Iron Homeostasis Regulation in Anemia Mechanisms

Iron is essential for oxygen transport, DNA synthesis and myriad enzymatic processes. Systemic iron homeostasis is orchestrated by the hepatic peptide hepcidin, which binds to the cellular iron exporter ferroportin to reduce dietary iron absorption and iron release from macrophages. Hepcidin expression is induced by bone morphogenetic protein (BMP) signalling through the co-receptor hemojuvelin and is suppressed by the liver serine protease TMPRSS6 (matriptase-2). At the cellular level, transferrin receptors mediate iron uptake and ferritin stores excess iron, while erythropoietic signals adjust hepcidin to match red-cell production. Disruption of any component of this network leads to anaemias ranging from common iron deficiency to genetic disorders such as iron-refractory iron deficiency anaemia (IRIDA). Recent work has revealed non-proteolytic roles for TMPRSS6 in setting basal hepcidin, alternative cleavage targets for matriptase-2 beyond hemojuvelin, and the impact of genetic heterogeneity on individual susceptibility. Understanding these mechanisms is vital to address the global burden of anaemia, which affects over two billion people. Emerging diagnostic and therapeutic strategies include hepcidin antagonists, BMP pathway modulators and TMPRSS6-targeted approaches, offering prospects for personalised management of iron-related disorders in diverse clinical settings.

Research from Nature Portfolio

Functional studies in liver cancer cell models have characterised common and disease-associated TMPRSS6 variants, revealing that IRIDA-linked mutations (V795I, G603R) markedly reduce proteolytic activity and hepcidin suppression, whereas widespread polymorphisms (V736A) retain function. Differential expression of TMPRSS6 isoforms across hepatocellular carcinoma lines highlighted structural domains critical for substrate specificity and provided a refined in vitro framework for investigating matriptase-2’s role in systemic iron regulation.

Iron Homeostasis Regulation in Anemia Mechanisms publication trend

The graph below shows the total number of articles in iron homeostasis regulation in anemia mechanisms 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 ferroportin and triggering its degradation.

Ferroportin: The sole known cellular iron exporter, present on enterocytes, macrophages and hepatocytes, whose activity is regulated by hepcidin.

TMPRSS6 (matriptase-2): A transmembrane serine protease expressed in hepatocytes that downregulates hepcidin, chiefly by modulating BMP-SMAD signalling.

Hemojuvelin (HJV): A glycosylphosphatidylinositol-anchored BMP co-receptor that potentiates BMP-mediated induction of hepcidin in the liver.

Bone morphogenetic protein (BMP) signalling: A pathway involving BMP6, type I/II receptors and SMAD transcription factors that drives hepcidin transcription in response to iron.

Iron-refractory iron deficiency anaemia (IRIDA): A rare autosomal recessive disorder caused by TMPRSS6 mutations, characterised by high hepcidin, poor oral iron response and microcytic anaemia.

References

1. Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism. Journal of Biological Chemistry (2023).
2. The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia. Orphanet Journal of Rare Diseases (2023).
3. Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. Journal of Biological Chemistry (2017).
4. The role of TMPRSS6/matriptase-2 in iron regulation and anemia. Frontiers in Pharmacology (2014).
5. The Role of Hepatocyte Hemojuvelin in the Regulation of Bone Morphogenic Protein-6 and Hepcidin Expression in Vivo *. Journal of Biological Chemistry (2010).
6. Crosstalk between Iron Metabolism and Erythropoiesis. Advances in Hematology (2010).
7. Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines. Scientific Reports (2018).