Ferroptosis Project

Bottom line: ferroptosis is iron-dependent regulated cell death driven by
peroxidation of polyunsaturated phospholipids, and GO treats it as an evolved
programmed process (GO:0097707).
We reviewed all 22 human genes that supply its substrates and iron, the four
parallel defence systems that suppress it (GPX4–glutathione, FSP1–CoQ10,
DHODH–CoQ10, GCH1–BH4), and its transcriptional regulators, and captured the
mechanism as a decomposable ferroptosis module.
We did this because the defence pathways were discovered from 2019 onward and
the question was whether GO had caught up with them. The 22 reviews cover 2,362
existing annotations plus 10 proposed new ones (872 existing on TP53, where 344
were removed); the core
suppressors carry GO:0110076 negative regulation of ferroptosis, accepted on
GPX4, SLC7A11, AIFM2/FSP1, FTH1 and NFE2L2 and proposed as new for DHODH. A
2026 second pass on GPX4, SLC7A11, ACSL4 and AIFM2 left a few evidence
follow-ups open.

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

• ELOVL5 - Fatty acid elongase
• FADS1/FADS2 - Fatty acid desaturases

Genes for Review (Priority Order)

Priority 1: Core Machinery (~8 genes)

Priority 2: Regulatory Network (~8 genes)

Priority 3: Supporting Genes (~6 genes)

Key Recent Discoveries (2020+)

1. FSP1/CoQ10 pathway (Nature 2019) - GPX4-independent ferroptosis suppression
2. DHODH in mitochondria (Nature 2021) - Mitochondrial ferroptosis defense
3. GCH1/BH4 pathway (Nature 2022) - Third parallel defense system
4. MBOAT1/2 (Nature 2023) - Sex hormone-regulated ferroptosis resistance
5. Membrane lipid remodeling (Cell 2020+) - Role of specific phospholipids

Disease Relevance

• Cancer: Ferroptosis induction as therapy; resistance mechanisms
• Neurodegeneration: Ferroptosis in Parkinson's and Huntington's disease and amyotrophic lateral sclerosis
• Ischemia-reperfusion: Organ damage
• Kidney disease: Acute kidney injury

Module

The ferroptosis mechanism is captured as a recursively decomposable module
(grounded to UniProt and GO, validated against the ModuleReview schema):

• Ferroptosis module — one execution node
  (GO:0097707) fed by PUFA-phospholipid and labile-iron driver arms, and
  redundantly suppressed by four independent defense axes (GPX4–GSH,
  FSP1–CoQ10, DHODH–CoQ10, GCH1–BH4) plus a transcriptional regulatory layer
  (NRF2/KEAP1, ATF4, p53). Source: modules/ferroptosis.yaml.

Slides

• Slides (Marp source: FERROPTOSIS-slides.md) — AI generated

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 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 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 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 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 (Q6P1A2) ✓
- 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

1. Gene Reviews: 22 comprehensive AI gene review YAML files
2. Pathway Summary: genes/human/FERROPTOSIS-pathway.md created with:
3. Comprehensive ferroptosis mechanism overview
4. Three parallel defense systems documented (GPX4-GSH, FSP1-CoQ10, DHODH-CoQ10)
5. Emerging GCH1-BH4 system
6. Transcriptional regulation (NRF2/ARE pathway)
7. p53 context-dependent roles
8. Disease relevance and therapeutic implications
9. Full mermaid pathway diagram
10. 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