Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications
Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of f...
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| Format: | Article |
| Language: | English |
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MDPI AG
2025-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/5/527 |
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| author | Nurzhan Abdukarimov Kamilya Kokabi Jeannette Kunz |
| author_facet | Nurzhan Abdukarimov Kamilya Kokabi Jeannette Kunz |
| author_sort | Nurzhan Abdukarimov |
| collection | DOAJ |
| description | Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc<sup>−</sup>-glutathione-GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer’s disease (AD) and Parkinson’s disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention. |
| format | Article |
| id | doaj-art-0ec058bf8d5648c1965e0f0741d9a093 |
| institution | DOAJ |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-0ec058bf8d5648c1965e0f0741d9a0932025-08-20T03:14:29ZengMDPI AGAntioxidants2076-39212025-04-0114552710.3390/antiox14050527Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease ImplicationsNurzhan Abdukarimov0Kamilya Kokabi1Jeannette Kunz2Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, KazakhstanDepartment of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, KazakhstanDepartment of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana 010000, KazakhstanIron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc<sup>−</sup>-glutathione-GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer’s disease (AD) and Parkinson’s disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention.https://www.mdpi.com/2076-3921/14/5/527ferroptosisiron homeostasiscell deathAlzheimer’s diseaseParkinson’s disease |
| spellingShingle | Nurzhan Abdukarimov Kamilya Kokabi Jeannette Kunz Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications Antioxidants ferroptosis iron homeostasis cell death Alzheimer’s disease Parkinson’s disease |
| title | Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications |
| title_full | Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications |
| title_fullStr | Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications |
| title_full_unstemmed | Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications |
| title_short | Ferroptosis and Iron Homeostasis: Molecular Mechanisms and Neurodegenerative Disease Implications |
| title_sort | ferroptosis and iron homeostasis molecular mechanisms and neurodegenerative disease implications |
| topic | ferroptosis iron homeostasis cell death Alzheimer’s disease Parkinson’s disease |
| url | https://www.mdpi.com/2076-3921/14/5/527 |
| work_keys_str_mv | AT nurzhanabdukarimov ferroptosisandironhomeostasismolecularmechanismsandneurodegenerativediseaseimplications AT kamilyakokabi ferroptosisandironhomeostasismolecularmechanismsandneurodegenerativediseaseimplications AT jeannettekunz ferroptosisandironhomeostasismolecularmechanismsandneurodegenerativediseaseimplications |