Pharmacological Targeting of the Hepcidin/Ferroportin Axis
Open accessAbstract
The iron regulatory hormone hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Hepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis. Similar responses are also observed in iron-loading anemias due to ineffective erythropoiesis (such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes) and in chronic liver diseases. On the other hand, excessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages. This reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis (such as anemia of chronic disease and iron-refractory iron-deficiency anemia). Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic. This review summarizes the principles underlying the development of hepcidin-based therapies for the treatment of iron-related disorders, and discusses the emerging strategies for manipulating hepcidin pathways.
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Written from the paper’s full text.
TL;DR
This review summarizes how pharmacological targeting of the hepcidin/ferroportin axis could correct iron traffic in disorders of hepcidin deficiency or excess. It surveys hepcidin inducers/mimetics and antagonists, emphasizing that therapy must restore hepcidin within a narrow physiological window.
Key findings
- Hepcidin binds ferroportin (FPN) and promotes its internalization and lysosomal degradation, thereby limiting iron efflux from macrophages and enterocytes; hepcidin deficiency causes hyperabsorption of dietary iron, hyperferremia, and tissue iron overload, while hepcidin excess causes hypoferremia and iron-restricted erythropoiesis.
- In hereditary hemochromatosis, dietary iron absorption can reach up to 8–10 mg/day; adult body iron is 3–5 g, erythroblasts require ~20–30 mg/day and non-erythroid cells ~5 mg/day, while the transferrin iron pool is ~3 mg and turns over >10 times/day.
- Disorders with hepcidin deficiency include hereditary hemochromatosis, iron-loading anemias (thalassemias, dyserythropoietic anemias, myelodysplastic syndromes), and chronic liver diseases; disorders with hepcidin excess include anemia of chronic disease, anemia of chronic kidney disease, iron-refractory iron deficiency anemia, and anemia of Castleman disease.
- Therapeutic strategies include restoring hepcidin via Tmprss6 RNAi/antisense oligonucleotides, recombinant BMP6, steroids, mini-hepcidins, and LJPC-401, and reducing hepcidin via IL-6/STAT3 or BMP/SMAD inhibitors, heparin derivatives, vitamin D, anti-hepcidin antibodies/anticalins/Spiegelmers, and anti-ferroportin antibodies; high-dose PR65 caused anemia, and Tmprss6 disruption caused microcytic anemia in Hfe−/− mice, showing the need for titration.
Methods
- Narrative review of the principles and emerging strategies for pharmacological targeting of the hepcidin/ferroportin axis.
- Evidence base consists of cited preclinical and clinical studies, including mouse models, cell culture, chemical screens, and clinical trials; no primary experimental data are reported.
- Main synthesis is thematic, with summary tables of hepcidin inducers/mimetics (Table 2) and antagonists (Table 3) validated in vivo.
Limitations
- The paper states that a major challenge is maintaining physiological circulating hepcidin concentrations to avoid shifting from hepcidin deficiency to excess and vice versa; it also notes that high doses of PR65 caused anemia and that Tmprss6 disruption caused microcytic anemia in Hfe−/− mice.
- The paper states limitations for specific approaches: oligonucleotide therapeutics may have off-target effects, toxicity, delivery/clearance problems, and high cost; many small-molecule hepcidin inducers have broad target specificity and untested in vivo capacity; steroids carry potential long-term side effects; hepcidin peptide therapy is costly, difficult to fold correctly, and rapidly cleared.
- Evident from the text: as a narrative review, it does not describe a systematic search strategy or quantitative synthesis, and its clinical development status reflects the literature available at the time of publication.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 114 cited sources checked · 0 supported · 0 flagged
- Interpretationcitation
Eradication of hepatitis C virus with direct-acting antiviral (DAA) drugs is expected to restore hepcidin expression without need for further interventions.
“Eradication of hepatitis C virus with direct-acting antiviral (DAA) drugs (Zopf et al., 2016) is expected to restore hepcidin expression without need for further interventions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zopf et al., 2016 source
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- Premisecitation
Hereditary hemochromatosis (HH) is an endocrine disorder of systemic iron overload that is caused by hepcidin insufficiency.
“Hereditary hemochromatosis (HH) is an endocrine disorder of systemic iron overload that is caused by hepcidin insufficiency (Pietrangelo, 2015; Powell et al., 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
Strategies to lower hepcidin levels could complement ACD management by mitigating erythropoietic iron-restriction.
“Therefore, they could be complemented by strategies to lower hepcidin levels, thereby mitigating erythropoietic iron-restriction.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Interpretationreasoning
Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic.
“Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
Excessive hepcidin expression is commonly observed in chronic inflammatory conditions due to infectious or autoimmune disorders or cancer.
“Excessive hepcidin expression is commonly observed in chronic inflammatory conditions due to infectious or autoimmune disorders or cancer (Weiss, 2015; Wang and Babitt, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Weiss, 2015 source
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- cites Wang and Babitt, 2016
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- Premisenone given
HH patients fail to mount appropriate iron-dependent hepcidin induction due to mutations in upstream regulators of iron signaling to hepcidin (HFE, TfR2 or HJV) or disruption of the hepcidin gene (HAMP).
“HH patients fail to mount appropriate iron-dependent hepcidin induction due to mutations in upstream regulators of iron signaling to hepcidin (HFE, TfR2 or HJV; see Figure 2) or disruption of the hepcidin gene (HAMP).”
Quote in the paperSubstantial claim - Premisereasoning
ACD management with erythropoiesis-stimulating agents (ESAs), combined or not with oral or intravenous iron administration or RBC transfusions, is not always efficacious because hepcidin overexpression blunts responses to ESAs and maintains iron unavailable to erythroblasts.
“Nevertheless, these approaches are not always efficacious because hepcidin overexpression blunts responses to ESAs and maintains iron unavailable to erythroblasts.”
Quote in the paperSubstantial claim - Premisecitation
Patients with non-classical ferroportin disease carrying mutations in ferroportin that prevent hepcidin binding develop clinical features of HH due to hepcidin resistance.
“Patients with non-classical ferroportin disease, carrying mutations in ferroportin that prevent hepcidin binding, develop clinical features of HH due to hepcidin resistance (Mayr et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mayr et al., 2010 source
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- Premisecitation
Inhibition of hepcidin expression contributes to iron overload observed in chronic hepatitis C and other chronic liver diseases.
“Inhibition of hepcidin expression also contributes to iron overload observed in chronic hepatitis C and other chronic liver diseases (Sebastiani and Pantopoulos, 2011; Pietrangelo, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Sebastiani and Pantopoulos, 2011
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- cites Pietrangelo, 2016 source
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- Premisecitation
Persistent chronic hypoferremia restricts iron availability for erythropoiesis.
“However, persistent chronic hypoferremia restricts iron availability for erythropoiesis (Ganz and Nemeth, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ganz and Nemeth, 2015 source
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- Premisecitation
The standard of care for all forms of HH is reduction of iron burden via therapeutic phlebotomy.
“The standard of care for all forms of HH is reduction of iron burden via therapeutic phlebotomy (Sivakumar and Powell, 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sivakumar and Powell, 2016
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- Interpretationreasoning
Hepcidin-lowering strategies could improve therapeutic outcomes in CKD.
“Thus, hepcidin-lowering strategies could improve therapeutic outcomes.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
Hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells.
“The iron regulatory hormone hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells.”
- Also stated in: § Introduction · plain
“Iron efflux to the bloodstream is physiologically restrained by hepcidin, an antimicrobial peptide and master hormonal regulator of systemic iron metabolism (Ganz, 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Also stated in: § Introduction · plain
- Interpretationreasoning
Broad target specificity may disqualify many of the above-described drugs for pharmacological applications to stimulate hepcidin.
“Broad target specificity may disqualify many of the above-described drugs for pharmacological applications to stimulate hepcidin.”
Quote in the paperNot a substantial claim - Premisecitation
Downstream inhibition of the IL-6/STAT3 signaling pathway by small molecule inhibitors of STAT3 (curcumin, AG490 and PpYLKTK) decreases hepcidin in cell and mouse models.
“Studies with cell and mouse models showed that downstream inhibition of the IL-6/STAT3 signaling pathway by using small molecule inhibitors of STAT3 (curcumin, AG490 and PpYLKTK) likewise decreases hepcidin (Jiao et al., 2009; Fatih et al., 2010; Zhang et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Administration of the mini-hepcidin mimetic PR73 protected Hamp−/− mice against infection with the siderophilic bacterium Vibrio vulnificus.
“Interestingly, administration of the mini-hepcidin mimetic PR73 protected Hamp−∕− mice against infection with the siderophilic bacterium Vibrio vulnificus (Arezes et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Arezes et al., 2015 source
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- Interpretationreasoning
Targeted delivery of hepcidin antagonists to hepcidin-overexpressing tumors may sensitize them to anti-cancer therapies.
“Therefore, targeted delivery of hepcidin antagonists to hepcidin-overexpressing tumors may sensitize them to anti-cancer therapies.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Interpretationcitation
Titration of hepcidin levels within a physiological window is imperative to prevent adverse effects of hepcidin excess.
“It should be noted that disruption of both Tmprss6 alleles offered optimal correction of iron overload but also caused microcytic anemia in Hfe−∕− mice (Finberg et al., 2011), suggesting that titration of hepcidin levels within a physiological window is imperative to prevent adverse effects of hepcidin excess.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Finberg et al., 2011 source
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- Interpretationreasoning
These data highlight another possible application of hepcidin agonists.
“Considering that infections with extracellular siderophilic pathogens can be lethal to HH patients (Frank et al., 2011), these data highlight another possible application of hepcidin agonists.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Frank et al., 2011 source
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- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Interpretationcitation
Adverse effects of hepcidin inactivation in mouse models of malaria infection or microbial sepsis suggest a therapeutic potential of hepcidin agonists in the context of these pathologies.
“Finally, the adverse effects of hepcidin inactivation in mouse models of malaria infection (Portugal et al., 2011) or microbial sepsis suggest a therapeutic potential of hepcidin agonists in the context of these pathologies (Zeng et al., 2015).”
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- cites Zeng et al., 2015 source
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- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
Administration of progesterone to women in the context of standard fertility treatments resulted in hepcidin induction.
“Administration of progesterone to women in the context of standard fertility treatments resulted in hepcidin induction (Li et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2016
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- Premisecitation
Suppression of hepatic Tmprss6 by using RNAi or antisense oligonucleotides increased hepcidin expression in wild type, Hfe−/− and Hbbth3/+ mice.
“In fact, suppression of hepatic Tmprss6 by using RNAi (Schmidt et al., 2013) or antisense oligonucleotides (Guo et al., 2013a) increased hepcidin expression in wild type, Hfe−∕− and Hbbth3∕+ mice.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Schmidt et al., 2013 source
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- cites Guo et al., 2013a
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- Premisecitation
Mini-hepcidin analogs containing a minimal core of 7-9 N-terminal amino acids with a single cysteine suffice to trigger ferroportin internalization and degradation in cells and mice.
“This led to the development of mini-hepcidin analogs containing a minimal core of 7–9 N-terminal amino acids with a single cysteine, which suffice to trigger ferroportin internalization and degradation in cells and mice (Preza et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Preza et al., 2011 source
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- Premisecitation
Manipulation of hepcidin levels by transgenic expression or Tmprss6 disruption also improved erythropoiesis in Hbbth3/+ mice.
“Moreover, manipulation of hepcidin levels by these strategies also improved erythropoiesis in Hbbth3∕+ mice (Gardenghi et al., 2010; Nai et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Hepcidin-inducing steroids or drugs that lower 17β-estradiol or testosterone could be applied for pharmacological restoration of hepcidin.
“Hepcidin-inducing steroids or drugs that lower 17β-estradiol or testosterone could be applied for pharmacological restoration of hepcidin.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisenone given
TMPRSS6 encodes matriptase-2, a transmembrane serine protease that negatively regulates BMP/SMAD signaling to hepcidin.
“TMPRSS6 encodes matriptase-2, a transmembrane serine protease that negatively regulates BMP/SMAD signaling to hepcidin (see Figure 2).”
Quote in the paperSubstantial claim - Premisecitation
Transgenic expression of hepcidin prevented iron overload in Hfe−/− and Hbbth3/+ mice, models of HH and β-thalassemia intermedia, respectively.
“Thus, transgenic expression of hepcidin prevented iron overload in Hfe−∕− (Nicolas et al., 2003) and Hbbth3∕+ (Gardenghi et al., 2010) mice, models of HH and β-thalassemia intermedia, respectively.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Targeting of hepcidin pathways is expected to correct defects triggered by excessive hepcidin expression.
“Targeting of hepcidin pathways is expected to correct defects triggered by excessive hepcidin expression.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
Cell culture studies and chemical screens identified several small molecules capable of stimulating hepcidin transcription in vitro.
“Cell culture studies and chemical screens identified several small molecules capable of stimulating hepcidin transcription in vitro, such as genistein (Zhen et al., 2013), SB204741, daunorubicin, ethacridine, phenazopyridine, 9-aminoacridine, amlexanox, lansoprazole, leflunomide, ipriflavone, AS252424, pterostilbene, AG1296, GTP14564, SU6668, leflunomide, 10058-F4 and vorinostat (Gaun et al., 2014”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Treatment of multicentric Castleman disease patients with therapeutic monoclonal antibodies against IL-6 receptor (tocilizumab) or IL-6 (siltuximab) reduced hepcidin levels and improved anemia.
“Supporting evidence is provided by studies with multicentric Castleman disease patients who were treated with therapeutic monoclonal antibodies against IL-6 receptor (tocilizumab) or IL-6 (siltuximab). These treatments reduced hepcidin levels and improved anemia (Song et al., 2010; Casper et al., 2015).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
An RNAi screen identified sorafenib, wortmannin, rapamycin and metformin as inducers of hepcidin mRNA expression.
“An RNAi screen identified sorafenib, wortmannin, rapamycin and metformin as inducers of hepcidin mRNA expression (Mleczko-Sanecka et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mleczko-Sanecka et al., 2014 source
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- Premisecitation
Infections with extracellular siderophilic pathogens can be lethal to HH patients.
“Considering that infections with extracellular siderophilic pathogens can be lethal to HH patients (Frank et al., 2011), these data highlight another possible application of hepcidin agonists.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Frank et al., 2011 source
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- Premisecitation
17β-estradiol inhibits hepcidin transcription via an estrogen-responsive promoter element.
“Contrary to progesterone, 17β-estradiol inhibits hepcidin transcription via an estrogen-responsive promoter element (Yang et al., 2012).”
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- Premisecitation
Progesterone, epitiostanol, and mifepristone stimulate hepcidin transcription independently of the BMP/SMAD and IL-6/STAT3 pathways, by a mechanism requiring progesterone receptor membrane component-1 (PGRMC1).
“Progesterone, epitiostanol, and mifepristone were shown to stimulate hepcidin transcription independently of the BMP/SMAD and IL-6/STAT3 pathways, by a mechanism requiring progesterone receptor membrane component-1 (PGRMC1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2016
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- Premisecitation
Administration of recombinant BMP6 improved iron signaling to hepcidin and corrected systemic iron homeostasis in Hfe−/− mice, even though endogenous BMP6 expression is appropriately induced in these animals.
“Administration of recombinant BMP6 was shown to improve iron signaling to hepcidin and correct systemic iron homeostasis in Hfe−∕− mice, even though endogenous BMP6 expression is appropriately induced in these animals (Corradini et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Corradini et al., 2010 source
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- Premisecitation
Hepcidin generated by breast or prostate cancer epithelial cells promotes iron retention via autocrine degradation of ferroportin, which favors survival and growth.
“For instance, hepcidin generated by breast or prostate cancer epithelial cells promotes iron retention via autocrine degradation of ferroportin, which in turn favors survival and growth (Pinnix et al., 2010; Tesfay et al., 2015).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Neutralizing hepcidin antibodies modulate iron metabolism in mice and cynomolgus monkeys.
“Neutralizing hepcidin antibodies were shown to modulate iron metabolism in mice and cynomolgus monkeys; moreover, they improved erythropoiesis and responses to ESA therapy in mouse models of ACD (Sasu et al., 2010; Cooke et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
NOX-H94 operates as a specific inhibitor of hepcidin.
“This PEGylated non-natural mirror-image L-oligoribonucleotide binds with high affinity to hepcidin and operates as a specific inhibitor.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schwoebel et al., 2013 source
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- Interpretationreasoning
These findings underline the potential pharmacological value of vitamin D as a hepcidin-lowering agent.
“These findings underline the potential pharmacological value of vitamin D as a hepcidin-lowering agent, which needs to be further explored in animal models and randomized controlled trials.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
NOX-H94 binds with high affinity to hepcidin.
“This PEGylated non-natural mirror-image L-oligoribonucleotide binds with high affinity to hepcidin and operates as a specific inhibitor.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schwoebel et al., 2013 source
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- Premisecitation
NOX-H94 prevented hypoferremia in experimental human endotoxemia with LPS-injected volunteers.
“Moreover, NOX-H94 prevented hypoferremia in experimental human endotoxemia with LPS-injected volunteers (Van Eijk et al., 2014) (ClinicalTrials.gov Identifier: NCT01522794).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Van Eijk et al., 2014 source
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- Interpretationcitation
Neutralization of hepcidin is possible by using relatively high molecular weight antagonists.
“Neutralization of hepcidin is also possible by using relatively high molecular weight antagonists.”
Quote in the paperSubstantial claim - Interpretationcitation
Dorsomorphin and LDN-193189 are unlikely to be considered for clinical application due to lack of target specificity.
“Nevertheless, dorsomorphin and LDN-193189 are unlikely to be considered for clinical application due to lack of target specificity (Boergermann et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Boergermann et al., 2010 source
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- Premisecitation
PRS-080 specifically binds to hepcidin.
“Pieris Pharmaceuticals Inc generated PRS-080, a PEGylated anticalin protein that specifically binds to hepcidin and inhibits its activity.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hohlbaum et al., 2011 source
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- Premisecitation
TP-0184, a specific ALK2 inhibitor, blocked inflammatory induction of hepcidin in mouse models of ACD and cancer-induced anemia.
“TP-0184, a specific ALK2 inhibitor developed by Tolero Pharmaceuticals, was recently shown to block inflammatory induction of hepcidin in mouse models of ACD and cancer-induced anemia (Peterson et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Peterson et al., 2015 source
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- Premisecitation
NOX-H94 (Lexaptepid Pegol) is a Spiegelmer hepcidin antagonist.
“NOXXON Pharma AG generated NOX-H94 (Lexaptepid Pegol), a Spiegelmer hepcidin antagonist.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schwoebel et al., 2013 source
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- Premisecitation
Fursultiamine binds to ferroportin on C326.
“A chemical screen for small molecule hepcidin antagonists identified fursultiamine, a thiol-reactive thiamine derivative that binds to ferroportin on C326 and thereby precludes the binding of hepcidin (Fung et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fung et al., 2013 source
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- Premisecitation
Humanized monoclonal HJV antibodies corrected anemia via hepcidin inhibition in rat and mouse models of ACD, and in Tmprss6−/− mice.
“Moreover, they corrected anemia via hepcidin inhibition in rat and mouse models of ACD, and in Tmprss6−∕− mice (Kovac et al., 2016).”
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- Premisecitation
HJV is a BMP co-receptor that enhances iron signaling to hepcidin.
“HJV is a BMP co-receptor that enhances iron signaling to hepcidin (Babitt et al., 2006).”
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- Premisecitation
NOX-H94 is currently being evaluated in three Phase 1 and Phase 2 clinical trials on patients with cancer-related anemia, ACD or CKD.
“NOX-H94 is currently being evaluated in another three Phase 1 and Phase 2 clinical trials on patients with cancer-related anemia, ACD or CKD (ClinicalTrials.gov Identifiers: NCT01691040, NCT01372137, and NCT02079896).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ClinicalTrials.gov Identifiers: NCT01691040, NCT01372137, and NCT02079896
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- Premisecitation
PRS-080 inhibits hepcidin activity.
“Pieris Pharmaceuticals Inc generated PRS-080, a PEGylated anticalin protein that specifically binds to hepcidin and inhibits its activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hohlbaum et al., 2011 source
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- Premisecitation
NOX-H94 administration improved inflammation-related anemia in cynomolgus monkeys.
“NOX-H94 administration improved inflammation-related anemia in cynomolgus monkeys (Schwoebel et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schwoebel et al., 2013 source
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- Premisecitation
Fursultiamine binding to ferroportin on C326 precludes the binding of hepcidin.
“A chemical screen for small molecule hepcidin antagonists identified fursultiamine, a thiol-reactive thiamine derivative that binds to ferroportin on C326 and thereby precludes the binding of hepcidin (Fung et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fung et al., 2013 source
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- Premisecitation
Vitamin D supplementation can decrease hepcidin levels in healthy volunteers and early stage CKD patients.
“Importantly, pilot clinical studies demonstrated that vitamin D supplementation can decrease hepcidin levels in healthy volunteers (Bacchetta et al., 2014) and early stage CKD patients (Zughaier et al., 2014).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Highly sulfated heparins with low anticoagulant activity inhibited hepcidin in cells and mice.
“Highly sulfated heparins with low anticoagulant activity likewise inhibited hepcidin in cells and mice (Poli et al., 2014b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Poli et al., 2014b
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- Premisecitation
Neutralization of HJV by humanized monoclonal HJV antibodies reduced hepcidin expression in rats and cynomolgus monkeys.
“Its neutralization by using humanized monoclonal HJV antibodies (developed by Abbvie) reduced hepcidin expression in rats and cynomolgus monkeys (Böser et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Böser et al., 2015 source
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- Premisecitation
Neutralizing hepcidin antibodies improve erythropoiesis and responses to ESA therapy in mouse models of ACD.
“Neutralizing hepcidin antibodies were shown to modulate iron metabolism in mice and cynomolgus monkeys; moreover, they improved erythropoiesis and responses to ESA therapy in mouse models of ACD (Sasu et al., 2010; Cooke et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Binding of 1,25-dihydroxy-vitamin D to its receptor directly suppresses hepcidin transcription by binding to a promoter element.
“Biochemical studies showed that binding of 1,25-dihydroxy-vitamin D to its receptor directly suppresses hepcidin transcription by binding to a promoter element (Bacchetta et al., 2014).”
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- Premisecitation
Small molecule inhibitors of the BMP/SMAD pathway have been tested and shown to act as hepcidin-lowering agents.
“Small molecule inhibitors of the BMP/SMAD pathway have been tested and shown to act as hepcidin-lowering agents.”
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LY2787106 treatment increased reticulocyte count relative to baseline in patients with cancer-associated anemia.
“The antibody treatment was well tolerated and resulted in transient iron mobilization and increased reticulocyte count relative to baseline (Vadhan-Raj et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vadhan-Raj et al., 2015 source
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- Interpretationcitation
These findings suggest that pharmacological targeting of hepcidin may be valuable beyond the context of improving erythropoiesis.
“These findings suggest that pharmacological targeting of hepcidin may be valuable beyond the context of improving erythropoiesis.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
- Premisecitation
A chemical screen for small molecule hepcidin antagonists identified fursultiamine.
“A chemical screen for small molecule hepcidin antagonists identified fursultiamine, a thiol-reactive thiamine derivative that binds to ferroportin on C326 and thereby precludes the binding of hepcidin (Fung et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fung et al., 2013 source
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- Premisereasoning
Further development of STAT3 inhibitors as hepcidin inhibitors is hindered by lack of specificity, competing iron chelating properties, or poor pharmacokinetics.
“However, further development of this class of drugs as hepcidin inhibitors is hindered by lack of specificity (all STAT3 inhibitors), competing iron chelating properties (curcumin) or poor pharmacokinetics (AG490 and PpYLKTK).”
Quote in the paperNot a substantial claim - Premisecitation
LY2787106 treatment resulted in transient iron mobilization relative to baseline in patients with cancer-associated anemia.
“The antibody treatment was well tolerated and resulted in transient iron mobilization and increased reticulocyte count relative to baseline (Vadhan-Raj et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vadhan-Raj et al., 2015 source
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Preservation of high sulfation grade and molecular weight are critical for the hepcidin inhibitory activity of heparins.
“Preservation of high sulfation grade and molecular weight are critical for their hepcidin inhibitory activity (Asperti et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Asperti et al., 2016 source
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- Premisecitation
A secreted soluble HJV form (sHJV) functions as a competitive inhibitor of BMP binding to BMP receptors.
“A secreted soluble HJV form (sHJV) functions as a competitive inhibitor of BMP binding to BMP receptors (Lin et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lin et al., 2005 source
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- Premisecitation
LY2787106 treatment was well tolerated in patients with cancer-associated anemia.
“The antibody treatment was well tolerated and resulted in transient iron mobilization and increased reticulocyte count relative to baseline (Vadhan-Raj et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vadhan-Raj et al., 2015 source
Not checked in the free run.
- Premisecitation
LY2928057 increased iron mobilization in cynomolgus monkeys.
“Along these lines, Eli Lily and Company developed a monoclonal ferroportin antibody (LY2928057), which increased iron mobilization in cynomolgus monkeys by binding to ferroportin and thereby inhibiting access to hepcidin (Witcher et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Witcher et al., 2013 source
Not checked in the free run.
- Premisecitation
Fursultiamine efficiently protected ferroportin against hepcidin in cultured cells.
“While it efficiently protected ferroportin against hepcidin in cultured cells, it failed to exhibit in vivo anti-hepcidin activity, possibly due to rapid plasma turnover.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fung et al., 2013 source
Not checked in the free run.
- Interpretationnone given
Several agonists and antagonists of hepcidin have been developed.
“Several agonists and antagonists of hepcidin have been developed.”
Quote in the paperNot a substantial claim - Premisecitation
Eli Lily and Company developed a monoclonal ferroportin antibody (LY2928057).
“Along these lines, Eli Lily and Company developed a monoclonal ferroportin antibody (LY2928057), which increased iron mobilization in cynomolgus monkeys by binding to ferroportin and thereby inhibiting access to hepcidin (Witcher et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Witcher et al., 2013 source
Not checked in the free run.
- Premisecitation
LY2928057 binds to ferroportin.
“Along these lines, Eli Lily and Company developed a monoclonal ferroportin antibody (LY2928057), which increased iron mobilization in cynomolgus monkeys by binding to ferroportin and thereby inhibiting access to hepcidin (Witcher et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Witcher et al., 2013 source
Not checked in the free run.
- Premisecitation
LY2928057 inhibits access of hepcidin to ferroportin.
“Along these lines, Eli Lily and Company developed a monoclonal ferroportin antibody (LY2928057), which increased iron mobilization in cynomolgus monkeys by binding to ferroportin and thereby inhibiting access to hepcidin (Witcher et al., 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Witcher et al., 2013 source
Not checked in the free run.
- Interpretationnone given
Correction of hepcidin levels can offer therapeutic benefits to other disorders (thalassemia, ACD).
“Correction of hepcidin levels can provide an etiologic cure to some of these disorders (HH, IRIDA), or offer therapeutic benefits to others (thalassemia, ACD).”
Quote in the paperSubstantial claim - Premisecitation
Fursultiamine failed to exhibit in vivo anti-hepcidin activity.
“While it efficiently protected ferroportin against hepcidin in cultured cells, it failed to exhibit in vivo anti-hepcidin activity, possibly due to rapid plasma turnover.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fung et al., 2013 source
Not checked in the free run.
- Premisecitation
LY2928057 is currently being evaluated in two Phase 1 clinical trials with healthy volunteers and anemic CKD patients.
“LY2928057 is currently being evaluated in two Phase 1 clinical trials with healthy volunteers and anemic CKD patients (ClinicalTrials.gov Identifiers: NCT01330953 and NCT01991483).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ClinicalTrials.gov Identifiers: NCT01330953 and NCT01991483
Not checked in the free run.
- Interpretationnone given
Correction of hepcidin levels can provide an etiologic cure to some disorders (HH, IRIDA).
“Correction of hepcidin levels can provide an etiologic cure to some of these disorders (HH, IRIDA), or offer therapeutic benefits to others (thalassemia, ACD).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Blocking the hepcidin-binding site of ferroportin offers another option for pharmacological targeting the hepcidin/ferroportin axis.
“Nevertheless, they also show that blocking the hepcidin-binding site of ferroportin offers another option for pharmacological targeting the hepcidin/ferroportin axis.”
Quote in the paperSubstantial claim
- May combine two claims. 43
- Classified as probably not a substantial claim. 14
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationTogether with immune-driven reduced proliferation and life span of RBCs, diversion of iron traffic contributes to pathogenesis of the anemia of chronic disease (ACD), the most frequent anemia among hospitalized patients.
“Together with immune-driven reduced proliferation and life span of RBCs, the diversion of iron traffic contributes to pathogenesis of the anemia of chronic disease (ACD), or anemia of inflammation, the most frequent anemia among hospitalized patients (Weiss, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Weiss, 2015 source
Not checked in the free run.
May combine two claims.
Premisenone givenInflammatory induction of hepcidin is primarily mediated by IL-6 and leads to hypoferremia due to ferroportin degradation and iron sequestration in tissue macrophages.
“Inflammatory induction of hepcidin is primarily mediated by IL-6 and leads to hypoferremia due to ferroportin degradation and iron sequestration in tissue macrophages.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenHepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis.
“Hepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis.”
Quote in the paperSubstantial claimMay combine two claims.
PremisereasoningExcessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages.
“On the other hand, excessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages.”
Quote in the paperSubstantial claimMay combine two claims.
PremisereasoningHigh hepcidin levels in CKD are associated with iron-restricted erythropoiesis, contribute to anemia, and negatively affect therapy with ESAs and oral or intravenous iron.
“This is associated with iron-restricted erythropoiesis and contributes to anemia. Moreover, it negatively affects therapy with ESAs and oral or intravenous iron.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningRestoration of hepcidin could prevent iron overload in non-transfused patients with mild iron-loading anemias and improve the efficacy of iron chelation therapy in transfused patients.
“Restoration of hepcidin could prevent iron overload in the former and improve the efficacy of iron chelation therapy in the latter.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenInflammatory IL-6 triggers hepcidin induction via IL-6/STAT signaling, in crosstalk with the BMP/SMAD pathway.
“Inflammatory IL-6 triggers hepcidin induction via IL-6/STAT signaling, in crosstalk with the BMP/SMAD pathway.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationMisregulation of hepcidin is etiologically linked or contributes to iron-related disorders, and pharmacological targeting of the hepcidin/ferroportin axis to restore physiological hepcidin levels is expected to offer therapeutic benefits.
“Misregulation of hepcidin is etiologically linked or contributes to iron-related disorders (listed in Table 1), in which pharmacological targeting of the hepcidin/ferroportin axis to restore physiological hepcidin levels is expected to offer therapeutic benefits”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Poli et al., 2014c
Not checked in the free run.
- cites Ruchala and Nemeth, 2014
Not checked in the free run.
- cites Schmidt and Fleming, 2014
Not checked in the free run.
- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningHH patients who are intolerant, have low acceptance or compliance to life-long phlebotomy, or present contraindications are good candidates for new therapies based on restoration of appropriate hepcidin levels.
“However, some patients are intolerant, or have low acceptance and compliance to a life-long treatment, or present contraindications (severe heart disease or anemia). These patients are good candidates for new therapies based on restoration of appropriate hepcidin levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
May combine two claims.
PremisecitationPatients with chronic kidney disease (CKD) accumulate high hepcidin levels in the bloodstream due to reduced renal clearance and inflammatory induction of hepcidin transcription.
“Patients with chronic kidney disease (CKD) accumulate high hepcidin levels in the bloodstream due to reduced renal clearance, but also due to inflammatory induction of hepcidin transcription (Tsuchiya and Nitta, 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tsuchiya and Nitta, 2013
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenIncreased erythropoietic activity orchestrated by erythropoietin leads to hepcidin suppression via erythroferrone (ERFE) and other cytokines.
“Increased erythropoietic activity orchestrated by erythropoietin leads to hepcidin suppression via erythroferrone (ERFE) and other cytokines.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenHH is characterized by chronic hyperabsorption of dietary iron (up to 8-10 mg/day) and unrestricted release of iron from macrophages.
“It constitutes the most frequent genetic disorder in populations of Northern European ancestry and is characterized by chronic hyperabsorption of dietary iron (up to 8–10 mg/day) and unrestricted release of iron from macrophages.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningExcessive hepcidin expression reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis, such as anemia of chronic disease and iron-refractory iron-deficiency anemia.
“This reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis (such as anemia of chronic disease and iron-refractory iron-deficiency anemia).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationErythropoietic suppression of hepcidin triggers iron overload in non-transfused patients with mild forms of iron loading anemias, and aggravates secondary iron overload in transfused patients.
“Erythropoietic suppression of hepcidin triggers iron overload in non-transfused patients with mild forms of iron loading anemias, and aggravates secondary iron overload in transfused patients (Ginzburg and Rivella, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ginzburg and Rivella, 2011
Not checked in the free run.
May combine two claims.
PremisecitationHepcidin deficiency is common in hematological disorders associated with ineffective erythropoiesis, such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes, and contributes to iron overload.
“Hepcidin deficiency is common in hematological disorders associated with ineffective erythropoiesis, such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes, and contributes to iron overload (Ginzburg and Rivella, 2011; Camaschella and Nai, 2016).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Ginzburg and Rivella, 2011
Not checked in the free run.
- cites Camaschella and Nai, 2016 source
Not checked in the free run.
May combine two claims.
PremisecitationGenetic inactivation of the TMPRSS6 gene leads to unrestricted hepcidin production in spite of low body iron stores, which underlies the pathogenesis of iron-refractory iron deficiency anemia (IRIDA).
“Genetic inactivation of the TMPRSS6 gene leads to unrestricted hepcidin production in spite of low body iron stores, which underlies the pathogenesis of iron-refractory iron deficiency anemia (IRIDA) (Heeney and Finberg, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Heeney and Finberg, 2014
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenIncreased serum or tissue iron levels, reflected in transferrin saturation or hepatic BMP6 expression, promote hepcidin induction via BMP/SMAD signaling.
“Increased serum or tissue iron levels (reflected in transferrin saturation or expression of hepatic BMP6, respectively) promote hepcidin induction via BMP/SMAD signaling.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationProlonged BMP6 application caused peritoneal calcifications, indicative of lack of target specificity, which may lead to further pleiotropic side effects.
“Nevertheless, prolonged BMP6 application caused peritoneal calcifications, indicative of lack of target specificity, which may lead to further pleiotropic side effects.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenHigh doses of PR65 caused anemia, emphasizing the importance of titration.
“High doses of PR65 caused anemia, emphasizing the importance of titration.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenBiochemical studies revealed that hepcidin interacts with ferroportin via its N-terminal region, and that C-terminal amino acid residues are dispensable.
“Biochemical studies revealed that hepcidin interacts with ferroportin via its N-terminal region (highlighted in Figure 4), and that C-terminal amino acid residues are dispensable.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationHepcidin is produced in response to inflammation or other signals by heart cardiomyocytes and by brain astrocytes and microglia.
“Hepcidin is also produced in response to inflammation or other signals by heart cardiomyocytes (Merle et al., 2007) and by brain astrocytes and microglia (Urrutia et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisenone givenSynthetic or recombinant hepcidin is rapidly cleared in the circulation and therefore pharmacological concentrations cannot be sustained.
“Moreover, synthetic or recombinant hepcidin is rapidly cleared in the circulation and therefore pharmacological concentrations cannot be sustained.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationEncapsulation of hepcidin into biocompatible nanocarriers suitable for controlled release could theoretically address rapid clearance.
“Encapsulation of hepcidin into biocompatible nanocarriers suitable for controlled release of therapeutics (Cheng et al., 2015) could theoretically address this issue.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cheng et al., 2015 source
Not checked in the free run.
May combine two claims.
PremisecitationSuppression of hepatic Tmprss6 reduced systemic iron overload in Hfe−/− and Hbbth3/+ mice, and ameliorated anemia in Hbbth3/+ mice.
“Importantly, it reduced systemic iron overload in Hfe−∕− and Hbbth3∕+ mice, and ameliorated anemia in Hbbth3∕+ mice.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenChemical synthesis of hepcidin or its expression as recombinant peptide is costly, while appropriate folding to the biologically active form is complicated by the presence of 8 cysteine residues within the 25 amino acids of the mature peptide forming 4 disulfide bridges.
“However, the chemical synthesis of hepcidin or its expression as recombinant peptide is costly, while appropriate folding to the biologically active form is complicated by the presence of 8 cysteine residues within the 25 amino acids of the mature peptide forming 4 disulfide bridges (Figure 4).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGenetic disruption of Tmprss6 enhanced BMP/SMAD signaling, increased endogenous hepcidin expression and prevented iron overload in Hfe−/− and Hbbth3/+ mice.
“Likewise, genetic disruption of Tmprss6 enhanced BMP/SMAD signaling, increased endogenous hepcidin expression and prevented iron overload in Hfe−∕− (Finberg et al., 2011) and Hbbth3∕+ mice (Nai et al., 2012).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningCorrection of hepcidin excess in IRIDA would improve responsiveness to iron therapy and provide an etiologic cure.
“Here, correction of hepcidin excess would not only improve responsiveness to iron therapy, but also provide an etiologic cure.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
May combine two claims.
PremisecitationCastleman disease is caused by tumors overproducing IL-6, which promotes an inflammatory state and excessive hepcidin expression.
“Castleman disease is caused by tumors overproducing IL-6, which in turn promotes an inflammatory state and excessive hepcidin expression (Arlet et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Arlet et al., 2010 source
Not checked in the free run.
May combine two claims.
PremisecitationTocilizumab administration lowered hepcidin and improved anemia in rheumatoid arthritis patients and in a monkey arthritis model.
“Tocilizumab administration also lowered hepcidin and improved anemia in rheumatoid arthritis patients (Isaacs et al., 2013; Song et al., 2013) and in a monkey arthritis model (Hashizume et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisereasoningHepcidin overexpression appears to be the sole driver of IRIDA, which is microcytic and hypochromic.
“It appears that hepcidin overexpression is the sole driver of IRIDA, which is microcytic and hypochromic.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTreatment of rheumatoid arthritis patients with antibodies against TNFα (golimumab or infliximab) produced similar reductions in hepcidin and improvements in anemia, possibly as an indirect result of concomitant suppression of IL-6.
“Similar results were obtained when rheumatoid arthritis patients were treated with antibodies against TNFα (golimumab or infliximab), possibly as an indirect result of concomitant suppression of IL-6 (Doyle et al., 2013; Song et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPR73 caused hypoferremia in these animals in spite of tissue iron overload, which restricted circulating iron from V. vulnificus and thereby inhibited its growth.
“PR73 caused hypoferremia to these animals in spite of tissue iron overload, which restricted circulating iron from V. vulnificus and thereby inhibited its growth.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
InterpretationreasoningPharmacological reduction of hepcidin could offer another option for anemia management in Castleman disease.
“Pharmacological reduction of hepcidin could offer another option for anemia management.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
May combine two claims.
PremisecitationThe mini-hepcidin pro-drug M009 is metabolized to active mini-hepcidin M004 and improved erythropoiesis in Hbbth3/+ mice and in a mouse model of polycythemia vera.
“The mini-hepcidin pro-drug M009 is metabolized to active mini-hepcidin M004 and was recently shown to improve erythropoiesis in Hbbth3∕+ mice and in a mouse model of polycythemia vera (Casu et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Casu et al., 2016 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningLocalized targeting of hepcidin excess in the heart or brain may be important in the context of cardiovascular or neurodegenerative disorders.
“Considering that the hepcidin/ferroportin axis is crucial for cardiac function (Lakhal-Littleton et al., 2015) and that inflammatory induction of hepcidin causes iron accumulation in nervous system cells (Urrutia et al., 2013), localized targeting of hepcidin excess in the heart or brain may be important in the context of cardiovascular or neurodegenerative disorders.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Lakhal-Littleton et al., 2015 source
Not checked in the free run.
- cites Urrutia et al., 2013 source
Not checked in the free run.
- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
May combine two claims.
PremisecitationTestosterone inhibits hepcidin by enhancing negative epidermal growth factor receptor (EGFR) signaling and by competing positive BMP signaling via androgen receptor binding to SMAD proteins.
“Testosterone likewise inhibits hepcidin but operates by enhancing negative epidermal growth factor receptor (EGFR) signaling (Latour et al., 2014), and by competing positive BMP signaling via androgen receptor binding to SMAD proteins (Guo et al., 2013b).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Latour et al., 2014 source
Not checked in the free run.
- cites Guo et al., 2013b
Not checked in the free run.
May combine two claims.
Premisenone givenThe exact mechanisms of action of the identified hepcidin-inducing drugs are not well understood and their capacity to control hepcidin expression in vivo has not been examined.
“Their exact mechanisms of action are not well understood and their capacity to control hepcidin expression in vivo has not been examined.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningHigh hepcidin levels render IRIDA patients unresponsive to oral and partially responsive to intravenous iron therapy.
“High hepcidin levels render IRIDA patients unresponsive to oral and partially responsive to intravenous iron therapy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTreatment with an engineered mini-hepcidin mimetic (PR65) prevented iron overload in iron-depleted hepcidin-deficient Hamp−/− mice, but was less efficient in correcting iron traffic when these mice were already iron overloaded.
“Treatment with an engineered mini-hepcidin mimetic (PR65) prevented iron overload in iron-depleted hepcidin-deficient Hamp−∕− mice, but was less efficient in correcting iron traffic when these mice were already iron overloaded (Ramos et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ramos et al., 2012 source
Not checked in the free run.
May combine two claims.
PremisereasoningThe anemia in Castleman disease is refractory to oral iron therapy and can be reversed by resection of the tumor, which eliminates the hepcidin inducer (IL-6).
“The ensuing anemia is refractory to oral iron therapy and can be reversed by resection of the tumor, which eliminates the hepcidin inducer (IL-6).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningGlycol-split and highly sulfated heparins are good candidates for pharmacological targeting of hepcidin in clinical settings and are amenable to further development.
“Glycol-split and highly sulfated heparins are good candidates for pharmacological targeting of hepcidin in clinical settings and are amenable to further development.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
May combine two claims.
PremisecitationSuppression of hepcidin by LDN-193189 was associated with anti-atherogenic responses in apoE−/− mice, which were reversed by exogenous hepcidin.
“Interestingly, suppression of hepcidin by LDN-193189 was associated with anti-atherogenic responses in apoE−∕− mice, which were reversed by exogenous hepcidin (Saeed et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Saeed et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTwo clinical trials using sHJV.Fc (FMX-8) for treatment of patients with renal disease were not completed due to inability to recruit patients meeting eligibility criteria.
“Two clinical trials sponsored by Ferrumax Pharmaceuticals Inc aimed to use sHJV.Fc (FMX-8) for the treatment of patients with renal disease, but were not completed due to inability to recruit patients meeting eligibility criteria (ClinicalTrials.gov Identifiers: NCT01873534 and NCT02228655).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites ClinicalTrials.gov Identifiers: NCT01873534 and NCT02228655
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFursultiamine is a thiol-reactive thiamine derivative.
“A chemical screen for small molecule hepcidin antagonists identified fursultiamine, a thiol-reactive thiamine derivative that binds to ferroportin on C326 and thereby precludes the binding of hepcidin (Fung et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fung et al., 2013 source
Not checked in the free run.
May combine two claims.
InterpretationcitationTargeting the BMP/SMAD pathway has the potential to efficiently antagonize hepcidin induction under inflammatory conditions because the IL-6/STAT3 and BMP/SMAD signaling pathways are tightly connected.
“As the IL-6/STAT3 and BMP/SMAD signaling pathways are tightly connected (Wang and Babitt, 2016), targeting the latter has the potential to efficiently antagonize hepcidin induction under inflammatory conditions.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang and Babitt, 2016
Not checked in the free run.
May combine two claims.
PremisecitationAnemia in elderly persons with chronic inflammatory conditions and in CKD patients is often associated with vitamin D deficiency.
“Anemia in elderly persons with chronic inflammatory conditions (Perlstein et al., 2011) and in CKD patients (Zughaier et al., 2014), is often associated with vitamin D deficiency.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationHeparin inhibits hepcidin expression in cells and mice by sequestering BMPs, and patients treated with heparin for prevention of deep vein thrombosis had reduced serum hepcidin levels.
“Thus, heparin was shown to inhibit hepcidin expression in cells and mice by sequestering BMPs, while patients treated with heparin for prevention of deep vein thrombosis had reduced serum hepcidin levels (Poli et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Poli et al., 2011 source
Not checked in the free run.
May combine two claims.
PremisecitationDorsomorphin, an inhibitor of type I BMP receptors ALK2, ALK3, and ALK6, prevented hepcidin induction by IL-6 in cells and induced hyperferremia due to hepcidin suppression in mice.
“Thus, dorsomorphin, an inhibitor of the type I BMP receptors ALK2, ALK3, and ALK6, prevented hepcidin induction by IL-6 in cells and induced hyperferremia due to hepcidin suppression in mice (Yu et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yu et al., 2008
Not checked in the free run.
May combine two claims.
PremisecitationAdministration of sHJV.Fc reduced hepcidin and ameliorated anemia in a rat model of ACD.
“Administration of sHJV.Fc, a fusion of sHJV with the Fc fragment of immunoglobulin G, reduced hepcidin and ameliorated anemia in a rat model of ACD (Theurl et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Theurl et al., 2011 source
Not checked in the free run.
May combine two claims.
PremisecitationGlycol-split non-anticoagulant heparins are equally effective as hepcidin inhibitors and improved anemia in mouse models of inflammation.
“Because the anticoagulant properties of heparin are undesired for interventions to reduce hepcidin excess, glycol-split non-anticoagulant heparins were tested and found to be equally effective as hepcidin inhibitors; moreover they improved anemia in mouse models of inflammation (Poli et al., 2014a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Poli et al., 2014a
Not checked in the free run.
May combine two claims.
PremisecitationLDN-193189 antagonized inflammatory induction of hepcidin in cells and mitigated anemia in rat and mouse models of ACD, and in a rat model of kidney disease.
“Furthermore, the dorsomorphin derivative LDN-193189, antagonized inflammatory induction of hepcidin in cells and mitigated anemia in rat (Theurl et al., 2011) and mouse (Steinbicker et al., 2011; Mayeur et al., 2015) models of ACD, and in a rat model of kidney disease (Sun et al., 2013).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenMisregulation of hepcidin is associated with a broad spectrum of disorders ranging from iron overload states to anemias with iron-restricted erythropoiesis.
“Misregulation of hepcidin is associated with a broad spectrum of disorders ranging from iron overload states to anemias with iron-restricted erythropoiesis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenHepcidin is a master hormonal regulator of systemic iron homeostasis.
“Hepcidin is a master hormonal regulator of systemic iron homeostasis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenA major challenge for using hepcidin therapeutics is to maintain physiological concentrations of circulating hepcidin, and thereby avoid a shift from hepcidin deficiency to excess and vice versa.
“A major challenge for using hepcidin therapeutics is to maintain physiological concentrations of circulating hepcidin, and thereby avoid a shift from hepcidin deficiency to excess and vice versa.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenUnder physiological conditions, hepcidin expression remains within a relatively narrow window.
“Under physiological conditions, its expression remains within a relatively narrow window.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenPromising candidates are currently being further evaluated in randomized controlled trials.
“Promising candidates are currently being further evaluated in randomized controlled trials.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenThese drugs act at different levels through the hepcidin/ferroportin axis.
“These drugs act at different levels through the hepcidin/ferroportin axis.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Findings from mouse models of iron overload and hepcidin manipulation are predictive of therapeutic effects in humans.
“The therapeutic potential of restoring hepcidin levels in iron overload states is highlighted by genetic studies in mice.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Fpn1 is the only known cellular iron exporter and a target of hepcidin, which promotes Fpn1 internalization and the inhibition of cellular iron egress.
“Fpn1 is the only known cellular iron exporter and a target of hepcidin, which promotes Fpn1 internalization and the inhibition of cellular iron egress (36, 37).”
From Dopamine Is a Siderophore-Like Iron Chelator That Promotes <i>Salmonella enterica</i> Serovar Typhimurium Virulence in Mice (2019) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Anticalin drug identifier differs between text and Table 3
MinorThe text identifies Pieris Pharmaceuticals' PEGylated anticalin as PRS-080, but Table 3 lists the same type of drug from the same company as PRS-808.
“Pieris Pharmaceuticals Inc generated PRS-080, a PEGylated anticalin protein that specifically binds to hepcidin and inhibits its activity.”
“| PRS-808 (PEGylated anticalin) | Hepcidin | Pieris Pharmaceuticals Inc (www.pieris.com) |”
Cites
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
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“HJV is a BMP co-receptor that enhances iron signaling to hepcidin (Babitt et al., 2006).”
BackgroundIron homeostasis in host defence and inflammation
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“The ones that have been validated in preclinical or clinical settings are summarized in Table 2 (inducers/mimetics) and Table 3 (antagonists).”
BackgroundDeletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia
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A hepcidin-binding peptide ameliorates anemia of chronic kidney disease in a mouse model
Tsuboi, S., Sato, M., Suzuki, T., Οhyama, C., & Hatakeyama, S. (2025) · Blood Red Cells & Iron · doi:10.1016/j.brci.2025.100033 · Cited by 1 · see citing works
Huang, T., Xiao, X., Ma, J., Fang, J., & Bao, Y. (2026) · European journal of medical research · doi:10.1186/s40001-026-03871-6 · Cited by 1 · see citing works
Metabolism of Iron Ions and Its Role in Regulating the Functions of Immune System Cells
Orlova, E. G., & Gorbunova, O. L. (2026) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093026020018 · Cited by 1 · see citing works
- Authors
- Sebastiani, G., Wilkinson, N., & Pantopoulos, K.
- Affiliations
- Royal Victoria Hospital (CA)
- Jewish General Hospital (CA)
- Corresponding author
- Pantopoulos, Kostas
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2016-06-21
- Volume
- 7
- Pages
- 160-160
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC4914558
- OpenAlex
- W2470713331
- Semantic Scholar
- f5869774ab853ed0520093c5bda3ba710dbf3962
- Cited by
- 127
- References
- 100
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 6 · 2023: 9 · 2022: 14 · 2021: 22 · 2020: 11 · 2019: 15 · 2018: 18 · 2017: 11 · 2016: 3
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-86514)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hepcidin, ferroportin, iron homeostasis, hereditary hemochromatosis, iron overload, iron-refractory iron deficiency anemia, anemia of chronic disease, thalassemia, dyserythropoiesis, myelodysplastic syndrome, chronic liver disease, iron absorption, erythropoiesis, iron regulatory hormone
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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