Iron Metabolism in Neurodegenerative Disorders and Oxidative Stress

Iron is indispensable for central nervous system function, participating in mitochondrial respiration, myelin synthesis and neurotransmitter production. Its redox activity, however, underlies the Fenton reaction, driving the generation of reactive oxygen species and lipid peroxidation. In healthy brain tissue, iron uptake, storage and export are tightly orchestrated by transferrin, ferritin, ferroportin and regulatory peptides such as hepcidin. Neurodegenerative disorders—including Alzheimer’s disease, Parkinson’s disease and acute ischaemic injury—feature region-specific iron accumulation or deficiency, exacerbating oxidative damage, protein misfolding and mitochondrial dysfunction. Emerging evidence implicates iron-dependent cell death, ferroptosis, as a critical mechanism linking iron dyshomeostasis to neuronal loss. Advances in non-invasive imaging and molecular assays have illuminated spatiotemporal variations in iron environments, while mechanistic studies in cellular and animal models reveal how inflammatory signals and astrocyte-derived factors provoke local iron surges and ferroptotic cascades. Therapeutic strategies under investigation range from iron chelation to modulation of iron-handling proteins and antioxidant pathways. Together, these developments underscore the global importance of restoring iron balance to preserve neural integrity and combat oxidative stress in ageing and disease.

Research from Nature Portfolio

Recent studies have introduced an advanced magnetic resonance relaxivity approach that distinguishes ferritin, transferrin and ferrous ion environments in vivo, enabling non-invasive mapping of regional iron homeostasis in the human brain. This technique correlates with ex vivo iron quantification and gene expression, revealing age-related shifts in iron mobilization and offering enhanced tumour-normal tissue contrast without contrast agents. In foundational work, cerebrospinal fluid ferritin levels were shown to predict longitudinal cognitive decline in individuals ranging from healthy volunteers to those with mild cognitive impairment and Alzheimer’s, linking elevated brain iron with genetic risk factors and accelerated conversion to dementia. These insights provide quantifiable biomarkers for iron-linked neurodegeneration and open new avenues for early diagnosis and patient stratification.

Iron Metabolism in Neurodegenerative Disorders and Oxidative Stress publication trend

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

Technical terms

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

Hepcidin: A peptide hormone that controls cellular iron export by inducing ferroportin degradation.

Ferroportin: The sole known iron exporter protein, facilitating iron release from cells.

Transferrin: A plasma protein that binds ferric iron; exists in apo- (iron-free) and holo- (iron-bound) forms.

Ferritin: The principal intracellular iron storage complex, sequestering iron in a non-reactive form.

Reactive oxygen species (ROS): Highly reactive molecules formed by oxygen reduction, capable of damaging lipids, proteins and DNA.

References

1. Non-invasive assessment of normal and impaired iron homeostasis in the brain. Nature Communications (2023).
2. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nature Communications (2015).
3. HMGB1 induces hepcidin upregulation in astrocytes and causes an acute iron surge and subsequent ferroptosis in the postischemic brain. Experimental & Molecular Medicine (2023).
4. Iron imbalance in neurodegeneration. Molecular Psychiatry (2024).
5. Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation. Journal of Biomedical Science (2023).