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

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).

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.

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.

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.

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.

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).

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.

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.

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.