Iron Homeostasis and Oxidative Stress in Cancer Biology

Iron is indispensable for fundamental cellular processes, including oxygen transport, DNA synthesis and energy metabolism. Homeostatic mechanisms regulate iron uptake, storage and export through coordinated action of the transferrin receptor, divalent metal transporter 1, ferritin and the hepcidin–ferroportin axis, with additional fine-tuning by iron regulatory proteins. In cancer, these pathways are often rewired so that cells accrue labile iron pools, which catalyse formation of reactive oxygen species via Fenton chemistry. Elevated oxidative stress drives genomic instability, lipid peroxidation and redox-sensitive signalling, fostering tumour initiation, progression and metastasis. Paradoxically, iron-dependent lipid peroxidation can also trigger ferroptosis, a non-apoptotic form of cell death that offers therapeutic potential. Moreover, mitochondrial iron transporters, such as mitoferrins, govern intramitochondrial iron delivery and influence the metabolic shift towards aerobic glycolysis. Collectively, the interplay between iron homeostasis and oxidative stress shapes tumour biology at multiple levels, highlighting opportunities to exploit iron modulation for diagnostic imaging, targeted chelation and induction of ferroptotic cell death.

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Iron Homeostasis and Oxidative Stress in Cancer Biology publication trend

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Technical terms

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including hydroxyl radicals, that can damage DNA, proteins and lipids.

Fenton reaction: Iron-catalysed reaction between hydrogen peroxide and ferrous iron yielding hydroxyl radicals and ferric iron.

Ferroptosis: Iron-dependent form of regulated cell death characterised by lipid peroxidation and loss of membrane integrity.

Transferrin receptor (TfR1): Cell-surface glycoprotein that mediates uptake of iron-loaded transferrin via endocytosis.

Divalent metal transporter 1 (DMT1): Endosomal transporter responsible for releasing iron from transferrin into the cytosol.

Hepcidin–ferroportin axis: Systemic regulator of iron export in which hepatic hepcidin binds ferroportin to trigger its internalisation and degradation.

Iron regulatory proteins (IRP1/2): Cytosolic sensors that bind iron-responsive elements in mRNAs to post-transcriptionally regulate iron metabolism genes.

Mitoferrin: Mitochondrial inner membrane transporter that imports ferrous iron for haem and Fe–S cluster biogenesis.

Ferritin: Intracellular protein complex that stores iron in a non-reactive form and releases it in a controlled manner.

References

1. Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer. PLOS ONE (2012).
2. Human NRAMP2/DMT1, Which Mediates Iron Transport across Endosomal Membranes, Is Localized to Late Endosomes and Lysosomes in HEp-2 Cells*. Journal of Biological Chemistry (2000).
3. Iron and thiols as two major players in carcinogenesis: friends or foes?. Frontiers in Pharmacology (2014).
4. Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect through reactive oxygen species in osteosarcoma. Cancer Cell International (2020).