Abstract
Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis — the lethal outcome of iron-dependent (phospho)lipid peroxidation — stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.
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Acknowledgements
M.C. received funding from the Deutsche Forschungsgemeinschaft (DFG) (CO 291/7-1), the Priority Program SPP 2306 (CO 291/9-1, #461385412; CO 291/10-1, #461507177; CO 291/9-2, CO 291/10-2, CO 291/14-1) and the CRC TRR 353 (CO 291/11-1, #471011418), the German Federal Ministry of Education and Research (BMBF) FERROPATH (01EJ2205B) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. GA 884754).
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M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH and holds patents for some of the compounds described herein. A.W. declares no competing interests.
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Glossary
- Apoptosis
-
A caspase-dependent programmed cell death pathway controlled by the BCL-2 protein family and mitochondrial factors that maintains tissue homeostasis and eliminates damaged or unwanted cells in a controlled manner by orchestrating distinct cellular changes, including chromatin condensation, DNA fragmentation and membrane blebbing.
- Drug-tolerant persister cells
-
A subpopulation of cancer cells that enter a reversible, slow-cycling state, allowing them to survive targeted therapies or chemotherapy without acquiring permanent genetic resistance.
- Epithelial–mesenchymal transition
-
A biological process crucial for embryonic development, wound healing and tissue regeneration that is often hijacked by cancer cells, in which epithelial cells lose their polarity and adhesion properties, transforming into a more migratory and invasive mesenchymal state.
- Fenton-type chemistry
-
A process, named after British chemist H. J. H. Fenton, describing reactions that produce highly reactive oxygen species (ROS), especially hydroxyl radicals (·OH), by iron ions (Fe²âº) reacting with hydrogen peroxide (Hâ‚‚Oâ‚‚).
- Ferritinophagy
-
A process in which the protein nuclear receptor coactivator 4 (NCOA4) transports ferritin, the protein that stores iron, to autophagosomes for recycling leading to the release of iron into the cytoplasm.
- Lipidomic surveys
-
Studies of the lipidome, a complete set of lipids within a cell, tissue or organism, including their structures, functions and interactions, that help understand metabolic disorders, neurodegenerative diseases and cancer.
- Necroinflammation
-
The inflammatory responses that emerge when cells die via inflammatory cell death modalities such as necroptosis or pyroptosis which trigger the uncontrolled release of cellular contents (so-called ‘danger signals’) into surrounding tissues leading to activation of immune cells that drive inflammation.
- Necroptosis
-
A regulated form of necrotic cell death triggered by cellular stress or infection that leads to plasma membrane rupture and the release of damage-associated molecular patterns (DAMPs), triggering inflammation.
- Pyroptosis
-
A form of programmed cell death triggered by infection or cellular stress that is, unlike apoptosis, characterized by inflammation as it involves the activation of inflammasomes and caspase-1, leading to cell swelling, membrane rupture and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18.
- Radical-trapping antioxidant
-
(RTA). A molecule that neutralizes free radicals, typically with lipid peroxyl radicals (LOO·), by donating an electron or a hydrogen atom, thereby preventing oxidative damage to biomolecules including the lipid peroxidation chain reaction in lipid bilayers, thereby preventing ferroptosis.
- Reactive oxygen species
-
(ROS). Highly reactive oxygen-containing molecules such as superoxide (Oâ‚‚â»), hydrogen peroxide (Hâ‚‚Oâ‚‚), hydroxyl radicals (·OH) and peroxyl radicals (·OOH) that are by-products of cellular metabolism that at low levels function in cell signalling and immune defence, but when produced in excess result in oxidative stress, damaging cellular structures such as DNA, proteins and lipids.
- The Lands cycle
-
A biochemical mechanism that modifies cell membrane phospholipids by exchanging fatty acids, particularly at the sn-2 position that helps maintain membrane fluidity, facilitates cell signalling and protects against oxidative damage.
- The Warburg effect
-
A metabolic phenomenon driven by oncogenes, hypoxia and metabolic reprogramming in which cancer cells preferentially utilize glycolysis for energy production, even in the presence of oxygen, rather than relying on oxidative phosphorylation, which contributes to tumour growth and survival.
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Wahida, A., Conrad, M. Decoding ferroptosis for cancer therapy. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00864-1
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DOI: https://doi.org/10.1038/s41568-025-00864-1
