Motor neurons with ALS proteostasis stress may upregulate ACSL4/LPCAT3-dependent PUFA-phospholipid remodeling, creating membranes that are unusually sensitive to iron-catalyzed peroxidation. Inhibiting this substrate-loading step should lower ferroptosis without broad iron depletion.
Curated pathway from expert analysis
flowchart TD A["ALS proteostasis stress"] --> B["ACSL4 upregulation"] B --> C["LPCAT3 activity enhanced"] C --> D["PUFA-phospholipid remodeling"] D --> E["Ferroptosis-prone membrane lipid composition"] E --> F["Iron accumulation in motor neurons"] F --> G["Iron-catalyzed lipid peroxidation"] G --> H["Ferroptosis execution"] H --> I["Motor neuron degeneration"] J["ACSL4 inhibition"] --> K["Reduced PUFA membrane loading"] K --> L["Lower ferroptosis sensitivity"] J -->|" blocks "| C J -->|" prevents "| D L --> M["Protected motor neuron survival"]
No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ACSL4 yet. Search RCSB →
Median TPM across 13 brain regions for ACSL4 from GTEx v10.
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 ACSL4.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.