GPX4

Summary

GPX4 (glutathione peroxidase 4, HGNC:4556) is a protein-coding gene on chromosome 19p13.3, encoding Phospholipid hydroperoxide glutathione peroxidase GPX4 (P36969). Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins. It is a selective cancer dependency (DepMap: 60.4% of cell lines).

The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a ‘moonlighting’ protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3’ UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization.

Source: NCBI Gene 2879 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylometaphyseal dysplasia, Sedaghatian type (Strong, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 235 total — 8 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 60.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002085

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4556
Approved symbol	GPX4
Name	glutathione peroxidase 4
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PHGPx, MCSP
Ensembl gene	ENSG00000167468
Ensembl biotype	protein_coding
OMIM	138322
Entrez	2879

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 retained_intron

ENST00000354171, ENST00000585362, ENST00000585480, ENST00000587648, ENST00000587932, ENST00000588919, ENST00000589115, ENST00000592940, ENST00000593032, ENST00000611653, ENST00000614791, ENST00000706713, ENST00000706714, ENST00000706715

RefSeq mRNA: 4 — MANE Select: NM_002085 NM_001039847, NM_001039848, NM_001367832, NM_002085

CCDS: CCDS42457, CCDS92476

Canonical transcript exons

ENST00000354171 — 7 exons

Exon	Start	End
ENSE00001399156	1103994	1104127
ENSE00003420595	1105186	1105280
ENSE00003518554	1105366	1105510
ENSE00003734802	1106540	1106779
ENSE00003996685	1106400	1106459
ENSE00003996686	1106242	1106266
ENSE00003996692	1105658	1105809

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 517.0435 / max 3528.1905, expressed in 1828 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172874	490.6884	1828
172877	10.4527	1744
172873	7.0324	1742
172882	2.7149	1308
172876	1.8217	1008
172883	1.5048	915
172885	1.1746	717
172878	0.6892	284
172884	0.4223	200
172881	0.2812	91

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.91	gold quality
right testis	UBERON:0004534	99.90	gold quality
adult organism	UBERON:0007023	99.76	gold quality
adipose tissue	UBERON:0001013	99.60	gold quality
pigmented layer of retina	UBERON:0001782	99.58	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.52	gold quality
connective tissue	UBERON:0002384	99.50	gold quality
omental fat pad	UBERON:0010414	99.50	gold quality
peritoneum	UBERON:0002358	99.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.49	gold quality
left adrenal gland cortex	UBERON:0035825	99.48	gold quality
pituitary gland	UBERON:0000007	99.46	gold quality
left adrenal gland	UBERON:0001234	99.45	gold quality
adenohypophysis	UBERON:0002196	99.45	gold quality
right adrenal gland cortex	UBERON:0035827	99.45	gold quality
nucleus accumbens	UBERON:0001882	99.44	gold quality
adrenal cortex	UBERON:0001235	99.43	gold quality
right adrenal gland	UBERON:0001233	99.42	gold quality
right frontal lobe	UBERON:0002810	99.40	gold quality
metanephros cortex	UBERON:0010533	99.39	gold quality
stromal cell of endometrium	CL:0002255	99.35	gold quality
apex of heart	UBERON:0002098	99.35	gold quality
sperm	CL:0000019	99.34	gold quality
male germ cell	CL:0000015	99.31	gold quality
prefrontal cortex	UBERON:0000451	99.31	gold quality
mucosa of stomach	UBERON:0001199	99.31	gold quality
synovial joint	UBERON:0002217	99.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.30	gold quality
caudate nucleus	UBERON:0001873	99.29	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	3509.68
E-CURD-122	yes	1942.08
E-CURD-46	yes	1564.62
E-MTAB-6819	yes	478.25
E-HCAD-1	yes	83.45
E-GEOD-125970	yes	74.91
E-HCAD-4	yes	36.49
E-MTAB-9221	yes	21.93
E-HCAD-6	yes	19.16
E-HCAD-5	yes	17.79
E-GEOD-135922	yes	17.67
E-MTAB-6701	yes	16.05
E-MTAB-10042	yes	13.69
E-MTAB-8498	yes	9.12
E-MTAB-7316	yes	7.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPE, CREM, TFAP2A

miRNA regulators (miRDB)

12 targeting GPX4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-1909-5P	98.94	64.01	484
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 60.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Glutathione peroxidase is a moonlighting protein that functions both as a peroxidase as well as a structural protein in mature spermatozoa. (PMID:11898409)
• an examination of gene expression (PMID:12152199)
• sperm content of phospholipid hydroperoxide glutathione peroxidase is correlated with fertility-related parameters and can be considered a predictive measure for fertilization capacity in humans (PMID:12193409)
• tissue distribution of alternatively spliced snGPx (PMID:12427732)
• data from screening of the region of the GPX4 gene corresponding to the 3’UTR show a T/C variant at position 718 that affects the levels of lymphocyte 5-lipoxygenase total products (PMID:12490284)
• Gpx-4 polymorphism cannot generally account for the correlation of phospholipid hydroperoxide glutathione peroxidase content of sperm and fertility-related parameters. Further examination of this gene as a potential cause of infertility is warranted. (PMID:12606444)
• PhGPx can lower the peroxide tone, which might change the cellular redox environment resulting in a delay in G1 transit (PMID:12868489)
• GPX4 up-regulates arachidonate metabolism in a epidermoid carcinoma tumor cell line. (PMID:12958179)
• lipids, cytokines and antioxidants modulate GPx4 in a complex manner that in the presence of adequate selenium, may favour protection against potentially proatherogenic processes. (PMID:14642406)
• No statistically significant differences for glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, and glutathione reductase were encountered between normal values and those of asthenozoospermic patients. (PMID:15149466)
• Sperm nucleus PHGPx expression is mediated by the transcription factor CREM-tau, which acts as a cis-acting element localized in the first intron of the PHGPx gene. (PMID:15225122)
• This review addresses the role of mitochondrial phospholipid hydroperoxide glutathione peroxidase in the regulation of apoptosis. (PMID:15256721)
• PHGPx modulates the induction of MMP-1 and collagenase. (PMID:15308634)
• Intracellular sperm GSH system components GPX-4 and GSH are altered in infertile men, and these alterations seem to be linked to sperm morphology. (PMID:15474074)
• Increased activities of erythrocyte glutathione peroxidase is associated with cerebral palsy (PMID:15978628)
• Oligoasthenozoospermia is associated with a decrease in the level of expression of PHGPx in the spermatozoa of some infertile men but is not linked to mutations in PHGPx gene. (PMID:16872467)
• We have been able to correlate embryo morphology on day 3 with the sperm expression of GPX family members. (PMID:16979635)
• we investigated both GPx-4 activity and localization in subcellular fractions of human platelets. Confocal immunofluorescence microscopy localized mainly GPx-4 to membranes of activated platelets in contrast to cytoplasm in the resting cells. (PMID:17020817)
• Role for selenium in risk of lung cancer and independent regulation of GPX4 in a tumor cell line. (PMID:17052796)
• Phospholipid hydroperoxide glutathione peroxidase expression is downregulated in poorly differentiated breast invasive ductal carcinoma (PMID:17516241)
• Results show the he crystal structure of the catalytically active U46C mutant of GPx4 and site-directed mutagenesis revealed amino acid residues important for catalysis and covalent protein polymerization. (PMID:17630701)
• These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer. (PMID:17634480)
• The GPX4c718t SNP both alters protein binding to the 3’UTR in vitro and influences the concentration of lymphocyte GPx4 and other selenoproteins in vivo (PMID:18400727)
• No significant risk for GPX4 in colorectal adenoma. (PMID:18483336)
• preeclampsia is associated with a specific antioxidant response in both maternal and fetal circulations, likely in response to the deleterious oxidative stress observed in this syndrome (PMID:19285650)
• Short form Gpx4 protein is present in mitochondria and is essential for survival and protection against apoptosis, whereas the long form Gpx4 protein is important for male fertility. (PMID:19744930)
• We have shown highly significant reductions in expression of all three major classes of GPx in placentae from women with preeclampsia. (PMID:20303587)
• a direct role of nuclear GPx4 in the (selenium-dependent) prevention of oxidative damage in the gastrointestinal tract. (PMID:21252226)
• the T/C variant GPX4 (rs713041) alters the pattern of selenoprotein synthesis if selenium intake is low (PMID:21459128)
• The SNPs of 5’-UTR region of the GPx4 gene might not be associated with oligo- or asthenozoospermic male infertility (PMID:21644221)
• genetic association studies in a Han Chinese population in Shaanxi province: Data indicate that 2 SNP in GPx4 (rs713041, rs4807542) and down-regulation of expression of GPx4 mRNA may be related to development of Kashin-Beck disease. (PMID:21733339)
• It was shown for the first time that the C718T polymorphism in the 3’-untranslated region of the GPX4 gene could be considered as a genetic marker of susceptibility to cerebral stroke in patients with essential hypertension. (PMID:22158110)
• GPx4, through effects on AIF, plays a major role in maintaining the oxidative phosphorylation system and protecting mitochondria from oxidative damage. (PMID:22634395)
• Methamphetamine increases oxidative stress by reducing GPx1/4 levels, and this can be reversed with addition of selenium. (PMID:23721877)
• neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes. (PMID:23919599)
• GPX4c718t SNP is functional and that variants of this SNP can have detrimental consequences on endothelial function leading to a greater risk of vascular disease. (PMID:23934705)
• Erythrocyte glutathione peroxidase activity is modified by single nucleotide polymorphisms in SEPP1, GPX4 and GPX1 and by estrogens. (PMID:24039907)
• A membrane glycoprotein GPX4 was shown to play a significant role in gamete interactions. (PMID:24191733)
• Identification of truncating mutations in GPX4 in two families affected with Sedaghatian-type spondylometaphyseal dysplasia. (PMID:24706940)
• Hepatitis C virus (HCV) induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. (PMID:25516417)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpx4b	ENSDARG00000076836
mus_musculus	Gpx4	ENSMUSG00000075706
rattus_norvegicus	Gpx4	ENSRNOG00000013604
caenorhabditis_elegans		WBGENE00019846
caenorhabditis_elegans		WBGENE00020373

Paralogs (7): GPX7 (ENSG00000116157), GPX8 (ENSG00000164294), GPX2 (ENSG00000176153), GPX6 (ENSG00000198704), GPX3 (ENSG00000211445), GPX5 (ENSG00000224586), GPX1 (ENSG00000233276)

Protein

Protein identifiers

Phospholipid hydroperoxide glutathione peroxidase GPX4 — P36969 (reviewed: P36969)

Alternative names: Glutathione peroxidase 4

All UniProt accessions (10): A0A087X247, A0A0A0MTT1, A0A9L9PXS3, P36969, K7EJ20, K7EKX7, K7ENB4, K7ERP4, Q6PJX4, R4GNE4

UniProt curated annotations — full annotation on UniProt →

Function. Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins. Can also reduce cholesterol hydroperoxide and thymine hydroperoxide. Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation. Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species. The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis. The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures. May be required to protect cells from the toxicity of ingested lipid hydroperoxides. Required for normal sperm development and male fertility. Essential for maturation and survival of photoreceptor cells. Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion. Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism. Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway. Can reduce fatty acid-derived hydroperoxides. Can also reduce small soluble hydroperoxides such as H2O2, cumene hydroperoxide and tert-butyl hydroperoxide.

Subunit / interactions. Monomer. Has a tendency to form higher mass oligomers. Interacts with FUNDC1; this interaction promotes GPX4 recruitment into mitochondria through TOM/TIM complex where it is degraded by mitophagy. Interacts (via KFERQ motif) with HSPA8; promoting its association with LAMP2 and degradation via chaperone-mediated autophagy.

Subcellular location. Mitochondrion Cytoplasm.

Tissue specificity. Present primarily in testis. Expressed in platelets (at protein level).

Post-translational modifications. Degraded via chaperone-mediated autophagy, promoting ferroptosis. Hydroxylation by EGLN3/PHD3 promotes its stabilization by preventing degradation via chaperone-mediated autophagy.

Disease relevance. Spondylometaphyseal dysplasia, Sedaghatian type (SMDS) [MIM:250220] A form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDS is a neonatal lethal form characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glutathione peroxidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P36969-1	Mitochondrial	yes
P36969-2	Cytoplasmic

RefSeq proteins (4): NP_001034936, NP_001034937, NP_001354761, NP_002076* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000889	Glutathione_peroxidase	Family
IPR029759	GPX_AS	Active_site
IPR029760	GPX_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00255

Enzyme classification (BRENDA):

• EC 1.11.1.12 — phospholipid-hydroperoxide glutathione peroxidase (BRENDA: 26 organisms, 94 substrates, 12 inhibitors, 23 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TERT-BUTYL HYDROPEROXIDE	0.0056–4.344	4
CUMENE HYDROPEROXIDE	0.0017–608	3
H2O2	0.0009–0.799	3
LINOLEIC ACID HYDROPEROXIDE	0.0006–0.0827	3
1-PALMITOYL-2-(13-HYDROPEROXY-CIS-9,TRANS-11-OCT	0.0001–0.0362	2
PHOSPHATIDYLCHOLINE DILINOLEOYL HYDROPEROXIDE	0.0121–0.0249	2
PHOSPHATIDYLCHOLINE HYDROPEROXIDE	0.0002–0.0111	2
GLUTATHIONE	1.37	1
L-ALPHA-PHOSPHATIDYLCHOLINE HYDROPEROXIDE	0.0007	1
PHOSPHOLIPID HYDROPEROXIDE	0.011	1
TERT-BUTYL-HYDROPEROXIDE	2.932	1
(BETA-(13-HYDROPEROXY-CIS-9,TRANS-11-OCTADECADIE	—	0

Catalyzed reactions (Rhea), 12 shown:

• 2 glutathione + H2O2 = glutathione disulfide + 2 H2O (RHEA:16833)
• a hydroperoxy polyunsaturated fatty acid + 2 glutathione = a hydroxy polyunsaturated fatty acid + glutathione disulfide + H2O (RHEA:19057)
• (5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + 2 glutathione = (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + glutathione disulfide + H2O (RHEA:48620)
• (13S)-hydroperoxy-(9Z,11E)-octadecadienoate + 2 glutathione = (13S)-hydroxy-(9Z,11E)-octadecadienoate + glutathione disulfide + H2O (RHEA:48888)
• (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + 2 glutathione = (12S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + glutathione disulfide + H2O (RHEA:50708)
• tert-butyl hydroperoxide + 2 glutathione = tert-butanol + glutathione disulfide + H2O (RHEA:69412)
• cumene hydroperoxide + 2 glutathione = 2-phenylpropan-2-ol + glutathione disulfide + H2O (RHEA:69651)
• (9S)-hydroperoxy-(10E,12Z)-octadecadienoate + 2 glutathione = (9S)-hydroxy-(10E,12Z)-octadecadienoate + glutathione disulfide + H2O (RHEA:76687)
• (12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + 2 glutathione = (12R)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + glutathione disulfide + H2O (RHEA:76691)
• (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + 2 glutathione = (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + glutathione disulfide + H2O (RHEA:76695)
• (5S)-hydroperoxy-(6E,8Z,11Z,14Z,17Z)-eicosapentaenoate + 2 glutathione = (5S)-hydroxy-(6E,8Z,11Z,14Z,17Z)-eicosapentaenoate + glutathione disulfide + H2O (RHEA:76699)
• (12S)-hydroperoxy-(5Z,8Z,10E,14Z,17Z)-eicosapentaenoate + 2 glutathione = (12S)-hydroxy-(5Z,8Z,10E,14Z,17Z)-eicosapentaenoate + glutathione disulfide + H2O (RHEA:76703)

UniProt features (37 total): strand 10, helix 9, sequence variant 3, mutagenesis site 3, turn 3, short sequence motif 2, modified residue 2, transit peptide 1, chain 1, active site 1, non-standard amino acid 1, splice variant 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
6HN3	X-RAY DIFFRACTION	1.01
5H5Q	X-RAY DIFFRACTION	1.1
5H5R	X-RAY DIFFRACTION	1.2
6ELW	X-RAY DIFFRACTION	1.3
7L8K	X-RAY DIFFRACTION	1.38
7L8Q	X-RAY DIFFRACTION	1.48
7L8R	X-RAY DIFFRACTION	1.52
6HKQ	X-RAY DIFFRACTION	1.54
2OBI	X-RAY DIFFRACTION	1.55
7U4N	X-RAY DIFFRACTION	1.6
7L8L	X-RAY DIFFRACTION	1.61
7U4K	X-RAY DIFFRACTION	1.69
7U4J	X-RAY DIFFRACTION	1.81
5H5S	X-RAY DIFFRACTION	1.85
2GS3	X-RAY DIFFRACTION	1.9
8Q8N	X-RAY DIFFRACTION	1.9
9RF1	X-RAY DIFFRACTION	1.9
7U4M	X-RAY DIFFRACTION	1.93
7U4I	X-RAY DIFFRACTION	1.97
8Q8J	X-RAY DIFFRACTION	2
7L8M	X-RAY DIFFRACTION	2.07
7U4L	X-RAY DIFFRACTION	2.25
9J6L	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P36969 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 73

Post-translational modifications (2): 40, 186

Mutagenesis-validated functional residues (3):

Position	Phenotype
73	loss of enzyme activity.
73	almost complete loss of enzyme activity.
186	abolished hydroxylation by egln3, leading to degradation by chaperone-mediated autophagy.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2142688	Synthesis of 5-eicosatetraenoic acids
R-HSA-2142712	Synthesis of 12-eicosatetraenoic acid derivatives
R-HSA-2142770	Synthesis of 15-eicosatetraenoic acid derivatives
R-HSA-9018676	Biosynthesis of D-series resolvins
R-HSA-9018896	Biosynthesis of E-series 18(S)-resolvins
R-HSA-9020265	Biosynthesis of aspirin-triggered D-series resolvins
R-HSA-9023661	Biosynthesis of E-series 18(R)-resolvins

MSigDB gene sets: 377 (showing top): GOBP_DENDRITE_DEVELOPMENT, MODULE_93, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_METENCEPHALON_DEVELOPMENT, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ESTRADIOL, MODULE_151, CROONQUIST_NRAS_SIGNALING_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_GROWTH, DITTMER_PTHLH_TARGETS_UP, HSIAO_HOUSEKEEPING_GENES, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEUROGENESIS

GO Biological Process (17): chromatin organization (GO:0006325), phospholipid metabolic process (GO:0006644), apoptotic process (GO:0006915), response to oxidative stress (GO:0006979), spermatogenesis (GO:0007283), dendrite development (GO:0016358), arachidonate metabolic process (GO:0019369), lipoxygenase pathway (GO:0019372), cerebellum development (GO:0021549), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), multicellular organism growth (GO:0035264), long-chain fatty acid biosynthetic process (GO:0042759), protein polymerization (GO:0051258), negative regulation of ferroptosis (GO:0110076), lipid metabolic process (GO:0006629), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (7): glutathione peroxidase activity (GO:0004602), selenium binding (GO:0008430), identical protein binding (GO:0042802), phospholipid-hydroperoxide glutathione peroxidase activity (GO:0047066), peroxidase activity (GO:0004601), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (7): nucleus (GO:0005634), nuclear envelope (GO:0005635), mitochondrion (GO:0005739), cytosol (GO:0005829), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Arachidonate metabolism	3
Biosynthesis of DHA-derived SPMs	2
Biosynthesis of EPA-derived SPMs	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
long-chain fatty acid metabolic process	2
icosanoid metabolic process	2
response to lipid	2
response to oxygen-containing compound	2
peroxidase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cellular anatomical structure	2
cellular component organization	1
lipid metabolic process	1
organophosphate metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to stress	1
developmental process involved in reproduction	1
male gamete generation	1
neuron projection development	1
unsaturated fatty acid metabolic process	1
olefinic compound metabolic process	1
fatty acid metabolic process	1
metencephalon development	1
response to molecule of bacterial origin	1
multicellular organismal process	1
developmental growth	1
fatty acid biosynthetic process	1
protein-containing complex assembly	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
primary metabolic process	1
cellular detoxification	1
small molecule binding	1
protein binding	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
binding	1
catalytic activity	1
nucleus	1

Protein interactions and networks

STRING

2849 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPX4	GRSF1	Q12849	964
GPX4	HSPA5	P11021	953
GPX4	ACSL4	O60488	834
GPX4	SLC7A11	Q9UPY5	819
GPX4	SECISBP2	Q96T21	816
GPX4	AIFM2	Q9BRQ8	810
GPX4	GCLC	P48506	803
GPX4	TXNRD1	Q16881	759
GPX4	GCLM	P48507	748
GPX4	FTH1	P02794	745
GPX4	SELENOF	O60613	742
GPX4	TXNRD2	Q9NNW7	734
GPX4	SEPHS2	Q99611	733
GPX4	TP53	P04637	730
GPX4	SLC3A2	P08195	730
GPX4	SELENOT	P62341	730

IntAct

60 interactions, top by confidence:

A	B	Type	Score
DBNL	HERC2	psi-mi:“MI:0914”(association)	0.670
CDA	LIN7A	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
CYB561	PTPRA	psi-mi:“MI:0914”(association)	0.530
LHFPL4	ATP5F1B	psi-mi:“MI:0914”(association)	0.530
CD53	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PPIB	GPX4	psi-mi:“MI:0915”(physical association)	0.400
ZP2	GPX4	psi-mi:“MI:0915”(physical association)	0.400
ZP3	GPX4	psi-mi:“MI:0915”(physical association)	0.400
ZP4	GPX4	psi-mi:“MI:0915”(physical association)	0.400
IL18	GPX4	psi-mi:“MI:0915”(physical association)	0.400
RPE	GPX4	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
MAPK13	GPX4	psi-mi:“MI:0915”(physical association)	0.370
PRDX6	GPX4	psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ORF69	PEPD	psi-mi:“MI:0914”(association)	0.350
SDHAF4	GPX4	psi-mi:“MI:0914”(association)	0.350
LACTB	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
OTUD5	TP53	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (127): AKR1B1 (Co-fractionation), ALDOA (Co-fractionation), ALDOC (Co-fractionation), DUT (Co-fractionation), ENO1 (Co-fractionation), ENO2 (Co-fractionation), ENO3 (Co-fractionation), FKBP1A (Co-fractionation), GLRX2 (Co-fractionation), GPX4 (Co-fractionation), GPX4 (Co-fractionation), GPX4 (Co-fractionation), GPX4 (Co-fractionation), GPX4 (Co-fractionation), GPX4 (Co-fractionation)

ESM2 similar proteins: A9PCL4, O02621, O04922, O22448, O22711, O22850, O23814, O23968, O23970, O24031, O32770, O49069, O59858, O62327, O75715, P04041, P11352, P11909, P18283, P28714, P30708, P36968, P36969, P38143, P40581, P52035, P64290, P64291, P73824, P74250, P99097, Q00277, Q0EF98, Q32QL6, Q4AEG9, Q4AEH0, Q4AEH1, Q4AEH2, Q4AEH9, Q4AEI0

Diamond homologs: A1KV41, A6QLY2, G9JJU2, O02621, O04922, O08368, O18994, O22448, O22850, O23814, O23968, O23970, O24031, O24296, O32770, O46607, O48646, O49069, O59858, O62327, O70325, O75715, P00435, P04041, P06610, P07203, P0A0T4, P0A0T5, P0C2T0, P11352, P11909, P18283, P21765, P22352, P28714, P30708, P30710, P35666, P36014, P36968

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NFE2L2	“up-regulates quantity by expression”	GPX4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

235 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	91
Likely benign	82
Benign	27

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
140616	NM_002085.5(GPX4):c.477-8_477-4del	Pathogenic
140617	NM_002085.5(GPX4):c.270C>A (p.Tyr90Ter)	Pathogenic
2056682	NM_002085.5(GPX4):c.85-346dup	Pathogenic
2193296	NM_002085.5(GPX4):c.85-403C>T	Pathogenic
3242659	NC_000019.9:g.(?1091474)(1105774_?)del	Pathogenic
4700090	NM_002085.5(GPX4):c.330dup (p.Gly111fs)	Pathogenic
4723361	NM_002085.5(GPX4):c.85-295C>T	Pathogenic
871898	NM_002085.5(GPX4):c.509_510del (p.Ile170fs)	Pathogenic
1332848	NM_002085.5(GPX4):c.536G>A (p.Arg179His)	Likely pathogenic
2444499	NM_002085.5(GPX4):c.365del (p.Gly122fs)	Likely pathogenic
2705523	NM_002085.5(GPX4):c.85-1G>A	Likely pathogenic
2776240	NM_002085.5(GPX4):c.502-1_508del	Likely pathogenic
4076406	NM_002085.5(GPX4):c.324+1G>A	Likely pathogenic
451510	NM_002085.5(GPX4):c.502-1del	Likely pathogenic
4849283	NM_002085.5(GPX4):c.48_49del (p.Cys16fs)	Likely pathogenic
808416	NM_002085.5(GPX4):c.153_160del (p.Gly51_His52insTer)	Likely pathogenic

SpliceAI

1131 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1105184:A:AG	acceptor_gain	1.0000
19:1105185:G:GG	acceptor_gain	1.0000
19:1105275:G:GG	donor_gain	1.0000
19:1105364:A:AG	acceptor_gain	1.0000
19:1105364:AG:A	acceptor_gain	1.0000
19:1105364:AGG:A	acceptor_gain	1.0000
19:1105365:G:GG	acceptor_gain	1.0000
19:1105365:GG:G	acceptor_gain	1.0000
19:1105365:GGG:G	acceptor_gain	1.0000
19:1105458:C:G	donor_gain	1.0000
19:1105504:G:GT	donor_gain	1.0000
19:1105504:G:T	donor_gain	1.0000
19:1105507:GCAG:G	donor_gain	1.0000
19:1105508:CAG:C	donor_loss	1.0000
19:1105509:AG:A	donor_loss	1.0000
19:1105510:GG:G	donor_loss	1.0000
19:1105511:GTGG:G	donor_loss	1.0000
19:1105650:C:A	acceptor_gain	1.0000
19:1105656:A:AC	acceptor_loss	1.0000
19:1105656:A:AG	acceptor_gain	1.0000
19:1105656:AG:A	acceptor_gain	1.0000
19:1105657:G:GG	acceptor_gain	1.0000
19:1105657:GG:G	acceptor_gain	1.0000
19:1105657:GGA:G	acceptor_gain	1.0000
19:1105657:GGAGC:G	acceptor_gain	1.0000
19:1105763:TGG:T	donor_gain	1.0000
19:1105765:G:GT	donor_gain	1.0000
19:1105765:G:T	donor_gain	1.0000
19:1105774:G:GT	donor_gain	1.0000
19:1105790:G:GT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000651715 (19:1103114 C>T), RS1000843303 (19:1103477 A>C), RS1001016264 (19:1102840 C>T), RS1001333094 (19:1105014 G>A,T), RS1001603921 (19:1105905 G>A,C,T), RS1002333916 (19:1103908 A>C,G,T), RS1003047478 (19:1105996 C>T), RS1003429854 (19:1104180 C>A,G,T), RS1003805199 (19:1104345 G>A,C,T), RS1004351987 (19:1102071 C>T), RS1005009607 (19:1103621 A>T), RS1005345308 (19:1102575 G>A), RS1005459877 (19:1102379 C>T), RS1005965014 (19:1107184 G>T), RS1006008336 (19:1103028 G>A)

Disease associations

OMIM: gene MIM:138322 | disease phenotypes: MIM:250220

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylometaphyseal dysplasia, Sedaghatian type	Strong	Autosomal recessive

Mondo (1): spondylometaphyseal dysplasia, Sedaghatian type (MONDO:0009593)

Orphanet (1): Spondylometaphyseal dysplasia, Sedaghatian type (Orphanet:93317)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000262	Turricephaly
HP:0000358	Posteriorly rotated ears
HP:0000470	Short neck
HP:0000772	Abnormal rib morphology
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000782	Abnormal scapula morphology
HP:0000878	11 pairs of ribs
HP:0000887	Cupped ribs
HP:0000926	Platyspondyly
HP:0001156	Brachydactyly
HP:0001252	Hypotonia
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001321	Cerebellar hypoplasia
HP:0001582	Redundant skin
HP:0001631	Atrial septal defect
HP:0001678	Atrioventricular block
HP:0001762	Talipes equinovarus
HP:0001831	Short toe
HP:0002093	Respiratory insufficiency
HP:0002132	Porencephalic cyst
HP:0002657	Spondylometaphyseal dysplasia
HP:0002663	Delayed epiphyseal ossification
HP:0002750	Delayed skeletal maturation
HP:0002869	Flared iliac wing
HP:0003021	Metaphyseal cupping
HP:0003025	Metaphyseal irregularity

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000879_36	Crohn’s disease	8.000000e-12
GCST001729_23	Crohn’s disease	8.000000e-22
GCST003219_41	Advanced age-related macular degeneration	3.000000e-08
GCST004131_43	Inflammatory bowel disease	5.000000e-17
GCST004132_20	Crohn’s disease	1.000000e-20
GCST004600_104	Eosinophil percentage of white cells	5.000000e-15
GCST004606_43	Eosinophil count	1.000000e-11
GCST004617_131	Eosinophil percentage of granulocytes	3.000000e-11
GCST004623_90	Neutrophil percentage of granulocytes	5.000000e-09
GCST004624_25	Sum eosinophil basophil counts	2.000000e-09
GCST007443_3	Nasal polyps	8.000000e-08
GCST007995_8	Asthma (childhood onset)	2.000000e-08
GCST008870_42	Keratinocyte cancer (MTAG)	2.000000e-08
GCST008871_25	Basal cell carcinoma	3.000000e-09
GCST012134_1	hemolysis of donated blood (oxidative)	4.000000e-14
GCST90002381_126	Eosinophil count	2.000000e-21
GCST90002382_497	Eosinophil percentage of white cells	3.000000e-25
GCST90002407_173	White blood cell count	6.000000e-11
GCST90013406_171	Liver enzyme levels (alkaline phosphatase)	4.000000e-12

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0010176	keratinocyte carcinoma
EFO:0009473	hemolysis
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535798	Spondylometaphyseal dysplasia, Sedaghatian type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL4295754 (SINGLE PROTEIN), CHEMBL5465208 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465231 (PROTEIN-PROTEIN INTERACTION), CHEMBL6196147 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Selenoenzymes

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
GPX4 inhibitor C18	Inhibition	6.92	pIC50
ML162	Inhibition	5.31	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5597052	IC50	10000 nM

ChEMBL bioactivities

104 potent at pChembl≥5 of 136 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	EC50	12	nM	CHEMBL4747331
7.69	Kd	20.4	nM	CHEMBL6169767
7.63	EC50	23.26	nM	CHEMBL5406796
7.61	Kd	24.7	nM	CHEMBL4870989
7.59	EC50	25.64	nM	CHEMBL5406796
7.55	EC50	28	nM	CHEMBL1499544
7.52	EC50	30	nM	CHEMBL5410624
7.44	Kd	36	nM	CHEMBL5618406
7.37	EC50	42.69	nM	CHEMBL5406796
7.36	EC50	44	nM	CHEMBL1951048
7.36	Kd	43.7	nM	CHEMBL4747331
7.32	Kd	48	nM	CHEMBL5619271
7.32	Kd	48	nM	CHEMBL5619371
6.94	Kd	114	nM	CHEMBL5618916
6.92	IC50	120	nM	CHEMBL5422297
6.89	IC50	130	nM	CHEMBL5415644
6.87	EC50	136	nM	CHEMBL5406796
6.87	EC50	135	nM	CHEMBL5400214
6.82	EC50	150	nM	CHEMBL4792343
6.80	Kd	160	nM	CHEMBL5620092
6.77	Kd	170	nM	CHEMBL5619589
6.70	EC50	200	nM	CHEMBL5428324
6.68	EC50	210	nM	CHEMBL4760983
6.60	Kd	253	nM	CHEMBL5618596
6.50	Kd	315	nM	CHEMBL5618364
6.47	EC50	340	nM	CHEMBL1578061
6.43	EC50	370	nM	CHEMBL4780750
6.42	Kd	384	nM	CHEMBL5619014
6.40	EC50	400	nM	CHEMBL5421807
6.38	EC50	420	nM	CHEMBL4757878
6.37	Kd	426	nM	CHEMBL5619466
6.27	IC50	542.5	nM	CHEMBL5570241
6.23	Ki	590	nM	CHEMBL5415644
6.22	EC50	600	nM	CHEMBL4748785
6.20	Ki	630	nM	CHEMBL5422297
6.19	EC50	650	nM	CHEMBL1951048
6.14	Kd	717	nM	CHEMBL5618088
6.11	Kd	784	nM	CHEMBL5618889
6.09	Kd	809	nM	CHEMBL5619657
6.08	Kd	835	nM	CHEMBL5619112
6.03	Kd	931	nM	CHEMBL5618453
6.00	EC50	1000	nM	CHEMBL4751224
5.98	Kd	1050	nM	CHEMBL5618933
5.94	Kd	1140	nM	CHEMBL5618737
5.92	EC50	1200	nM	CHEMBL4779501
5.92	EC50	1200	nM	CHEMBL4800659
5.91	Kd	1230	nM	CHEMBL5618450
5.90	Kd	1270	nM	CHEMBL5619904
5.85	EC50	1400	nM	CHEMBL4800659
5.82	Kd	1510	nM	CHEMBL5619835

PubChem BioAssay actives

99 with measured affinity, of 553 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.0120	uM
methyl (1S,3R)-2-(2-chloroacetyl)-1-[4-[4-[13-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]tridecyl]piperazine-1-carbonyl]phenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate	1991922: Induction of GPX4 degradation in human HT-1080 cells measured for 6 hrs by Western blot analysis	ec50	0.0233	uM
2-(3-chloro-N-(2-chloroacetyl)-4-methoxyanilino)-N-(2-phenylethyl)-2-thiophen-2-ylacetamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.0280	uM
4-[3-[4-[[1-[2-[4-[(4-chlorophenyl)-[4-(5-methyl-4-nitro-1,2-oxazole-3-carbonyl)piperazin-1-yl]methyl]phenoxy]acetyl]piperidin-4-yl]methyl]piperazin-1-yl]propylamino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione	1974573: PROTAC activity at CRBN/GPX4 in human HT-1080 cells assessed as induction of GPX4 degradation incubated for 24 hrs by Western blot analysis	ec50	0.0300	uM
3,4-dimethoxy-N-[[1-[5-(4-propylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]aniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.0360	uM
[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]-(5-methyl-4-nitro-1,2-oxazol-3-yl)methanone	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.0440	uM
1-(3-methoxyphenyl)-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]methanamine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.0480	uM
3,5-dimethoxy-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]aniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.0480	uM
1-(2,4-dimethoxyphenyl)-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]methanamine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.1140	uM
2-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(4-fluoro-3,5-dimethoxyphenyl)acetamide	1998401: Inhibition of GPX4 (unknown origin) incubated for 1 hrs in presence of glutathione and glutathione reductase by microplate reader analysis	ic50	0.1200	uM
2-bromo-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-(4-fluoro-3,5-dimethoxyphenyl)acetamide	1998401: Inhibition of GPX4 (unknown origin) incubated for 1 hrs in presence of glutathione and glutathione reductase by microplate reader analysis	ic50	0.1300	uM
(2S,4R)-1-[(2S)-2-[10-[4-[(4-chlorophenyl)-[4-(5-methyl-4-nitro-1,2-oxazole-3-carbonyl)piperazin-1-yl]methyl]phenoxy]decanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1993397: PROTAC activity at VHL/GPX4 in human HT-1080 cells assessed as induction of protein degradation by Western blot analysis	ec50	0.1350	uM
N-(3-chloro-4-methoxyphenyl)-N-[2-oxo-2-(2-phenylethylamino)-1-thiophen-2-ylethyl]prop-2-ynamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.1500	uM
1-(4-methoxyphenyl)-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]methanamine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.1600	uM
5-[2-[(3,4-dimethoxyanilino)methyl]pyrrol-1-yl]-1,3,4-thiadiazol-2-amine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.1700	uM
2-[3-chloro-N-(2-chloroacetyl)-4-[[1-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methoxy]anilino]-N-(2-phenylethyl)-2-thiophen-2-ylacetamide	1993405: PROTAC activity at CRBN/GPX4 (unknown origin)	ec50	0.2000	uM
N-(3-chloro-4-methoxyphenyl)-N-[2-oxo-2-(2-phenylethylamino)-1-thiophen-2-ylethyl]-3-trimethylsilylprop-2-ynamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.2100	uM
3-methoxy-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]aniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.2530	uM
1-(5-amino-1,3,4-thiadiazol-2-yl)-N-(3,4-dimethoxyphenyl)pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.3150	uM
2-chloro-N-heptyl-N-(3-methylphenyl)acetamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.3400	uM
N-(3-chloro-4-methoxyphenyl)-N-[2-oxo-2-(2-phenylethylamino)-1-thiophen-2-ylethyl]-3-triethylsilylprop-2-ynamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.3700	uM
N-(4-methoxyphenyl)-1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.3840	uM
3-[7-[9-[4-[2-[4-[(4-chlorophenyl)-[4-(5-methyl-4-nitro-1,2-oxazole-3-carbonyl)piperazin-1-yl]methyl]phenoxy]acetyl]piperazin-1-yl]nonylamino]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione	1974573: PROTAC activity at CRBN/GPX4 in human HT-1080 cells assessed as induction of GPX4 degradation incubated for 24 hrs by Western blot analysis	ec50	0.4000	uM
1-[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]-2-chloroethanone	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.4200	uM
2,4-dimethoxy-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]aniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.4260	uM
3-[4-[[2-chloro-4-[(2-chloroacetyl)-[2-oxo-2-(2-phenylethylamino)-1-thiophen-2-ylethyl]amino]phenoxy]methyl]triazol-1-yl]-N-[3-[(E)-[2-(2-hydroxy-6-methoxy-1H-indol-3-yl)indol-3-ylidene]amino]oxypropyl]propanamide	2088644: Inhibition of GPX4 (unknown origin) incubated for 1 hr followed by NADPH and cumene hydroperoxide addition	ic50	0.5425	uM
2-(N-(2-bromoacetyl)-3-chloro-4-methoxyanilino)-N-(2-phenylethyl)-2-thiophen-2-ylacetamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	0.6000	uM
N-[(1-imidazo[2,1-b][1,3,4]thiadiazol-2-ylpyrrol-2-yl)methyl]-2,4-dimethoxyaniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.7170	uM
1-(5-benzamido-1,3,4-thiadiazol-2-yl)-N-(3,4-dimethoxyphenyl)pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.7840	uM
N-(3,4-dimethoxyphenyl)-1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.8090	uM
N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]-2,3-dihydro-1,4-benzodioxin-6-amine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.8350	uM
N-[5-[2-[(3,4-dimethoxyanilino)methyl]pyrrol-1-yl]-1,3,4-thiadiazol-2-yl]-3-fluorobenzamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	0.9310	uM
N-(3-chloro-4-methoxyphenyl)-3-[dimethyl(phenyl)silyl]-N-[2-oxo-2-(2-phenylethylamino)-1-thiophen-2-ylethyl]prop-2-ynamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	1.0000	uM
N-[[1-(6-chloro-2-pyridinyl)pyrrol-2-yl]methyl]-3,4-dimethoxyaniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.0500	uM
N-[[1-(4-chlorophenyl)pyrrol-2-yl]methyl]-3,4-dimethoxyaniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.1400	uM
2-chloro-1-(1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)ethanone	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	1.2000	uM
1-[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]prop-2-yn-1-one	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	1.2000	uM
1-(3,4-dimethoxyphenyl)-N-[[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]methyl]methanamine	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.2300	uM
N-[5-[2-[(3,4-dimethoxyanilino)methyl]pyrrol-1-yl]-1,3,4-thiadiazol-2-yl]benzamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.2700	uM
N-(3,4-dimethoxyphenyl)-1-[5-[(4-fluorobenzoyl)amino]-1,3,4-thiadiazol-2-yl]pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.5100	uM
N-(3,4-dimethoxyphenyl)-1-[6-(4-methylpiperazin-1-yl)-2-pyridinyl]pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.5600	uM
N-(1,3-benzodioxol-5-yl)-2-chloro-N-[(2-prop-2-enoxyphenyl)methyl]acetamide	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	1.6000	uM
1-(4-chlorophenyl)-N-(3,4-dimethoxyphenyl)pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.7200	uM
2,4-dimethoxy-N-[1-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrrol-2-yl]benzamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	1.7900	uM
1-[4-[bis(4-chlorophenyl)methyl]piperazin-1-yl]-3-trimethylsilylprop-2-yn-1-one	1676456: Inhibition of GPX4 in human LOX IMVI cells assessed as ferroptosis-mediated cell death measured as cell viability	ec50	1.8000	uM
3,4-dimethoxy-N-[[1-[6-(4-methylpiperazin-1-yl)-2-pyridinyl]pyrrol-2-yl]methyl]aniline	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	2.1000	uM
2-[2-[(3-methoxyphenoxy)methyl]pyrrol-1-yl]-5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazole	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	2.2800	uM
N-(3,4-dimethoxyphenyl)-1-(5-morpholin-4-yl-1,3,4-thiadiazol-2-yl)pyrrole-2-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	2.7000	uM
N-(3,4-dimethoxyphenyl)-3-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]imidazole-4-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	3.1900	uM
N-(3,4-dimethoxyphenyl)-2-[5-(4-methylpiperazin-1-yl)-1,3,4-thiadiazol-2-yl]pyrazole-3-carboxamide	2128793: Binding affinity to GPX4 (unknown origin) assessed as dissociation constant by surface plasmon resonance	kd	3.3400	uM

CTD chemical–gene interactions

175 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrostatin-1	affects cotreatment, decreases reaction, increases abundance, increases expression, affects reaction (+1 more)	23
sodium arsenite	decreases expression, affects reaction, increases abundance, decreases response to substance, decreases activity (+3 more)	8
Deferoxamine	decreases expression, decreases reaction, increases abundance	7
Chloroquine	decreases expression, decreases reaction, increases abundance	5
Selenium	increases activity, decreases expression, increases expression	5
Particulate Matter	decreases reaction, increases abundance, affects cotreatment, increases expression, decreases expression	5
bisphenol A	affects reaction, affects expression, decreases expression, decreases reaction	4
erastin	decreases expression, decreases reaction, affects reaction	4
Cisplatin	increases response to substance, decreases expression, increases reaction, decreases reaction, affects reaction	4
Tobacco Smoke Pollution	affects expression, decreases expression, increases methylation	4
Sodium Selenite	affects expression, affects reaction, decreases reaction, increases expression, affects response to substance (+4 more)	4
deoxynivalenol	increases reaction, decreases reaction, decreases expression	3
mono-(2-ethylhexyl)phthalate	decreases expression, increases expression, increases reaction, decreases reaction	3
Arsenic Trioxide	decreases expression, increases expression	3
Cadmium	increases palmitoylation, decreases expression, increases reaction, decreases reaction, increases abundance	3
Lipopolysaccharides	decreases expression, decreases reaction, increases expression, affects reaction	3
Paraquat	decreases expression, decreases reaction, affects cotreatment	3
Valproic Acid	affects reaction, decreases expression, increases methylation	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases reaction	3
cobaltous chloride	decreases expression, affects reaction, decreases abundance, increases expression	2
ochratoxin A	decreases expression, increases reaction, decreases reaction, increases acetylation, increases expression	2
4-phenylbutyric acid	decreases expression, decreases reaction	2
RSL3 compound	decreases response to substance, decreases expression, increases reaction, decreases activity	2
Dimethyl Fumarate	decreases expression, decreases reaction, increases metabolic processing	2
Sorafenib	decreases expression, decreases reaction, increases reaction	2
Resveratrol	decreases expression, decreases reaction, increases expression, increases reaction	2
Ropivacaine	decreases expression, increases reaction, increases response to substance, affects reaction	2
Acetylcysteine	decreases expression, decreases reaction	2
Air Pollutants	decreases expression, increases abundance	2
Antimony	decreases expression, decreases reaction, increases abundance, increases degradation, increases localization (+1 more)	2

ChEMBL screening assays

176 unique, capped per target: 176 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118643	Binding	Binding affinity to GPX4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1T8	Abcam HeLa GPX4 KO	Cancer cell line	Female
CVCL_SQ52	HAP1 GPX4 (-) 1	Cancer cell line	Male
CVCL_XP35	HAP1 GPX4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.