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Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review)

  • Authors:
    • Wenjing Chen
    • Heng Tian
    • Ran Wei
    • Xiaomei Chen
    • Yiwen Jia
  • View Affiliations / Copyright

    Affiliations: Second Clinical Medical College, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, First Clinical Medical College, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of Gastroenterology, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230071, P.R. China
    Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 119
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    Published online on: March 12, 2026
       https://doi.org/10.3892/ijmm.2026.5790
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Abstract

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive loss of neurons. Although the precise pathogenesis of such diseases is complex and multifactorial, several molecular pathways have been implicated, including the aggregation of misfolded proteins, mitochondrial dysfunction, oxidative stress, neuroinflammation and disrupted iron homeostasis. Emerging evidence has underscored the pivotal role of ferroptosis, an iron‑dependent, non‑apoptotic form of cell death, in neurodegenerative disease progression. Ferritin, characterized by a 24‑subunit hollow sphere structure composed of heavy and light chains, plays a key role in the network regulating cerebral iron homeostasis. In response to cellular iron overload, ferritin expression is upregulated to sequester labile iron and mitigate Fenton reaction‑mediated toxicity, thus exerting a cytoprotective function. Paradoxically, ferritin can be degraded via ferritinophagy, a selective autophagic process that releases toxic ferrous iron and directly triggers ferroptosis. This review systematically reviews the role of ferritin within the iron homeostasis network to elucidate the connection between the dysregulation of iron metabolism and the pathological mechanisms of neurodegenerative diseases. The study focused on the potential role of ferritin as a biomarker for early diagnosis, therapeutic strategies targeting ferritin pathways to restore iron homeostasis and the clinical translational value of magnetic resonance imaging‑based non‑invasive quantification of cerebral iron deposition. It is crucial to elucidate the multidimensional roles of ferritin in neurodegeneration to provide a theoretical foundation for precision diagnostic and therapeutic approaches.
View Figures

Figure 1

Iron uptake and ferritinophagy
pathway. Cellular iron is acquired via TfR-mediated endocytosis or
through the DMT1 transporter. Cytosolic Fe2+ is
chaperoned by proteins such as PCBP and is subsequently stored in
ferritin. NCOA4-mediated ferritinophagy targets ferritin to
autolysosomes for degradation, thereby releasing Fe2+.
Overactivation of this process results in cellular iron overload,
which subsequently generates excessive ROS via the Fenton reaction
and induces lipid peroxidation. DMT1, divalent metal transporter 1;
NCOA4, nuclear receptor coactivator 4; PCBP, poly(rC)-binding
protein; ROS, reactive oxygen species; STEAP3, six-transmembrane
epithelial antigen of the prostate 3; Tf, transferrin; TfR,
transferrin receptor.

Figure 2

IRP/IRE system. The IRP/IRE system
regulates cellular iron homeostasis post-transcriptionally. Low
iron: High-affinity IRP-IRE binding inhibits FTH1/FTL translation
and stabilizes TfR1 mRNA. High Iron: Reduced IRP binding
derepresses ferritin synthesis and allows TfR1 mRNA degradation.
FTH1, ferritin heavy chain 1; FTL, ferritin light chain; IRP, iron
regulatory protein; IRE, iron-responsive element; TfR, transferrin
receptor.

Figure 3

The Keap1/Nrf2/ARE axis in cellular
iron homeostasis. FPN mediates cellular iron efflux, a process
negatively regulated by hepcidin. Cytosolic oxidative stress such
as ROS generated from the Fenton reaction between Fe2+
and H2O2 triggers the dissociation of Keap1
from Nrf2, thus enabling Nrf2 nuclear translocation. Nuclear Nrf2
binds to ARE and initiates the transcription of cytoprotective
genes FTH and FPN. BACH1 antagonizes Nrf2 by competing for ARE
binding. Fenton reaction-derived ROS also stimulates lipid
peroxidation, contributing to neurodegenerative pathologies such as
amyloid plaques and α-synuclein aggregates. ARE, antioxidant
response element; BACH1, BTB and CNC homology 1; FPN, ferroportin;
Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor
erythroid 2-related factor 2; PCBP, poly(rC)-binding protein; ROS,
reactive oxygen species.

Figure 4

Lipid peroxidation and the
Xc−/GSH/GPX axis. The oxidation of membrane-integrated
PUFA-PLs is an example of ferroptosis. Lipid peroxidation is
promoted by LOXs or Fe2+ through the Fenton reaction.
The selenoenzyme GPX4 serves as a central defense node by reducing
phospholipid hydroperoxides using GSH. GSH synthesis depends on
cystine uptake through the system Xc− transporter.
Pharmacological induction of ferroptosis can be achieved by
exposure to erastin (system Xc− inhibitor) or RSL3 (GPX4
inhibitor). ACSL4, acyl-CoA synthetase long-chain family member 4;
GSH, glutathione; GPX4, glutathione peroxidase 4; LOX,
lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3;
PUFA, polyunsaturated fatty acid; PL, phospholipid; PL-OOH,
phospholipid hydroperoxide; RSL3, RAS-selective lethal 3.
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Spandidos Publications style
Chen W, Tian H, Wei R, Chen X and Jia Y: Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review). Int J Mol Med 57: 119, 2026.
APA
Chen, W., Tian, H., Wei, R., Chen, X., & Jia, Y. (2026). Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review). International Journal of Molecular Medicine, 57, 119. https://doi.org/10.3892/ijmm.2026.5790
MLA
Chen, W., Tian, H., Wei, R., Chen, X., Jia, Y."Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 57.5 (2026): 119.
Chicago
Chen, W., Tian, H., Wei, R., Chen, X., Jia, Y."Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 119. https://doi.org/10.3892/ijmm.2026.5790
Copy and paste a formatted citation
x
Spandidos Publications style
Chen W, Tian H, Wei R, Chen X and Jia Y: Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review). Int J Mol Med 57: 119, 2026.
APA
Chen, W., Tian, H., Wei, R., Chen, X., & Jia, Y. (2026). Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review). International Journal of Molecular Medicine, 57, 119. https://doi.org/10.3892/ijmm.2026.5790
MLA
Chen, W., Tian, H., Wei, R., Chen, X., Jia, Y."Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 57.5 (2026): 119.
Chicago
Chen, W., Tian, H., Wei, R., Chen, X., Jia, Y."Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 119. https://doi.org/10.3892/ijmm.2026.5790
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