TXN

Summary

TXN (thioredoxin, HGNC:12435) is a protein-coding gene on chromosome 9q31.3, encoding Thioredoxin (P10599). Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions. It is a common-essential gene (DepMap: required in 96.9% of cancer cell lines).

The protein encoded by this gene acts as a homodimer and is involved in many redox reactions. The encoded protein is active in the reversible S-nitrosylation of cysteines in certain proteins, which is part of the response to intracellular nitric oxide. This protein is found in the cytoplasm. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7295 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 11 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 96.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_003329

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12435
Approved symbol	TXN
Name	thioredoxin
Location	9q31.3
Locus type	gene with protein product
Status	Approved
Aliases	TRX, Trx80, TXN1
Ensembl gene	ENSG00000136810
Ensembl biotype	protein_coding
OMIM	187700
Entrez	7295

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000374515, ENST00000374517, ENST00000487892, ENST00000879758, ENST00000879759, ENST00000879760, ENST00000919885, ENST00000919886

RefSeq mRNA: 2 — MANE Select: NM_003329 NM_001244938, NM_003329

CCDS: CCDS35103, CCDS59139

Canonical transcript exons

ENST00000374517 — 5 exons

Exon	Start	End
ENSE00000806081	110244778	110244843
ENSE00000806082	110250820	110250879
ENSE00000806083	110251358	110251462
ENSE00001463713	110256412	110256507
ENSE00003849018	110243810	110244219

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 451.0075 / max 11743.9498, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101920	363.5356	1824
101922	46.4991	1818
101921	40.9728	1816

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	99.87	gold quality
gingival epithelium	UBERON:0001949	99.87	gold quality
gingiva	UBERON:0001828	99.86	gold quality
tongue squamous epithelium	UBERON:0006919	99.84	gold quality
oral cavity	UBERON:0000167	99.80	gold quality
epithelium of nasopharynx	UBERON:0001951	99.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.69	gold quality
esophagus mucosa	UBERON:0002469	99.68	gold quality
lower esophagus mucosa	UBERON:0035834	99.65	gold quality
colonic mucosa	UBERON:0000317	99.63	gold quality
mucosa of transverse colon	UBERON:0004991	99.57	gold quality
penis	UBERON:0000989	99.55	gold quality
body of tongue	UBERON:0011876	99.54	gold quality
nasal cavity epithelium	UBERON:0005384	99.53	gold quality
nasal cavity mucosa	UBERON:0001826	99.51	gold quality
jejunal mucosa	UBERON:0000399	99.50	gold quality
right uterine tube	UBERON:0001302	99.50	gold quality
rectum	UBERON:0001052	99.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.44	gold quality
islet of Langerhans	UBERON:0000006	99.43	gold quality
stromal cell of endometrium	CL:0002255	99.41	gold quality
squamous epithelium	UBERON:0006914	99.40	gold quality
epithelium of esophagus	UBERON:0001976	99.39	gold quality
endometrium	UBERON:0001295	99.38	gold quality
esophagus squamous epithelium	UBERON:0006920	99.36	gold quality
trachea	UBERON:0003126	99.34	gold quality
mammalian vulva	UBERON:0000997	99.33	gold quality
esophagus	UBERON:0001043	99.33	gold quality
dorsal root ganglion	UBERON:0000044	99.31	gold quality
transverse colon	UBERON:0001157	99.30	gold quality

Single-cell (SCXA)

Detected in 31 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	42400.43
E-HCAD-8	yes	11208.46
E-CURD-46	yes	10011.09
E-CURD-120	yes	7229.04
E-GEOD-139324	yes	6289.67
E-MTAB-8410	yes	6019.09
E-MTAB-6308	yes	5711.34
E-HCAD-1	yes	5588.94
E-CURD-114	yes	4937.88
E-HCAD-5	yes	3291.41
E-MTAB-8207	yes	2941.92
E-CURD-55	yes	1129.03
E-HCAD-4	yes	793.68
E-MTAB-10287	yes	102.91
E-CURD-122	yes	73.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ASCL1, ATF1, ESR1, FOXO3, HAND1, HIF1A, HSF1, HSF2, JUN, MYC, NFE2L2, PARK7, PARP1, PAX5, PAX8, PPARA, PPARD, SP1, TBPL2, TCF3, TP53, TTF1

miRNA regulators (miRDB)

26 targeting TXN, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-506-5P	98.02	67.41	1065

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• The roles of thioredoxin in protection against oxidative stress-induced apoptosis (PMID:11751890)
• overexpressed TRX, induced by HTLV-I Tax, may play an important role in HTLV-I infection (PMID:11841832)
• serum levels may reflect the status of insulin resistance in Type 2 diabetic patients (PMID:11972307)
• Enhanced resistancy of thioredoxin-transgenic mice against influenza virus-induced pneumonia (PMID:12008049)
• Results suggest that glutaredoxin plays an important role during implantation, while Trx levels remained constant during the secretory phase. (PMID:12029072)
• C-propeptide region of human pro alpha 1 type 1 collagen interacts with thioredoxin (PMID:12099690)
• Glutathionylation; crossstalk between the glutathione and thioredoxin systems (PMID:12119401)
• decrease in mRNA levels in prostate cancer cells related to induction of thioredoxin-binding protein-2 (PMID:12189205)
• Trx is essential for maintaining the content of S-nitrosylated molecules in endothelial cells. Trx can exert its complete redox regulatory and anti-apoptotic functions in endothelial cells only when cysteine 69 is S-nitrosylated (PMID:12244325)
• N-acetylcysteine does not block nonclassic pathway for Trx secretion. Mutations in active site or dimerization site of Trx do not alter its secretion. Nonclassic secretion of Trx is not dependent on redox status of cell or protein. (PMID:12529245)
• role in redox regulation of the antioxidant response element in electrophile response (PMID:12660821)
• Trx-1 may play a role in the redox regulation of SSAT expression and polyamine homeostasis that could contribute to the biological effects of Trx-1 (PMID:12804587)
• human thioredoxin 1 redox potential and examination of dithiol/disulfide motifs (PMID:12816947)
• TRX is upregulated in myocarditis and cardiomyopathies with active necrotic stage associated with DNA damage (PMID:12870673)
• increased TXN-1 expression is a relatively late event in colorectal carcinogenesis and provides evidence in a small group of subjects with colorectal cancer of Dukes stages A through D; thioredoxin-1 expression may be an independent marker of prognosis (PMID:12878985)
• Human lens thioredoxin: molecular cloning and functional characterization. (PMID:12882768)
• Secreted Trx may participate in removing inhibitors of collagen-degrading metalloproteinases. (PMID:14503974)
• novel deregulatory effect of extracellular Trx upon morphological capillary differentiation that appears to depend upon the reduction of laminin and destabilisation of its interaction with galectin-3 (PMID:14644168)
• A redox-active site in TRX is essential for its release from T lymphocytes in response to hydrogen peroxide (H2O2): extracellular TRX regulates its own H2O2-induced release. (PMID:14688353)
• Exposure to low Trx concentrations (1 microM) caused significant increases in the percentage of liquid phase of sputum in cystic fibrosis patients. (PMID:14695120)
• Prx I and Trx expression is increased in lung cancer cells following hypoxia and in human lung cancer tissues (PMID:14703116)
• Thioredoxin is a regulator of gene expression. (PMID:14730345)
• Data show that oxidant-injured and stressed airway epithelial cells upregulate thioredoxin, but produce little IL-8, which may be important in airway epithelial cell-mediated multistep navigation of neutrophils to sites of oxidant injury. (PMID:15096327)
• reduced thioredoxin activity through interaction with Txnip is an important mechanism for vascular oxidative stress in diabetes mellitus (PMID:15128745)
• Trx may regulate cell cycle and growth through a novel modulation of AP-1 activity and p27Kip1 degradation with Jab1 (PMID:15480426)
• A truncated form of endogenous thioredoxin (Trx80) is an early signal in response to danger which can stimulate CD14+ monocytes to differentiate into a novel cell population that may play a major role in triggering innate immune responses. (PMID:15494431)
• Mitogenic cytokine truncated thioredoxin (Trx80) inhibits Epstein-Barr virus-induced B-cell transformation in cord blood mononuclear cells in vitro via T cells that are activated by IL-15 and IL-12 produced by monocytes. (PMID:15507528)
• Thioredoxin is elevated after angioplasty for peripheral artery disease. Thioredoxin impairs chemotaxis and attenuates ischemia reperfusion injury. It acts as both as a marker of oxidative stress and as a therapeutic agent. (PMID:15694802)
• AlphaAR-stimulated hypertrophic signaling in adult rat ventricular myocytes is mediated via a TRX1-sensitive posttranslational oxidative modification of thiols on Ras. (PMID:15723974)
• hepatopoietin association with thioredoxin constitutes a redox signal transduction in activation of AP-1/NF-kappaB (PMID:15894171)
• different redox-active cysteines are important for Trx chemotactic action, whereas its desensitizing action does not have these requirements, which suggests a redox-independent mechanism (PMID:16115022)
• thioredoxin-1 inhibits lipopolysaccharide-induced interleukin-1beta expression in human monocyte-derived macrophages (PMID:16207716)
• CatD induces apoptosis via degradation of Trx protein, which is an essential anti-apoptotic and reactive oxygen species scavenging protein in endothelial cells (PMID:16263712)
• Abeta neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. (PMID:16311508)
• Thioredoxin inhibited the binding of PPARalpha to the PPAR-response element (PMID:16492688)
• indicate an intrinsic form of control of promoter activity by the thioredoxin system itself (PMID:16712525)
• identified two Txnip cysteines that are important for thioredoxin binding and showed that this interaction is consistent with a disulfide exchange reaction between oxidized Txnip and reduced thioredoxin (PMID:16766796)
• Thioredoxin-1 nitration plays a causative role in postischemic cardiomyocyte apoptosis. (PMID:16966583)
• In this review, we will summarize the cardiac effects of thioredoxin and the mechanisms by which thioredoxin mediates inhibition of ventricular remodeling. (PMID:17007870)
• overexpression of hTRX-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls (PMID:17045827)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	txna	ENSDARG00000031435
danio_rerio	txnb	ENSDARG00000044125
mus_musculus	Txn1	ENSMUSG00000028367
rattus_norvegicus	Txn1	ENSRNOG00000086087

Paralogs (4): TXNL1 (ENSG00000091164), TXN2 (ENSG00000100348), TXNDC2 (ENSG00000168454), TXNDC8 (ENSG00000204193)

Protein

Protein identifiers

Thioredoxin — P10599 (reviewed: P10599)

Alternative names: ATL-derived factor, Surface-associated sulphydryl protein

All UniProt accessions (2): P10599, H9ZYJ2

UniProt curated annotations — full annotation on UniProt →

Function. Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions. Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity. Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity. ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).

Subunit / interactions. Homodimer; disulfide-linked. Interacts with TXNIP through the redox-active site. Interacts with MAP3K5 and CASP3. In case of infection, interacts with S.typhimurium protein slrP. Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner.

Subcellular location. Nucleus. Cytoplasm. Secreted.

Post-translational modifications. In the fully reduced protein, both Cys-69 and Cys-73 are nitrosylated in response to nitric oxide (NO). When two disulfide bonds are present in the protein, only Cys-73 is nitrosylated. Cys-73 can serve as donor for nitrosylation of target proteins. In case of infection, ubiquitinated by S.typhimurium protein slrP, leading to its degradation.

Induction. Up-regulated by ionizing radiation.

Similarity. Belongs to the thioredoxin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P10599-1	1	yes
P10599-2	2

RefSeq proteins (2): NP_001231867, NP_003320* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005746	Thioredoxin	Family
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085

UniProt features (44 total): mutagenesis site 10, modified residue 8, strand 6, helix 4, turn 3, site 3, disulfide bond 2, sequence conflict 2, active site 2, initiator methionine 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4OO4	X-RAY DIFFRACTION	0.97
3M9J	X-RAY DIFFRACTION	1.1
2IFQ	X-RAY DIFFRACTION	1.2
2HSH	X-RAY DIFFRACTION	1.35
5DQY	X-RAY DIFFRACTION	1.4
3M9K	X-RAY DIFFRACTION	1.5
4OO5	X-RAY DIFFRACTION	1.54
1ERV	X-RAY DIFFRACTION	1.65
2HXK	X-RAY DIFFRACTION	1.65
1ERT	X-RAY DIFFRACTION	1.7
2IIY	X-RAY DIFFRACTION	1.7
3KD0	X-RAY DIFFRACTION	1.7
1ERW	X-RAY DIFFRACTION	1.8
4POM	X-RAY DIFFRACTION	1.85
1AIU	X-RAY DIFFRACTION	2
4LL1	X-RAY DIFFRACTION	2
3E3E	X-RAY DIFFRACTION	2.01
1AUC	X-RAY DIFFRACTION	2.1
1ERU	X-RAY DIFFRACTION	2.1
3QFA	X-RAY DIFFRACTION	2.2
4POK	X-RAY DIFFRACTION	2.52
3QFB	X-RAY DIFFRACTION	2.6
4LL4	X-RAY DIFFRACTION	2.7
4POL	X-RAY DIFFRACTION	2.8
4PUF	X-RAY DIFFRACTION	3.3
1CQG	SOLUTION NMR
1CQH	SOLUTION NMR
1MDI	SOLUTION NMR
1MDJ	SOLUTION NMR
1MDK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10599-F1	97.64	0.99

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 (5): 32 (nucleophile); 35 (nucleophile); 26 (deprotonates c-terminal active site cys); 33 (contributes to redox potential value); 34 (contributes to redox potential value)

Post-translational modifications (8): 39, 62, 69, 73, 94, 94, 3, 8

Disulfide bonds (2): 32–35, 73

Mutagenesis-validated functional residues (10):

Position	Phenotype
32	loses its reducing activity, interaction with apex1 and transcription activation; when associated with s-35.
35	loses its reducing activity, interaction with apex1 and transcription activation; when associated with s-32.
60	loss of ph-dependence of dimerization.
62	retains its reducing activity. retains interaction with apex1 and transcription activation; when associated with s-69 an
69	no effect on reducing activity, interaction with apex1 and on s-nitrosylation of c-73. retains interaction with apex1 an
70	strongly reduced interaction with casp3; when associated with a-72.
72	strongly reduced interaction with casp3; when associated with a-70.
73	strongly reduced s-nitrosylation of casp3.
73	loss of nitrosylation, and loss of s-nitrosylating activity towards casp3. retains interaction with apex1 and transcript
73	retains its reducing activity.

Function

Pathways and Gene Ontology

Reactome pathways

32 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5676934	Protein repair
R-HSA-844456	The NLRP3 inflammasome
R-HSA-9617629	Regulation of FOXO transcriptional activity by acetylation
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9818027	NFE2L2 regulating anti-oxidant/detoxification enzymes
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-392499	Metabolism of proteins
R-HSA-5663205	Infectious disease
R-HSA-622312	Inflammasomes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9614085	FOXO-mediated transcription
R-HSA-9658195	Leishmania infection
R-HSA-9664424	Cell recruitment (pro-inflammatory response)
R-HSA-9711123	Cellular response to chemical stress
R-HSA-9755511	KEAP1-NFE2L2 pathway

MSigDB gene sets: 407 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, HARRIS_HYPOXIA, MODULE_169, KAAB_FAILED_HEART_ATRIUM_DN, REACTOME_THE_NLRP3_INFLAMMASOME, REACTOME_INFLAMMASOMES, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, MODULE_522, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, HSIAO_HOUSEKEEPING_GENES, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), response to radiation (GO:0009314), positive regulation of DNA binding (GO:0043388), cell redox homeostasis (GO:0045454), negative regulation of protein export from nucleus (GO:0046826), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular detoxification of hydrogen peroxide (GO:0061692), response to nitric oxide (GO:0071731), cellular homeostasis (GO:0019725)

GO Molecular Function (6): RNA binding (GO:0003723), thioredoxin-disulfide reductase (NADPH) activity (GO:0004791), protein-disulfide reductase activity (GO:0015035), protein homodimerization activity (GO:0042803), protein-disulfide reductase [NAD(P)H] activity (GO:0047134), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Cellular Senescence	1
Cellular response to chemical stress	1
Metabolism of nucleotides	1
Transcriptional Regulation by TP53	1
Metabolism of proteins	1
Inflammasomes	1
FOXO-mediated transcription	1
Cell recruitment (pro-inflammatory response)	1
Nuclear events mediated by NFE2L2	1
Metabolism	1
Immune System	1
Innate Immune System	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
response to abiotic stimulus	1
DNA binding	1
positive regulation of binding	1
regulation of DNA binding	1
cellular homeostasis	1
protein export from nucleus	1
negative regulation of nucleocytoplasmic transport	1
regulation of protein export from nucleus	1
maintenance of protein location in nucleus	1
negative regulation of intracellular protein transport	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
detoxification of hydrogen peroxide	1
cellular response to hydrogen peroxide	1
cellular oxidant detoxification	1
response to nitrogen compound	1
response to oxygen-containing compound	1
homeostatic process	1
nucleic acid binding	1
antioxidant activity	1
protein-disulfide reductase [NAD(P)H] activity	1
disulfide oxidoreductase activity	1
catalytic activity, acting on a protein	1
identical protein binding	1
protein dimerization activity	1
protein-disulfide reductase activity	1
oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as acceptor	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

5785 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXN	TXNIP	Q9H3M7	999
TXN	MAP3K5	Q99683	997
TXN	TXNRD1	Q16881	994
TXN	GLRX	P35754	959
TXN	GP5	P40197	955
TXN	TXNRD3	Q86VQ6	928
TXN	GPX2	P18283	927
TXN	PRDX1	P35703	915
TXN	GPX3	P22352	914
TXN	GPX7	Q96SL4	902
TXN	GPX8	Q8TED1	900
TXN	GPX6	P59796	896
TXN	GPX5	O75715	895
TXN	GSR	P00390	892
TXN	ERP44	Q9BS26	888

IntAct

296 interactions, top by confidence:

A	B	Type	Score
EGFR	TXN	psi-mi:“MI:0915”(physical association)	0.790
TXN	CASP3	psi-mi:“MI:0915”(physical association)	0.750
TXN	CASP3	psi-mi:“MI:0407”(direct interaction)	0.750
TXN	CASP3	psi-mi:“MI:0570”(protein cleavage)	0.750
TXNIP	TXN	psi-mi:“MI:0915”(physical association)	0.740
TXN	TXNIP	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MAP3K5	TXN	psi-mi:“MI:0915”(physical association)	0.680
MAP3K5	TXN	psi-mi:“MI:0914”(association)	0.680
GAPDH	TXN	psi-mi:“MI:0915”(physical association)	0.680
TXN	slrP	psi-mi:“MI:0915”(physical association)	0.630
slrP	TXN	psi-mi:“MI:0414”(enzymatic reaction)	0.630
slrP	TXN	psi-mi:“MI:0915”(physical association)	0.630
TXN	MYD88	psi-mi:“MI:0915”(physical association)	0.600
PRDX2	TXN	psi-mi:“MI:0914”(association)	0.560
STAT3	TXN	psi-mi:“MI:0915”(physical association)	0.560
TXN	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
TXN	SERTAD3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (477): NR3C1 (Reconstituted Complex), TXN (Reconstituted Complex), TXNIP (Two-hybrid), TXNIP (Reconstituted Complex), Txnip (Reconstituted Complex), TXNIP (Affinity Capture-Western), TXN (Affinity Capture-Western), TXN (Affinity Capture-Western), TXNIP (Affinity Capture-Western), TXN (Affinity Capture-Western), TXNIP (Reconstituted Complex), TXN (Two-hybrid), MAP3K5 (Affinity Capture-Western), TXNIP (Affinity Capture-Western), TXN (Affinity Capture-Western)

ESM2 similar proteins: A2YIW7, O14463, O81187, O96952, O97508, O97680, P08628, P08629, P0A4L1, P0A4L2, P10599, P10639, P11232, P12243, P12309, P22803, P29429, P29448, P29451, P34723, P50254, P50413, P51225, P52231, P55142, P55143, P68176, P68177, P80028, P82460, Q07090, Q0D840, Q1RQI9, Q1RQJ0, Q39239, Q39241, Q39362, Q42403, Q5R9M3, Q5XJ54

Diamond homologs: A2YIW7, C9K7C5, G4NFB7, O14463, O17486, O64394, O64432, O64764, O65049, O84544, O94504, O96952, O97508, O97680, P07591, P08628, P08629, P0A0K4, P0A0K5, P0A0K6, P0A4L1, P0A4L2, P10472, P10599, P10639, P11232, P12243, P14949, P22217, P22803, P29429, P29448, P29449, P29451, P34723, P37395, P42115, P47938, P48384, P50413

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“hydrogen peroxide”	up-regulates	TXN	“chemical activation”
NFE2L2	“up-regulates quantity by expression”	TXN	“transcriptional regulation”
PPARD	“up-regulates quantity by expression”	TXN	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ERBB2 TMD/JMD mutants	5	23.6×	3e-04
Downregulation of ERBB2 signaling	6	22.6×	1e-04
Signaling by ERBB2 KD Mutants	5	20.9×	5e-04
Signaling by ERBB2	6	20.6×	1e-04
Aggrephagy	5	12.3×	4e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	9	8.6×	2e-04
Constitutive Signaling by Aberrant PI3K in Cancer	6	7.5×	9e-03
PIP3 activates AKT signaling	11	7.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of type I interferon production	5	17.4×	1e-03
mitophagy	6	15.8×	5e-04
intrinsic apoptotic signaling pathway	5	14.8×	2e-03
autophagosome maturation	5	14.5×	2e-03
autophagosome assembly	7	13.0×	3e-04
epidermal growth factor receptor signaling pathway	6	12.3×	1e-03
positive regulation of fibroblast proliferation	5	12.2×	4e-03
positive regulation of epithelial cell proliferation	6	12.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	2
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
563674	GRCh37/hg19 9q31.1-31.3(chr9:106487247-114541579)x1	Pathogenic

SpliceAI

480 predictions. Top by Δscore:

Variant	Effect	Δscore
9:110244773:CGTA:C	donor_loss	1.0000
9:110244774:GTA:G	donor_loss	1.0000
9:110244775:TACCT:T	donor_loss	1.0000
9:110244776:A:T	donor_loss	1.0000
9:110244840:CATC:C	acceptor_gain	1.0000
9:110244843:CCTGG:C	acceptor_gain	1.0000
9:110250876:GGGA:G	acceptor_gain	1.0000
9:110250880:C:CC	acceptor_gain	1.0000
9:110250888:T:TC	acceptor_gain	1.0000
9:110250889:T:C	acceptor_gain	1.0000
9:110250889:T:TC	acceptor_gain	1.0000
9:110251350:ATACT:A	donor_loss	1.0000
9:110251352:ACT:A	donor_loss	1.0000
9:110251353:CTC:C	donor_loss	1.0000
9:110251354:TCA:T	donor_loss	1.0000
9:110251355:CACAT:C	donor_loss	1.0000
9:110251356:A:AC	donor_gain	1.0000
9:110251356:ACA:A	donor_loss	1.0000
9:110251357:C:CC	donor_gain	1.0000
9:110251357:C:CG	donor_loss	1.0000
9:110251458:GCAGT:G	acceptor_gain	1.0000
9:110251459:CAGT:C	acceptor_gain	1.0000
9:110251459:CAGTC:C	acceptor_gain	1.0000
9:110251461:GT:G	acceptor_gain	1.0000
9:110251463:C:CC	acceptor_gain	1.0000
9:110251468:A:T	acceptor_gain	1.0000
9:110256408:GTAC:G	donor_loss	1.0000
9:110256411:CCTTG:C	donor_gain	1.0000
9:110244772:ACGT:A	donor_loss	0.9900
9:110244776:A:AC	donor_gain	0.9900

AlphaMissense

702 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:110244809:G:T	P75Q	0.999
9:110244810:G:A	P75S	0.999
9:110244810:G:T	P75T	0.999
9:110251383:C:T	C35Y	0.999
9:110251394:C:A	W31C	0.999
9:110251394:C:G	W31C	0.999
9:110251396:A:G	W31R	0.999
9:110251396:A:T	W31R	0.999
9:110251401:G:T	A29D	0.999
9:110244185:A:T	L97H	0.998
9:110244203:C:T	G91E	0.998
9:110244821:A:T	V71D	0.998
9:110251382:G:C	C35W	0.998
9:110251384:A:G	C35R	0.998
9:110251392:C:T	C32Y	0.998
9:110251393:A:G	C32R	0.998
9:110251406:G:C	F27L	0.998
9:110251406:G:T	F27L	0.998
9:110251408:A:G	F27L	0.998
9:110251413:A:T	V25D	0.998
9:110244802:G:C	F77L	0.997
9:110244802:G:T	F77L	0.997
9:110244803:A:G	F77S	0.997
9:110244804:A:G	F77L	0.997
9:110244809:G:C	P75R	0.997
9:110244836:G:T	A66D	0.997
9:110250831:C:G	D60H	0.997
9:110251383:C:A	C35F	0.997
9:110251391:A:C	C32W	0.997
9:110251392:C:A	C32F	0.997

dbSNP variants (sampled 300 via entrez): RS1000108507 (9:110258128 G>A), RS1000423606 (9:110253273 A>T), RS1000890485 (9:110248960 AT>A), RS1001086090 (9:110254991 A>G), RS1001164347 (9:110246618 A>G), RS1001391076 (9:110252868 C>A), RS1001592340 (9:110252957 A>G), RS1001868693 (9:110253187 A>T), RS1002198424 (9:110254247 G>A), RS1002279746 (9:110246677 G>C,T), RS1002676875 (9:110254592 T>C), RS1002691244 (9:110245802 T>C), RS1002944329 (9:110249600 G>C), RS1003164872 (9:110243656 G>A,C), RS1003807542 (9:110254725 G>A)

Disease associations

OMIM: gene MIM:187700 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004865_42	Itch intensity from mosquito bite adjusted by bite size	3.000000e-07
GCST90002390_394	Mean corpuscular hemoglobin	6.000000e-09
GCST90002396_413	Mean reticulocyte volume	8.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2010624 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 324 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL406050	PX-12	2	324

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 16 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.05	IC50	90	nM	CHEMBL2315295
6.77	IC50	170	nM	CHEMBL2315297
6.62	IC50	240	nM	CHEMBL2315294
6.54	IC50	290	nM	CHEMBL2315292
6.47	IC50	340	nM	CHEMBL2315306
6.35	IC50	450	nM	CHEMBL2315290
6.29	IC50	510	nM	CHEMBL2315299
6.27	IC50	540	nM	CHEMBL2315288
5.68	IC50	2110	nM	PX-12
5.51	Ki	3110	nM	GAMBOGIC ACID
5.14	IC50	7310	nM	CHEMBL2315305
5.00	IC50	1e+04	nM	CHEMBL5290420

PubChem BioAssay actives

12 with measured affinity, of 114 total; 12 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
2-(cyclohexyldisulfanyl)-6-nitro-1H-benzimidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.0900	uM
5-chloro-2-(cyclohexyldisulfanyl)-6-fluoro-1H-benzimidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.1700	uM
[2-(cyclohexyldisulfanyl)-3H-benzimidazol-5-yl]-phenylmethanone	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.2400	uM
2-amino-8-(cyclohexyldisulfanyl)-1,7-dihydropurin-6-one	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.2900	uM
2-(ethyldisulfanyl)-1H-benzimidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.3400	uM
2-(cyclohexyldisulfanyl)-5-phenyl-1H-imidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.4500	uM
2-(cyclohexyldisulfanyl)-1,3-benzothiazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.5100	uM
3-(cyclohexyldisulfanyl)-5-phenyl-1,2,4-triazol-4-amine	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	0.5400	uM
2-(butan-2-yldisulfanyl)-1H-imidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	2.1100	uM
(Z)-4-[(1S,2S,8R,17S,19R)-12-hydroxy-8,21,21-trimethyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-14,18-dioxo-3,7,20-trioxahexacyclo[15.4.1.02,15.02,19.04,13.06,11]docosa-4(13),5,9,11,15-pentaen-19-yl]-2-methylbut-2-enoic acid	716711: Inhibition of human recombinant TRX-1 up to 60 mins by insulin reduction assay	ki	3.1100	uM
2-(tert-butyldisulfanyl)-1H-benzimidazole	722340: Inhibition of human recombinant thioredoxin-mediated TG2 activation expressed in T84 cells assessed as blockade of 5-biotinamidopentylamine incorporation after 3 hrs by fluorescence microscopic analysis	ic50	7.3100	uM
4,6-dichloro-N-[4-(4-fluorophenyl)phenyl]-1,3,5-triazin-2-amine	1924185: Inhibition of human TXN incubated for 30 mins by fluorescence based plate reader analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, affects expression, decreases expression, increases abundance, increases expression (+1 more)	12
Arsenic Trioxide	decreases response to substance, affects expression, increases expression, increases oxidation, affects reaction (+1 more)	7
Cadmium Chloride	increases oxidation, decreases reaction, affects localization, increases expression	7
Tobacco Smoke Pollution	affects cotreatment, increases expression, increases reaction, affects expression	6
sulforaphane	affects cotreatment, increases expression, increases reaction, decreases methylation	5
Cisplatin	decreases expression, decreases response to substance, affects cotreatment, increases expression	5
Acrolein	decreases activity, decreases reaction, increases oxidation, affects metabolic processing	4
Hydrogen Peroxide	affects cotreatment, increases expression, increases oxidation, decreases response to substance	4
Particulate Matter	increases phosphorylation, decreases expression, increases abundance, affects cotreatment, increases expression (+1 more)	4
bisphenol A	decreases expression, affects cotreatment, affects expression	3
arsenite	increases reaction, increases abundance, decreases reaction, increases expression, affects binding	3
chromium hexavalent ion	affects binding, decreases reaction, increases oxidation, increases abundance, increases expression	3
1-methylpropyl-2-imidazolyl disulfide	decreases reaction, increases expression, decreases expression, decreases activity	3
Acetaminophen	decreases expression, increases expression	3
Acetylcysteine	decreases reaction, increases oxidation, decreases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	increases expression	3
Mercuric Chloride	decreases expression, decreases reaction, affects metabolic processing, decreases activity, increases oxidation	3
Paraquat	decreases response to substance	3
indole-3-carbinol	decreases expression, decreases reaction	2
zinc chromate	increases abundance, increases expression, increases oxidation	2
sodium chromate(VI)	increases oxidation, decreases reaction	2
cupric chloride	increases expression	2
diallyl trisulfide	increases reaction, decreases expression, decreases reduction, increases expression	2
phenethyl isothiocyanate	increases expression, affects binding	2
tris(2-carboxyethyl)phosphine	decreases reaction, increases oxidation	2
Resveratrol	increases expression	2
Vorinostat	decreases expression, increases expression	2
Arsenic	increases expression, affects response to substance, affects abundance, affects cotreatment, increases abundance	2
Auranofin	decreases reaction, increases expression, increases oxidation	2

ChEMBL screening assays

37 unique, capped per target: 36 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2015576	Binding	Binding affinity to human recombinant Trx-1 expressed in Escherichia coli by mass spectrometry analysis	Studies toward novel peptidomimetic inhibitors of thioredoxin-thioredoxin reductase system. — J Med Chem
CHEMBL4131172	ADMET	Substrate activity at human Trx expressed in Escherichia coli at 10 uM preincubated for 3 mins followed by NADPH addition measured at 2 secs interval for 5 mins by UV-Vis spectroscopy	2-Substituted 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7PT	WEHI-7.2 Trx5	Cancer cell line
CVCL_C7PU	WEHI-7.2 Trx6	Cancer cell line

Clinical trials (associated diseases)

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