Research on the imbalance of metal homeostasis and ferroptosis mechanisms in neurodegenerative diseases

Abstract

Objective: To investigate the associations between urinary and serum metal levels and neurodegenerative diseases (NGDs) as well as all-cause mortality, and identify research trends through bibliometric. Methods: This study first analyzed data from a large-scale national cross-sectional survey (2005–2018) involving 6288 participants. Multivariable regression models were used to assess the associations of urinary metals (Ba, Cd, Co, Cs, Mo, Pb, Sb, Tl, W) and serum metals (Fe, Cd, Pb, Hg) with the risk of neurodegenerative diseases (NGDs) and all-cause mortality. Subsequently, a bibliometric analysis was conducted on literature pertaining to "metals" and "NGDs" retrieved from the Web of Science Core Collection to identify research trends and key underlying mechanisms. Results: Epidemiological analyses revealed significant associations between several metals—such as Cd, Cs, Mo, Hg, and Pb—and either NGDs risk or all-cause mortality, with some exhibiting nonlinear patterns (e.g. L-shaped or inverted U-shaped relationships). Subsequent bibliometric analysis of 34,313 publications identified "iron" as a central hub keyword linking "metal exposure" to "neurodegenerative diseases". Mechanisms related to Fe—including "oxidative stress" and "lipid peroxidation"—emerged as research hotspot keywords. Notably, the cluster labeled "ferroptosis" demonstrated substantial scale in co-citation clustering. Research trajectories have evolved from broad pathological observations toward molecular-level investigations of the NLRP3 inflammasome, glutathione peroxidase 4 (GPX4), ultimately converged on the ferroptosis pathway. Conclusion: Exposure to multiple metals is significantly associated with the risk and prognosis of NGDs. Integrated bibliometric evidence highlights ferroptosis as the central mechanism bridging metal dyshomeostasis and neuronal injury, offering a cohesive evidence chain from population data to mechanistic insights.

Keywords

Metal exposure / Ferroptosis / Neurodegenerative diseases / Alzheimer’s disease / Parkinson’s disease

Ethics approval and consent to participate

The National Center for Health Statistics (NCHS) Research Ethics Review Board approved the NHANES survey protocol. All participants signed a written informed consent form. In addition, all information in the NHANES database is available to the public, and thus our research ethics review was exempt.

Author contributions

P.Z., W.J., X.L. and S.Z. designed the study and wrote the original manuscript. These authors contributed equally to this work and share first authorship. Y.L., Y.C. and L.H. created visualizations. L.L. supervised the research, and reviewed and edited the manuscript. All authors read and approved the final version of the manuscript.

Consent for publication

Not applicable.

Informed consent statement

Informed consent was received from all NHANES participants.

Clinical trial number

The authors of this study utilized data from NHANES (The National Health and Nutrition Examination Survey of the U.S., which provides open access to datasets). No clinical trial was conducted by the authors, and therefore, a clinical trial number was not available.

Funding

This work was supported by the 2024 General Scientific Research Project of Zhejiang Provincial Department of Education - Special Project for Reform of Professional Degree Graduate Training Mode (No.: Y202456415) and Zhejiang Key Research Projects of Traditional Chinese Medicine (No.: GZY-ZJ-KJ-23017, GZY-ZJ-KJ-24016).

Data availability statement

Publicly available datasets were analyzed in this study. This data can be found here: www.cdc.gov/nchs/nhanes/.

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

Acknowledgements

Not applicable.

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