ID: h-dd0ccf93cb
Hypothesis
Iron-driven lipid peroxidation and GPX4 failure create a ferroptotic amplification loop
Labile Fe2+ converts H2O2 into hydroxyl radicals, driving phospholipid peroxidation that consumes GSH and disables GPX4-dependent detoxification.
EvidencePending (0%)📖 8 cit🗣 1 debates✓ 8 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
Labile Fe2+ converts H2O2 into hydroxyl radicals, driving phospholipid peroxidation that consumes GSH and disables GPX4-dependent detoxification. Membrane damage, mitochondrial failure, and further ROS production then increase the substrate load for Fenton chemistry, reinforcing ferroptotic commitment. This loop is especially plausible in substantia nigra neurons with high iron and oxidative burden.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["GPX4; SLC7A11; ACSL4; TFRC; FTH1; FTL<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix8 supports2 contradicts
Supports
Iron is elevated in substantia nigra in PD, supporting a Fenton-chemistry amplification axis.
Supports
Deferiprone reduced iron burden and improved outcomes in PD trials, showing translational relevance.
Supports
Ferroptosis inhibitors protect dopaminergic neurons and GPX4 activity is impaired in PD models.
Supports
SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1.
Supports
GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.
Supports
Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis.
Supports
Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice.
Contradicts
Iron elevation does not by itself prove labile iron is the proximal driver rather than a byproduct of degeneration.
Contradicts
The source paper describes mixed cell-death programs, so ferroptosis may explain only a subset of the loop.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — GPX4;
No curated PDB or AlphaFold mapping for GPX4; yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for GPX4; SLC7A11; ACSL4; TFRC; FTH1; FTL from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for GPX4; SLC7A11; ACSL4; TFRC; FTH1; FTL.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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Timeline
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary neurons from substantia nigra with high labile Fe2+ are treated with the iron chelator deferoxamine (100 μM, 24h), THEN intracellular lipid peroxidation (measured by C11-BODIPY 581/591 oxid | Lipid peroxidation reduced ≥40%; neuronal viability increased ≥25% | — no observation — | pending | 0.78 |
| IF SLC7A11-mediated cystine import is enhanced by neuronal or endothelial SLC7A11 overexpression in an iron-overload model, THEN brain glutathione reserves will increase and ferroptosis markers will d | Reduced glutathione increases by at least 30%, PTGS2 and 4-HNE fall by at least 35%, and rotarod latency improves by at least 20% compared with matched high-iro | — no observation — | pending | 0.72 |
🔮 Falsifiable Predictions (2)
pendingconf 78%
IF primary neurons from substantia nigra with high labile Fe2+ are treated with the iron chelator deferoxamine (100 μM, 24h), THEN intracellular lipid peroxidation (measured by C11-BODIPY 581/591 oxidation via flow cytometry) will decrease by ≥40% compared to vehicle-treated neurons, and cell viabil
Predicted outcome: Lipid peroxidation reduced ≥40%; neuronal viability increased ≥25%
Falsification: No significant reduction in lipid peroxidation markers (C11-BODIPY, 4-HNE immunostaining, or MDA assay) OR no improvement in neuronal viability after iron chelation, indicating iron-dependent amplific
pendingconf 72%
IF SLC7A11-mediated cystine import is enhanced by neuronal or endothelial SLC7A11 overexpression in an iron-overload model, THEN brain glutathione reserves will increase and ferroptosis markers will decline, with improved motor performance relative to iron-overload controls.
Predicted outcome: Reduced glutathione increases by at least 30%, PTGS2 and 4-HNE fall by at least 35%, and rotarod latency improves by at least 20% compared with matche
Falsification: If increasing SLC7A11 expression fails to raise glutathione or lower ferroptosis markers despite confirmed transgene expression, then cystine import is not the limiting node in the proposed ferroptoti
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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