Ferroptosis: Iron-Dependent Lipid-Peroxidation Cell Death

An evolved, programmed cell-death process — not a pathological accident

Chris Mungall | AI-Assisted Gene Review

2026-06-22

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Why Ferroptosis?

• A form of regulated cell death driven by iron-dependent peroxidation of
  PUFA-containing membrane phospholipids — ending in membrane rupture.
• Mechanistically distinct from apoptosis, necroptosis, and pyroptosis:
  no caspase cascade, no dedicated executioner enzyme.
• In GO it is a programmed process (GO:0097707),
  so it should be modelled as an evolved program, not as damage.
• The underlying chemistry (iron + O₂ + PUFA membranes) is ancient and
  conserved; ferroptosis-like death is reported in plants, fungi, and protozoa.
• Major therapeutic interest in cancer (induce it) and neurodegeneration /
  ischemia–reperfusion (block it).

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Key Biology / Mechanism

1. PUFAs are esterified into membrane phospholipids (ACSL4 → LPCAT3),
   creating the oxidisable substrate.
2. Labile iron (from TFRC import, NCOA4 ferritinophagy) catalyses radical
   chemistry and feeds lipoxygenases.
3. Lipid peroxidation generates phospholipid hydroperoxides (PL-OOH).
4. Defense systems detoxify PL-OOH or quench radicals.
5. When defenses are overwhelmed, propagating radicals rupture the
   membrane → cell death.

The defining feature is the balance between drivers and several independent
defense arms — not a linear cascade.

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A Network, Not a Linear Pathway

• Drivers (set the substrate + catalyst):
• PUFA-phospholipid supply — ACSL4, LPCAT3 (and FADS1, ELOVL5)
• Labile-iron supply — TFRC, NCOA4 (vs. protective FTH1, SLC40A1)
• One execution node: iron-catalysed PUFA-PL peroxidation → rupture.
• Four independent suppressor arms, each a parallel negative regulator:
• GPX4–glutathione (canonical)
• FSP1 (AIFM2)–CoQ10
• DHODH–CoQ10 (mitochondrial)
• GCH1–BH4 (tetrahydrobiopterin)
• The redundancy of the defenses is the scientifically important structure.

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Defense Arm 1: GPX4–Glutathione (Canonical)

Gene	UniProt	Function
SLC7A11	Q9UPY5	Cystine/glutamate antiporter (xCT) — cysteine supply
SLC3A2	P08195	xCT chaperone partner (4F2hc)
GCLC	P48506	Rate-limiting glutathione synthesis
GSS	P48637	Glutathione synthase
GPX4	P36969	Reduces phospholipid hydroperoxides — central suppressor

GPX4 inhibition (e.g. RSL3) is the canonical way to trigger ferroptosis.

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Defense Arms 2–4: Parallel & Redundant

Arm	Gene	UniProt	Mechanism
FSP1–CoQ10	AIFM2	Q9BRQ8	Regenerates ubiquinol (radical trap), GPX4-independent
DHODH–CoQ10	DHODH	Q02127	Reduces CoQ in mitochondrial inner membrane
GCH1–BH4	GCH1	P30793	Rate-limiting BH4 (radical-trapping antioxidant)
GCH1–BH4	PTS	Q03393	BH4 synthesis
GCH1–BH4	SPR	P35270	Final-step BH4 synthesis

Each arm independently suppresses execution — losing one is buffered by the others.

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Iron Supply & Regulatory Layer

Iron (sets the threshold):

Gene	UniProt	Role
TFRC	P02786	Iron import — sensitizing
NCOA4	Q13772	Ferritinophagy — releases iron, sensitizing
FTH1	P02794	Ferritin storage — protective
SLC40A1	Q9NP59	Iron export — protective

Transcriptional set-point: NFE2L2 (Q16236, NRF2) induces defenses;
KEAP1 (Q14145) represses NRF2; ATF4 (P18848) induces SLC7A11;
TP53 (P04637) is context-dependent (canonically represses SLC7A11).

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Key Recent Discoveries (2019+)

1. FSP1–CoQ10 pathway (Nature 2019, PMID:31634900 / PMID:31634899) —
   GPX4-independent suppression via ubiquinol regeneration.
2. DHODH in mitochondria (Nature 2021) — mitochondrial CoQ-based defense.
3. GCH1/BH4 pathway (2020) — third parallel radical-trapping antioxidant axis.
4. Membrane lipid remodelling — specific PUFA-phospholipids (esp. PE) as the
   critical substrate.

These discoveries reframed ferroptosis from "GPX4 failure" to a
multi-arm, redundant defense network.

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The Approach: AI Gene Review

• Systematically review existing GO annotations for each pathway gene using
  strict GO guidelines.
• Synthesize with literature evidence and bioinformatic inference.
• Distinguish core functions from over-annotation (e.g. generic "cell death"
  terms with only indirect support).
• Capture the integrated mechanism as a validated, decomposable
  ferroptosis module grounded to UniProt + GO.
• Status: 22 human genes reviewed and validated.

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Conclusions & Future Directions

• Ferroptosis: iron-dependent regulated cell death by PUFA-phospholipid
  peroxidation — best modelled as one execution node with redundant
  suppressor arms.
• Curation target: 22 genes across drivers, four defense arms, and regulators.
• An evolved, conserved program — appropriate to model as biology, not pathology.
• Next steps:
• [ ] Fold in 2023–2026 papers (MBOAT1/2, new suppressors)
• [ ] Ontology-gap assessment for the parallel-defense structure
• [ ] Cross-link the module to production GO-CAM models
• Parallels the Cuproptosis project as a
  metal-dependent regulated-cell-death program.