Ferroptosis (iron-dependent lipid-peroxidation cell death) module

A decomposition of ferroptosis: the iron-dependent form of regulated cell death in which polyunsaturated-fatty-acid (PUFA) phospholipids in cellular membranes undergo iron-catalysed peroxidation to lipid hydroperoxides, ultimately rupturing the membrane. Ferroptosis is morphologically and biochemically distinct from apoptosis, necroptosis, and pyroptosis: there is no caspase cascade and no dedicated executioner enzyme. Instead the program is defined by the balance between (a) a driver arm that supplies the oxidisable substrate (PUFA phospholipids) and the redox-active iron that catalyses peroxidation, and (b) several biochemically independent defense arms that detoxify lipid hydroperoxides or quench the propagating radicals. Death occurs when the defenses are overwhelmed, so ferroptosis is best modelled as one execution node negatively regulated, in parallel and redundantly, by multiple suppressor systems. Design intent: the module is organized as a driver layer (PUFA-phospholipid supply and labile-iron supply) that provides input to a central execution node (GO:0097707 ferroptosis), opposed by four independent suppressor sub-modules that each NEGATIVELY_REGULATE the execution node: the canonical GPX4-glutathione axis, the FSP1-CoQ10 axis, the mitochondrial DHODH-CoQ10 axis, and the GCH1-BH4 (tetrahydrobiopterin) axis. A transcriptional/regulatory sub-module (NRF2/KEAP1, ATF4, p53) tunes the set point of these defenses and is kept optional. The module is framed for the human/mammalian implementation, where ferroptosis was defined, but the core chemistry (iron + O2 + PUFA membranes) and the principal defenses (GPX4, the CoQ system) are deeply conserved across eukaryotes, with ferroptosis-like death reported in plants, fungi, and protozoa. Genes are grounded to UniProt and GO ids taken from the matching per-gene reviews under genes/human/; GO ids are used only in their correct aspect (MF in function, BP in processes/concepts, CC in locations).

MODULE:ferroptosisDRAFTBiological Processmodules/ferroptosis.yaml
ferroptosisGO:0097707
GO:0097707
ferroptosis
The module is grounded in the GO biological-process term for ferroptosis, defined by GO as a programmed cell death involving iron and reactive oxygen species accumulation - i.e. an evolved process, not merely a pathological accident.
PMID:31634900
The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
Established FSP1 (AIFM2) as a glutathione/GPX4-independent ferroptosis suppressor that regenerates reduced CoQ10 at the membrane, defining the second, parallel defense axis modelled here.
file:projects/FERROPTOSIS.md
Ferroptosis project page
The sibling gene-by-gene ferroptosis curation project (22 reviewed human genes) that this module generalizes into a recursively decomposable mechanistic plan; all UniProt/GO groundings here are taken from those reviews.

Ferroptosis has no single linear execution effector, which is the key contrast with cuproptosis: the interesting structure is several biochemically independent suppressor arms (GPX4-GSH, FSP1-CoQ, DHODH-CoQ, GCH1-BH4) acting as redundant NEGATIVELY_REGULATES edges onto one execution node, so loss of any single arm is buffered by the others. The execution node is modelled as a process-level effect (GO:0097707) with an ANY_PARTICIPANT annoton rather than a distinct MF, because the lethal event is radical-chain lipid peroxidation and membrane rupture, for which there is no exact GO molecular function. Iron handling and PUFA-phospholipid biosynthesis are upstream physiology that set the death threshold: NCOA4-driven ferritinophagy and TFRC import raise the labile-iron pool (pro-ferroptotic), while FTH1 storage and SLC40A1 export lower it (protective). p53 (TP53) is included as a context-dependent regulator that is pro-ferroptotic in the canonical SLC7A11-repression context. Scope boundaries: general fatty-acid/phospholipid metabolism (FADS1/2, ELOVL5, LPCAT3's housekeeping remodelling), general glutathione and one-carbon metabolism, and the broader NRF2 antioxidant program are adjacent and are treated here only insofar as they supply substrate to, or gate, ferroptosis.

18Nodes
17Parts
0Variant Sets
0Variants
27Annotons
14Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:ferroptosis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

1 leaf node(s) with no concrete protein grounding:

Template conformance

6 conformance issue(s):

  • gpx4_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 1 function GO:0047066 does not match template None
  • gpx4_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 2 function GO:0030674 does not match template None
  • gpx4_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 3 function GO:0031545 does not match template None
  • slc7a11_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 1 function GO:0015327 does not match template None
  • slc7a11_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 2 function GO:1990756 does not match template None
  • slc7a11_abundance_switch → ferroptosis_defense_factor_switch [info]
    tier 3 function GO:0004843 does not match template None

Gene-review completeness (21/24 grounded genes reviewed)

16 complete review(s) · 20 with deep research · 3 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
ACSL4 O60488 ✓ ✓ ✓
AIFM2 Q9BRQ8 ✓ ✓ ✓
ATF4 P18848 ✓ 215/216 ✓
DHODH Q02127 ✓ ✓ ✓
FTH1 P02794 ✓ ✓ ✓
GCH1 P30793 ✓ 69/70 ✓
GCLC P48506 ✓ ✓ ✓
GPX4 P36969 ✓ 52/55 ✓
GSS P48637 ✓ ✓ ✓
KCTD10 Q9H3F6 ✓ ✓ ✗
KEAP1 Q14145 ✓ ✓ ✓
LPCAT3 Q6P1A2 ✓ 66/72 ✓
NCOA4 Q13772 ✓ 23/25 ✓
NFE2L2 Q16236 ✓ ✓ ✓
LAMP2 (LAMP2A) P13473 ✗ — —
PTS Q03393 ✓ ✓ ✓
EGLN3 (PHD3) Q9H6Z9 ✗ — —
USP18 Q9UMW8 ✗ — —
SLC3A2 P08195 ✓ ✓ ✓
SLC40A1 Q9NP59 ✓ ✓ ✓
SLC7A11 Q9UPY5 ✓ ✓ ✓
SPR P35270 ✓ ✓ ✓
TFRC P02786 ✓ ✓ ✓
TP53 P04637 ✓ ✓ ✓

Details

Context
eukaryotes (defined in human/mammalian cells; defenses deeply conserved)
cellular membranes (PUFA-phospholipid bilayers)
FerroptosisBiological Processferroptosis
ferroptosisGO:0097707
Context
eukaryotes (defined in human/mammalian cells; defenses deeply conserved)
cellular membranes (PUFA-phospholipid bilayers)

Connections

PUFA-phospholipids are the oxidisable substrate consumed in the execution event.
Labile Fe(II) catalyses the radical chemistry that peroxidises PUFA-phospholipids.
gpx4_gsh_defense -> ferroptosis_execution Negatively Regulates
GPX4 reduces phospholipid hydroperoxides, the canonical suppressor of execution.
fsp1_coq_defense -> ferroptosis_execution Negatively Regulates
FSP1-regenerated ubiquinol traps lipid radicals, suppressing execution in parallel with GPX4.
dhodh_coq_defense -> ferroptosis_execution Negatively Regulates
DHODH-reduced CoQ defends mitochondrial membranes against peroxidation, parallel to GPX4.
gch1_bh4_defense -> ferroptosis_execution Negatively Regulates
BH4 is a radical-trapping antioxidant protecting PUFA-phospholipids, a third parallel suppressor.
nrf2_master_antioxidant -> gpx4_gsh_defense Positively Regulates
NRF2 transcriptionally induces system xc-, glutathione synthesis, and GPX4.
KEAP1 targets NRF2 for degradation, lowering defense expression.
atf4_isr_inducer -> gpx4_gsh_defense Positively Regulates
ATF4 induces SLC7A11, supplying cysteine to the GPX4 axis.
tp53_context_regulator -> gpx4_gsh_defense Negatively Regulates
p53 represses SLC7A11, lowering the GPX4 axis and (canonically) promoting ferroptosis.
Part 1: PUFA-phospholipid supply (provides the oxidisable substrate)
PUFA-phospholipid supplyBiological Processpufa_phospholipid_supply

Esterification of polyunsaturated fatty acids into membrane phospholipids generates the bis-allylic substrate that is peroxidised during ferroptosis. ACSL4 activates PUFAs as acyl-CoAs and LPCAT3 inserts them into phospholipids; cells enriched in PUFA-PLs are ferroptosis-sensitive. FADS1/FADS2 and ELOVL5 (reviewed in the project) feed the upstream PUFA pool.

Annotons

ACSL4 PUFA-CoA synthesis
acsl4_pufa_activation
Participant: Gene Product: ACSL4
Gene Product:
ACSL4UniProtKB:O60488

Function

arachidonate-CoA ligase activityGO:0047676
Substrates: arachidonic acid / adrenic acid (PUFA)
Products: arachidonoyl-CoA (PUFA-CoA)

Processes

positive regulation of ferroptosisGO:0160020

Locations

endoplasmic reticulum membraneGO:0005789

Preferentially activates long-chain PUFAs; loss of ACSL4 depletes PUFA-phospholipids and confers ferroptosis resistance, making ACSL4 a pro-ferroptotic driver.

LPCAT3 PUFA incorporation into phospholipids
lpcat3_pufa_incorporation
Participant: Gene Product: LPCAT3 (MBOAT5)
Gene Product:
LPCAT3 (MBOAT5)UniProtKB:Q6P1A2

Function

1-acylglycerophosphocholine O-acyltransferase activityGO:0047184

Processes

phosphatidylethanolamine acyl-chain remodelingGO:0036152

Locations

endoplasmic reticulum membraneGO:0005789

Re-acylates lysophospholipids with PUFA-CoA, installing the oxidisable PUFA chains (esp. in phosphatidylethanolamine) that are the peroxidation substrate; cooperates with ACSL4 as a driver.

Part 2: labile-iron supply (catalyses peroxidation; sets the threshold)
Labile-iron supply and bufferingBiological Processlabile_iron_supply

Redox-active Fe(II) catalyses lipid-radical generation (Fenton chemistry) and is a cofactor of lipoxygenases. Import (TFRC) and ferritinophagy (NCOA4) raise the labile-iron pool and sensitize cells; ferritin storage (FTH1) and export (SLC40A1) lower it and protect.

Annotons

TFRC transferrin-bound iron import
tfrc_iron_import
Participant: Gene Product: TFRC (CD71)
Gene Product:
TFRC (CD71)UniProtKB:P02786

Function

transferrin receptor activityGO:0004998

Processes

iron ion transportGO:0006826

Locations

external side of plasma membraneGO:0009897

Principal route of transferrin-bound iron uptake; higher import raises the labile-iron pool and ferroptosis sensitivity (TFRC is also used as a ferroptosis marker).

NCOA4 ferritinophagy (iron release)
ncoa4_ferritinophagy
Participant: Gene Product: NCOA4
Gene Product:
NCOA4UniProtKB:Q13772

Function

autophagy cargo adaptor activityGO:0160247

Processes

intracellular iron ion homeostasisGO:0006879

Locations

autophagosomeGO:0005776

Selective autophagy receptor that delivers ferritin to the lysosome; ferritinophagy releases stored iron into the labile pool, a pro-ferroptotic input.

FTH1 ferritin iron storage (protective)
fth1_iron_storage
Participant: Gene Product: FTH1
Gene Product:
FTH1UniProtKB:P02794

Function

iron ion sequestering activityGO:0140315

Processes

negative regulation of ferroptosisGO:0110076

Locations

cytosolGO:0005829

Ferroxidase subunit of the ferritin complex that sequesters iron in a redox-inert form, lowering the labile-iron pool; protective against ferroptosis (and a NCOA4 substrate).

SLC40A1 (ferroportin) iron export (protective)
slc40a1_iron_export
Participant: Gene Product: SLC40A1 (ferroportin)
Gene Product:
SLC40A1 (ferroportin)UniProtKB:Q9NP59

Function

ferrous iron transmembrane transporter activityGO:0015093

Locations

plasma membraneGO:0005886

The only known cellular iron exporter; export lowers intracellular iron and is protective against ferroptosis.

Part 3: execution of ferroptosis (lipid peroxidation -> membrane rupture)
Ferroptosis executionBiological Processferroptosis_execution

Iron-catalysed (enzymatic via lipoxygenases/POR and non-enzymatic autoxidative) peroxidation of PUFA-phospholipids generates lipid hydroperoxides; when these outrun the suppressor arms, propagating radicals and reactive breakdown products destabilize and rupture the membrane, killing the cell.

ferroptosisGO:0097707

Annotons

PUFA-phospholipid peroxidation and membrane rupture
lipid_peroxidation_execution
Participant: Any Participant: Cell-level outcome integrating PUFA-PL peroxidation, radical propagation, and membrane rupture; not a single gene product.
Cell-level outcome integrating PUFA-PL peroxidation, radical propagation, and membrane rupture; not a single gene product.

Function

ferroptosis (execution) Process-level death execution by radical-chain lipid peroxidation; no exact GO MF exists for the lethal membrane event, so only the BP is grounded.

Processes

ferroptosisGO:0097707

Integrates PUFA-PL peroxidation and iron-catalysed radical propagation into membrane-rupturing cell death; the node that every suppressor arm negatively regulates.

GO:0097707
GO defines ferroptosis as an iron- and ROS-dependent programmed cell death.
Part 4: GPX4-glutathione defense (canonical suppressor)
GPX4-glutathione defenseBiological Processgpx4_gsh_defense

The classical ferroptosis-suppressing axis: system xc- (SLC7A11/SLC3A2) imports cystine for glutathione synthesis (GCLC then GSS), and GPX4 uses glutathione to reduce phospholipid hydroperoxides to non-reactive alcohols. GPX4 is the central suppressor node.

Annotons

SLC7A11 (xCT) cystine/glutamate antiport
slc7a11_cystine_import
Participant: Gene Product: SLC7A11 (xCT)
Gene Product:
SLC7A11 (xCT)UniProtKB:Q9UPY5

Function

cystine:glutamate antiporter activityGO:0015327

Processes

negative regulation of ferroptosisGO:0110076

Locations

plasma membraneGO:0005886

Imports cystine in exchange for glutamate, supplying cysteine for glutathione synthesis; the rate-limiting input to the GPX4 axis and the target of erastin and of p53-mediated repression.

SLC3A2 (4F2hc) xCT chaperone subunit
slc3a2_xct_partner
Participant: Gene Product: SLC3A2 (4F2hc)
Gene Product:
SLC3A2 (4F2hc)UniProtKB:P08195

Function

protein heterodimerization activityGO:0046982

Locations

plasma membraneGO:0005886

Obligate heavy-chain partner that traffics and stabilizes SLC7A11 at the plasma membrane; required for system xc- function.

GCLC rate-limiting glutathione synthesis
gclc_gsh_synthesis
Participant: Gene Product: GCLC
Gene Product:
GCLCUniProtKB:P48506

Function

glutamate-cysteine ligase activityGO:0004357

Catalyses the rate-limiting step of glutathione biosynthesis (gamma-glutamylcysteine formation); supplies the GPX4 cofactor.

GSS glutathione synthase
gss_gsh_synthesis
Participant: Gene Product: GSS
Gene Product:
GSSUniProtKB:P48637

Function

glutathione synthase activityGO:0004363

Completes glutathione synthesis from gamma-glutamylcysteine and glycine; provides the reducing cofactor for GPX4.

GPX4 phospholipid-hydroperoxide reduction (central suppressor)
gpx4_plooh_reduction
Participant: Gene Product: GPX4
Gene Product:
GPX4UniProtKB:P36969

Function

phospholipid-hydroperoxide glutathione peroxidase activityGO:0047066
Substrates: phospholipid hydroperoxide (PL-OOH) glutathione (GSH)
Products: phospholipid alcohol (PL-OH) glutathione disulfide (GSSG)

Processes

negative regulation of ferroptosisGO:0110076

Locations

cytosolGO:0005829 mitochondrionGO:0005739

The central ferroptosis suppressor: directly reduces phospholipid hydroperoxides to alcohols using glutathione, defusing the lethal substrate. GPX4 inhibition (e.g. RSL3) is the canonical way to trigger ferroptosis.

Part 5: FSP1-CoQ10 defense (GPX4-independent, parallel)
FSP1-CoQ10 defenseMolecular Functionfsp1_coq_defense

A glutathione/GPX4-independent suppressor axis: FSP1 (AIFM2) reduces ubiquinone (CoQ10) to ubiquinol, a lipophilic radical-trapping antioxidant that halts lipid-peroxidation chain propagation at the membrane. Parallel to and redundant with GPX4.

Annotons

FSP1 (AIFM2) CoQ10 reduction
fsp1_coq_reduction
Participant: Gene Product: FSP1 (AIFM2)
Gene Product:
FSP1 (AIFM2)UniProtKB:Q9BRQ8

Function

oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptorGO:0016655
Substrates: ubiquinone (CoQ10) NAD(P)H
Products: ubiquinol (CoQ10-H2, radical-trapping antioxidant)

Processes

negative regulation of ferroptosisGO:0110076 ubiquinone metabolic processGO:0006743

Locations

plasma membraneGO:0005886 lipid dropletGO:0005811

Myristoylation-targeted NAD(P)H:ubiquinone oxidoreductase that regenerates ubiquinol at membranes to trap lipid radicals, suppressing ferroptosis independently of glutathione/GPX4.

PMID:31634900
FSP1 acts parallel to GPX4, using NAD(P)H to regenerate reduced CoQ10 and inhibit ferroptosis.
Part 6: DHODH-CoQ10 defense (mitochondrial, parallel)
DHODH-CoQ10 defense (mitochondrial)Molecular Functiondhodh_coq_defense

The mitochondrial inner-membrane arm of CoQ-based defense: DHODH reduces CoQ to ubiquinol in the inner membrane (coupled to its role in de novo pyrimidine synthesis), counteracting mitochondrial lipid peroxidation in parallel with mitochondrial GPX4.

Annotons

DHODH dihydroorotate:CoQ oxidoreduction
dhodh_coq_reduction
Participant: Gene Product: DHODH
Gene Product:
DHODHUniProtKB:Q02127

Function

dihydroorotate dehydrogenase (quinone) activityGO:0106430
Substrates: dihydroorotate ubiquinone (CoQ)
Products: orotate ubiquinol (CoQ-H2)

Locations

mitochondrial inner membraneGO:0005743

Reduces CoQ to ubiquinol at the mitochondrial inner membrane; proposed to defend mitochondrial membranes against lipid peroxidation in parallel with GPX4, especially where GPX4 is low.

Part 7: GCH1-BH4 defense (tetrahydrobiopterin antioxidant, parallel)
GCH1-BH4 defenseBiological Processgch1_bh4_defense

GTP cyclohydrolase I (GCH1) is rate-limiting for biosynthesis of tetrahydrobiopterin (BH4), a lipophilic radical-trapping antioxidant that protects membrane PUFAs (and helps regenerate CoQ); PTS and SPR complete BH4 synthesis. A third independent suppressor axis.

tetrahydrobiopterin biosynthetic processGO:0006729

Annotons

GCH1 rate-limiting BH4 synthesis
gch1_bh4_synthesis
Participant: Gene Product: GCH1
Gene Product:
GCH1UniProtKB:P30793

Function

GTP cyclohydrolase I activityGO:0003934

Processes

tetrahydrobiopterin biosynthetic processGO:0006729

Locations

cytosolGO:0005829

Rate-limiting enzyme of BH4 synthesis; GCH1/BH4 levels set ferroptosis resistance by supplying a radical-trapping antioxidant that protects PUFA-phospholipids.

PTS (PTPS) BH4 synthesis
pts_bh4_synthesis
Participant: Gene Product: PTS (PTPS)
Gene Product:
PTS (PTPS)UniProtKB:Q03393

Function

6-pyruvoyltetrahydropterin synthase activityGO:0003874

Processes

tetrahydrobiopterin biosynthetic processGO:0006729

Second enzyme of de novo BH4 synthesis, downstream of GCH1.

SPR final-step BH4 synthesis
spr_bh4_synthesis
Participant: Gene Product: SPR
Gene Product:
SPRUniProtKB:P35270

Function

sepiapterin reductase (NADP+) activityGO:0004757

Processes

tetrahydrobiopterin biosynthetic processGO:0006729

Catalyses the final step of de novo BH4 synthesis, completing the antioxidant supply of the GCH1-BH4 axis.

Part 8: transcriptional and modulatory regulators (optional)
Transcriptional and modulatory regulatorsRegulatory Stepferroptosis_transcriptional_regulation

Transcriptional set-point controllers of the defense arms: NRF2 (NFE2L2) induces SLC7A11, GPX4, GCLC, FTH1, and FSP1; KEAP1 represses NRF2; ATF4 (integrated stress response) induces SLC7A11; p53 (TP53) is context-dependent and, in the canonical context, represses SLC7A11 to promote ferroptosis.

Annotons

NFE2L2 (NRF2) antioxidant transcription factor
nrf2_master_antioxidant
Participant: Gene Product: NFE2L2 (NRF2)
Gene Product:
NFE2L2 (NRF2)UniProtKB:Q16236

Function

DNA-binding transcription factor activity, RNA polymerase II-specificGO:0000981

Locations

nucleusGO:0005634

Master antioxidant-response transcription factor; induces multiple ferroptosis defenses (system xc-, GPX4, glutathione synthesis, ferritin, FSP1), so a positive regulator of the suppressor arms.

KEAP1 NRF2 repressor (substrate adaptor)
keap1_nrf2_repressor
Participant: Gene Product: KEAP1
Gene Product:
KEAP1UniProtKB:Q14145

Function

ubiquitin-like ligase-substrate adaptor activityGO:1990756
Targets: NFE2L2 (NRF2)

CUL3 substrate adaptor that targets NRF2 for degradation under basal conditions; by repressing NRF2 it lowers defense expression and is permissive for ferroptosis.

ATF4 integrated-stress-response transcription factor
atf4_isr_inducer
Participant: Gene Product: ATF4
Gene Product:
ATF4UniProtKB:P18848

Function

DNA-binding transcription activator activity, RNA polymerase II-specificGO:0001228

Locations

nucleusGO:0005634

Integrated-stress-response transcription factor that induces SLC7A11 and other adaptive genes; generally a positive regulator of the GPX4 axis (cysteine supply).

TP53 (p53) context-dependent regulator
tp53_context_regulator
Participant: Gene Product: TP53 (p53)
Gene Product:
TP53 (p53)UniProtKB:P04637

Function

transcription cis-regulatory region bindingGO:0000976

Locations

nucleusGO:0005634

Context-dependent regulator; canonically pro-ferroptotic by transcriptionally repressing SLC7A11 (and via SAT1/ALOX), though it can be anti-ferroptotic in other contexts. Modelled here as a negative regulator of the GPX4 axis.

Part 9: defense-factor abundance control (regulated suppressor stability) (optional)
Defense-factor abundance controlRegulatory Stepdefense_factor_abundance_control

Post-translational set-point control of the two principal defense factors, abstracted from curated GO-CAMs. Each child realization embeds the ferroptosis_defense_factor_switch motif (an opposed destabilizer/stabilizer pair acting on one suppressor) via conforms_to, and is grounded to the production GO-CAM(s) that realize it.

Part 1: GPX4 abundance switch
GPX4 abundance switch (CMA degradation vs EGLN3 hydroxylation)Regulatory Stepgpx4_abundance_switch

GPX4 abundance is lowered by chaperone-mediated autophagy (HSPA8/LAMP2A) and preserved by EGLN3/PHD3 prolyl hydroxylation, which masks GPX4 from CMA recognition.

Connections

CMA lowers GPX4 abundance, promoting ferroptosis.
gpx4_phd3_stabilizer -> gpx4_defense_factor Positively Regulates
EGLN3 hydroxylation preserves GPX4, suppressing ferroptosis.
Part 1: defense node
GPX4 (defense node)Regulatory Stepgpx4_defense_factor

Annotons

GPX4 peroxidase (suppressor)
gpx4_switch_node
Participant: Gene Product: GPX4
Gene Product:
GPX4UniProtKB:P36969

Function

phospholipid-hydroperoxide glutathione peroxidase activityGO:0047066

Processes

negative regulation of ferroptosisGO:0110076

The regulated defense factor.

Part 2: destabilizer arm
Chaperone-mediated autophagy of GPX4 (LAMP2A)Regulatory Stepgpx4_cma_destabilizer

Annotons

LAMP2A CMA receptor (destabilizer)
gpx4_cma
Participant: Gene Product: LAMP2 (LAMP2A)
Gene Product:
LAMP2 (LAMP2A)UniProtKB:P13473

Function

protein-macromolecule adaptor activityGO:0030674

Processes

positive regulation of ferroptosisGO:0160020

Locations

lysosomal membraneGO:0005765

CMA delivers GPX4 for lysosomal degradation, lowering it.

Part 3: stabilizer arm
EGLN3/PHD3 hydroxylation of GPX4Regulatory Stepgpx4_phd3_stabilizer

Annotons

EGLN3 prolyl hydroxylase (stabilizer)
gpx4_phd3
Participant: Gene Product: EGLN3 (PHD3)
Gene Product:
EGLN3 (PHD3)UniProtKB:Q9H6Z9

Function

peptidyl-proline 4-dioxygenase activityGO:0031545

Processes

negative regulation of ferroptosisGO:0110076

Hydroxylates GPX4, masking it from CMA and stabilizing it.

Part 2: SLC7A11 abundance switch
SLC7A11 abundance switch (CRL3 degradation vs USP18 rescue)Regulatory Stepslc7a11_abundance_switch

SLC7A11 abundance is lowered by a CUL3-KCTD10-RBX1 (CRL3) ubiquitin ligase and restored by the deubiquitinase USP18.

Connections

CRL3 lowers SLC7A11 abundance, promoting ferroptosis.
USP18 restores SLC7A11, suppressing ferroptosis.
Part 1: defense node
SLC7A11 (defense node)Regulatory Stepslc7a11_defense_factor

Annotons

SLC7A11 antiporter (suppressor)
slc7a11_switch_node
Participant: Gene Product: SLC7A11 (xCT)
Gene Product:
SLC7A11 (xCT)UniProtKB:Q9UPY5

Function

cystine:glutamate antiporter activityGO:0015327

Processes

negative regulation of ferroptosisGO:0110076

The regulated defense factor.

Part 2: destabilizer arm
CRL3 (KCTD10) ubiquitination of SLC7A11Regulatory Stepslc7a11_crl3_destabilizer

Annotons

KCTD10 CRL3 substrate adaptor (destabilizer)
slc7a11_crl3
Participant: Gene Product: KCTD10
Gene Product:
KCTD10UniProtKB:Q9H3F6

Function

ubiquitin-like ligase-substrate adaptor activityGO:1990756

Processes

positive regulation of ferroptosisGO:0160020

CRL3 ubiquitinates SLC7A11 for degradation, lowering it.

Part 3: stabilizer arm
USP18 deubiquitination of SLC7A11Regulatory Stepslc7a11_dub_stabilizer

Annotons

USP18 deubiquitinase (stabilizer)
slc7a11_dub
Participant: Gene Product: USP18
Gene Product:
USP18UniProtKB:Q9UMW8

Function

cysteine-type deubiquitinase activityGO:0004843

Processes

negative regulation of ferroptosisGO:0110076

Removes ubiquitin from SLC7A11 to stabilize it (MF flagged UNCERTAIN in the GO-CAM review: USP18 is canonically ISG15-specific).