Ferroptosis Mechanisms in Gynecologic Oncology

Ferroptosis is a regulated form of cell death driven by iron-dependent peroxidation of membrane lipids. In gynaecologic malignancies—including ovarian, endometrial and cervical cancers—ferroptosis pathways intersect with oncogenic signalling, metabolic rewiring and the tumour immune microenvironment. Dysregulation of iron metabolism leads to accumulation of ferrous ions that catalyse lipid peroxidation in polyunsaturated fatty acids, overcoming antioxidant defences and triggering lethal membrane damage. Key regulators include the cystine–glutamate antiporter system (XC–), which imports cystine for glutathione synthesis, and glutathione peroxidase 4 (GPX4), which detoxifies lipid hydroperoxides. Aberrant expression of iron-handling proteins, mitochondrial redox enzymes and transcription factors such as NRF2 and HIF1α modulates ferroptotic sensitivity. In ovarian cancer, metabolic flexibility confers resistance through enhanced glutamine and lipid metabolism, while in endometrial and cervical tumours epigenetic modification of ferroptosis gene promoters and oncogene-driven antioxidant programmes support survival. Therapeutic strategies to induce ferroptosis via system XC– inhibition, GPX4 blockade or modulation of mitochondrial carriers show promise in preclinical models. Integration of ferroptosis induction with conventional chemotherapy and radiotherapy may overcome drug resistance and improve outcomes across gynaecologic oncology.

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Ferroptosis Mechanisms in Gynecologic Oncology publication trend

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Technical terms

Ferroptosis: Iron-dependent form of regulated cell death characterised by accumulation of lipid hydroperoxides in cellular membranes.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in membranes, leading to cell damage and death.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including peroxides and free radicals, that can induce cellular stress.

System XC– (SLC7A11): Cystine–glutamate antiporter that imports cystine for glutathione synthesis, essential for antioxidant defence against ferroptosis.

Glutathione peroxidase 4 (GPX4): Lipid hydroperoxide-reducing enzyme that prevents ferroptosis by converting lipid peroxides to non-toxic alcohols using glutathione.

References

1. Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells. Cell Death & Disease (2023).
2. Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells. Stem Cells International (2022).
3. GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1. BMC Cancer (2022).