EP4 Receptor Agonism for SLC7A11 Upregulation
🧪 Overview
PGE₂ signaling through EP4 receptor transcriptionally upregulates SLC7A11, enhancing cystine uptake and GSH synthesis to convert ferroptosis-susceptible brain cells to resistant phenotype. However, EP4 signaling is highly pleiotropic (vasodilation, inflammation, platelet inhibition), and any neuroprotection is difficult to attribute specifically to SLC7A11. PGE₂/EP4 signaling may be pro-inflammatory in the acute post-CA setting. EP4 polymorphisms are associated with cardiovascular risk.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["SLC7A11/System Xc-<br/>Cystine-Glutamate Antiporter"]
B["Cystine Import<br/>Glutathione Precursor Supply"]
C["Glutathione Synthesis<br/>GPX4 Antioxidant Capacity"]
D["Lipid Peroxide Detoxification<br/>Ferroptosis Restraint"]
E["Endothelial Tight Junctions<br/>Barrier Integrity Preserved"]
F["AQP4 Polarization<br/>Astrocyte End-foot Support"]
G["Neurovascular Unit Protection<br/>Reduced BBB Leakage"]
H["SLC7A11 Failure<br/>Oxidative Stress and Ferroptosis"]
A --> B
B --> C
C --> D
D --> E
D --> F
E --> G
F --> G
H -.->|"impairs"| A
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style G fill:#1b5e20,stroke:#81c784,color:#81c784
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PTGER4
No curated PDB or AlphaFold mapping for PTGER4 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for PTGER4 (EP4 receptor) → SLC7A11 transcription 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 PTGER4 (EP4 receptor) → SLC7A11 transcription.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary murine cortical neurons or human iPSC-derived neurons are treated with a selective EP4 receptor agonist (e.g., ONO-AE1-329 at 100 nM) for 24 hours under normoxic conditions, THEN intracellu | SLC7A11 protein expression increases ≥40% following EP4 agonism in neuronal cells. | — no observation — | pending | 0.65 |
| IF C57BL/6J mice subjected to permanent middle cerebral artery occlusion (pMCAO) receive twice-daily intraperitoneal EP4 agonist (ONO-AE1-329, 3 mg/kg) for 7 days starting 1 hour post-stroke, THEN bra | Brain infarct volume decreases ≥35% and cortical GSH/GSSG ratio increases ≥50% with EP4 agonist treatment post-stroke. | — no observation — | pending | 0.55 |
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |