Iron Homeostasis and Regulatory Mechanisms in Biological Systems

Iron is indispensable for oxygen transport, electron transfer and enzymatic catalysis, yet free iron catalyses harmful reactive oxygen species. To reconcile these demands, organisms regulate iron at systemic and cellular levels. Dietary iron absorption is governed by transporters such as DMT1 and ferroportin, the latter controlled by the liver‐derived hormone hepcidin. In circulation, transferrin binds ferric iron for delivery to tissues, where uptake occurs via transferrin receptor‐mediated endocytosis. Intracellularly, the IRP/IRE system adjusts synthesis of ferritin, transferrin receptor and other proteins in response to iron availability. Ferritinophagy—selective autophagic degradation of ferritin via NCOA4—releases stored iron when needed. Additional layers of control arise from signalling pathways, noncoding RNAs and rhythmic cues that fine‐tune IRP activity and ferritinophagy. Dysregulation contributes to anaemia, neurodegeneration, cancer progression and susceptibility to infection, underscoring the clinical importance of deciphering these networks and their therapeutic potential.

Research from Nature Portfolio

Recent studies have uncovered a long noncoding RNA, LncRIM, that links the Hippo–YAP signalling cascade to cellular iron uptake. LncRIM binds NF2 to inhibit its interaction with LATS1, thereby activating YAP and upregulating DMT1 and transferrin receptor 1. This positive feedback loop elevates intracellular iron and promotes tumour cell proliferation. Clinically, high LncRIM expression correlates with poorer survival, highlighting its promise as both biomarker and therapeutic target.

Iron Homeostasis and Regulatory Mechanisms in Biological Systems publication trend

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

Technical terms

Iron regulatory protein (IRP): RNA‐binding proteins (IRP1 and IRP2) that sense cellular iron and bind to iron‐responsive elements to regulate mRNA translation or stability.

Iron‐responsive element (IRE): Conserved stem‐loop structures in untranslated regions of mRNAs that mediate post‐transcriptional control by IRPs.

Hepcidin: Liver‐derived peptide hormone that induces internalisation of ferroportin, reducing cellular iron efflux.

Ferritinophagy: Autophagic process by which the cargo receptor NCOA4 delivers ferritin to lysosomes for iron release.

Ferroptosis: Form of iron‐dependent cell death characterised by lipid peroxidation and membrane damage.

Long noncoding RNA (lncRNA): Transcripts longer than 200 nucleotides that modulate gene expression through diverse mechanisms, including protein–RNA interactions.

References

1. LncRNA modulates Hippo-YAP signaling to reprogram iron metabolism. Nature Communications (2023).
2. FOXO1‐NCOA4 Axis Contributes to Cisplatin‐Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy. Advanced Science (2024).
3. Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms. Genome Biology (2024).
4. LACTB suppresses liver cancer progression through regulation of ferroptosis. Redox Biology (2024).
5. The Role of NCOA4-Mediated Ferritinophagy in Health and Disease. Pharmaceuticals (2018).
6. The physiological functions of iron regulatory proteins in iron homeostasis - an update. Frontiers in Pharmacology (2014).
7. Oxidative Stress and the Homeodynamics of Iron Metabolism. Biomolecules (2015).