Hepcidin Regulation and Iron Homeostasis Mechanisms

Systemic iron balance is orchestrated by hepcidin, a liver‐derived peptide hormone that controls dietary iron absorption and macrophage iron recycling by inducing internalisation and degradation of ferroportin, the sole known cellular iron exporter. Hepcidin synthesis is modulated by integrated signals reflecting body iron stores, erythropoietic demand and inflammatory status. Under high‐iron or inflammatory cues, the bone morphogenetic protein (BMP)/SMAD pathway is activated via hepatic co‐receptors such as hemojuvelin and transferrin receptor 2, driving hepcidin transcription. Conversely, increased erythropoiesis induces erythroferrone, which suppresses hepcidin through inhibition of BMP‐mediated signalling. Additional regulators include the serine protease TMPRSS6, which dampens hepcidin in iron‐deficient states, and pro‐inflammatory cytokines such as interleukin-6, which utilise STAT3 to boost hepcidin in infection. Epigenetic mechanisms further fine‐tune hepcidin output, linking histone modifications to acute and chronic alterations in iron metabolism. Dysregulation of this axis underlies disorders ranging from hereditary haemochromatosis and iron‐loading anaemias to iron‐restricted anaemia of inflammation. Improved understanding of these interconnected pathways offers prospects for targeted interventions to correct iron disorders and mitigate associated organ damage.

Research from Nature Portfolio

Recent studies have elucidated an epigenetic layer of hepcidin control, demonstrating that histone deacetylase 3 and its cofactor NCOR1 bind directly to the hepcidin promoter, enforcing dynamic changes in H3K9 acetylation and H3K4 methylation. Inhibition of histone deacetylase 3 preserves activating histone marks, counteracts hepcidin suppression in models of iron deficiency, erythropoietic drive and genetic iron overload, and restores hepcidin expression in thalassaemia and haemochromatosis settings. This revelation of chromatin‐based regulation underscores novel therapeutic avenues for modulating systemic iron availability.

Hepcidin Regulation and Iron Homeostasis Mechanisms publication trend

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

Technical terms

Hepcidin: A 25‐amino‐acid peptide hormone produced by hepatocytes that regulates systemic iron by inducing degradation of the iron exporter ferroportin.

Ferroportin: The only known iron exporter on enterocytes, macrophages and hepatocytes; its surface expression is blocked by hepcidin binding.

BMP‐SMAD pathway: A signalling cascade initiated by bone morphogenetic proteins binding to serine/threonine kinase receptors and co‐receptors (e.g. hemojuvelin), leading to SMAD phosphorylation and hepcidin gene activation.

Erythroferrone: A hormone secreted by erythroblasts that down‐regulates hepcidin during increased erythropoiesis.

Histone deacetylase 3 (HDAC3): An enzyme that removes acetyl groups from histone tails at the hepcidin locus, dynamically repressing or permitting transcription in response to iron and erythropoietic cues.

References

1. Managing the Dual Nature of Iron to Preserve Health. International Journal of Molecular Sciences (2023).
2. Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Frontiers in Pharmacology (2014).
3. Inherited Disorders of Iron Overload. Frontiers in Nutrition (2018).
4. Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. Nature Communications (2017).