ID: hypothesis-h-3156f6bcd349
Hypothesis

GPX4 reserve failure gates selective ALS motor-neuron ferroptosis

ALS-linked proteostasis stress lowers effective GPX4 reserve in vulnerable motor neurons, allowing oxidized phospholipids to cross a ferroptotic death threshold.
🧬 GPX4🩺 neurodegeneration🎯 Composite 74%💱 $0.59▼18.3%proposed
EvidenceStrong (70%)📖 8 cit🗣 1 debates 8 support 2 oppose
✓ All Quality Gates Passed
Mechanistic 0.82 (15%) Evidence 0.72 (15%) Novelty 0.61 (12%) Feasibility 0.72 (12%) Impact 0.86 (12%) Druggability 0.64 (10%) Safety 0.58 (8%) Competition 0.55 (6%) Data Avail. 0.65 (5%) Reproducible 0.62 (5%) KG Connect 0.58 (8%) 0.745 composite
🏆 ChallengeResolve: GPX4 Reserve Enhancement Blocks Selective Motor Neuron Ferroptosis in A$500K →

🧪 Overview

ALS-linked proteostasis stress lowers effective GPX4 reserve in vulnerable motor neurons, allowing oxidized phospholipids to cross a ferroptotic death threshold. Restoring GPX4 activity or glutathione availability should rescue motor-neuron survival more strongly than generic antioxidants.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

flowchart TD
A["ALS proteostasis stress"] --> B["GPX4 reserve depletion"]
A --> C["Glutathione depletion"]
B --> D["Oxidized phospholipid accumulation"]
C --> D
D --> E{"Ferroptotic threshold crossed?"}
E -->|" Yes "| F["Ferroptosis activation"]
F --> G["Motor neuron death"]
E -->|" No "| H["Motor neuron survival"]
B --> I["GPX4 activity restoration"]
C --> J["Glutathione supplementation"]
I --> K["Neuroprotection"]
J --> K
K -->|" Rescues "| G

style A fill:#ffd54f,color:#0d0d1a
style B fill:#4fc3f7,color:#0d0d1a
style C fill:#4fc3f7,color:#0d0d1a
style D fill:#4fc3f7,color:#0d0d1a
style E fill:#ef5350,color:#0d0d1a
style F fill:#ef5350,color:#0d0d1a
style G fill:#ef5350,color:#0d0d1a
style I fill:#81c784,color:#0d0d1a
style J fill:#81c784,color:#0d0d1a
style K fill:#81c784,color:#0d0d1a

⚖️ Evidence

⚖️ Evidence Matrix6 supports1 contradicts
Supports
Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity.
Nat Cancer2025PMID:40108413
Supports
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.
Int J Mol Sci2019PMID:31185581medium
Supports
The genetics of amyotrophic lateral sclerosis.
Curr Opin Neurol2024PMID:38967083medium
Supports
Stress Granules and ALS: A Case of Causation or Correlation?
Adv Neurobiol2018PMID:29916020medium
Supports
Endogenous retroviruses are dysregulated in ALS.
iScience2024PMID:38989463medium
Supports
Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.
Cells2024PMID:38891021medium
Contradicts
The essential elements of Alzheimer's disease.
J Biol Chem2021PMID:33219130
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — GPX4

🧬 PDB 2OBI Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for GPX4 from GTEx v10.

Nucleus accumbens basal ganglia293 Frontal Cortex BA9286 Hypothalamus259 Substantia nigra259 Cortex257 Anterior cingulate cortex BA24257 Caudate basal ganglia230 Spinal cord cervical c-1229median TPM (GTEx v10)

💉 Clinical Trials (1)Relevance: 86%

0
Active
0
Completed
0
Total Enrolled
Unknown·

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for GPX4 →

No DepMap CRISPR Chronos data found for GPX4.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

🏆 Tournament

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📊 Market Indicators

7d Trend
Stable
7d Momentum
▼ 1.0%
Volatility
Medium
0.0333
Events (7d)
3
Price History
▼18.3%

💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

Metadata
_origin{'url': None, 'type': 'internal', 'tracked_at': '2026-04-28T14:43:01.422985'}
descriptionALS-linked proteostasis stress lowers effective GPX4 reserve in vulnerable motor neurons, allowing oxidized phospholipids to cross a ferroptotic death threshold. Restoring GPX4 activity or glutathione
_schema_version1
📊 Evidence Profile
Evidence Balance
+0%
Certainty
5%
Debates
0
Incoming
1
Outgoing
0
0 supporting 0 contradicting 0 neutral
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