Ferroptosis Mechanisms in Cancer Radiotherapy

Ferroptosis is an iron-dependent form of regulated cell death driven by peroxidative damage to membrane phospholipids. In the context of radiotherapy, ionising radiation generates reactive oxygen species (ROS) that can overwhelm cellular antioxidant defences, notably glutathione and glutathione peroxidase 4 (GPX4). When antioxidant buffering is compromised—through inhibition of cystine uptake, depletion of glutathione or targeted degradation of GPX4—lipid peroxidation proceeds unchecked, triggering ferroptotic cell death. This pathway can be harnessed to overcome radioresistance, particularly in tumours that rely on robust redox homeostasis. Recent work has unveiled strategies to modulate ferroptosis during radiotherapy, including the use of nanocarriers to deliver iron chelators and ROS scavengers to healthy tissue, and the deployment of radiosensitising nanoparticles or genetic interventions to enhance lipid peroxidation selectively in cancer cells. The interplay between tumour microenvironmental factors—such as hypoxia and acidosis—and regulators of iron metabolism further shapes ferroptotic sensitivity, opening avenues for combination therapies that integrate radiotherapy with ferroptosis inducers or immunomodulatory agents.

Research from Nature Portfolio

One recent study described an orally administered emulsion stabilised by halloysite clay nanotubes on which a ceria nanozyme was grown and into whose lumen deferiprone was loaded. In models of radiation-induced colitis, this dual-action system scavenged ROS and chelated labile iron, thereby inhibiting lipid peroxidation and rescuing cells from ferroptosis in the inflamed intestinal microenvironment. The formulation provided significant protection in both cell culture and animal studies, suggesting a prospective strategy to shield normal tissue during pelvic radiotherapy without compromising tumour control.

Ferroptosis Mechanisms in Cancer Radiotherapy publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in cancer radiotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: Iron-dependent regulated cell death driven by lipid peroxidation of cellular membranes.

Radiotherapy: Treatment of cancer using ionising radiation to induce DNA damage and cell death.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in membranes, leading to loss of membrane integrity.

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

Glutathione peroxidase 4 (GPX4): Enzyme that reduces lipid hydroperoxides to non-toxic lipid alcohols, preventing ferroptosis.

SLC7A11: Membrane cystine/glutamate antiporter that imports cystine for glutathione synthesis and protection against ferroptosis.

Lysosomal membrane permeabilisation (LMP): Disruption of lysosomal membrane integrity, releasing hydrolases and promoting lipid peroxidation and cell death.

References

1. A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy. Nature Communications (2023).
2. Radiotherapy-activated NBTXR3 nanoparticles promote ferroptosis through induction of lysosomal membrane permeabilization. Journal of Experimental & Clinical Cancer Research (2024).
3. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death & Differentiation (2022).
4. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein & Cell (2021).