor complex, which includes the glycoprotein 130 (gp130) subunit, leading to activation of Janus kinase 2 (JAK2). This phosphorylation event recruits and activates signal transducer and activator of transcription 3 (STAT3), which dimerizes and translocates to the nucleus to directly bind to specific STAT3-responsive elements in the promoter region of the HAMP gene, the primary hepcidin-encoding gene.^[34] This pathway ensures rapid induction of hepcidin synthesis in hepatocytes, resulting in ferroportin degradation and sequestration of iron within macrophages and enterocytes to limit its availability to pathogens.^[5] Studies in both human cell lines and mouse models have confirmed that IL-6 is the dominant cytokine mediating this response, with hepcidin mRNA levels increasing up to 100-fold in response to inflammatory stimuli.^[35] In contrast to inflammatory induction, hypoxia suppresses hepcidin to enhance iron mobilization for erythropoiesis. Hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α, play central roles in this regulation by binding to hypoxia-responsive elements (HREs) in the HAMP promoter, thereby repressing transcription.^[5] HIF stabilization under low oxygen conditions also indirectly inhibits bone morphogenetic protein (BMP) signaling through upregulation of proteases like furin and transmembrane protease serine 6 (TMPRSS6), which cleave membrane-bound hemojuvelin (HJV), a co-receptor essential for BMP-SMAD pathway activation.^[5] Soluble HJV acts as a decoy antagonist, further dampening BMP-mediated hepcidin induction. Although early growth response 1 (EGR1) has been implicated in hypoxia-responsive gene networks, its direct role in hepcidin suppression remains less characterized but may contribute via transcriptional repression in hypoxic hepatocytes.^[5] This adaptive response is evident in conditions like high-altitude exposure, where serum hepcidin levels drop significantly within hours.^[5] Erythropoietic demands also potently suppress hepcidin to supply iron for hemoglobin production. Erythroferrone (ERFE), a hormone secreted by maturing erythroblasts in response to erythropoietin (EPO) stimulation, is the primary erythroid regulator of hepcidin. ERFE promotes the cleavage of HJV by TMPRSS6, thereby inhibiting the BMP-SMAD signaling pathway and reducing HAMP transcription in hepatocytes.^[36] In mouse models of acute blood loss or phenylhydrazine-induced hemolysis, ERFE knockout leads to persistent hepcidin elevation and impaired iron mobilization, underscoring its essential role.^[36] EPO itself contributes by expanding the erythroblast population that produces ERFE, creating a feedback loop that fine-tunes iron availability during stress erythropoiesis.^[37] This mechanism ensures that during periods of increased red blood cell production, such as recovery from anemia, systemic iron absorption and recycling are prioritized.^[38] Additional regulators provide finer modulation of hepcidin under physiological variations. Vitamin D, acting through its receptor (VDR), suppresses hepcidin expression by interfering with inflammatory signaling pathways like NF-κB and STAT3, as demonstrated in human hepatocyte cultures where 1,25-dihydroxyvitamin D3 reduced HAMP mRNA by up to 60%.^[39] Sex hormones exhibit sex-specific effects: testosterone represses hepcidin via inhibition of BMP/SMAD signaling, contributing to lower hepcidin levels in males, while 17β-estradiol inhibits HAMP transcription through an estrogen receptor α-mediated interaction with an ERE half-site in the promoter, helping to offset menstrual iron losses in females.^[40]^[41] In obesity, elevated leptin from adipose tissue upregulates hepcidin via JAK2/STAT3 activation in hepatocytes, promoting iron retention and potentially exacerbating anemia of chronic disease, though this effect is secondary to IL-6-driven inflammation.^[42]^[43] These factors collectively integrate environmental and metabolic cues to maintain iron balance beyond iron-centric sensing.

Clinical Significance

Associated Diseases

Hepcidin dysregulation plays a central role in various iron-related disorders, where either deficient or excessive production disrupts systemic iron homeostasis, leading to overload or deficiency states. In iron overload conditions, inappropriately low hepcidin levels fail to suppress intestinal iron absorption and macrophage iron release, resulting in progressive tissue accumulation and organ damage. Conversely, elevated hepcidin in inflammatory contexts restricts iron availability for erythropoiesis, contributing to anemia. Iron overload disorders are prominently associated with hepcidin deficiency. Hereditary hemochromatosis, the most common form, arises from mutations in the HFE gene, which impair the iron-sensing pathway and lead to inappropriately low hepcidin expression despite elevated iron stores. This results in excessive duodenal iron uptake and hepatic iron deposition, often manifesting in adulthood with symptoms like fatigue, arthropathy, and liver cirrhosis. Juvenile hemochromatosis, a rarer and more severe variant, is frequently caused by mutations in the HJV gene (encoding hemojuvelin), which disrupt BMP-SMAD signaling and cause profound hepcidin suppression, leading to early-onset iron overload, cardiac arrhythmias, hypogonadism, and liver failure typically before age 30. African iron overload, observed in sub-Saharan populations, involves low hepcidin levels potentially linked to environmental factors like dietary iron exposure and genetic variants in ferroportin, resulting in hepatic and pancreatic iron accumulation without typical HFE mutations. Anemia of chronic disease (ACD), also known as anemia of inflammation, features elevated hepcidin driven by proinflammatory cytokines such as IL-6, which activate the STAT3 pathway to upregulate hepcidin transcription. This excess hepcidin degrades ferroportin on enterocytes and macrophages, causing functional iron deficiency by limiting dietary absorption and recycling of senescent red blood cells, even when total body iron stores are normal or increased. ACD is prevalent in chronic infections (e.g., tuberculosis), malignancies (e.g., solid tumors and lymphomas), and autoimmune diseases (e.g., rheumatoid arthritis), where persistent inflammation sustains high hepcidin, exacerbating fatigue and reduced exercise tolerance in affected patients. In hemoglobinopathies like thalassemias, hepcidin is often suppressed due to ineffective erythropoiesis and elevated growth differentiation factor 15 (GDF15), which antagonizes hepcidin expression, promoting hyperabsorption of dietary iron and compounding overload from frequent blood transfusions. This leads to secondary hemochromatosis with cardiac, endocrine, and hepatic complications, despite chelation therapy efforts. Non-transfusion-dependent thalassemia patients are particularly vulnerable to this dysregulation, as low hepcidin exacerbates intestinal iron uptake in the absence of exogenous iron loads. Rare conditions highlight direct genetic impacts on hepcidin. Mutations in the HAMP gene, encoding hepcidin itself, cause severe juvenile hemochromatosis (type 2B) through complete or near-complete loss of functional hepcidin, resulting in uncontrolled iron absorption, rapid organ iron deposition, and early mortality if untreated. In contrast, iron-refractory iron deficiency anemia (IRIDA) stems from biallelic mutations in TMPRSS6 (encoding matriptase-2), a negative regulator of hepcidin; these defects prevent cleavage of hemojuvelin, leading to unchecked hepcidin elevation, microcytic hypochromic anemia, and poor response to oral iron supplementation from birth.

Biomarkers and Therapeutics

Hepcidin serves as a key biomarker for assessing iron status in various disorders, with serum levels measured through assays such as enzyme-linked immunosorbent assay (ELISA) and mass spectrometry to aid in diagnosing iron deficiency and overload conditions.^[44] These methods quantify the bioactive hepcidin-25 isoform, providing a direct indicator of ferroportin regulation and iron availability, which traditional markers like ferritin may not capture accurately in inflammatory states.^[45] Low serum hepcidin levels are associated with iron overload diseases, while elevated levels signal functional iron deficiency.^[46] In clinical practice, hepcidin measurements predict responsiveness to oral iron therapy in anemia of chronic disease (ACD), where high levels (>40 ng/mL) often indicate non-responsiveness due to suppressed iron absorption and release.^[47] For instance, patients with ACD and hepcidin levels above this threshold show limited hemoglobin improvement post-treatment, guiding the shift to intravenous iron.^[48] In hereditary hemochromatosis, monitoring hepcidin helps track disease progression and therapeutic efficacy, as blunted responses to iron challenge correlate with HFE mutations and persistent overload risk.^[49] Therapeutic strategies targeting hepcidin address its dysregulation in iron disorders, with agonists developed for overload conditions like β-thalassemia, where hepcidin deficiency exacerbates ineffective erythropoiesis and excess absorption. Mini-hepcidins, synthetic peptides mimicking hepcidin's N-terminal structure, bind ferroportin to reduce iron uptake and improve anemia in preclinical models of thalassemia intermedia.^[50] For example, lipidated mini-hepcidin analogs administered subcutaneously in murine β-thalassemia models decreased serum iron and splenomegaly while enhancing red blood cell production.^[51] To treat iron-restricted anemias such as ACD, hepcidin antagonists lower levels and liberate iron stores. Anti-hepcidin monoclonal antibodies, including LY2787106, neutralize circulating hepcidin, increasing serum iron and hemoglobin in inflammation-associated models without exacerbating infection risk.^[52] TMPRSS6 inhibitors, such as monoclonal antibodies targeting the matriptase-2 protease, elevate hepcidin indirectly by disrupting its negative regulation, showing promise in reducing iron overload and supporting erythropoiesis in β-thalassemia mouse models.^[53] Post-2023 developments include clinical trials of hepcidin mimetics like rusfertide (PTG-300) for polycythemia vera, where phase 3 data from the VERIFY trial demonstrated superior hematocrit control (<45%) and reduced phlebotomy needs compared to placebo when added to standard care. In August 2025, rusfertide received FDA Breakthrough Therapy Designation based on VERIFY results, with a New Drug Application planned for submission by the end of 2025.^[54]^[55] Gene therapies targeting HAMP regulation, such as RNAi silencing of hepcidin suppressors (e.g., HJV or TMPRSS6), blunt inflammation-induced hepcidin spikes in animal models, potentially mitigating ACD anemia.^[56] In October 2025, preclinical studies demonstrated that a hepcidin-binding peptide ameliorates anemia in a mouse model of chronic kidney disease by neutralizing hepcidin activity.^[57] Vitamin D supplementation trials explore hepcidin modulation, with high-dose regimens (e.g., 50,000 IU weekly) attenuating levels via NF-κB and STAT3 pathway inhibition in CKD patients, though effects on erythropoiesis vary across cohorts.^[58]^[59] Challenges in hepcidin therapeutics stem from its short plasma half-life (minutes), necessitating modified analogs like pegylated or lipid-conjugated mini-hepcidins to extend duration and efficacy.^[60] Multi-pathway regulation complicates specificity, as interventions must balance iron-sensing (BMP/SMAD), inflammatory (IL-6/STAT3), and erythropoietic signals to avoid unintended overload or deficiency.^[61]

History

Discovery

Hepcidin was first identified in 1998 when its sequence was deposited in the Swiss-Prot database by researchers in the laboratory of Tomas Ganz, based on its high expression in the liver, though this finding remained unpublished at the time. Independently, in 2000, the Krause laboratory isolated a novel 25-amino-acid peptide from human blood ultrafiltrate, naming it LEAP-1 (liver-expressed antimicrobial peptide-1) due to its antimicrobial activity and hepatic origin; they also cloned the corresponding cDNA from the HAMP gene on chromosome 19. Concurrently, the same year, researchers led by Charles Pigeon cloned the murine ortholog of this gene, observing its strong upregulation in response to iron overload and inflammation in mouse models. In early 2001, the Ganz laboratory reported the isolation of the same peptide from human urine, naming it hepcidin to reflect its hepatic production and antimicrobial properties, and confirmed isoforms such as hepcidin-20 and hepcidin-22 as N-terminally truncated variants. Building on these findings, Nicolas et al. demonstrated in 2002 that transgenic overexpression of hepcidin in mice led to severe iron deficiency anemia, while its absence in iron-overloaded HFE-knockout mice suggested a central role in iron homeostasis, proposing hepcidin as the key iron-regulatory hormone. These initial reports appeared in high-impact journals, including FEBS Letters for LEAP-1, the Journal of Biological Chemistry for both the murine gene and the urinary peptide, and PNAS for the functional insights.

Key Developments

Between 2003 and 2005, researchers identified ferroportin as the primary cellular iron exporter targeted by hepcidin, demonstrating that hepcidin binding induces ferroportin internalization and degradation, thereby regulating iron release from enterocytes, macrophages, and hepatocytes. Follow-up studies during this period elucidated hepcidin's regulation by iron levels through the HFE protein, showing that HFE mutations disrupt this feedback, leading to inappropriately low hepcidin expression and iron overload in hereditary hemochromatosis. From 2006 to 2010, the bone morphogenetic protein (BMP)/SMAD signaling pathway was established as a central mechanism for hepcidin induction in response to iron, with hemojuvelin acting as a BMP co-receptor to activate SMAD1/5/8 transcription factors that bind the hepcidin promoter.^[62] Reviews during this era highlighted hepcidin's pivotal role in the anemia of inflammation, where inflammatory cytokines like interleukin-6 upregulate hepcidin via STAT3 signaling, sequestering iron in macrophages and limiting availability for erythropoiesis. Concurrently, the first hepcidin knockout mouse models were developed, revealing severe iron overload, multiorgan iron deposition, and embryonic lethality in homozygous mutants, underscoring hepcidin's essential function in iron homeostasis. During 2011 to 2020, erythroferrone emerged as a key erythroid hormone that suppresses hepcidin during stress erythropoiesis, with its discovery linking erythropoietin-driven erythroblast expansion to increased iron availability for hemoglobin synthesis.^[63] TMPRSS6 (matriptase-2) was confirmed as a critical negative regulator of hepcidin, cleaving membrane hemojuvelin to inhibit BMP/SMAD signaling and prevent iron deficiency anemia.^[64] Initial human trials of hepcidin mimetics, such as synthetic peptides designed to mimic hepcidin's ferroportin-binding activity, commenced around 2018, targeting conditions like polycythemia vera to reduce erythrocytosis by limiting iron supply. Post-2023 advancements include preclinical studies demonstrating that hepcidin mimetics induce iron-restricted erythropoiesis, improving hemolysis, inflammation, and organ damage in mouse models of sickle cell disease.^[65] In June 2025, phase 3 trial results for rusfertide, a hepcidin mimetic, in polycythemia vera showed it significantly reduced the need for phlebotomy when added to standard care.^[66]

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Suppression of Iron-Regulatory Hepcidin by Vitamin D - PMC - NIH
Vitamin D is a potent regulator of the hepcidin-ferroportin axis in humans and highlight a potential new strategy for the management of anemia.
[38]
Regulation of the Iron Homeostatic Hormone Hepcidin - PMC - NIH
Jan 11, 2017 · The sex hormone testosterone has also been reported to have suppressive effects on hepcidin, whereas the effects of estrogen are less clear.
[39]
17β-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen ...
These results suggest that estrogen deficiency up-regulates hepcidin, which inhibits intestinal iron absorption, leading to lower serum iron levels, as well as ...
[40]
Leptin increases the expression of the iron regulatory hormone ...
These data suggest that leptin upregulates hepatic hepcidin expression through the JAK2/STAT3 signaling pathway.
[41]
The role of iron metabolism in chronic diseases related to obesity
Nov 5, 2022 · ① In obese individuals, adipose tissue can regulate expression of hepcidin and HJV through overproduction of pro-inflammatory adipokines ...
[42]
Hepcidin in the diagnosis of iron disorders - PMC - NIH
Conclusions. Hepcidin is a promising tool to be added to the present battery of diagnostic tests for iron status, especially in ID, because it has the ...
[43]
Serum hepcidin measured by immunochemical and mass ... - Nature
Aug 12, 2014 · Hepcidin plays a central role in regulating dietary iron absorption and body iron distribution. It induces the internalization and degradation ...
[44]
Immunochemical and mass-spectrometry-based serum hepcidin ...
Hepcidin is instrumental in the diagnosis and monitoring of iron metabolism disorders, but reliable methods for its quantification in serum are sparse, as is ...
[45]
Hepcidin in the diagnosis of iron disorders | Blood - ASH Publications
Hepcidin, a liver-derived peptide hormone, is a key regulator of systemic iron homeostasis, and its unbalanced production contributes to the pathogenesis of a ...
[46]
Hepcidin levels predict nonresponsiveness to oral iron therapy in ...
Levels of hepcidin, a major regulator of iron homeostasis, may identify patients with iron deficiency anemia (IDA) who will not respond to oral iron therapy.
[47]
Blunted hepcidin response to oral iron challenge in HFE-related ...
The hepcidin response to oral iron is blunted in HFE-related hemochromatosis and not improved after iron depletion. The findings support the involvement of HFE ...
[48]
Minihepcidins are rationally designed small peptides that ... - JCI
Nov 1, 2011 · We developed a series of 7– to 9–amino acid peptides, “minihepcidins,” that mimic the activity of hepcidin in cell-based bioassays and in mice.<|control11|><|separator|>
[49]
Minihepcidins improve ineffective erythropoiesis and splenomegaly ...
Jul 1, 2020 · Minihepcidins are hepcidin agonists that have been previously shown to reverse iron overload and improve erythropoiesis in mice affected by non-transfusion- ...<|separator|>
[50]
Anti-hepcidin therapy for iron-restricted anemias - PMC - NIH
Oct 24, 2013 · (B) Neutralization of hepcidin by anti-hepcidin antibodies increases plasma iron levels and improves anemia. Anti-hepcidin therapeutics alone or ...Missing: LY2784544 inhibitors
[51]
TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis ...
Jan 23, 2023 · In hepatocytes, TMPRSS6 negatively regulates the expression of the systemic iron-regulatory hormone hepcidin.Missing: anti- antibodies LY2784544
[52]
VERIFY: A randomized controlled phase 3 study of the hepcidin ...
VERIFY is a multicenter, global, randomized trial comparing efficacy and safety of rusfertide (starting dose: 20 mg subcutaneously once weekly) vs. placebo.
[53]
Targeting the Hepcidin Pathway with RNAi Therapeutics for the ...
Nov 18, 2011 · Treatment with HAMP-targeting siRNA was able to blunt hepcidin induction, hypoferremia, and the onset of anemia in a turpentine-induced mouse ...
[54]
Vitamin D supplementation ameliorates anemia of inflammation by ...
In conclusion, this study reveals that vitamin D supplementation effectively reduces hepcidin levels by inactivating NF-κB, JAK2/STAT3, and BMP6/SMAD pathways, ...
[55]
The effect of high-dose vitamin D supplementation on hepcidin-25 ...
Jan 25, 2023 · High-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort.
[56]
The pathophysiology and pharmacology of hepcidin - PMC
Hepcidin is synthesized as a preprohormone which is cleaved intracellularly ... length hepcidin and had a longer duration of action [48]. One of such ...Missing: prepro | Show results with:prepro
[57]
Manipulation of the hepcidin pathway for therapeutic purposes - PMC
Hepcidin, the liver-produced peptide hormone, is a principal regulator of iron homeostasis. Abnormal hepcidin production has emerged as a causative factor ...
[58]
Bone morphogenetic protein signaling by hemojuvelin regulates ...
Apr 9, 2006 · Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia.Missing: SMAD 2006-2010
[59]
Identification of erythroferrone as an erythroid regulator of ... - PubMed
We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis.Missing: discovery | Show results with:discovery
[60]
Membrane-bound serine protease matriptase-2 (Tmprss6) is an ...
Sep 15, 2008 · Because hepcidin is a negative regulator of iron export into plasma, we next explored the putative occurrence of iron deposits in the duodenum ...
[61]
Scientific Posters & Presentations - Protagonist Therapeutics Inc.
Iron Restricted Erythropoiesis under Hepcidin Mimetic Treatment (PN23114) Improves Disease Parameters in a Mouse Model for Sickle Cell Disease. VIEW DETAILS ...Missing: II | Show results with:II