Iron Metabolism and Hepcidin Regulation in Health and Disease

Iron is indispensable for oxygen transport, cellular energy production and DNA synthesis, yet its excess or deficiency can have profound clinical consequences. Systemic iron homeostasis is governed by hepcidin, a hepatic peptide that binds to the iron exporter ferroportin, triggering its internalisation and degradation. In conditions of iron sufficiency or inflammation, hepcidin levels rise, restricting iron release from enterocytes, macrophages and hepatocytes, thereby reducing circulating iron. Conversely, suppressed hepcidin production under iron deficiency or increased erythropoietic demand allows ferroportin to remain on cell surfaces, promoting iron absorption and mobilisation. Dysregulation of this axis underlies disorders ranging from iron‐refractory iron deficiency anaemia and anaemia of chronic disease to hereditary haemochromatosis and the iron‐avid tumour microenvironment. Recent advances have shed light on upstream regulators of hepcidin, including inflammatory cytokines via the IL-6/STAT3 pathway, iron‐sensing BMP/SMAD signalling and hypoxia-inducible factors (HIFs). Therapeutic manipulation of these pathways offers new avenues for correcting iron imbalance in diverse clinical settings.

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Iron Metabolism and Hepcidin Regulation in Health and Disease publication trend

The graph below shows the total number of articles in iron metabolism and hepcidin regulation in health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: A liver-derived peptide hormone that controls systemic iron levels by binding to the iron exporter ferroportin and inducing its degradation.

Ferroportin: The sole known cellular iron exporter present on enterocytes, macrophages and hepatocytes, regulated by hepcidin to control iron release.

Hypoxia-Inducible Factor (HIF): A transcription factor stabilised under low oxygen or through pharmacological inhibition of prolyl hydroxylases, upregulating genes involved in iron absorption and erythropoiesis.

BMP/SMAD Pathway: A signalling cascade initiated by bone morphogenetic proteins that modulates hepcidin transcription in response to body iron levels.

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation, representing a potential vulnerability in iron-addicted cancer cells.

References

1. Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia. Advanced Science (2024).
2. A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia. Journal of Hematology & Oncology (2017).
3. Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy. Cancers (2020).