Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis

Jiang, Xiaoying; Wu, Kaiyu; Ye, Xiang‐Yang; Xie, Tian; Zhang, Pengfei; Blass, Benjamin E.; Bai, Renren

doi:10.1002/med.21939

Cited by 15 publications

(5 citation statements)

References 163 publications

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“…The process of ferroptosis depends on iron ions and is characterized by three basic features such as the utilization of redox‐active iron, loss of lipid peroxide (LOOH) repair capacity and the oxidation of polyunsaturated fatty acid (PUFA)‐containing membrane phospholipids 17 . A growing body of evidence suggested that ferroptosis is associated with various human diseases, such as cancer, neurodegenerative diseases, infections and inflammation 18–20 …”

Section: Ferroptosismentioning

confidence: 99%

Role of oxidative stress‐induced ferroptosis in cancer therapy

Li,

Fan,

Chen

et al. 2024

J Cellular Molecular Medi

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Ferroptosis is a distinct mode of cell death, distinguishing itself from typical apoptosis by its reliance on the accumulation of iron ions and lipid peroxides. Cells manifest an imbalance between oxidative stress and antioxidant equilibrium during certain pathological contexts, such as tumours, resulting in oxidative stress. Notably, recent investigations propose that heightened intracellular reactive oxygen species (ROS) due to oxidative stress can heighten cellular susceptibility to ferroptosis inducers or expedite the onset of ferroptosis. Consequently, comprehending role of ROS in the initiation of ferroptosis has significance in elucidating disorders related to oxidative stress. Moreover, an exhaustive exploration into the mechanism and control of ferroptosis might offer novel targets for addressing specific tumour types. Within this context, our review delves into recent fundamental pathways and the molecular foundation of ferroptosis. Four classical ferroptotic molecular pathways are well characterized, namely, glutathione peroxidase 4‐centred molecular pathway, nuclear factor erythroid 2‐related factor 2 molecular pathway, mitochondrial molecular pathway, and mTOR‐dependent autophagy pathway. Furthermore, we seek to elucidate the regulatory contributions enacted by ROS. Additionally, we provide an overview of targeted medications targeting four molecular pathways implicated in ferroptosis and their potential clinical applications. Here, we review the role of ROS and oxidative stress in ferroptosis, and we discuss opportunities to use ferroptosis as a new strategy for cancer therapy and point out the current challenges persisting within the domain of ROS‐regulated anticancer drug research and development.

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Section: Ferroptosismentioning

confidence: 99%

Role of oxidative stress‐induced ferroptosis in cancer therapy

Li,

Fan,

Chen

et al. 2024

J Cellular Molecular Medi

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“…Biochemical and transcriptomic analyses of mediators of iron metabolism, antioxidant defenses, oxidative stress, and lipid peroxidation in experimental disease models, autopsy material, and induced pluripotent stem cell (iPSCs) derived from patients indicate that ferroptosis is a major mechanism of cell death in a wide range of neurologic disorders. These include Alzheimer disease (AD), 64,72,76-82 Parkinson disease (PD), 55,83-87 amyotrophic lateral sclerosis (ALS), 88-92 Huntington disease, 93-95 Friedreich ataxia, 96-98 multiple sclerosis, 99-101 ischemic stroke, 47,102-105 intracerebral hemorrhage, 106,107 traumatic brain injury, 108 spinal cord injury, 109,110 epilepsy, 111-113 and glioma, 114 among others. This topic has been extensively reviewed, 16-21,115,116 and only few concepts will be emphasized in this study.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

“…Both oxidative stress due to impaired mitochondrial complex I and decreased CoQ, GSH, and GPX4 levels and iron dyshomeostasis, reflected by increased TfR1 and DMT1 and decreased ceruloplasmin and ferritin expression, promote abnormal iron accumulation and ferroptosis in both dopaminergic neurons and glial cells. 28,83,125 α-Synuclein can form complexes with iron, act as a ferrireductase, and increase DMT1-mediated iron uptake in the cytosol. 126 In human dopaminergic neuron models, endogenous levels of α-synuclein can affect the availability of ether-linked phospholipids required for ferroptosis.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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Ferroptosis is a unique form of programmed cell death pathway that is mechanistically different from necrosis, apoptosis, or autophagy.1 Ferroptosis is induced by reactive oxygen species (ROS) originating from multiple sources, especially accumulation of free intracellular divalent iron (Fe2+), leading to peroxidation of polyunsaturated fatty acids (PUFAs) and resulting in membrane damage (Figure). One major trigger of ferroptosis is decreased availability of intracellular antioxidant enzymes, particularly glutathione peroxidases (GPXs).1-7 Because of its high lipid concentration and oxygen consumption rate, the nervous tissue is extremely vulnerable to oxidative damage and ferroptosis. With aging, iron accumulates in the brain, which predisposes to and exacerbates these processes.8 Iron promotes ferroptosis both directly and as a cofactor required for the activity of enzymes mediating redox reactions and lipid peroxidation.9,10 Epigenetic regulation can determine cell sensitivity to ferroptosis by affecting intracellular iron levels, oxidative stress, and lipid metabolism.11 Ferroptosis affects all cell types in the nervous system, including neurons, glial cells, and pericytes.12 Microglia are the primary iron-accumulating cells in disease.13,14 Recent evidence indicates that iron-laden microglia have a critical role in ferroptosis associated with neurodegeneration.15 Studies in vitro, in experimental disease models, and in human brain tissue indicate that iron accumulation, oxidative stress, and lipid peroxidation are major disease mechanisms in a wide range of neurologic disorders. These studies also suggest that the different components of the ferroptosis pathway are potential targets for therapeutic intervention. The mechanisms of ferroptosis and its role in neurologic disorders have been the subject of several recent comprehensive reviews.7,8,16-21 Some of these concepts pertinent to neurodegeneration will be emphasized in this study.

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“…Ferroptosis is an iron dependent cell death form, which has attacked more and more attentions in PD pathogenesis (Chen and Xie, 2020;Jiang et al, 2023). Further investigations focused on the ferroptosis in these iron deposited brain regions of fear circuit may yield new mechanism and perspective for the development of anxiety in PD.…”

Section: A Commentary Onmentioning

confidence: 99%

“…In addition, changes of iron related proteins, which response for the iron import, iron storage and iron export, might occur in these brain regions of fear circuit during the development of anxiety in PD. Ferroptosis is an iron dependent cell death form, which has attacked more and more attentions in PD pathogenesis (Chen and Xie, 2020 ; Jiang et al, 2023 ). Further investigations focused on the ferroptosis in these iron deposited brain regions of fear circuit may yield new mechanism and perspective for the development of anxiety in PD.…”

mentioning

confidence: 99%