Targeting ferroptosis in rotenone-induced Parkinson’s disease: from mechanistic insights to pharmacological interventions
7 affiliations
- 1Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine
- 2Aerospace Medical Center, Aerospace Center Hospital
- 3GENERTEC Key Laboratory of Aerospace Medical Research and Transformation
- 4Department of Neurology, Hohhot First Hospital, Fifth Clinical Medical College, Inner Mongolia Medical University
- 5Department of Neurology, The Affiliated Hospital of Chifeng University
- 6Department of Neurology, Zhongnan Hospital of Wuhan University
- 7Hubei Provincial Clinical Research Center for Dementia and Cognitive Impairment
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to disabling motor and non-motor symptoms. Ferroptosis, an iron-dependent oxidative cell death driven by lethal lipid peroxidation, has emerged in preclinical models as a candidate pathogenic mechanism in PD, although its causal centrality in human PD remains to be established. Rotenone, a mitochondrial complex I inhibitor widely used to model PD, recapitulates key clinical and pathological features of the disease. Accumulating evidence demonstrates that rotenone induces ferroptosis through a coordinated network of iron dyshomeostasis, inactivation of the System Xc ⁻ –GPX4 antioxidant axis, dysregulated lipid metabolism, mitochondrial dysfunction, ferritinophagy-mediated iron release, neuroinflammation, and SIRT1–Nrf2 pathway suppression. Importantly, pharmacological targeting of these ferroptotic nodes—with agents such as Fer-1, iron chelators, Nrf2 activators, and modulators of ferritinophagy—effectively attenuates rotenone-induced neurodegeneration and restores motor function in preclinical models. This review systematically dissects the molecular circuitry of ferroptosis in rotenone -based PD models and evaluates the therapeutic potential of ferroptosis inhibitors, aiming to inform the development of disease-modifying strategies for PD.
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BibTeX
@article{wang2026targeting,
title = {{Targeting ferroptosis in rotenone-induced Parkinson’s disease: from mechanistic insights to pharmacological interventions}},
author = {Hongquan Wang and Zhiji Wang and Qiang Li and Shuang Wu and Yumin Wang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1976646},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1976646/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting ferroptosis in rotenone-induced Parkinson’s disease: from mechanistic insights to pharmacological interventions
AU - Hongquan Wang
AU - Zhiji Wang
AU - Qiang Li
AU - Shuang Wu
AU - Yumin Wang
PY - 2026
DA - 2026/10/28
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1976646
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1976646/full
AB - Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to disabling motor and non-motor symptoms. Ferroptosis, an iron-dependent oxidative cell death driven by lethal lipid peroxidation, has emerged in preclinical models as a candidate pathogenic mechanism in PD, although its causal centrality in human PD remains to be established. Rotenone, a mitochondrial complex I inhibitor widely used to model PD, recapitulates key clinical and pathological features of the disease. Accumulating evidence demonstrates that rotenone induces ferroptosis through a coordinated network of iron dyshomeostasis, inactivation of the System Xc ⁻ –GPX4 antioxidant axis, dysregulated lipid metabolism, mitochondrial dysfunction, ferritinophagy-mediated iron release, neuroinflammation, and SIRT1–Nrf2 pathway suppression. Importantly, pharmacological targeting of these ferroptotic nodes—with agents such as Fer-1, iron chelators, Nrf2 activators, and modulators of ferritinophagy—effectively attenuates rotenone-induced neurodegeneration and restores motor function in preclinical models. This review systematically dissects the molecular circuitry of ferroptosis in rotenone -based PD models and evaluates the therapeutic potential of ferroptosis inhibitors, aiming to inform the development of disease-modifying strategies for PD.
SN - 1663-9812
ER -