Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This comprehensive review synthesizes current evidence on the molecular mechanisms of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, and its intersection with disrupted iron homeostasis in the context of major neurodegenerative diseases. The authors meticulously examined how dysregulated brain iron metabolism, particularly through the blood-brain barrier and within neuronal and glial cells, creates an environment conducive to ferroptotic cell death, thereby fueling the pathological progression of conditions like Alzheimer’s and Parkinson’s disease.
Who was reviewed?
The review encompasses a broad synthesis of pre-clinical and clinical studies, drawing from cellular models, animal models of neurodegeneration, and human patient data, including post-mortem brain tissue analyses and neuroimaging studies. The evidence is contextualized around the vulnerability of specific brain cell types, including neurons, astrocytes, microglia, and oligodendrocytes, to iron dysregulation and ferroptosis, with a particular focus on the pathological mechanisms observed in human patients with Alzheimer’s disease and Parkinson’s disease.
Most important findings
| Finding | Relevance to Heavy Metal Toxicity & Certification |
|---|---|
| Iron as a Central Driver: Ferroptosis is fundamentally an iron-dependent process where redox-active ferrous iron (Fe²⁺) catalyzes lipid peroxidation via the Fenton reaction, leading to catastrophic membrane damage and cell death. | Directly implicates iron, a heavy metal, as a primary toxic agent in a defined cell death pathway, underscoring the need to monitor and manage its levels. |
| Blood-Brain Barrier (BBB) Dysfunction: Breakdown of the BBB, common in neurodegeneration, allows unregulated iron influx into the brain, bypassing normal homeostatic controls and leading to regional iron accumulation. | Highlights a critical pathway for heavy metal entry into the CNS, suggesting that BBB integrity is a potential biomarker for susceptibility to iron-mediated damage. |
| Disease-Specific Iron Accumulation: Iron overload is not uniform; it occurs in vulnerable regions like the hippocampus in Alzheimer’s disease and the substantia nigra in Parkinson’s disease, correlating with local protein aggregation and cell loss. | Indicates that certification programs could target specific, high-risk brain regions or associated biomarkers for more precise risk assessment. |
| Therapeutic Targeting Challenges: Clinical trials with the iron chelator deferiprone showed it could reduce brain iron but failed to slow disease progression in Parkinson’s and worsened cognition in Alzheimer’s, highlighting the complexity of therapeutic iron manipulation. | Suggests that simply reducing total iron may be insufficient or even harmful; a more nuanced approach to managing the specific redox-active iron pool is needed. |
| Parallel Cell Death Pathways: Neurodegeneration often involves a convergence of ferroptosis with other cell death pathways (e.g., apoptosis, pyroptosis), indicating that iron toxicity is part of a broader pathological network. | Implies that a singular focus on iron may be inadequate; a holistic certification standard should consider multiple interconnected cell death mechanisms. |
Key implications
The primary regulatory impact is the formal recognition of iron as a potent neurotoxic heavy metal when dysregulated, necessitating its consideration in safety assessments. This creates a demand for certification requirements that verify products do not contribute to iron-mediated oxidative stress or disrupt neuronal iron homeostasis. Industry applications include developing nutraceuticals and pharmaceuticals that support healthy iron metabolism or protect against ferroptosis. A significant research gap exists in defining safe and effective levels of brain iron and validating biomarkers of ferroptosis for human use. Practical recommendations involve prioritizing the development of interventions that selectively target pathological iron pools without disrupting their essential physiological functions.
Citation
Abdulkarimov N, Kokabi K, Kunz J. Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications. Antioxidants (Basel). 2025;14(3):527. doi:10.3390/antiox14030527
Heavy metals are high-density elements that accumulate in the body and environment, disrupting biological processes. Lead, cadmium, arsenic, mercury, nickel, tin, aluminum, and chromium are of greatest concern due to persistence, bioaccumulation, and health risks, making them central to the HMTC program’s safety standards.
