Iron Metabolism and Transport Mechanisms in Eukaryotic Systems

Iron is a vital micronutrient required for oxygen transport, DNA synthesis and redox reactions. In eukaryotes, systemic and cellular iron homeostasis is achieved through coordinated mechanisms of absorption, distribution, storage and excretion. Dietary non-haem iron is reduced at the apical surface of duodenal enterocytes by ferrireductases and taken up via the divalent metal transporter 1. Within cells, iron joins the labile iron pool before incorporation into haem or iron–sulphur clusters or storage in ferritin. Export across the basolateral membrane is mediated by the iron exporter ferroportin, coupled to oxidation by multicopper ferroxidases. In plasma, iron binds transferrin and is delivered to tissues through transferrin receptor–mediated endocytosis. Systemic regulation is governed by the peptide hormone hepcidin, which controls ferroportin abundance, while intracellular regulation depends on iron regulatory proteins that sense cellular iron and adjust expression of metabolic genes. Dysregulation underlies iron deficiency anaemia and iron-overload disorders, and influences processes from erythropoiesis to tumour growth.

Research from Nature Portfolio

Recent studies have revealed epigenetic regulation as a critical modifier of iron homeostasis in disease. In one investigation, a histone methyltransferase was shown to repress expression of a key multicopper ferroxidase, lowering ferroxidase activity, elevating intracellular labile iron and promoting tumour proliferation. Pharmacological or genetic inhibition of this methyltransferase restored ferroxidase levels, depleted labile iron pools and impeded cancer cell growth, highlighting an epigenetic–iron axis in oncogenesis. In a separate study, dual knockout of two multicopper ferroxidases in mice led to iron accumulation in renal cortex and medulla, altered expression of iron importers and exporters, and increased urinary iron excretion and proteinuria. These findings demonstrate that multicopper ferroxidases protect renal architecture by facilitating iron export and preventing cellular iron toxicity.

Iron Metabolism and Transport Mechanisms in Eukaryotic Systems publication trend

The graph below shows the total number of articles in iron metabolism and transport mechanisms in eukaryotic systems across all publications each year (not limited to Nature Index journals).

Technical terms

Enterocyte: Intestinal epithelial cell responsible for nutrient and iron absorption.

Ferrireductase: Enzyme that reduces ferric (Fe³⁺) to ferrous (Fe²⁺) iron for cellular uptake.

Divalent metal transporter 1 (DMT1): Membrane protein mediating H⁺-coupled uptake of Fe²⁺ into cells.

Ferroportin: Sole known iron exporter that transports Fe²⁺ across the cell membrane into plasma.

Multicopper ferroxidase: Enzyme that oxidises Fe²⁺ to Fe³⁺ to facilitate iron export and transferrin loading.

Transferrin: Plasma protein that binds Fe³⁺ for safe transport to tissues.

Ferritin: Intracellular storage protein that sequesters excess iron in a safe, bioavailable form.

Hepcidin: Liver-derived peptide hormone that limits iron export by inducing ferroportin degradation.

Labile iron pool: Cytosolic pool of weakly bound iron that is readily available for metabolic processes.

References

1. Iron transport proteins: Gateways of cellular and systemic iron homeostasis. Journal of Biological Chemistry (2017).
2. G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin. Nature Communications (2017).
3. Hephaestin and ceruloplasmin facilitate iron metabolism in the mouse kidney. Scientific Reports (2016).
4. Vitamin C-Dependent Uptake of Non-Heme Iron by Enterocytes, Its Impact on Erythropoiesis and Redox Capacity of Human Erythrocytes. Antioxidants (2024).
5. A whole-body mechanistic physiologically-based pharmacokinetic modeling of intravenous iron. Drug Delivery and Translational Research (2024).
6. Relationship of Iron Intake, Ferritin, and Hepcidin with the Transverse Relaxation Rate of Water Protons in the Pancreas. Nutrients (2023).