Ferroptosis Mechanisms in Hematological Malignancies

Ferroptosis is a regulated form of cell death driven by iron-dependent accumulation of lipid hydroperoxides and reactive oxygen species. In hematological malignancies—including acute myeloid leukaemia (AML), lymphoma and multiple myeloma—dysregulation of iron metabolism, antioxidant defences and lipid homeostasis creates a vulnerability to ferroptotic triggers. Key protective systems such as the cystine/glutamate antiporter (system Xc–) and the lipid hydroperoxidase glutathione peroxidase 4 (GPX4) counteract peroxidation of polyunsaturated fatty acid-containing membranes. Transcriptional programmes centred on NRF2 and other stress sensors maintain redox balance, and perturbation of these pathways can tip cells towards lethal lipid oxidation. Recent mechanistic studies reveal that agents which remodel cellular lipids or overload intracellular iron pools can sensitise malignant haematopoietic cells to ferroptosis, overcoming apoptotic resistance and enhancing response to standard therapies. Preclinical models demonstrate that combining ferroptosis inducers with chemotherapeutics or targeted inhibitors may improve disease control. Efforts to translate these insights are under way, but challenges remain in predicting sensitivity, limiting off-target toxicity and identifying robust biomarkers of ferroptotic engagement.

Research from Nature Portfolio

Recent studies in AML have uncovered a novel mechanism by which the telomerase inhibitor imetelstat induces ferroptosis to enhance antileukaemic efficacy. Integrated genomic, transcriptomic and lipidomic profiling in patient-derived xenografts identified regulators of polyunsaturated fatty acid-containing phospholipid formation as critical mediators of imetelstat activity. The drug promotes lipid peroxidation and oxidative stress, and genetic or pharmacological blockade of ferroptotic pathways markedly reduces its cytotoxic effect. Building on these findings, co-administration of oxidative stress-inducing chemotherapy has been optimised to potentiate imetelstat-triggered ferroptosis, offering a precision approach to AML treatment that exploits tumour-specific redox vulnerabilities.

Ferroptosis Mechanisms in Hematological Malignancies publication trend

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

Technical terms

Ferroptosis: Iron-dependent regulated cell death characterised by lethal accumulation of lipid hydroperoxides.

Lipid peroxidation: Oxidative degradation of polyunsaturated membrane lipids leading to loss of membrane integrity.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides and prevents ferroptotic cell death.

Ferritinophagy: Autophagic process mediating degradation of ferritin to release intracellular iron.

Reactive oxygen species (ROS): Chemically reactive oxygen-containing molecules that can damage proteins, lipids and DNA.

References

1. Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia. Nature Cancer (2023).
2. Targeting NRF2 uncovered an intrinsic susceptibility of acute myeloid leukemia cells to ferroptosis. Experimental Hematology & Oncology (2023).
3. Mechanisms of ferroptosis and targeted therapeutic approaches in lymphoma. Cell Death & Disease (2023).
4. From Iron Chelation to Overload as a Therapeutic Strategy to Induce Ferroptosis in Leukemic Cells. Frontiers in Oncology (2020).
5. Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies. Frontiers in Oncology (2021).
6. Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy. Frontiers in Oncology (2022).