Ferroptosis Regulation Project
Overview
Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Distinct from apoptosis, necrosis, and autophagy, ferroptosis involves the accumulation of lipid reactive oxygen species (ROS) when glutathione-dependent lipid repair systems are compromised. The field has exploded since 2020 with discoveries of parallel defense pathways.
Model Species
Primary: Homo sapiens (human)
- UniProt species code: HUMAN
- Best characterized system with therapeutic relevance
- Cancer therapy and neurodegeneration applications
Core Pathway Architecture
1. Lipid Peroxidation Substrates
Genes that supply polyunsaturated fatty acids (PUFAs) to phospholipids:
- ACSL4 - Acyl-CoA synthetase long-chain family member 4 (activates PUFAs)
- LPCAT3 - Lysophosphatidylcholine acyltransferase 3 (incorporates PUFAs into membranes)
2. Iron Metabolism
Iron is essential for lipid peroxidation:
- TFRC - Transferrin receptor (iron import)
- SLC40A1 - Ferroportin (iron export)
- NCOA4 - Nuclear receptor coactivator 4 (ferritinophagy receptor)
- FTH1/FTL - Ferritin heavy/light chains (iron storage)
3. GPX4-Dependent Defense (Classical Pathway)
The glutathione peroxidase system:
- GPX4 - Glutathione peroxidase 4 (THE key ferroptosis suppressor)
- SLC7A11 - Solute carrier family 7 member 11 / xCT (cystine import)
- SLC3A2 - 4F2 heavy chain (xCT partner)
- GSS - Glutathione synthetase
- GCLC/GCLM - Glutamate-cysteine ligase (rate-limiting for GSH synthesis)
4. FSP1/CoQ10 Pathway (Discovered 2019-2020)
GPX4-independent ferroptosis suppression:
- FSP1 (AIFM2) - Ferroptosis suppressor protein 1 (CoQ10 reductase)
- DHODH - Dihydroorotate dehydrogenase (mitochondrial CoQ10 reduction)
5. GCH1/BH4 Pathway (Discovered 2020-2022)
Tetrahydrobiopterin-mediated protection:
- GCH1 - GTP cyclohydrolase 1 (rate-limiting for BH4 synthesis)
- PTS - 6-pyruvoyltetrahydropterin synthase
- SPR - Sepiapterin reductase
6. Transcriptional Regulators
- NFE2L2 (NRF2) - Master antioxidant regulator
- KEAP1 - NRF2 inhibitor
- ATF4 - Integrated stress response transcription factor
- TP53 - p53, context-dependent regulator
7. Membrane Lipid Composition
Genes for Review (Priority Order)
Priority 1: Core Machinery (~8 genes)
| Gene | UniProt | Function |
|---|---|---|
| GPX4 | P36969 | Lipid hydroperoxide reduction |
| SLC7A11 | Q9UPY5 | Cystine/glutamate antiporter |
| ACSL4 | O60488 | PUFA-CoA synthesis |
| FSP1/AIFM2 | Q9BRQ8 | CoQ10-dependent lipid repair |
| DHODH | Q02127 | Mitochondrial CoQ10 reduction |
| GCH1 | P30793 | BH4 synthesis |
| LPCAT3 | Q6NVY1 | PUFA incorporation |
| NCOA4 | Q13772 | Ferritinophagy receptor |
Priority 2: Regulatory Network (~8 genes)
| Gene | UniProt | Function |
|---|---|---|
| NFE2L2 | Q16236 | NRF2 - antioxidant response |
| KEAP1 | Q14145 | NRF2 inhibitor |
| TFRC | P02786 | Iron import |
| FTH1 | P02794 | Iron storage |
| ATF4 | P18848 | Stress response TF |
| SLC40A1 | Q9NP59 | Iron export |
| GCLC | P48506 | GSH synthesis |
| TP53 | P04637 | Context-dependent regulator |
Priority 3: Supporting Genes (~6 genes)
| Gene | UniProt | Function |
|---|---|---|
| SLC3A2 | P08195 | xCT partner (4F2hc) |
| GSS | P48637 | GSH synthesis |
| PTS | Q03393 | BH4 pathway |
| SPR | P35270 | BH4 pathway |
| FADS1 | O60427 | PUFA synthesis |
| ELOVL5 | Q9NYP7 | PUFA elongation |
Key Recent Discoveries (2020+)
- FSP1/CoQ10 pathway (Nature 2019) - GPX4-independent ferroptosis suppression
- DHODH in mitochondria (Nature 2021) - Mitochondrial ferroptosis defense
- GCH1/BH4 pathway (Nature 2022) - Third parallel defense system
- MBOAT1/2 (Nature 2023) - Sex hormone-regulated ferroptosis resistance
- Membrane lipid remodeling (Cell 2020+) - Role of specific phospholipids
Disease Relevance
- Cancer: Ferroptosis induction as therapy; resistance mechanisms
- Neurodegeneration: Ferroptosis in Parkinson's, Huntington's, ALS
- Ischemia-reperfusion: Organ damage
- Kidney disease: Acute kidney injury
Key References
- Stockwell BR et al. (2017) Cell - Foundational review
- Doll S et al. (2019) Nature - FSP1 discovery
- Mao C et al. (2021) Nature - DHODH
- Kraft VAN et al. (2020) ACS Cent Sci - GCH1
- Jiang X et al. (2021) Nat Rev Mol Cell Biol - Comprehensive review
- Chen X et al. (2021) Signal Transduct Target Ther - Mechanisms update
Project Status
- [x] Create gene folders and fetch UniProt/GOA data
- [x] Priority 1 genes review (8/8 genes)
- [x] Priority 2 genes review (8/8 genes)
- [x] Priority 3 genes review (6/6 genes)
- [x] Pathway summary and integration
STATUS
All 22 ferroptosis genes reviewed and validated (2025-12-28)
✓ All gene folders created with UniProt/GOA data
✓ All 22 genes have completed AI reviews
✓ All reviews validated (0 errors)
✓ Pathway summary document created (FERROPTOSIS-pathway.md)
✓ Ready for PR
NOTES
2026-01-19 (codex review)
- [x] GPX4: manual second pass complete;
just validate human [GPX4](../../genes/human/GPX4/GPX4-ai-review.html)clean (info-only aliases) - [x] GPX4: updated HTP/HDA evidence summaries for mitochondrial/nuclear/exosome entries to clarify high-throughput scope; kept ACCEPT for mitochondrion/nucleus, set exosome to UNDECIDED, and set spermatogenesis ISS to UNDECIDED pending direct cached evidence
- [ ] GPX4: follow-up to add explicit primary evidence for nuclear/spermatogenesis localization (e.g., PMID:21618532 nGPX4 nuclear matrix; PMID:19417079 mGPX4 male infertility)
- [x] SLC7A11: manual second pass complete;
just validate human [SLC7A11](../../genes/human/SLC7A11/SLC7A11-ai-review.html)clean (info-only aliases) - [x] SLC7A11: added deep-research support for core antiporter activity to clear validation warning
- [ ] SLC7A11: consider incorporating 2025–2026 disease/regulation papers if needed (e.g., HSPB1 axis in HCC; GPAT4/SLC7A11 platinum resistance in ovarian cancer; CRPC resistance studies)
- [x] ACSL4: manual second pass complete;
just validate human [ACSL4](../../genes/human/ACSL4/ACSL4-ai-review.html)clean (info-only aliases) - [x] ACSL4: added missing supporting_text for membrane/exosome HDA entries to clear validation warning
- [x] ACSL4: folded in 2025 context papers (IBD fibroblast ACSL4; TRIM28/OPTN autophagy control after SCI; H3K27cr–SQSTM1/autophagy control in diabetic wound healing)
- [x] AIFM2/FSP1: manual second pass complete;
just validate human [AIFM2](../../genes/human/AIFM2/AIFM2-ai-review.html)clean (info-only aliases) - [x] AIFM2/FSP1: resolved missing supporting_text in references; updated iFSP1 paper findings to match abstract; refreshed deep-research-falcon
- [x] AIFM2/FSP1: integrated new papers (RNF126 ubiquitination/localization; temsirolimus direct FSP1 inhibition and ferroptosis induction)
- [ ] Next gene: select from remaining Priority 1 list (DHODH, GCH1, LPCAT3, NCOA4)
2025-12-28
Completion Session - Full Project Finished
Gene Review Completion Summary
Priority 1 (Core Machinery) - COMPLETED
- GPX4 (P36969) ✓
- SLC7A11 (Q9UPY5) ✓
- ACSL4 (O60488) ✓
- FSP1/AIFM2 (Q9BRQ8) ✓
- DHODH (Q02127) ✓
- GCH1 (P30793) ✓
- LPCAT3 (Q6NVY1) ✓
- NCOA4 (Q13772) ✓
Priority 2 (Regulatory Network) - COMPLETED
- NFE2L2 (Q16236) ✓
- KEAP1 (Q14145) ✓
- TFRC (P02786) ✓
- FTH1 (P02794) ✓
- ATF4 (P18848) ✓
- SLC40A1 (Q9NP59) ✓
- GCLC (P48506) ✓
- TP53 (P04637) ✓
Priority 3 (Supporting Genes) - COMPLETED
- SLC3A2 (P08195) ✓
- GSS (P48637) ✓
- PTS (Q03393) ✓
- SPR (P35270) ✓
- FADS1 (O60427) ✓
- ELOVL5 (Q9NYP7) ✓
Validation Results
- Total files validated: 592 (across entire codebase)
- Ferroptosis genes: 22/22 validated successfully
- Validation errors: 0
- Validation warnings: Present but manageable (mostly missing supporting text citations in some genes)
- All genes pass core validation
Deliverables
- Gene Reviews: 22 comprehensive AI gene review YAML files
- Pathway Summary:
genes/human/FERROPTOSIS-pathway.mdcreated with: - Comprehensive ferroptosis mechanism overview
- Three parallel defense systems documented (GPX4-GSH, FSP1-CoQ10, DHODH-CoQ10)
- Emerging GCH1-BH4 system
- Transcriptional regulation (NRF2/ARE pathway)
- p53 context-dependent roles
- Disease relevance and therapeutic implications
- Full mermaid pathway diagram
- 15+ peer-reviewed citations
Next Steps
Ready for PR creation with branch ferroptosis-completion containing:
- All 22 gene review YAML files
- Supporting publications (PMIDs)
- Pathway summary document
- Updated project status