Iron Metabolism and Ferroptosis in Cancer Stem Cells

In recent years, the interplay between iron metabolism and ferroptosis has become a central theme in cancer stem cell (CSC) research. CSCs are a distinct subpopulation within tumours endowed with self-renewal, differentiation potential and enhanced resistance to conventional therapies. These cells exhibit an iron-addicted phenotype characterised by up-regulated iron uptake, altered ferritin storage and diminished iron export, resulting in an expanded labile iron pool. This elevated iron availability fuels reactive oxygen species generation and lipid peroxidation, processes that both sustain CSC survival and simultaneously prime them for ferroptosis—a regulated form of cell death driven by iron-dependent accumulation of lipid hydroperoxides. Exploitation of this vulnerability through modulation of iron homeostasis pathways—such as ferritinophagy and inhibition of the cystine/glutamate antiporter—offers promising avenues for selectively targeting CSCs. Advances in this field hold significant global implications for overcoming therapeutic resistance, preventing tumour relapse and improving patient outcomes across diverse cancer types.

Research from Nature Portfolio

Recent studies have shown that CSC-regulated phenotypic plasticity influences metastatic colonisation and ferroptosis sensitivity. In a breast cancer model, secretion of the Wnt antagonist DKK1 by CSCs prompts differentiation of disseminated cells and up-regulates expression of the cystine/glutamate antiporter SLC7A11, conferring resistance to lipid peroxidation and ferroptosis. Combined inhibition of DKK1 and pharmacological induction of ferroptosis produces a synergistic reduction in metastatic burden. In cholangiocarcinoma, analysis of stem-like spheroids reveals dysregulated expression of iron regulatory proteins, including reduced ferritin and ferroportin levels alongside increased transferrin receptor abundance. Iron chelation diminishes sphere formation and stem-cell marker expression, highlighting the dependence of hepatic CSCs on iron availability and suggesting the therapeutic potential of targeted iron depletion.

Iron Metabolism and Ferroptosis in Cancer Stem Cells publication trend

The graph below shows the total number of articles in iron metabolism and ferroptosis in cancer stem cells across all publications each year (not limited to Nature Index journals).

Technical terms

Cancer stem cells (CSCs): A subpopulation of tumour cells with self-renewal capacity, multi-lineage differentiation potential and potent tumourigenic ability.

Ferroptosis: A regulated form of cell death dependent on iron-driven lipid peroxidation and accumulation of lipid hydroperoxides.

Labile iron pool: The cellular reservoir of redox-active iron that is readily available for metabolic reactions and redox cycling.

Ferritinophagy: Autophagic degradation of ferritin complexes that releases stored iron into the labile pool, modulating ferroptosis sensitivity.

Cystine/glutamate antiporter (system xC−): A plasma-membrane exchanger that imports cystine in exchange for glutamate, critical for glutathione synthesis and protection against ferroptosis.

References

1. mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions. Cell Death & Disease (2023).
2. Inhibition of lysosomal TRPML1 channel eliminates breast cancer stem cells by triggering ferroptosis. Cell Death Discovery (2024).
3. Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis. Nature Communications (2022).
4. Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells. Scientific Reports (2017).
5. Regulation of iron metabolism and ferroptosis in cancer stem cells. Frontiers in Oncology (2023).