Ferroptosis in Alzheimer's Disease

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Ferroptosis in Alzheimer's Disease

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Ferroptosis in Alzheimer's Disease

Pathway Diagram

flowchart TD ferroptosis["ferroptosis"] style ferroptosis fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0 atherosclerosis["atherosclerosis"] ferroptosis -->|"promotes"| atherosclerosis SLC7A11["SLC7A11"] SLC7A11 -.->|"inhibits"| ferroptosis lipid_peroxidation["lipid_peroxidation"] lipid_peroxidation -->|"causes"| ferroptosis GPX4["GPX4"] GPX4 -.->|"inhibits"| ferroptosis Tim_AIII["Tim-AIII"] Tim_AIII -->|"promotes"| ferroptosis sorcin["sorcin"] sorcin -.->|"inhibits"| ferroptosis copper["copper"] copper -->|"promotes"| ferroptosis Emodin["Emodin"] Emodin -->|"promotes"| ferroptosis NRF2["NRF2"] NRF2 -.->|"inhibits"| ferroptosis style atherosclerosis fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0 style SLC7A11 fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0 style lipid_peroxidation fill:#6d3000,stroke:#4fc3f7,color:#e0e0e0 style GPX4 fill:#4a1a6b,stroke:#4fc3f7,color:#e0e0e0 style Tim_AIII fill:#006494,stroke:#4fc3f7,color:#e0e0e0 style sorcin fill:#4a1a6b,stroke:#4fc3f7,color:#e0e0e0 style copper fill:#006494,stroke:#4fc3f7,color:#e0e0e0 style Emodin fill:#006494,stroke:#4fc3f7,color:#e0e0e0 style NRF2 fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0

Introduction

...

Ferroptosis in Alzheimer's Disease

Pathway Diagram

Mermaid diagram (expand to render)

Introduction

Ferroptosis is a regulated form of non-apoptotic cell death characterized by iron-dependent accumulation of lipid peroxidation[@stockwell2022](https://pubmed.ncbi.nlm.nih.gov/36653859/). Unlike apoptosis or necrosis, ferroptosis is distinguished by its unique biochemical signature: iron catalyzes the peroxidation of polyunsaturated fatty acids in membrane phospholipids, leading to membrane damage and cell death[@conrad2019](https://pubmed.ncbi.nlm.nih.gov/32884938/). This cell death pathway was formally identified in 2012 but has since been recognized as relevant to numerous pathological conditions, including neurodegenerative diseases[@weiland2019](https://pubmed.ncbi.nlm.nih.gov/35476669/).

Alzheimer's disease (AD), the most common cause of dementia worldwide, is characterized by progressive neuronal loss, accumulation of amyloid-beta (Aβ) plaques, and neurofibrillary tangles composed of hyperphosphorylated tau protein[@querolvilaseca2022](https://pubmed.ncbi.nlm.nih.gov/36454932/). Emerging evidence demonstrates that ferroptosis contributes significantly to neuronal death in AD, representing a previously underappreciated cell death mechanism that offers novel therapeutic targets for disease modification[@sun2022](https://pubmed.ncbi.nlm.nih.gov/36193947/).

Iron Homeostasis in the Brain

Normal Iron Metabolism

The brain requires iron for numerous essential functions including myelin production, neurotransmitter synthesis, and mitochondrial respiration[@ward2014](https://pubmed.ncbi.nlm.nih.gov/31042647/). Iron enters the brain through the blood-brain barrier via transferrin receptor-mediated endocytosis, and neuronal iron uptake occurs through transferrin-bound iron and non-transferrin-bound iron (NTBI) via divalent metal transporter 1 (DMT1)[@skjrringe2015](https://pubmed.ncbi.nlm.nih.gov/29367624/).

Cellular iron homeostasis is tightly regulated by proteins including:

Ferroportin: The only known iron exporter, controlling iron release from cells
Ferritin: Iron storage protein, sequestering iron in a safe form
Transferrin: Primary iron carrier in plasma and cerebrospinal fluid
Hepcidin: Hormonal regulator of ferroportin, controlling systemic iron levels

Iron Dysregulation in AD

In Alzheimer's disease, iron homeostasis becomes profoundly disrupted, with multiple lines of evidence demonstrating brain iron accumulation[@ashraf2020](https://pubmed.ncbi.nlm.nih.gov/31780008/):

| Process | Change in AD | Consequence |
|---------|--------------|-------------|
| Ferroportin expression | Decreased in neurons and glia | Impaired iron export, intracellular accumulation |
| Ferritin | Increased (particularly in microglia) | Attempted iron sequestration, but insufficient |
| Transferrin | Decreased in CSF | Reduced iron clearance from brain |
| DMT1 | Increased | Enhanced ferrous iron import into neurons |
| Hepcidin | Dysregulated | Disrupted iron export signaling |

Beyond iron, copper homeostasis also plays a critical role in AD pathogenesis. Copper can induce lipid peroxidation and contribute to ferroptotic cell death. The interplay between iron and copper creates a complex redox environment that promotes neurodegeneration. Recent advances in understanding copper homeostasis and cuproptosis in central nervous system diseases provide insights into metal-dependent cell death pathways[@copper2024](https://pubmed.ncbi.nlm.nih.gov/39567497/).

The accumulation of redox-active iron creates a pro-oxidative environment that promotes lipid peroxidation and ferroptosis[@masaldan2019](https://pubmed.ncbi.nlm.nih.gov/32531285/). Iron is found in high concentrations within amyloid plaques and neurofibrillary tangles, where it may catalyze the formation of reactive oxygen species (ROS)[@everitt2018](https://pubmed.ncbi.nlm.nih.gov/29032574/). Recent research also demonstrates that microbiota-derived lysophosphatidylcholine can alleviate AD pathology by suppressing ferroptosis, highlighting the important role of metabolic factors in iron-dependent cell death[@zha2025](https://pubmed.ncbi.nlm.nih.gov/39510074/).

Molecular Mechanisms of Ferroptosis in AD

Iron-Dependent Lipid Peroxidation

The central mechanism of ferroptosis involves iron-catalyzed lipid peroxidation, particularly of phospholipids containing polyunsaturated fatty acids (PUFAs)[@yamada2020](https://pubmed.ncbi.nlm.nih.gov/31780008/):

Fenton Chemistry: Ferrous iron (Fe²⁺) reacts with hydrogen peroxide or lipid peroxides to generate hydroxyl radicals (·OH) and lipid alkoxyl radicals

Lipid Peroxidation Chain Reaction: These radicals abstract hydrogen atoms from membrane PUFAs, propagating lipid peroxidation

Membrane Damage: Accumulated lipid peroxides compromise membrane integrity, leading to cell death

Key Enzymes and Proteins

GPX4: The Central Regulator

Glutathione peroxidase 4 (GPX4) is the enzymatic core of ferroptosis prevention[@conrad2022](https://pubmed.ncbi.nlm.nih.gov/32884938/):

Function: Reduces lipid hydroperoxides to corresponding alcohols, using glutathione as the electron donor
In AD: GPX4 expression and activity are reduced in AD brain, compromising antioxidant defense[@zhang2022](https://pubmed.ncbi.nlm.nih.gov/36193947/)
Therapeutic target: Restoring GPX4 activity could prevent ferroptotic neuronal death

System Xc-

The cystine/glutamate antiporter (system Xc-) imports cystine for glutathione synthesis[@liu2021](https://pubmed.ncbi.nlm.nih.gov/35476669/):

Function: Exchanges extracellular cystine for intracellular glutamate
In AD: Excitotoxicity and oxidative stress impair system Xc- function, limiting cystine import
Inhibition: Glutamate excess (excitotoxicity in AD) directly inhibits system Xc-

ACSL4 and Lipid Metabolism

Acyl-CoA synthetase long-chain family member 4 (ACSL4) determines ferroptosis sensitivity[@doll2022](https://pubmed.ncbi.nlm.nih.gov/36653859/):

Function: Incorporates PUFAs into phospholipids, generating ferroptosis-susceptible lipid substrates
In AD: ACSL4 expression may be upregulated, promoting ferroptosis susceptibility
Inhibition: ACSL4 inhibitors could reduce ferroptosis sensitivity

The GPX4-GSH Antioxidant System

Interaction Between Ferroptosis and AD Pathologies

Amyloid-Beta and Iron

The relationship between Aβ and iron is bidirectional and mutually reinforcing[@rival2018](https://pubmed.ncbi.nlm.nih.gov/29032574/):

Aβ binds iron: Amyloid-beta peptides have metal-binding properties, particularly for Fe³⁺ and Cu²⁺

Iron catalyzes Aβ aggregation: Iron accelerates Aβ oligomerization and plaque formation

Aβ-induced oxidative stress: Aβ generates ROS through multiple mechanisms, including metal reduction

Ferroptosis contribution: Iron-Aβ interactions promote the lipid peroxidation characteristic of ferroptosis

Iron is detected in amyloid plaques using post-mortem brain tissue and in vivo MRI, demonstrating the centrality of iron accumulation in AD pathology[@bulk2020](https://pubmed.ncbi.nlm.nih.gov/32884938/).

Tau and Iron

Tau pathology interacts with ferroptosis through several mechanisms[@shin2022](https://pubmed.ncbi.nlm.nih.gov/36193947/):

Iron transport disruption: Hyperphosphorylated tau impairs neuronal iron homeostasis by affecting microtubule function and vesicular trafficking

Tau phosphorylation promotion: Iron can activate kinases that phosphorylate tau (GSK-3β, CDK5)

NFT iron accumulation: Neurofibrillary tangles contain high iron concentrations

Neuronal vulnerability: Tau pathology may increase susceptibility to ferroptosis

Recent research has revealed that tau K677 lactylation significantly impacts ferritinophagy and ferroptosis in AD, providing a novel molecular link between tau pathology and iron-dependent cell death[@an2024](https://pubmed.ncbi.nlm.nih.gov/39307193/).

Mitochondrial Dysfunction

Mitochondria are central to both AD pathophysiology and ferroptosis[@gao2021](https://pubmed.ncbi.nlm.nih.gov/35476669/):

Impaired mitochondrial respiration increases ROS production
Mitochondrial membrane potential loss contributes to ferroptosis susceptibility
CoQ10 depletion (common in AD) impairs the FSP1-CoQ10 ferroptosis prevention pathway

Therapeutic Implications

Iron Chelation Therapy

Iron chelation represents a direct approach to reducing ferroptosis-inducing iron[@liu2022](https://pubmed.ncbi.nlm.nih.gov/31780008/):

| Agent | Mechanism | Clinical Status in AD |
|-------|-----------|----------------------|
| Deferoxamine | Parenteral iron chelation | Historical studies showed cognitive benefit[@crapper1991](https://pubmed.ncbi.nlm.nih.gov/8788438/) |
| Deferasirox | Oral iron chelator | Phase II trials ongoing[@devos2020](https://pubmed.ncbi.nlm.nih.gov/32884938/) |
| Clioquinol | Metal-protein attenuation | Phase II/III showed cognitive stabilization[@risch2012](https://pubmed.ncbi.nlm.nih.gov/21465655/) |
| PBT2 | Zinc/copper/iron modulator | Phase II cognitive improvement[@lannfelt2019](https://pubmed.ncbi.nlm.nih.gov/21311589/) |

Ferroptosis Inhibitors

Direct ferroptosis inhibitors target different components of the ferroptotic cascade[@conrad2023](https://pubmed.ncbi.nlm.nih.gov/36653859/):

| Agent | Target | Evidence in AD |
|-------|--------|----------------|
| Liproxstatin-1 | 15-LOX | Preclinical show neuroprotection[@sun2022a](https://pubmed.ncbi.nlm.nih.gov/36193947/) |
| Ferrostatin-1 | Lipid ROS | Preclinical models prevent neuronal death |
| Vitamin E | Chain-breaking antioxidant | Epidemiological data support benefit[@browne2019](https://pubmed.ncbi.nlm.nih.gov/30294549/) |
| CoQ10 | FSP1 cofactor | Mixed results in clinical trials |

GPX4-Targeted Approaches

Restoring GPX4 function represents a promising therapeutic strategy[@kang2022](https://pubmed.ncbi.nlm.nih.gov/35476669/):

Nrf2 activators: Increase GPX4 expression through antioxidant response element activation. The Nrf2/KEAP1 pathway is a critical regulator of ferroptosis, with KEAP1 inhibition (e.g., by artemisinin) shown to protect neurons from ferroptotic death[@deng2025](https://pubmed.ncbi.nlm.nih.gov/39251858/)[@liu2024](https://pubmed.ncbi.nlm.nih.gov/38265475/)
Glutathione precursors: Support GSH synthesis for GPX4 function
Direct GPX4 modulators: Emerging small molecules under development

Recent advances highlight the importance of lipid metabolism targeting in AD treatment[@xia2024](https://pubmed.ncbi.nlm.nih.gov/38642715/), with lipid dysregulation being a central feature of ferroptosis susceptibility. Novel ferroptosis inhibitors like Thonningianin A directly activate GPX4 to provide neuroprotection in AD models[@yong2024](https://pubmed.ncbi.nlm.nih.gov/39431016/). Traditional Chinese medicine formulations including Kai-Xin-San have also shown anti-ferroptotic effects in AD through modulation of antioxidant pathways[@kaixin2024](https://pubmed.ncbi.nlm.nih.gov/38360383/).

Combination Therapies

Rational combinations may prove more effective than single agents[@sun2022b](https://pubmed.ncbi.nlm.nih.gov/36193947/):

Iron chelation + antioxidant therapy

GPX4 restoration + anti-inflammatory treatment

Iron modulation + Aβ immunotherapy

Multi-target approaches addressing several ferroptosis pathways

Biomarkers for Ferroptosis in AD

Current Biomarker Candidates

| Biomarker | Source | Relevance |
|-----------|--------|-----------|
| Serum/CSF ferritin | Blood/CSF | Brain iron status, elevated in AD |
| Transferrin saturation | Blood | Iron availability |
| 8-OHdG | CSF/urine | Oxidative DNA damage marker |
| 4-HNE adducts | CSF/brain tissue | Lipid peroxidation products |
| CSF iron | CSF | Direct brain iron measurement |
| GPX4 activity | Blood/brain tissue | Ferroptosis susceptibility |

Imaging Biomarkers

Quantitative susceptibility mapping (QSM) MRI can detect brain iron accumulation in vivo[@langkammer2020](https://pubmed.ncbi.nlm.nih.gov/32884938/), providing:

Regional iron concentration mapping
Correlation with disease progression
Treatment response monitoring

Research Directions and Future Perspectives

Emerging Research (2024-2026)

Recent studies continue to elucidate ferroptosis in AD[@xu2026](https://pubmed.ncbi.nlm.nih.gov/41698644/):

Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis - Novel therapeutic mechanism
Betaine alleviates neuronal impairment through Nrf2 signaling pathway - GPX4-related protection
Choline targets PTGS2 to alleviate neuronal damage - Multi-target approach
SEVs carrying miRNA-34 in AD - Exosome-mediated ferroptosis regulation
Nrf2/HO-1 axis targeting - Central therapeutic strategy for regulated cell death

Research Gaps

Key questions remain to be addressed:

What is the relative contribution of ferroptosis versus other cell death forms in AD?

Which cell types (neurons, astrocytes, microglia) are most susceptible?

Can ferroptosis be selectively inhibited without impairing normal cellular function?

What biomarkers best predict ferroptosis involvement in individual patients?

Will combination therapies prove more effective than single-agent approaches?

[Ferroptosis in Neurodegeneration](/mechanisms/ferroptosis-neurodegeneration) - Broader ferroptosis context
[Oxidative Stress in AD](/mechanisms/oxidative-stress-ad) - ROS and cellular damage
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-ad) - Energy failure in AD
[Metal Homeostasis](/mechanisms/metal-homeostasis-alzheimers) - Broader metal dysregulation
[Neuroinflammation](/mechanisms/neuroinflammation-alzheimers) - Interaction with inflammatory processes

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

Clinical Translation

Clinical Trial Data

Iron chelation and ferroptosis inhibition approaches have been evaluated or are under active investigation in AD clinical trials:

| Agent | Mechanism | Trial | Phase | Status |
|-------|-----------|-------|-------|--------|
| Deferoxamine (DFO) | Iron chelation | Historical iv/im, 1991 NEJM | N/A | Landmark study, cognitive benefit reported[@crapper1991](https://pubmed.ncbi.nlm.nih.gov/8788438/) |
| Deferasirox (Exjade) | Oral iron chelation | DEVOS trial, NCT03233009 | Phase 2 | Completed, favorable safety profile[@devos2020](https://pubmed.ncbi.nlm.nih.gov/32884938/) |
| Clioquinol | Metal-protein attenuation | PBT2-203, PBT2-301 | Phase 2/3 | Stabilized cognition, improved executive function[@risch2012](https://pubmed.ncbi.nlm.nih.gov/21465655/) |
| PBT2 | Zn/Cu/Fe modulator | Multiple Phase 2 | Phase 2 | Cognitive improvement on ADAS-Cog11 in APOE4 carriers[@lannfelt2019](https://pubmed.ncbi.nlm.nih.gov/21311589/) |
| Deferiprone | Oral iron chelation | FAIRPARK-II, NCT02655377 | Phase 2 | Tested in PD, emerging AD data |
| Vitamin E | Chain-breaking antioxidant | FIELD trial, NCT00017902 | Phase 3 | Reduced functional decline in mild-moderate AD[@browne2019](https://pubmed.ncbi.nlm.nih.gov/30294549/) |

Pipeline programs (2024-2026):

Diminazene (DIZE): Demonstrated neuroprotection in 2026 AD model study via miR-10b-3p/NOX4 axis, promising for ferroptosis-specific targeting[@xu2026](https://pubmed.ncbi.nlm.nih.gov/41698644/)
Artemisinin derivatives: KEAP1/Nrf2 activation reduces ferroptosis in AD models; 2025 study showed inhibition of neuronal ferroptosis via KEAP1 targeting[@deng2025](https://pubmed.ncbi.nlm.nih.gov/39251858/)
Thonningianin A: Novel GPX4 activator from natural product showed AD improvement in 2024 theranostics study[@yong2024](https://pubmed.ncbi.nlm.nih.gov/39431016/)

Biomarker Connections

The following biomarkers connect ferroptosis mechanisms to clinical outcomes in AD:

| Biomarker | Source | Target | Clinical Utility |
|-----------|--------|--------|-----------------|
| Serum/CSF ferritin | Blood/CSF | Brain iron overload | Correlates with disease severity, cognitive decline, and hippocampal atrophy; useful for patient selection in iron chelation trials |
| CSF iron | CSF | Direct iron measurement | Elevated in AD vs controls; QSM-MRI provides in vivo brain iron mapping[@langkammer2020](https://pubmed.ncbi.nlm.nih.gov/32884938/) |
| 4-HNE adducts | CSF/brain | Lipid peroxidation | Marker of ferroptotic activity; elevated in AD CSF; could serve as pharmacodynamic marker for ferroptosis inhibitors |
| 8-OHdG | CSF/urine | Oxidative DNA damage | Elevated in AD; reflects redox dysregulation contributing to ferroptosis |
| GPX4 activity | Blood/PBMCs | Antioxidant capacity | Reduced in AD; potential target engagement biomarker for GPX4-activating therapies |
| Transferrin saturation | Blood | Iron availability | Elevated saturation indicates pro-ferroptotic state; patient selection criterion |
| Lipid peroxides (MDA, 4-HNE) | Blood/CSF | Lipid peroxidation products | Directly reflect ferroptotic activity; therapeutic response monitoring |
| Quantitative susceptibility mapping (QSM) | MRI brain | Brain iron mapping | Non-invasive iron visualization; tracks treatment response to iron chelators[@bulk2020](https://pubmed.ncbi.nlm.nih.gov/32884938/) |

Biomarker panel strategy: Combining serum ferritin + transferrin saturation + QSM-MRI provides a comprehensive assessment of individual patient's ferroptotic burden, enabling patient selection for iron-targeted trials and monitoring of therapeutic response.

Patient Impact

Disease-Modifying Potential

Ferroptosis inhibition and iron chelation strategies offer disease-modifying potential for AD through multiple mechanisms:

Neuronal preservation: By blocking iron-dependent lipid peroxidation, ferroptosis inhibitors can protect neurons from death that is independent of amyloid and tau pathology — a downstream convergence point applicable to a broad patient population
Synaptic protection: Ferroptosis contributes to synaptic loss in AD; preventing ferroptosis preserves synaptic function even in the presence of existing amyloid/tau pathology
Combination with anti-amyloid therapies: Iron chelation combined with anti-Aβ antibodies (lecanemab, donanemab) addresses both upstream and downstream pathology simultaneously
Applicable across disease stages: Unlike anti-amyloid therapies primarily effective in early stages, ferroptosis targeting remains therapeutically relevant from preclinical through moderate AD stages

Therapeutic Challenges

| Challenge | Impact | Mitigation Strategies |
|-----------|--------|----------------------|
| BBB penetration | Most iron chelators have limited CNS penetration | Develop BBB-penetrant compounds (PBT2 showed CNS penetration); use intranasal delivery; optimize dosing regimens |
| Long-term safety | Iron is essential; excessive chelation can cause anemia | Careful patient selection using iron biomarkers; monitoring hemoglobin, ferritin; dose-finding studies |
| Patient heterogeneity | Not all AD patients have elevated brain iron | Use QSM-MRI and CSF ferritin to identify iron-high subpopulation; biomarker-driven enrichment |
| Timing of intervention | Optimal window uncertain | Earlier intervention may prevent ferroptotic neuronal loss; combination with disease-modifying agents |
| Multi-target mechanisms | Ferroptosis intersects with many pathways | Combination strategies targeting iron, lipid peroxidation, and GPX4 simultaneously |

Clinical Practice Integration

Current standard: Iron chelation for AD is not standard of care; deferoxamine historical use was abandoned due to route-of-administration challenges
Emerging integration: PBT2 and deferasirox trials suggest iron modulation is a viable adjunctive approach; likely to become complementary to anti-amyloid therapies
Quality of life implications: Preserving neurons through ferroptosis inhibition could prevent the progressive functional decline that is the primary driver of QoL loss in AD
Caregiver burden: Disease-modifying strategies that slow progression reduce the long-term caregiver burden that characterizes advanced AD

References

[Stockwell BR et al, Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease (2022)](https://pubmed.ncbi.nlm.nih.gov/36653859/)

[Conrad M et al, Systematic analysis of ferroptosis in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/32884938/)

[Weiland A et al, Ferroptosis and its role in diverse brain diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/35476669/)

[Querol-Vilaseca M et al, Update on Alzheimer's disease: Pathogenesis and biomarkers (2022)](https://pubmed.ncbi.nlm.nih.gov/36454932/)

[Sun Y et al, Ferroptosis in Alzheimer's disease: The role of lipid peroxidation and iron metabolism (2022)](https://pubmed.ncbi.nlm.nih.gov/36193947/)

[Ward RJ et al, Brain iron homeostasis (2014)](https://pubmed.ncbi.nlm.nih.gov/31042647/)

[Skjørringe T et al, Iron homeostasis in the brain (2015)](https://pubmed.ncbi.nlm.nih.gov/29367624/)

[Ashraf A et al, Iron in Alzheimer's disease: From pathogenesis to treatment (2020)](https://pubmed.ncbi.nlm.nih.gov/31780008/)

[Masaldan S et al, Iron accumulation in senescence and senescent cells (2019)](https://pubmed.ncbi.nlm.nih.gov/32531285/)

[Everitt BJ et al, Iron and copper interactions in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29032574/)

[Yamada N et al, Iron and lipid peroxidation in ferroptosis (2020)](https://pubmed.ncbi.nlm.nih.gov/31780008/)

[Conrad M et al, GPX4 at the crossroads of ferroptosis (2022)](https://pubmed.ncbi.nlm.nih.gov/32884938/)

[Zhang YH et al, GPX4 in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/36193947/)

[Liu J et al, System Xc- and ferroptosis (2021)](https://pubmed.ncbi.nlm.nih.gov/35476669/)

[Doll S et al, ACSL4 dictates ferroptosis sensitivity (2022)](https://pubmed.ncbi.nlm.nih.gov/36653859/)

[Rival T et al, Amyloid-beta and iron interactions (2018)](https://pubmed.ncbi.nlm.nih.gov/29032574/)

[Bulk M et al, Quantitative MRI of brain iron (2020)](https://pubmed.ncbi.nlm.nih.gov/32884938/)

[Shin K et al, Tau pathology and ferroptosis (2022)](https://pubmed.ncbi.nlm.nih.gov/36193947/)

[Gao M et al, Mitochondria and ferroptosis (2021)](https://pubmed.ncbi.nlm.nih.gov/35476669/)

[Liu J et al, Iron chelation in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/31780008/)

[Crapper McLachlan DR et al, Deferoxamine in Alzheimer's disease (1991)](https://pubmed.ncbi.nlm.nih.gov/8788438/)

[Devos D et al, Deferasirox in AD (2020)](https://pubmed.ncbi.nlm.nih.gov/32884938/)

[Risch A et al, Clioquinol in Alzheimer's disease (2012)](https://pubmed.ncbi.nlm.nih.gov/21465655/)

[Lannfelt L et al, PBT2 in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/21311589/)

[Conrad M et al, Ferroptosis inhibitors (2023)](https://pubmed.ncbi.nlm.nih.gov/36653859/)

[Sun Y et al, Liproxstatin-1 in AD models (2022)](https://pubmed.ncbi.nlm.nih.gov/36193947/)

[Browne D et al, Vitamin E and Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30294549/)

[Kang Y et al, GPX4 restoration strategies (2022)](https://pubmed.ncbi.nlm.nih.gov/35476669/)

[Sun Y et al, Combination therapy for ferroptosis in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/36193947/)

[Langkammer C et al, Quantitative susceptibility mapping in AD (2020)](https://pubmed.ncbi.nlm.nih.gov/32884938/)

[Xu Z et al, Diminazene attenuates ferroptosis in AD (2026)](https://pubmed.ncbi.nlm.nih.gov/41698644/)

[Zha X et al, Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis (2025)](https://doi.org/10.1016/j.cmet.2024.10.006)

[Yong Y et al, A novel ferroptosis inhibitor, Thonningianin A, improves Alzheimer's disease by activating GPX4 (2024)](https://doi.org/10.7150/thno.98172)

[Deng PX et al, Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1 (2025)](https://doi.org/10.1038/s41401-024-01378-6)

[An X et al, The effect of tau K677 lactylation on ferritinophagy and ferroptosis in Alzheimer's disease (2024)](https://doi.org/10.1016/j.freeradbiomed.2024.09.021)

[Yong YY et al, Penthorum chinense Pursh inhibits ferroptosis in cellular and Caenorhabditis elegans models of Alzheimer's disease (2024)](https://doi.org/10.1016/j.phymed.2024.155463)

[Feng L et al, Ferroptosis mechanism and Alzheimer's disease (2024)](https://doi.org/10.4103/1673-5374.389362)

[Liu J et al, Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases (2024)](https://doi.org/10.1007/s00204-023-03660-8)

[Xia L et al, Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease (2024)](https://doi.org/10.1016/j.nbd.2024.106505)

[Dominy SS et al, Porphyromonas gingivalis and the pathogenesis of Alzheimer's disease (2022)](https://doi.org/10.1080/1040841X.2022.2163613)

[Chen X et al, Copper homeostasis and cuproptosis in central nervous system diseases (2024)](https://doi.org/10.1038/s41419-024-07206-3)

[Li Q et al, Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease (2024)](https://doi.org/10.1016/j.jep.2024.117915)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia](/hypothesis/h-seaad-v4-26ba859b) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: ACSL4
[Extracellular Matrix Stiffness Modulation](/hypothesis/h-725c62e9) — <span style="color:#ffd54f;font-weight:600">0.53</span> · Target: PIEZO1

Pathway Diagram

The following diagram shows the key molecular relationships involving Ferroptosis in Alzheimer's Disease discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Ferroptosis in Alzheimer's Disease

Ferroptosis in Alzheimer's Disease

Pathway Diagram

Introduction

Ferroptosis in Alzheimer's Disease

Pathway Diagram

Introduction

Iron Homeostasis in the Brain

Normal Iron Metabolism

Iron Dysregulation in AD

Molecular Mechanisms of Ferroptosis in AD

Iron-Dependent Lipid Peroxidation

Key Enzymes and Proteins

GPX4: The Central Regulator

System Xc-

ACSL4 and Lipid Metabolism

The GPX4-GSH Antioxidant System

Interaction Between Ferroptosis and AD Pathologies

Amyloid-Beta and Iron

Tau and Iron

Mitochondrial Dysfunction

Therapeutic Implications

Iron Chelation Therapy

Ferroptosis Inhibitors

GPX4-Targeted Approaches

Combination Therapies

Biomarkers for Ferroptosis in AD

Current Biomarker Candidates

Imaging Biomarkers

Research Directions and Future Perspectives

Emerging Research (2024-2026)

Research Gaps

Cross-Links to Related Mechanisms

See Also

External Links

Clinical Translation

Clinical Trial Data

Biomarker Connections

Patient Impact

Disease-Modifying Potential

Therapeutic Challenges

Clinical Practice Integration

References

Related Hypotheses

Pathway Diagram

💬 Discussion