Ferroptosis Mechanisms in Neurodegenerative Disorders

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and characterised by the accumulation of reactive oxygen species in polyunsaturated membrane lipids. In the central nervous system, dysregulation of iron homeostasis and antioxidant defences—most notably glutathione peroxidase 4 (GPX4) activity—renders neurons and glial cells vulnerable to ferroptotic injury. Emerging evidence implicates ferroptosis in the pathogenesis of a broad spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis. In these settings, iron dyshomeostasis exacerbates oxidative damage to neuronal membranes, while sublethal ferroptotic stress in microglia and astrocytes triggers inflammatory cascades that amplify neuronal loss. A deeper understanding of the molecular regulators of ferroptosis—such as vesicle‐trafficking components, lipid‐metabolising enzymes and redox transcription factors—has revealed interconnections between cell‐intrinsic death pathways and non‐cell‐autonomous mechanisms of neurotoxicity. The translational promise of this work is underscored by the discovery of small‐molecule inhibitors and natural compounds that restore redox balance, activate GPX4 or chelate excess iron, offering novel therapeutic avenues and prognostic biomarkers for neurodegenerative diseases.

Research from Nature Portfolio

Recent studies have illuminated the role of iron‐overloaded microglia in driving neuronal degeneration through ferroptosis. Work employing human induced pluripotent stem cell–derived microglia in tri‐culture systems demonstrated that excessive iron uptake induces a transcriptomic switch associated with Parkinson’s disease pathology and renders microglia susceptible to ferroptotic death. A genome‐wide screen identified the vesicle‐trafficking gene SEC24B as a critical regulator of this process, linking endoplasmic reticulum–Golgi transport to lipid‐peroxidation control. In a separate line of investigation, blood‐based biomarker panels reflecting lipid peroxidation, iron status and markers of neuronal integrity were shown to predict functional decline in ALS with high accuracy. Composite scores that integrate ferritin, hepcidin and indices of lipid‐derived aldehydes provided robust stratification of patients and highlight ferroptosis‐related pathways as both mechanistic drivers and clinical indicators of disease progression.

Ferroptosis Mechanisms in Neurodegenerative Disorders publication trend

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

Technical terms

Ferroptosis: A regulated cell death modality dependent on iron‐catalysed lipid peroxidation and distinct from apoptosis or necrosis.

Lipid peroxidation: Oxidative degradation of polyunsaturated lipids, leading to membrane damage and cell death.

Glutathione peroxidase 4 (GPX4): A specialised enzyme that detoxifies lipid hydroperoxides, preventing ferroptosis.

Microglia: Resident immune cells of the central nervous system that, when iron-overloaded, can undergo or propagate ferroptotic stress.

Iron dyshomeostasis: Disruption of iron uptake, storage or export processes, resulting in elevated labile iron and oxidative stress.

References

1. Microglial ferroptotic stress causes non-cell autonomous neuronal death. Molecular Neurodegeneration (2024).
2. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Cell Death & Differentiation (2023).
3. A novel ferroptosis inhibitor, Thonningianin A, improves Alzheimer's disease by activating GPX4. Theranostics (2024).
4. Ferroptosis Mechanisms Involved in Neurodegenerative Diseases. International Journal of Molecular Sciences (2020).
5. Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nature Neuroscience (2022).
6. A ferroptosis–based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis. Scientific Reports (2019).