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.
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for GPX4; yet. Search RCSB →
Median TPM across 13 brain regions for GPX4; SLC7A11; ACSL4; TFRC; FTH1; FTL from GTEx v10.
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.
| 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 |