Combining NAC (GSH precursor/peroxynitrite scavenger) with ferrostatin-1 (specific ferroptosis inhibitor) provides dual blockade against convergent injury pathways post-cardiac arrest. While mechanistically interesting, Ferrostatin-1 is not a clinical candidate (unknown PK, toxicity, BBB penetration). Attribution problem is compounded: if the combination works, which component mediates which effect? The peroxynitrite-GPX4 crosstalk is plausible but incompletely validated as primary mechanism in post-CA injury.
Curated pathway from expert analysis
flowchart TD
A["GSH Depletion<br/>Glutathione Synthesis Impairment"]
B["GPX4 Inactivation<br/>Phospholipid Peroxidase Loss"]
C["Lipid Peroxidation<br/>Polyunsaturated Fatty Acid Radical Chain"]
D["Peroxynitrite Formation<br/>Nitric Oxide plus Superoxide Convergence"]
E["Ferroptotic Cell Death<br/>Iron-Dependent Membrane Rupture"]
F["NAC Supplementation<br/>GSH Precursor and Peroxynitrite Scavenger"]
G["Ferrostatin-1<br/>Lipid Radical Termination and Ferroptosis Block"]
A --> B
B --> C
D --> C
C --> E
F -.->|"restores"| A
G -.->|"inhibits"| C
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#81c784,color:#81c784
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CONVERGENT: yet. Search RCSB →
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 Convergent: GSH depletion + peroxynitrite + lipid radical accumulation.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we use a rat cardiac arrest model (VF induction, 6min no-flow, resuscitation) and administer NAC (150mg/kg IP at 5min post-ROSC), ferrostatin-1 (10mg/kg IP at 5min post-ROSC), or combination for 3 | 4-HNE+ cell density (cells/mm^2) in motor cortex; neuron count in caudo-putamen; neurodeficit score; combination expected to show >50% reduction in 4-HNE vs. mo | — no observation — | pending | 0.55 |
| IF we stratify post-cardiac arrest patients by baseline plasma nitrotyrosine levels (high vs. low tertiles) and administer NAC (150mg/kg IV bolus then 50mg/kg/h for 24h) vs. placebo within 6 hours of | Neurofilament light chain (NfL) concentration at 72h post-ROSC; expected 25% reduction in high-nitrotyrosine group | — no observation — | pending | 0.45 |