Hepcidin and iron regulation, 10 years later Original paper
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Dr. Umar
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Dr. Umar
Read MoreClinical Pharmacist and Clinical Pharmacy Master’s candidate focused on antibiotic stewardship, AI-driven pharmacy practice, and research that strengthens safe and effective medication use. Experience spans digital health research with Bloomsbury Health (London), pharmacovigilance in patient support programs, and behavioral approaches to mental health care. Published work includes studies on antibiotic use and awareness, AI applications in medicine, postpartum depression management, and patient safety reporting. Developer of an AI-based clinical decision support system designed to enhance antimicrobial stewardship and optimize therapeutic outcomes.
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Dr. Umar
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Researched by:
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Dr. Umar
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Dr. Umar
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Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Dr. Umar
What was reviewed?
This review summarizes the first decade of research on hepcidin and iron regulation, focusing on how the peptide hormone hepcidin and its receptor/iron exporter ferroportin coordinate systemic iron absorption, recycling, and tissue distribution in health and disease. Ganz explains how hepcidin binding triggers ferroportin internalization and degradation, reducing iron efflux from duodenal enterocytes, macrophages recycling senescent erythrocytes, and hepatocytes that store iron, thereby lowering plasma iron availability. The article also revisits the historical physiologic observations that predicted a circulating “iron hormone,” then integrates genetic, animal-model, and mechanistic evidence that established the hepcidin–ferroportin axis as the central control point of iron homeostasis, including its feedback regulation by iron status, erythropoietic demand, and inflammation.
Who was reviewed?
Rather than a single cohort, the review synthesizes evidence from multiple sources: human genetic disorders (including hereditary hemochromatosis from HFE, TfR2, HJV, or HAMP mutations; ferroportin disease; and iron-refractory iron deficiency anemia from TMPRSS6 mutations), translational studies in volunteers (e.g., hepcidin rises after oral iron or IL-6 exposure), and diverse animal and cellular models used to define causal pathways. The “populations” therefore include patients with iron overload or iron-restricted anemia phenotypes, as well as experimental mice with hepcidin or ferroportin perturbations and hepatocyte/macrophage systems used to test signaling mechanisms.
Most important findings
The core conclusion is that hepcidin is the master systemic iron hormone and ferroportin is both its receptor and the only known cellular iron exporter required for iron transfer to plasma. Hepcidin’s rapid regulation of ferroportin explains how the body modulates dietary iron absorption, macrophage iron release, and hepatic iron mobilization, and why plasma iron responds quickly to hepcidin changes because the transferrin iron pool turns over within hours. Hepcidin transcription is primarily regulated by iron through BMP/Smad signaling (with BMP6 reflecting hepatic iron stores and HJV acting as a BMP co-receptor), by erythropoietic activity via marrow-derived suppressive signals, and by inflammation, largely through IL-6/STAT3 activation of the hepcidin promoter—linking iron withholding to innate defense but also driving anemia of inflammation. Clinically, the review frames iron disorders as disorders of hepcidin deficiency (iron overload) or hepcidin excess/inappropriately high hepcidin (iron restriction), supporting hepcidin assays and emerging therapies (hepcidin agonists for overload; antagonists or production inhibitors for inflammatory iron restriction).
| Microbiome-relevant concept | Key association for a signatures database |
|---|---|
| Iron withholding as host defense | High hepcidin → low luminal/systemic iron may select for iron-scavenging pathobionts |
| Inflammation-driven hypoferremia | IL-6–STAT3 hepcidin induction links inflammatory states to altered iron availability |
| Iron overload phenotypes | Low hepcidin/hepcidin resistance → increased circulating/tissue iron that can favor siderophore-producing microbes |
| Iron-restricted erythropoiesis | Mild hepcidin elevation can sustain iron restriction, potentially shifting microbial competition for iron |
Key implications
For clinicians, this framework makes iron disorders mechanistically legible: measure or infer hepcidin activity to distinguish true iron deficiency from iron restriction, understand why chronic inflammation causes functional iron deficiency, and anticipate when oral iron will fail (e.g., IRIDA or high-hepcidin states). For microbiome-facing practice, the review highlights iron as a contested ecological resource: host hepcidin responses reshape iron accessibility across compartments, plausibly altering microbial community structure and virulence strategies (e.g., siderophore systems) in ways that could be captured as iron-axis “signatures” alongside inflammatory biomarkers.
Citation
Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425-4433. doi:10.1182/blood-2011-01-258467