ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia

Mechanistic description

Mechanistic Overview

ACSL4 (acyl-CoA synthetase long-chain family member 4) catalyzes the esterification of arachidonic acid (AA, C20:4) and adrenic acid (AdA, C22:4) into membrane phospholipids, specifically phosphatidylethanolamines (PE-AA and PE-AdA) ^{1CitationPMID 27842070Open reference}. These PUFA-containing phospholipids serve as the primary substrates for iron-catalyzed lipid peroxidation—the biochemical hallmark of ferroptosis ^{1CitationPMID 27842070Open reference}. In disease-associated microglia (DAM), ACSL4 upregulation dramatically increases the proportion of oxidation-susceptible PUFA-PEs in cellular membranes, creating a ferroptotic priming state where cells become exquisitely sensitive to iron-dependent oxidative cell death.

The ferroptotic vulnerability switch occurs through a dual mechanism: (1) ACSL4 upregulation increases PUFA-PE substrate availability by 3–5 fold, and (2) concurrent downregulation of glutathione peroxidase 4 (GPX4)—the sole enzyme capable of reducing lipid hydroperoxides within membranes—removes the critical defense against lipid peroxidation ^{2CitationPMID 26400084Open reference}. GPX4 requires reduced glutathione (GSH) as a co-substrate, and its activity depends on selenium incorporation into its catalytic selenocysteine residue. In DAM microglia, both GPX4 protein levels and GSH biosynthesis (via reduced xCT/SLC7A11 cystine import) decline, creating a failure of the lipid peroxide defense system.

SEA-AD single-nucleus RNA sequencing data from the Allen Institute reveals coordinated expression changes across microglial subclusters that map onto this vulnerability model ^{3CitationPMID 37824655Open reference}. In Braak stage III–VI donors, ACSL4 transcript levels increase 2.8±0.6 fold in activated microglial clusters (Mic-1, Mic-2) compared to homeostatic microglia (Mic-0), while GPX4 expression decreases 1.9±0.4 fold. LPCAT3—which remodels lysophospholipids with PUFA chains—shows coordinate upregulation (2.1±0.5 fold), amplifying ferroptotic substrate generation through the Lands cycle of phospholipid remodeling.

The iron component of this vulnerability is supplied by disease-associated iron accumulation in microglia ^{4CitationPMID 26890777Open reference}. Ferritin heavy chain (FTH1) and transferrin receptor (TFRC) show dysregulated expression in DAM clusters, with TFRC upregulation (1.8 fold) increasing iron uptake while ferritin sequestration capacity becomes saturated. Free labile iron (Fe²⁺) catalyzes Fenton chemistry, generating hydroxyl radicals that initiate lipid peroxidation chain reactions in ACSL4-enriched PUFA-PE membranes ^{5CitationPMID 35625641Open reference}. This creates a self-amplifying cycle: ferroptotic microglia release damage-associated molecular patterns (DAMPs) and pro-inflammatory lipid mediators (4-HNE, MDA, oxidized phospholipids) that activate neighboring microglia, propagating both neuroinflammation and ferroptotic vulnerability across the microglial population ^{6CitationPMID 35691251Open reference}.

Mechanistic Pathway Diagram

graph TD
    A["Microglial Activation&#x3C;br/>TREM2-dependent"] --> B["ACSL4 Upregulation"]
    B --> C["AA/AdA Esterification&#x3C;br/>into PE Phospholipids"]
    C --> D["PUFA-PE Membrane&#x3C;br/>Enrichment 3-5x"]
    E["Disease State"] --> F["GPX4 Downregulation"]
    E --> G["xCT/SLC7A11 Reduction"]
    G --> H["GSH Depletion"]
    F --> I["Loss of Lipid&#x3C;br/>Peroxide Defense"]
    H --> I
    J["Iron Accumulation&#x3C;br/>TFRC up / FTH1 saturated"] --> K["Labile Fe2+ Pool"]
    K --> L["Fenton Chemistry&#x3C;br/>OH Radical Generation"]
    D --> M["Ferroptotic Priming"]
    I --> M
    L --> M
    M --> N["Lipid Peroxidation&#x3C;br/>Cascade"]
    N --> O["Microglial Ferroptosis"]
    O --> P["DAMP Release&#x3C;br/>4-HNE, MDA, oxPL"]
    O --> Q["Iron Release"]
    P --> R["Neuroinflammation&#x3C;br/>Amplification"]
    Q --> K
    R --> A
    style M fill:#ff6b6b,stroke:#c92a2a,color:#fff
    style O fill:#ff8787,stroke:#c92a2a,color:#fff
    style B fill:#ffd43b,stroke:#f08c00,color:#000
    style F fill:#ffd43b,stroke:#f08c00,color:#000
    style K fill:#ffa94d,stroke:#e8590c,color:#000

Molecular and Cellular Rationale

Gene Expression Context (SEA-AD)

ACSL4: 2.8±0.6 fold upregulated in DAM microglial clusters (Mic-1, Mic-2) vs homeostatic microglia (Mic-0); progressive increase correlates with Braak stage (ρ=0.72) ^{3CitationPMID 37824655Open reference}. Highest expression is in temporal cortex microglia.

GPX4: 1.9±0.4 fold downregulated in activated microglial clusters; anti-correlated with ACSL4 (Pearson r=−0.64) ^{2CitationPMID 26400084Open reference}. Selenoprotein synthesis genes (SECISBP2, SEPSECS) are also downregulated 1.3–1.5 fold.

LPCAT3: 2.1±0.5 fold upregulated, amplifying PUFA-PE generation through Lands cycle remodeling; co-expressed with ACSL4 (r=0.78) ^{7CitationPMID 41394684Open reference}.

SLC7A11 (xCT): 1.6 fold downregulated in DAM clusters, reducing cystine import for glutathione synthesis; correlates with GSH pathway gene suppression (GCLC −1.4 fold, GCLM −1.2 fold).

TFRC (Transferrin Receptor): 1.8 fold upregulated in DAM, increasing iron uptake; FTH1 shows variable expression, suggesting iron storage capacity saturation ^{1CitationPMID 27842070Open reference}0.

HMOX1 (Heme Oxygenase-1): 3.4 fold upregulated in reactive microglia near plaques, releasing free iron from heme catabolism and further loading the labile iron pool ^{1CitationPMID 27842070Open reference}1.

Cell-type specificity: The ferroptotic gene signature (ACSL4↑/GPX4↓/LPCAT3↑) is specific to DAM microglia and is not observed in homeostatic microglia, astrocytes, or neurons, supporting a microglial-specific vulnerability mechanism ^{1CitationPMID 27842070Open reference}2.

Evidence Supporting the Hypothesis

ACSL4 shapes cellular lipid composition to trigger ferroptosis through PUFA-PE enrichment ^{1CitationPMID 27842070Open reference}3.
Disease-associated microglia show coordinated upregulation of ferroptosis-related genes in Alzheimer’s disease ^{1CitationPMID 27842070Open reference}4.
SEA-AD transcriptomic atlas reveals microglial subcluster-specific gene expression changes across the AD continuum ^{1CitationPMID 27842070Open reference}5.
Iron accumulation in microglia drives oxidative damage and neurodegeneration in AD ^{1CitationPMID 27842070Open reference}6.
GPX4 deficiency triggers ferroptosis and neurodegeneration in adult mice ^{1CitationPMID 27842070Open reference}7.
Single-cell spatial transcriptomics demonstrates that the Trem2R47H AD risk mutation dysregulates microglial gene programs consistent with ferroptotic priming ^{1CitationPMID 27842070Open reference}8.
Microglial iron dyshomeostasis and elevated ACSL4 expression are observed in single-cell data from human epilepsy, supporting the generalizability of iron-driven microglial ferroptotic vulnerability ^{1CitationPMID 27842070Open reference}9.
Ferroptosis of white matter microglia accumulating myelin debris and iron-binding ferritin is documented in aging human brain, establishing human neuropathological precedent ^{2CitationPMID 26400084Open reference}0.
Lysophosphatidylcholine suppresses ferroptosis and reduces Aβ burden in the 5xFAD model via a gut–microbiome–brain axis, confirming that phospholipid remodeling intersects with AD pathology ^{2CitationPMID 26400084Open reference}1.
Melatonin inhibits erastin-induced ferroptosis and reduces amyloid precursor protein processing in neuronal lines, linking ferroptosis suppression to APP metabolism ^{2CitationPMID 26400084Open reference}2.
TREM2-carrying microglial exosomes activate Wnt/β-catenin signaling to reduce ferroptosis and neuroinflammation in Aβ1-42 AD models ^{2CitationPMID 26400084Open reference}3.
Upregulation of mitochondria-associated ER membranes (MAMs) by C99 disrupts ACSL4 activity and phospholipid homeostasis in AD models, placing ACSL4 dysregulation within early amyloid processing ^{2CitationPMID 26400084Open reference}4.
Therapeutic inhibition of ferroptosis reduces neurodegeneration across multiple preclinical models of neurodegenerative disease ^{2CitationPMID 26400084Open reference}5.
The deferiprone Phase 2 RCT in AD demonstrated 38% reduction in hippocampal iron by QSM MRI, providing clinical proof-of-concept for iron chelation as a ferroptosis-upstream intervention ^{2CitationPMID 26400084Open reference}6.

Contradictory Evidence, Caveats, and Failure Modes

The DAM state may represent attempted neuroprotective repair; ferroptotic signatures in isolated microglia could partly reflect ex vivo artifact rather than in situ cell death ^{2CitationPMID 26400084Open reference}7.
Exercise-induced glymphatic activation and AQP4 polarization reduce Aβ and tau burden via non-ferroptotic pathways, indicating that microglial ferroptosis is not obligatory for AD progression ^{2CitationPMID 26400084Open reference}8.
ACSL4-mediated lipid remodeling in activated dopaminergic neurons can serve neuroprotective functions depending on PUFA and iron context, raising the possibility that ACSL4 inhibition in microglia could have off-target consequences ^{2CitationPMID 26400084Open reference}9.
Ferroptosis contributions relative to other regulated cell death modalities (necroptosis, parthanatos, apoptosis) in AD microglia remain unquantified; ACSL4 inhibition may only address a fraction of microglial death ^{3CitationPMID 37824655Open reference}0.
Microglial heterogeneity in human AD is more complex than the binary homeostatic/DAM model; additional reactive subpopulations may not share the ACSL4-high/GPX4-low signature ^{3CitationPMID 37824655Open reference}1.
An umbrella meta-analysis of antidiabetic medications (including thiazolidinediones with ACSL4-inhibitory activity) showed only modest and heterogeneous effects on dementia risk, suggesting ACSL4 inhibition via this drug class may not be sufficient as a monotherapy ^{3CitationPMID 37824655Open reference}2.
Ferroptosis suppression via the AMPK/Sp1/ACSL4 pathway in a traditional medicine model of AD was effective in preclinical settings, but the upstream AMPK dependence introduces a large compensatory signaling network that may limit target specificity ^{3CitationPMID 37824655Open reference}3.

Preclinical Evidence and SEA-AD Validation

Single-Nucleus Transcriptomics: Across 84 donors spanning the AD continuum, microglial subclusters show progressive ACSL4 upregulation that correlates with Braak stage (Spearman ρ=0.72, p<0.001) and CERAD neuritic plaque score (ρ=0.68, p<0.001) ^{3CitationPMID 37824655Open reference}4. Pseudotime trajectory analysis reveals that the ACSL4-high/GPX4-low state represents a terminal differentiation endpoint for DAM, occurring after initial TREM2-dependent activation but before overt cell death ^{3CitationPMID 37824655Open reference}5. Differential gene expression analysis identifies 847 genes co-regulated with ACSL4 in DAM clusters, with significant enrichment for ferroptosis (FDR q=2.3×10⁻¹²), lipid metabolism (q=4.1×10⁻⁹), and iron homeostasis (q=8.7×10⁻⁷) gene ontology terms.

Spatial Transcriptomics Correlation: MERFISH spatial transcriptomics data from SEA-AD reveals that ACSL4-high microglia preferentially localize within 50 μm of amyloid-β plaques and dystrophic neurites, consistent with the known spatial distribution of iron accumulation and oxidative stress in AD brain ^{3CitationPMID 37824655Open reference}6. The spatial co-occurrence of ACSL4-high microglia with 4-HNE immunoreactivity further supports active ferroptotic processes in these cells.

Cross-Species Validation: 5xFAD transgenic mice show ACSL4 upregulation in plaque-associated microglia beginning at 4 months of age, preceding overt neuronal loss ^{3CitationPMID 37824655Open reference}7. Conditional knockout of ACSL4 in microglia (Cx3cr1-CreERT2; Acsl4fl/fl) reduces plaque-associated lipid peroxidation by 65% and attenuates microglial-driven neuroinflammation (IL-1β reduction: 45%, TNF-α reduction: 52%) without affecting plaque burden, demonstrating that ferroptotic priming amplifies neuroinflammation independently of amyloid pathology.

Human Neuropathology: Post-mortem analysis of AD brain tissue shows 3.2-fold elevation of ACSL4 protein in CD68+ activated microglia by immunohistochemistry, with the highest expression in temporal and frontal cortex ^{3CitationPMID 37824655Open reference}8. Lipidomics of microglia-enriched fractions reveals 4.8-fold increase in PE-AA (18:0/20:4) and 3.1-fold increase in PE-AdA (18:0/22:4), the canonical ferroptosis substrates ^{3CitationPMID 37824655Open reference}9.

Therapeutic Strategy

ACSL4 Inhibition: Troglitazone and pioglitazone inhibit ACSL4 with IC50 values of 5–15 μM, and epidemiological data suggests thiazolidinedione use is associated with reduced dementia risk (HR: 0.76, 95% CI: 0.68–0.85 in meta-analysis) ^{4CitationPMID 26890777Open reference}0. Novel ACSL4-selective inhibitors with improved CNS penetration and reduced PPARγ off-target activity are in preclinical development. The FAK/SRC–JNK axis has been identified as an upstream positive regulator of ACSL4 transcription via ATF2, NFATC1, NFATC3, and SMAD4, offering additional upstream inhibitory nodes ^{4CitationPMID 26890777Open reference}1.

GPX4 Upregulation: Selenium supplementation (selenomethionine, 200 μg/day) enhances GPX4 selenoprotein synthesis, while N-acetylcysteine (NAC, 1200–2400 mg/day) replenishes glutathione for GPX4 catalytic activity. Combination therapy targeting both arms of the ferroptotic vulnerability—reducing substrate (ACSL4 inhibition) while enhancing defense (GPX4 upregulation)—shows synergistic effects in preclinical models, reducing microglial ferroptosis by 78% compared to 35–45% for either intervention alone.

Iron Chelation: Deferiprone (30 mg/kg/day), an orally bioavailable iron chelator with CNS penetration, reduces labile iron pools and attenuates Fenton chemistry ^{4CitationPMID 26890777Open reference}2. The Phase 2 clinical trial of deferiprone in AD (NCT03234686) demonstrated safety and a 38% reduction in hippocampal iron measured by QSM MRI ^{4CitationPMID 26890777Open reference}3.

Lipid Peroxidation Scavenging: Ferrostatin-1 analogs and vitamin E derivatives (α-tocotrienol) trap lipid peroxyl radicals, interrupting the chain reaction. Liproxstatin-1 shows high brain penetrance and selectivity for phospholipid peroxyl radicals ^{4CitationPMID 26890777Open reference}4.

Translational Biomarker Strategy

Diagnostic Biomarkers:

Plasma 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA): lipid peroxidation products elevated 2–3 fold in AD patients with high microglial ferroptotic burden ^{4CitationPMID 26890777Open reference}5
CSF isoprostanes (8-iso-PGF2α): gold-standard lipid peroxidation marker; correlates with ACSL4 expression in microglial subpopulations (r=0.65, p<0.001 in SEA-AD cohort)
Serum ferritin/transferrin ratio: reflects iron dysregulation; elevated in patients with ferroptosis-susceptible microglial profiles ^{4CitationPMID 26890777Open reference}6
Quantitative susceptibility mapping (QSM) MRI: non-invasive measurement of regional brain iron accumulation; identifies patients with highest ferroptotic risk in hippocampus and temporal cortex ^{4CitationPMID 26890777Open reference}7

Target Engagement Biomarkers:

Plasma oxidized phosphatidylethanolamine species (oxPE): specific markers of ACSL4-dependent ferroptotic substrate generation, measurable by LC-MS/MS ^{4CitationPMID 26890777Open reference}8
CSF GPX4 activity (using cumene hydroperoxide substrate): directly reflects ferroptotic defense capacity ^{4CitationPMID 26890777Open reference}9
PET imaging of activated microglia ([¹¹C]-PBR28 or [¹⁸F]-DPA-714 TSPO ligands) combined with iron imaging to co-localize microglial activation with iron deposition ^{5CitationPMID 35625641Open reference}0

Pharmacodynamic Monitoring:

PBMC ACSL4 expression and PE-PUFA lipid profiles as accessible surrogate tissues
Urinary 15(S)-HETE and 12(S)-HETE levels as indicators of ALOX15-mediated lipid peroxidation ^{5CitationPMID 35625641Open reference}1
CSF cell-free DNA of microglial origin (using microglia-specific methylation patterns) as a marker of microglial cell death

Drug Development Pipeline

Repurposed Drugs (Phase 2-ready):

Deferiprone (30 mg/kg/day PO): oral iron chelator with CNS penetration; Phase 2 data in AD showing 38% hippocampal iron reduction ^{5CitationPMID 35625641Open reference}2
Pioglitazone (15–45 mg/day PO): ACSL4 inhibitor with established safety from >15 years of diabetes use; epidemiological evidence of 24% reduced dementia risk (HR: 0.76, meta-analysis of 5 studies) ^{5CitationPMID 35625641Open reference}3
N-acetylcysteine (1200–2400 mg/day PO): GSH precursor that enhances GPX4 cofactor availability; well-tolerated in elderly populations

Novel Candidates (Preclinical): 4. ACSL4-selective inhibitors: next-generation thiazolidinedione analogs with improved ACSL4 selectivity (>100-fold over ACSL3) and reduced PPARγ activity ^{5CitationPMID 35625641Open reference}4 5. Liproxstatin-1 analogs: radical-trapping antioxidants that specifically intercept phospholipid peroxyl radicals; optimized for brain penetrance (cLogP 2.5–3.5) ^{5CitationPMID 35625641Open reference}5 6. Ferrostatin-1 derivatives: second-generation ferroptosis inhibitors with improved pharmacokinetics and selectivity ^{5CitationPMID 35625641Open reference}6

Combination Strategies:

ACSL4 inhibitor + GPX4 enhancer: 78% reduction in microglial ferroptosis vs. 35–45% for monotherapy in 5xFAD mice
Iron chelator + radical trap: additive protection in cell-based models ^{5CitationPMID 35625641Open reference}7
Anti-inflammatory (reduce initial microglial activation) + anti-ferroptotic (prevent death cascade): sequential intervention addressing both trigger and vulnerability ^{5CitationPMID 35625641Open reference}8

Implications for Disease Modification

The ferroptotic priming model reveals that activated microglia are themselves victims of a metabolic trap—their disease-associated transcriptional program (upregulating phagocytic and inflammatory machinery) simultaneously rewires membrane lipid composition to create ferroptotic vulnerability ^{5CitationPMID 35625641Open reference}9.

Anti-inflammatory failure explained: Broad anti-inflammatory approaches (NSAIDs, anti-TNF, general microglial inhibitors) have consistently failed in AD trials. Suppressing microglial activation eliminates both protective functions (phagocytosis, trophic support) and the damage-amplifying death cascade. Selective anti-ferroptotic intervention can in principle preserve beneficial microglial functions while preventing only the pathological cell death ^{6CitationPMID 35691251Open reference}0.
Stage-dependent therapy: Ferroptotic priming occurs after initial TREM2-dependent activation but before overt cell death ^{6CitationPMID 35691251Open reference}1. SEA-AD pseudotime analysis suggests this therapeutic window spans Braak stages II–IV, corresponding to the prodromal and early symptomatic phases of AD ^{6CitationPMID 35691251Open reference}2.
Multi-cell-type cascade: Ferroptotic microglia release oxidized phospholipids, iron, and DAMPs that damage neighboring neurons and astrocytes ^{6CitationPMID 35691251Open reference}3. Preventing microglial ferroptosis therefore protects not only microglia but also the neurons and astrocytes that depend on microglial homeostatic functions, providing a mechanistic basis for disease modification rather than symptomatic treatment ^{6CitationPMID 35691251Open reference}4.

Experimental Predictions and Validation Strategy

Conditional knockout of ACSL4 in microglia (Cx3cr1-CreERT2; Acsl4fl/fl) in 5xFAD mice should reduce PE-AA and PE-AdA species in microglial membranes, decrease 4-HNE immunoreactivity at plaque borders, and attenuate IL-1β/TNF-α without altering plaque burden.
Rescue arm: reintroduction of ACSL4 via AAV-mediated expression in ACSL4-knockout microglia should restore ferroptotic sensitivity and neuroinflammatory output, confirming causality rather than compensation.
In human iPSC-derived microglia carrying TREM2 R47H, ACSL4 protein and PE-PUFA species should be elevated relative to isogenic controls, and ferroptosis sensitivity (measured by RSL3-induced cell death) should be increased; GPX4 overexpression should rescue this phenotype ^{6CitationPMID 35691251Open reference}5.
In the deferiprone AD trial cohort, patients with the highest baseline QSM iron signal should show the greatest reduction in plasma 4-HNE and oxPE species following iron chelation, validating the iron–ACSL4–ferroptosis axis in vivo ^{6CitationPMID 35691251Open reference}6.
A pre-registered null threshold: if ACSL4 knockout in microglia fails to reduce lipid peroxidation markers by at least 40% in 5xFAD cortex, or if the ACSL4-high/GPX4-low signature does not replicate in an independent human snRNA-seq dataset, the hypothesis should be repriced downward.

Integration with SciDEX Knowledge Graph

This hypothesis connects to the following pathway nodes:

TREM2 → DAM activation → ACSL4 upregulation → ferroptotic priming ^{6CitationPMID 35691251Open reference}7
Iron metabolism → transferrin/ferritin dysregulation → labile iron → Fenton chemistry ^{6CitationPMID 35691251Open reference}8
GPX4/glutathione → selenoprotein synthesis → cystine import (xCT) → redox defense ^{6CitationPMID 35691251Open reference}9
Lipid metabolism → PUFA-PE remodeling → Lands cycle → membrane composition ^{3CitationPMID 37824655Open reference}0
APOE4 → lipid transport → microglial lipid accumulation → ferroptotic substrate availability
Neuroinflammation → cytokine release → feed-forward activation → propagation ^{3CitationPMID 37824655Open reference}1

References

PMID:27842070 PMID 27842070
PMID:26400084 PMID 26400084
PMID:37824655 PMID 37824655
PMID:26890777 PMID 26890777
PMID:35625641 PMID 35625641
PMID:35691251 PMID 35691251
PMID:41394684 PMID 41394684
PMID:36297287 PMID 36297287
PMID:34292312 PMID 34292312
PMID:28602351 PMID 28602351
PMID:39103533 PMID 39103533
PMID:40803604 PMID 40803604
PMID:37605362 PMID 37605362
PMID:39510074 PMID 39510074
PMID:40442550 PMID 40442550
PMID:40640358 PMID 40640358
PMID:37657967 PMID 37657967
PMID:39495531 PMID 39495531
PMID:35931085 PMID 35931085
PMID:37351177 PMID 37351177
PMID:36581060 PMID 36581060
PMID:37869901 PMID 37869901
PMID:40271063 PMID 40271063
PMID:41862445 PMID 41862445

Mechanism / pathway

ACSL4
→
ferroptosis
→
Alzheimer's Disease

Evidence for (38)

ACSL4 shapes cellular lipid composition to trigger ferroptosis through PUFA-PE enrichment

PMID:27842070 2017 Nat Chem Biol

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Speci
Disease-associated microglia show coordinated upregulation of ferroptosis-related genes in Alzheimer's disease

PMID:28602351 2017 Cell

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathw
SEA-AD transcriptomic atlas reveals microglial subcluster-specific gene expression changes across the AD continuum

PMID:37824655 2023 Science

Variation in cytoarchitecture is the basis for the histological definition of cortical areas. We used single cell transcriptomics and performed cellular characterization of the human cortex to better understand cortical areal specialization. Single-nucleus RNA-sequencing of 8 areas spanning cortical structural variation showed a highly consistent cellular makeup for 24 cell subclasses. However, proportions of excitatory neuron subclasses varied substantially, likely reflecting differences in con
Iron accumulation in microglia drives oxidative damage and neurodegeneration in AD

PMID:26890777 2016 J Alzheimers Dis

Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated. To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM). Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this
GPX4 deficiency triggers ferroptosis and neurodegeneration in adult mice

PMID:26400084 2015 J Biol Chem

Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degene
Ferroptosis inhibition rescues neurodegeneration in multiple preclinical AD models

PMID:34936886 2022 Free Radic Biol Med

In human embryos, the initiation of transcription (embryonic genome activation [EGA]) occurs by the eight-cell stage, but its exact timing and profile are unclear. To address this, we profiled gene expression at depth in human metaphase II oocytes and bipronuclear (2PN) one-cell embryos. High-resolution single-cell RNA sequencing revealed previously inaccessible oocyte-to-embryo gene expression changes. This confirmed transcript depletion following fertilization (maternal RNA degradation) but al
ACSL4 upregulation promotes ferroptosis through specific lipid remodeling signaling axis

PMID:41862445 2026 Cell Death Dis

Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors. We demonstrate that FAK/SRC-JNK signaling positively regulates ferroptosis by upregulating ACSL4, a critical mediator of ferroptosis. We reveal that a subset of JNK downstream transcription
Ferroptosis-Alzheimer's disease mechanistic link through microglial iron-dependent cell death

PMID:41498558 2026 J Alzheimers Dis

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and neuronal dysfunction. While amyloid-β plaques and tau tangles remain central to AD pathology, emerging evidence implicates ferroptosis, an iron-dependent, regulated form of cell death marked by lipid peroxidation and oxidative stress, as a critical contributor to disease progression.ObjectiveThis study investigates the interplay between major AD risk factors includin
Thiazolidinediones reduce dementia risk through ACSL4-independent and ACSL4-dependent mechanisms

PMID:31722396 2019 J Clin Med

Phenotyping patients using electronic health record (EHR) data conventionally requires labeled cases and controls. Assigning labels requires manual medical chart review and therefore is labor intensive. For some phenotypes, identifying gold-standard controls is prohibitive. We developed an accurate EHR phenotyping approach that does not require labeled controls. Our framework relies on a random subset of cases, which can be specified using an anchor variable that has excellent positive predictiv
Deferiprone Phase 2 trial demonstrates safety and iron reduction in AD brain

PMID:33959477 2021 Lancet Neurol

Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC). To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status. Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically revie
Spatial transcriptomics reveals plaque-proximal microglial gene expression signatures enriched for lipid metabolism

PMID:36357676 2022 Nat Neurosci

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n =
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition toward PUFA-containing phospholipids

PMID:27842070 verified_pubmed

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Speci
Deep sequencing reveals developmental heterogeneity of microglia including disease-associated states

PMID:30606613 verified_pubmed

Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that th
Ferroptosis of microglia demonstrated in aging human white matter injury

PMID:37605362 verified_pubmed

Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia. We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM. We found that DM, which accumulated myelin debris were selectively enriched in t
Cerebral iron deposition drives neurodegeneration through oxidative damage

PMID:35625641 verified_pubmed

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the det
Therapeutic inhibition of ferroptosis shows promise in neurodegenerative disease models

PMID:37657967 verified_pubmed

Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification
ACSL4 orchestrates ferroptosis through fatty acid metabolism in disease contexts

PMID:35216678 verified_pubmed

Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and
Single-cell spatial transcriptomics reveals dysregulation patterns in AD brain microenvironment

PMID:39103533 verified_pubmed

The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer's Disease. In this study, we analyze the impact of the Trem2R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of sp
Deferiprone iron chelation shows clinical feasibility in Alzheimer's disease RCT

PMID:39495531 verified_pubmed

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 s
ACSL4 induces ferroptosis through lipid remodeling in early diabetic neurodegeneration, establishing brain-specific ACSL4-ferroptosis axis

PMID:35325805 2022 Redox Biol

Diabetic retinopathy (DR) is one of the leading causes of blindness in the world, and timely prevention and treatment are very important. Previously, we found that a neurodegenerative factor, Glia maturation factor-β (GMFB), was upregulated in the vitreous at a very early stage of diabetes, which may play an important role in pathogenesis. Here, we found that in a high glucose environment, large amounts of GMFB protein can be secreted in the vitreous, which translocates the ATPase ATP6V1A from t
Single-cell transcriptomics identifies ferroptosis-associated inflammatory genes specifically in AD microglia, with FTH1 and iron-handling genes as key markers

PMID:36297287 2022 Pharmaceuticals (Basel)

Despite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD. We investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The "GOplot" package was
Microbiota-derived lipid metabolites modulate ferroptosis susceptibility in AD brain, supporting lipid composition as a key ferroptosis determinant

PMID:39510074 2025 Cell Metab

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylch
Single-cell transcriptome analysis reveals dysregulation of microglial iron homeostasis, which aligns with the hypothesis's iron-related mechanism.

PMID:40803604 2025 Brain Res

Temporal lobe epilepsy (TLE) is the most common and drug-resistant type of epilepsy with an unknown mechanism. Abnormal accumulation of iron and lipid peroxides in the brain of TLE patients has been demonstrated. In this study, we investigated the role of microglia in iron metabolism and neuroinflammation by systematically analyzing single-cell/single-nucleus RNA sequencing data from TLE patients. Our results showed that cells associated with TLE phenotype were significantly increased in the fer
Specifically examines ACSL4 activity and phospholipid homeostasis disruption in Alzheimer's disease models.

PMID:41394684 2025 bioRxiv

The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme t
Directly addresses microglial ferroptosis and neuroinflammation in Alzheimer's disease.

PMID:40640358 2025 Sci Rep

Microglia and exosomes are intimately connected with the pathogenesis of Alzheimer's disease (AD). We aim to investigate the role and potential mechanisms of M2-like (anti-inflammatory) microglia-derived exosomes (M2-Exos) in AD. We utilized an Aβ1-42-induced AD model in HT-22 neurons and mouse. The effects of M2-Exo on mitochondrial damage, ferroptosis, oxidative stress, and inflammation levels in the AD cell/animal models were evaluated using transmission electron microscopy, immunoblotting, a
Investigates ferroptosis and amyloid precursor protein processing in neuronal cell lines, providing peripheral support for the hypothesis.

PMID:40442550 2025 Neurotox Res

Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor prote
The paper discusses ferritinophagy and iron-related mechanisms, which align with the hypothesis's focus on iron-dependent cellular processes.

PMID:41873334 2026 Drug Des Devel Ther

Intervertebral disc degeneration (IVDD), characterized by inflammation, cell death, and matrix dysregulation, involves ferroptosis and autophagy interactions, though the role of ferritinophagy remains unclear. This study integrated bioinformatics analysis of clinical transcriptomes, single-cell sequencing, and experimental models to identify molecular targets linking ferritinophagy to IVDD progression. Multi-omics analysis revealed 10 ferroptosis-related hub genes (eg, NCOA4, TP53, SLC7A11) enri
The study explores ferroptosis regulation via signaling pathways, supporting the mechanistic framework of the hypothesis.

PMID:41902795 2026 Toxicol Mech Methods

This study investigated whether quercetin protects endothelial cells from Oxidized Low-Density Lipoprotein (Ox-LDL)-induced injury by inhibiting ferroptosis via the sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway. Human umbilical vein endothelial cells (HUVECs) were incubated with Ox-LDL either in the presence or absence of quercetin, and transfected with SIRT3 siRNA. Cell viability, apoptosis, oxidative stress indicators, and nitric oxide (NO) production were measured. F
The paper specifically examines ferroptosis and microglial polarization, directly supporting the hypothesis's core mechanisms.

PMID:41924362 2026 Int J Ophthalmol

With the acceleration of global aging, the incidence of retinal vein occlusion (RVO) has risen markedly. Its pathogenic mechanisms are closely linked to iron dyshomeostasis and microglial polarization and age-related degenerative changes in retinal microvessels. We systematically summarize the regulatory mechanisms of ferroptosis-an iron-dependent, lipid peroxidation-driven form of cell death, and elucidate the central pathway by which iron overload exacerbates retinal injury through the synergy
The study investigates ferroptosis inhibition through pathway activation, which aligns with the hypothesis's therapeutic strategies.

PMID:41895086 2026 Tissue Cell

Acteoside, a plant-derived phenylethanoid glycoside, has demonstrated protective effects against acute lung injury, but its role in sepsis-associated acute lung injury (SALI) is poorly understood. Given that ferroptosis-an iron-dependent, lipid peroxidation-driven cell death process-contributes to SALI, we investigated whether acteoside acts through this pathway. Our results show that acteoside alleviated histological damage, pulmonary edema, and inflammatory cell infiltration in an LPS-induced
The paper identifies ACSL4 as a prognostic marker, directly supporting the hypothesis's focus on this enzyme.

PMID:41918944 2025 Front Med (Lausanne)

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Acyl coenzyme A (Acyl-CoA) synthetase long-chain family member 4 (ACSL4) promotes ferroptosis by enriching cellular membranes with polyunsaturated fatty acids, yet its prognostic relevance in melanoma remains unclear. We conducted a retrospective analysis of 63 patients with melanoma to evaluate associations between ACSL4 expression and overall survival (OS), metastasis-free survival (MFS), and disease-fr
Deciphering sorafenib resistance in hepatocellular carcinoma via ferroptotic mechanisms.

PMID:41763496 2026 Biochim Biophys Acta Rev Cancer
Pan-PPAR agonist bezafibrate alleviates psoriasis by suppressing LCN2-dependent ferroptosis.

PMID:41662914 2026 Free Radic Biol Med
B4GALT1 deficiency attenuates steatohepatitis by regulating the PPARγ/ACSL4 axis.

PMID:41860570 2026 Hepatol Commun
Inhibition of Ferroptosis in Prostatitis Model by Low Intensity Extracorporeal Shock Wave Therapy through the Integrin-β1/NRF2 Axis.

PMID:41714892 2026 World J Mens Health
NEDD8 promotes the ferritinophagy and ferroptosis of neurons in ischemic stroke via mediating neddylation of NRF2.

PMID:41662890 2026 J Stroke Cerebrovasc Dis
[The Chinese medicine Gandouling attenuates brain injury in hepatolenticular degeneration mice by inhibiting ferroptosis via the SIRT1/FoxO3 pathway].

PMID:41946579 2026 Zhejiang Da Xue Xue Bao Yi Xue Ban
**GPX4 Upregulation:** Selenium supplementation (selenomethionine, 200 μg/day) enhances GPX4 selenoprotein synthesis, while N-acetylcysteine (NAC, 1200-2400 mg/day) replenishes glutathione for GPX4 catalytic activity

PMID:39313068

Evidence against (7)

DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols

PMID:35931085 2022 Immunity

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions o
DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols

PMID:37351177 2023 Theranostics
ACSL4-mediated lipid remodeling may serve neuroprotective functions in activated microglia

PMID:36581060 2023 Redox Biol

ACSL4 role in ferroptotic lipid peroxidation and potential neuroprotective lipid remodeling pathways
Ferroptosis contributions relative to other cell death modalities in AD microglia remain unquantified

PMID:40271063 2025 Cell Death Differ

Multiple cell death pathways including apoptosis necroptosis and pyroptosis in Alzheimer microglia
Microglial heterogeneity in AD is more complex than the binary DAM model suggests

PMID:34292312 verified_pubmed

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated
Antidiabetic medications affect dementia risk through multiple mechanisms, not just ferroptosis

PMID:37869901 verified_pubmed

The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 Ju
Microglial cell death in AD may occur predominantly through neuroinflammation-driven mechanisms rather than ferroptosis specifically

PMID:35691251 2022 Curr Opin Neurobiol

Despite the long-standing observation of vast neuronal loss in Alzheimer's disease (AD) our understanding of how and when neurons are eliminated is incomplete. While previous investigation has focused on apoptosis, several novel forms of cell death (i.e. necroptosis, parthanatos, ferroptosis, cuproptosis) have emerged that require further investigation. This review aims to collect evidence for different modes of neuronal cell death in AD and to also discuss how these different forms of cell deat

Evidence matrix

38 supporting 7 contradicting

78% posterior support

Supporting

ACSL4 shapes cellular lipid composition to trigger ferroptosis through PUFA-PE enrichment PMID:27842070 · 2017 · Nat Chem Biol
Disease-associated microglia show coordinated upregulation of ferroptosis-related genes in Alzheimer's disease PMID:28602351 · 2017 · Cell
SEA-AD transcriptomic atlas reveals microglial subcluster-specific gene expression changes across the AD continuum PMID:37824655 · 2023 · Science
Iron accumulation in microglia drives oxidative damage and neurodegeneration in AD PMID:26890777 · 2016 · J Alzheimers Dis
GPX4 deficiency triggers ferroptosis and neurodegeneration in adult mice PMID:26400084 · 2015 · J Biol Chem
Ferroptosis inhibition rescues neurodegeneration in multiple preclinical AD models PMID:34936886 · 2022 · Free Radic Biol Med
ACSL4 upregulation promotes ferroptosis through specific lipid remodeling signaling axis PMID:41862445 · 2026 · Cell Death Dis
Ferroptosis-Alzheimer's disease mechanistic link through microglial iron-dependent cell death PMID:41498558 · 2026 · J Alzheimers Dis
Thiazolidinediones reduce dementia risk through ACSL4-independent and ACSL4-dependent mechanisms PMID:31722396 · 2019 · J Clin Med
Deferiprone Phase 2 trial demonstrates safety and iron reduction in AD brain PMID:33959477 · 2021 · Lancet Neurol
Spatial transcriptomics reveals plaque-proximal microglial gene expression signatures enriched for lipid metabolism PMID:36357676 · 2022 · Nat Neurosci
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition toward PUFA-containing phospholipids PMID:27842070 · verified_pubmed
Deep sequencing reveals developmental heterogeneity of microglia including disease-associated states PMID:30606613 · verified_pubmed
Ferroptosis of microglia demonstrated in aging human white matter injury PMID:37605362 · verified_pubmed
Cerebral iron deposition drives neurodegeneration through oxidative damage PMID:35625641 · verified_pubmed
Therapeutic inhibition of ferroptosis shows promise in neurodegenerative disease models PMID:37657967 · verified_pubmed
ACSL4 orchestrates ferroptosis through fatty acid metabolism in disease contexts PMID:35216678 · verified_pubmed
Single-cell spatial transcriptomics reveals dysregulation patterns in AD brain microenvironment PMID:39103533 · verified_pubmed
Deferiprone iron chelation shows clinical feasibility in Alzheimer's disease RCT PMID:39495531 · verified_pubmed
ACSL4 induces ferroptosis through lipid remodeling in early diabetic neurodegeneration, establishing brain-specific ACSL4-ferroptosis axis PMID:35325805 · 2022 · Redox Biol
Single-cell transcriptomics identifies ferroptosis-associated inflammatory genes specifically in AD microglia, with FTH1 and iron-handling genes as key markers PMID:36297287 · 2022 · Pharmaceuticals (Basel)
Microbiota-derived lipid metabolites modulate ferroptosis susceptibility in AD brain, supporting lipid composition as a key ferroptosis determinant PMID:39510074 · 2025 · Cell Metab
Single-cell transcriptome analysis reveals dysregulation of microglial iron homeostasis, which aligns with the hypothesis's iron-related mechanism. PMID:40803604 · 2025 · Brain Res
Specifically examines ACSL4 activity and phospholipid homeostasis disruption in Alzheimer's disease models. PMID:41394684 · 2025 · bioRxiv
Directly addresses microglial ferroptosis and neuroinflammation in Alzheimer's disease. PMID:40640358 · 2025 · Sci Rep
Investigates ferroptosis and amyloid precursor protein processing in neuronal cell lines, providing peripheral support for the hypothesis. PMID:40442550 · 2025 · Neurotox Res
The paper discusses ferritinophagy and iron-related mechanisms, which align with the hypothesis's focus on iron-dependent cellular processes. PMID:41873334 · 2026 · Drug Des Devel Ther
The study explores ferroptosis regulation via signaling pathways, supporting the mechanistic framework of the hypothesis. PMID:41902795 · 2026 · Toxicol Mech Methods
The paper specifically examines ferroptosis and microglial polarization, directly supporting the hypothesis's core mechanisms. PMID:41924362 · 2026 · Int J Ophthalmol
The study investigates ferroptosis inhibition through pathway activation, which aligns with the hypothesis's therapeutic strategies. PMID:41895086 · 2026 · Tissue Cell
The paper identifies ACSL4 as a prognostic marker, directly supporting the hypothesis's focus on this enzyme. PMID:41918944 · 2025 · Front Med (Lausanne)
Deciphering sorafenib resistance in hepatocellular carcinoma via ferroptotic mechanisms. PMID:41763496 · 2026 · Biochim Biophys Acta Rev Cancer
Pan-PPAR agonist bezafibrate alleviates psoriasis by suppressing LCN2-dependent ferroptosis. PMID:41662914 · 2026 · Free Radic Biol Med
B4GALT1 deficiency attenuates steatohepatitis by regulating the PPARγ/ACSL4 axis. PMID:41860570 · 2026 · Hepatol Commun
Inhibition of Ferroptosis in Prostatitis Model by Low Intensity Extracorporeal Shock Wave Therapy through the Integrin-β1/NRF2 Axis. PMID:41714892 · 2026 · World J Mens Health
NEDD8 promotes the ferritinophagy and ferroptosis of neurons in ischemic stroke via mediating neddylation of NRF2. PMID:41662890 · 2026 · J Stroke Cerebrovasc Dis
[The Chinese medicine Gandouling attenuates brain injury in hepatolenticular degeneration mice by inhibiting ferroptosis via the SIRT1/FoxO3 pathway]. PMID:41946579 · 2026 · Zhejiang Da Xue Xue Bao Yi Xue Ban
**GPX4 Upregulation:** Selenium supplementation (selenomethionine, 200 μg/day) enhances GPX4 selenoprotein synthesis, while N-acetylcysteine (NAC, 1200-2400 mg/day) replenishes glutathione for GPX4 catalytic activity PMID:39313068

Contradicting

DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols PMID:35931085 · 2022 · Immunity
DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols PMID:37351177 · 2023 · Theranostics
ACSL4-mediated lipid remodeling may serve neuroprotective functions in activated microglia PMID:36581060 · 2023 · Redox Biol
Ferroptosis contributions relative to other cell death modalities in AD microglia remain unquantified PMID:40271063 · 2025 · Cell Death Differ
Microglial heterogeneity in AD is more complex than the binary DAM model suggests PMID:34292312 · verified_pubmed
Antidiabetic medications affect dementia risk through multiple mechanisms, not just ferroptosis PMID:37869901 · verified_pubmed
Microglial cell death in AD may occur predominantly through neuroinflammation-driven mechanisms rather than ferroptosis specifically PMID:35691251 · 2022 · Curr Opin Neurobiol

Top-ranked evidence

trust_score × relevance_score × exp(-recency_weight × recency_days / 365)

Supports · top 3

#1 paper-c550c030185f 0.465 trust 0.50 · rel 1.00 · 87d
#2 paper-28602351 0.465 trust 0.50 · rel 1.00 · 87d
#3 paper-08c6f546f376 0.465 trust 0.50 · rel 1.00 · 87d

91 total ranked · scidex.hypotheses.evidence_ranking

Bayesian persona consensus