Ferroptosis and Iron Metabolism in Neurodegenerative Disorders

Iron is indispensable for neuronal function, yet its mismanagement can provoke oxidative stress and cell death pathways. Ferroptosis, an iron-dependent form of regulated cell death, arises from unchecked lipid peroxidation when antioxidant defences such as glutathione peroxidase 4 (GPX4) are compromised. In neurodegenerative disorders—including Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis and Huntington’s disease—regional iron accumulation, mitochondrial dysfunction and neuroinflammation intersect to trigger ferroptotic cascades. Excess labile iron catalyses Fenton chemistry, generating reactive oxygen species that peroxidise polyunsaturated fatty acids in membranes. Failure to detoxify lipid hydroperoxides, whether through depletion of glutathione or loss of GPX4 activity, culminates in membrane rupture and neuronal demise. Crosstalk between glial cells and neurons further amplifies ferroptotic signals via cytokine-driven iron uptake and disrupted redox homeostasis. Targeting iron metabolism and bolstering endogenous antioxidant pathways have emerged as promising therapeutic avenues to halt or slow neurodegeneration.

Research from Nature Portfolio

In a pivotal clinical study of early Parkinson’s disease, oral deferiprone administration over six months lowered iron levels in the dentate and caudate nuclei and was well tolerated, laying the groundwork for larger trials of central nervous system iron chelation. Separately, mechanistic work has delineated the role of the cytoprotective protein DJ-1 in guarding against ferroptosis by sustaining the transsulfuration pathway and glutathione synthesis. Loss of DJ-1 function disrupts homocysteine production, diminishes antioxidant capacity and heightens sensitivity to ferroptotic stimuli, revealing a conserved axis that may be exploitable across neurodegenerative contexts.

Ferroptosis and Iron Metabolism in Neurodegenerative Disorders publication trend

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

Technical terms

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation.

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

Glutathione peroxidase 4 (GPX4): An essential enzyme that reduces lipid hydroperoxides to non-toxic alcohols.

Iron chelation: The process of binding excess iron to prevent its participation in harmful redox reactions.

References

1. The biphasic role of Hspb1 on ferroptotic cell death in Parkinson's disease. Theranostics (2024).
2. Modeling ferroptosis in human dopaminergic neurons: Pitfalls and opportunities for neurodegeneration research. Redox Biology (2024).
3. Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons. Journal of Clinical Investigation (2023).
4. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Scientific Reports (2017).
5. The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Frontiers in Pharmacology (2014).
6. DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nature Communications (2020).
7. Ferroptosis in Parkinson’s disease: glia–neuron crosstalk. Trends in Molecular Medicine (2022).