TXNRD2

Summary

TXNRD2 (thioredoxin reductase 2, HGNC:18155) is a protein-coding gene on chromosome 22q11.21, encoding Thioredoxin reductase 2, mitochondrial (Q9NNW7). Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis.

The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3’ UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene.

Source: NCBI Gene 10587 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glucocorticoid deficiency 5 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 864 total — 3 pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006440

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18155
Approved symbol	TXNRD2
Name	thioredoxin reductase 2
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	TR, TRXR2, TR3, SELZ, TXNR2
Ensembl gene	ENSG00000184470
Ensembl biotype	protein_coding
OMIM	606448
Entrez	10587

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 6 retained_intron, 2 non_stop_decay, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000334363, ENST00000400518, ENST00000400519, ENST00000400521, ENST00000400525, ENST00000462330, ENST00000462843, ENST00000471835, ENST00000474308, ENST00000475995, ENST00000484672, ENST00000485358, ENST00000487165, ENST00000491939, ENST00000494454, ENST00000495655, ENST00000496729, ENST00000542719, ENST00000634471, ENST00000634537, ENST00000635155

RefSeq mRNA: 6 — MANE Select: NM_006440 NM_001282512, NM_001352300, NM_001352301, NM_001352302, NM_001352303, NM_006440

CCDS: CCDS42981, CCDS63402, CCDS86998, CCDS86999, CCDS87000, CCDS87001

Canonical transcript exons

ENST00000400521 — 18 exons

Exon	Start	End
ENSE00001543330	19875522	19875807
ENSE00002313984	19941701	19941818
ENSE00003487823	19880179	19880271
ENSE00003504118	19878090	19878187
ENSE00003517747	19880622	19880717
ENSE00003520397	19898039	19898130
ENSE00003541647	19915214	19915276
ENSE00003554198	19877040	19877234
ENSE00003573028	19919543	19919599
ENSE00003584986	19911377	19911447
ENSE00003598419	19883325	19883461
ENSE00003641779	19915765	19915843
ENSE00003654204	19899049	19899068
ENSE00003664003	19918143	19918217
ENSE00003675318	19895407	19895581
ENSE00003678714	19878366	19878437
ENSE00003692416	19931030	19931098
ENSE00003758434	19918860	19919004

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 95.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7362 / max 142.7997, expressed in 1757 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193173	13.5193	1706
193168	0.8534	312
193169	0.5159	251
193172	0.4328	204
193174	0.2120	81
193171	0.1304	44
193170	0.0724	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	95.27	gold quality
right adrenal gland cortex	UBERON:0035827	94.44	gold quality
apex of heart	UBERON:0002098	94.37	gold quality
right adrenal gland	UBERON:0001233	94.30	gold quality
left adrenal gland	UBERON:0001234	93.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.81	gold quality
left adrenal gland cortex	UBERON:0035825	93.65	gold quality
cerebellar hemisphere	UBERON:0002245	93.62	gold quality
cerebellar cortex	UBERON:0002129	93.40	gold quality
adrenal cortex	UBERON:0001235	93.06	gold quality
adrenal gland	UBERON:0002369	92.36	gold quality
cerebellum	UBERON:0002037	91.42	gold quality
body of stomach	UBERON:0001161	91.35	gold quality
gastrocnemius	UBERON:0001388	89.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.78	gold quality
heart left ventricle	UBERON:0002084	89.50	gold quality
muscle of leg	UBERON:0001383	89.26	gold quality
tibial nerve	UBERON:0001323	89.13	gold quality
cardiac ventricle	UBERON:0002082	89.08	gold quality
granulocyte	CL:0000094	89.07	gold quality
stomach	UBERON:0000945	89.00	gold quality
metanephros cortex	UBERON:0010533	88.87	gold quality
left ovary	UBERON:0002119	88.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.84	gold quality
liver	UBERON:0002107	88.77	gold quality
adenohypophysis	UBERON:0002196	88.76	gold quality
adrenal tissue	UBERON:0018303	88.40	gold quality
monocyte	CL:0000576	88.37	gold quality
right atrium auricular region	UBERON:0006631	88.28	gold quality
stromal cell of endometrium	CL:0002255	88.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF9, NR2C1

miRNA regulators (miRDB)

9 targeting TXNRD2, 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-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-665	97.60	65.64	1781

Literature-anchored findings (GeneRIF, showing 31)

• mammary tumors expressing the wild-type TR were readily suppressed by the IFN/RA combination. In contrast, the tumors bearing a mutant TR were resistant to regression. (PMID:12374691)
• Mitochondrial thioredoxin reductase and peroxiredoxin III are overexpressed in hepatocellular carcinomas. (PMID:12530083)
• Involvements of mitochondrial thioredoxin reductase in cell proliferation. (PMID:12705894)
• the function of TR3 is not limited to its role in Trx2 reduction (PMID:16774913)
• Nuclear extracts from rat lungs administered this reduced recombinant protein suggest a role for NF-kappaB in proinflammatory responses. (PMID:17395017)
• The GPX1 198 Pro/Pro and TXNRD2 370Arg/Arg genotypes might be associated with the genetic susceptibility of gastric cancer. (PMID:19035188)
• Observations underpin a likely critical antioxidant role for TrxR2 and TrxR1 in the endothelium. (PMID:19595745)
• Over-expression of TXNRD2, COMT and ARVCF affects incentive learning and working memory in transgenic mice. (PMID:19617637)
• No obvious correlation can be found between rs5748469 polymorphisms in TrxR2 gene and the susceptibility to Kashin-Beck disease. (PMID:20965815)
• study reveals significant differences between TrxR1 and TrxR2 in substrate specificity and metal compound inhibition in vitro and in cells (PMID:21172426)
• Mutation of this gene is involved in regulation of cellular redoc state in Dilated Cardiomyopathy. (PMID:21247928)
• A role of GPx2, TrxR2 and TrxR3 in proliferation, apoptosis and, therefore, also during cancer development. (PMID:22683372)
• Data suggest that dietary factor (selenium supplementation) up-regulates endogenous antioxidant systems and protects trophoblasts from oxidative stress; selenium upregulates GPX1 (glutathione peroxidase 1) and thioredoxin reductases (TXNRD1; TXNRD2). (PMID:23063346)
• Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance. (PMID:23597419)
• Single Nucleotide Polymorphisms in the genes GPX1 (rs1050450, rs1800668 and rs3811699), TrxR2 (rs5748469), and DIO2 (rs225014) may not be significantly associated with Kashin-Beck disease in a Tibetan population. (PMID:24058403)
• Absence of TXNRD2 in humans leads to glucocorticoid deficiency. (PMID:24601690)
• Data suggest TXNRD1 and TXRNRD2 function at the top of a redox pyramid that governs the oxidation state of peroxiredoxins and other protein factors, thereby dictating a hierarchy of phenotypic responses to oxidative insults. (PMID:24624337)
• The TXNRD2 rs 1548357 polymorphism might be a genetic risk factor for Myocardial infarction in subjects with T2 Diabetes mellitus of Slovenian origin. (PMID:25703281)
• Data suggest that TXNRD2 may represent a druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with osteosarcoma (OS). (PMID:26573231)
• A meta-analysis of the top SNPs identified three new associated loci in primary open angle glaucoma–TXNRD2, ATXN2, and FOXC1 (PMID:26752265)
• Evidence that the rs4485648 polymorphism of the TrxR2 gene might exert an independent effect on the development of Diabetic retinopathy. (PMID:26763822)
• TrxR2 deficiency-induced impaired proliferation and death of chondrocytes may be the pathological mechanism of the osteoarthropathy due to Selenium deficiency. (PMID:27107686)
• p53R2 acts as a positive regulator of TrxR2 activity in mitochondria both under normal physiological conditions and during the cellular response to DNA damage (PMID:27866984)
• TrxR2 was overexpressed in non-small-cell lung cancer cells; our results suggest that TrxR2 acts as an oncogenic gene in the context of lung cancer progression (PMID:28414076)
• Based on recent research, it has been reported that the modulation of the Trx/TrxR system may be considered as a new target in the management of the metabolic syndrome, insulin resistance, and type 2 diabetes, as well as in the treatment of hypertension and atherosclerosis. In this review evidence about a possible role of this system as a marker of the metabolic syndrome is reported. [review] (PMID:29327078)
• The aim of the study was to investigate the association between rs5859 in Sep15, rs1139793 in TrxR2 polymorphisms with the risks of KBD and to detect the expression of AP-1 pathway. (PMID:29653292)
• miR-195-5p exerts tumor-suppressive functions in human lung cancer cells through targeting TrxR2. (PMID:33332541)
• TXNRD2 (rs35934224) CT genotype as possible protective marker for primary open-angle glaucoma in a Brazilian population. (PMID:34431894)
• Association analysis of variants rs35934224 in TXNRD2 and rs6478746 in LMX1B in primary angle-closure and pseudoexfoliation glaucoma. (PMID:34461764)
• TXNRD2 (rs35934224) CT genotype and primary open-angle glaucoma: correspondenceReply to ““TXNRD2 (rs35934224) CT genotype and primary open-angle glaucoma: correspondence"“Primary open-angle glaucomaGenome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucomaGenome-wide association study of primary open-angle glaucoma in continental and admixed African popula… (PMID:35416905)
• Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant. (PMID:39097530)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	txnrd2.2	ENSDARG00000075923
danio_rerio	txnrd2.1	ENSDARG00000094470
mus_musculus	Txnrd2	ENSMUSG00000075704
rattus_norvegicus	Txnrd2	ENSRNOG00000001890
caenorhabditis_elegans		WBGENE00014028

Paralogs (7): DLD (ENSG00000091140), GSR (ENSG00000104687), PYROXD1 (ENSG00000121350), AIFM1 (ENSG00000156709), AIFM3 (ENSG00000183773), TXNRD3 (ENSG00000197763), TXNRD1 (ENSG00000198431)

Protein

Protein identifiers

Thioredoxin reductase 2, mitochondrial — Q9NNW7 (reviewed: Q9NNW7)

Alternative names: Selenoprotein Z, TR-beta, Thioredoxin reductase TR3

All UniProt accessions (12): Q9NNW7, A0A096LNY7, A0A096LP96, A0A096LPB7, A0A096LPD9, A0A096LPH4, A0A096LPK7, A0A0U1RQX0, A0A182DWF2, A0A182DWF3, D3YTF8, E7EWK1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis. Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in the prostate, ovary, liver, testis, uterus, colon and small intestine. Intermediate levels in brain, skeletal muscle, heart and spleen. Low levels in placenta, pancreas, thymus and peripheral blood leukocytes. According to PubMed:10608886, high levels in kidney, whereas according to PubMed:9923614, levels are low. High expression is observed in the adrenal cortex.

Disease relevance. Glucocorticoid deficiency 5 (GCCD5) [MIM:617825] A form of glucocorticoid deficiency, a rare autosomal recessive disorder characterized by resistance to ACTH action on the adrenal cortex, adrenal insufficiency and an inability of the adrenal cortex to produce cortisol. It usually presents in the neonatal period or in early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. In a small number of patients hypoglycemia can be sufficiently severe and persistent that it leads to serious long-term neurological damage or death. The diagnosis is readily confirmed with a low plasma cortisol measurement in the presence of an elevated ACTH level, and normal aldosterone and plasma renin measurements. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. The active site is a redox-active disulfide bond. The selenocysteine residue is essential for enzymatic activity.

Similarity. Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NNW7-1	1, Alpha	yes
Q9NNW7-2	2, Beta
Q9NNW7-3	3, SelZf2
Q9NNW7-4	4, SelZf1

RefSeq proteins (6): NP_001269441, NP_001339229, NP_001339230, NP_001339231, NP_001339232, NP_006431* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001100	Pyr_nuc-diS_OxRdtase	Family
IPR004099	Pyr_nucl-diS_OxRdtase_dimer	Domain
IPR006338	Thioredoxin/glutathione_Rdtase	Family
IPR012999	Pyr_OxRdtase_I_AS	Active_site
IPR016156	FAD/NAD-linked_Rdtase_dimer_sf	Homologous_superfamily
IPR023753	FAD/NAD-binding_dom	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR046952	GSHR/TRXR-like	Family

Pfam: PF02852, PF07992

Enzyme classification (BRENDA):

• EC 1.8.1.9 — thioredoxin-disulfide reductase (NADPH) (BRENDA: 75 organisms, 296 substrates, 269 inhibitors, 240 Km, 193 kcat entries)

Substrate kinetics (BRENDA)

59 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
THIOREDOXIN	0.0003–67.6	45
5,5’-DITHIOBIS(2-NITROBENZOIC ACID)	0.0186–172.4	36
NADPH	0.0004–4.5	33
THIOREDOXIN DISULFIDE	0.001–0.173	15
ARABIDOPSIS THALIANA THIOREDOXIN 3	0.0005–0.0543	10
HORDEUM VULGARE THIOREDOXIN 2	0.0007–0.06	10
NADH	0.011–0.736	9
DTNB	0.05–0.66	7
5,5’-DITHIO-BIS(2-NITROBENZOIC ACID)	0.032–11.9	6
LIPOAMIDE	0.0019–5.59	5
HORDEUM VULGARE THIOREDOXIN DISULFIDE H2	0.0009–0.0018	4
5-HYDROXY-1,4-NAPHTHOQUINONE	0.0023–0.0237	3
HORDEUM VULGARE THIOREDOXIN 2 MUTANT E86A	0.0004–0.0016	3
ESCHERICHIA COLI THIOREDOXIN	0.007–0.149	2
HORDEUM VULGARE THIOREDOXIN DISULFIDE H1	0.0011–0.0012	2

Catalyzed reactions (Rhea), 1 shown:

• [thioredoxin]-dithiol + NADP(+) = [thioredoxin]-disulfide + NADPH + H(+) (RHEA:20345)

UniProt features (19 total): sequence variant 5, splice variant 3, sequence conflict 2, modified residue 2, transit peptide 1, chain 1, active site 1, binding site 1, non-standard amino acid 1, disulfide bond 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q9NNW7 — 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): 497 (proton acceptor)

Ligand- & substrate-binding residues (1): 41–70

Post-translational modifications (3): 175, 329, 522–523

Disulfide bonds (1): 86–91

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species

MSigDB gene sets: 259 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, KYNG_DNA_DAMAGE_DN, GOBP_RESPONSE_TO_INCREASED_OXYGEN_LEVELS, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_CELL_REDOX_HOMEOSTASIS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_DETOXIFICATION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, KYNG_ENVIRONMENTAL_STRESS_RESPONSE_UP, PETROVA_ENDOTHELIUM_LYMPHATIC_VS_BLOOD_DN, GOCC_NEURON_PROJECTION, GOMF_ANTIOXIDANT_ACTIVITY, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_RESPONSE_TO_OXYGEN_RADICAL

GO Biological Process (6): response to oxygen radical (GO:0000305), response to selenium ion (GO:0010269), cell redox homeostasis (GO:0045454), response to hyperoxia (GO:0055093), response to oxidative stress (GO:0006979), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (8): thioredoxin-disulfide reductase (NADPH) activity (GO:0004791), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), flavin adenine dinucleotide binding (GO:0050660), nucleotide binding (GO:0000166), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on a sulfur group of donors, NAD(P) as acceptor (GO:0016668)

GO Cellular Component (7): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
binding	2
cellular anatomical structure	2
cytoplasm	2
neuron projection	2
response to reactive oxygen species	1
response to chemical	1
cellular homeostasis	1
response to increased oxygen levels	1
cellular detoxification	1
antioxidant activity	1
protein-disulfide reductase [NAD(P)H] activity	1
identical protein binding	1
protein dimerization activity	1
nucleotide binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
oxidoreductase activity, acting on a sulfur group of donors	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
dendritic tree	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

3625 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXNRD2	THRB	P10828	959
TXNRD2	TXN	P10599	868
TXNRD2	RXRA	P19793	864
TXNRD2	TXN2	Q99757	862
TXNRD2	THRA	P10827	861
TXNRD2	ARVCF	O00192	854
TXNRD2	PRDX3	P30048	808
TXNRD2	MSRB1	Q9NZV6	792
TXNRD2	SELENOT	P62341	790
TXNRD2	COMT	P21964	788
TXNRD2	SELENOK	Q9Y6D0	783
TXNRD2	SELENOF	O60613	780
TXNRD2	SELENOS	Q9BQE4	769
TXNRD2	SELENON	Q9NZV5	758
TXNRD2	SELENOO	Q9BVL4	758

IntAct

16 interactions, top by confidence:

A	B	Type	Score
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
FLRT1	TCAF2	psi-mi:“MI:0914”(association)	0.530
FOXR2	NME2P1	psi-mi:“MI:0914”(association)	0.530
PI4K2A	GABARAP	psi-mi:“MI:0914”(association)	0.530
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
TXNRD2	TXNRD1	psi-mi:“MI:0915”(physical association)	0.400
TXNRD2	CFAP418	psi-mi:“MI:0915”(physical association)	0.370
CFTR	TXNRD2	psi-mi:“MI:0915”(physical association)	0.370
NDUFA13	SLC22A20P	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
CYP2S1	ARVCF	psi-mi:“MI:0914”(association)	0.350
PNPLA2	PEX14	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): TXNRD2 (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), AKR1B1 (Co-fractionation), TXNRD2 (Co-fractionation), TXNRD2 (Co-fractionation), PSMC3 (Two-hybrid), TXNRD2 (Affinity Capture-MS), TXNRD1 (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), TXNRD2 (Synthetic Lethality), TXNRD2 (Co-fractionation), TXNRD2 (Co-fractionation)

ESM2 similar proteins: A2TIL1, B9A1H3, C3K4W1, F4JLP5, O22229, O62768, O89049, P00390, P13110, P27456, P28593, P30635, P39050, P39051, P41921, P42770, P47791, P48640, P48641, P48642, P70619, P78965, P80461, P91938, Q16881, Q25861, Q41219, Q43154, Q48KI8, Q5NVA2, Q6BPI1, Q6FRV2, Q6HA23, Q70G58, Q74ZK4, Q84PW3, Q86VQ6, Q873E8, Q8S3R2, Q8T137

Diamond homologs: A2TIL1, B9A1H3, D0VWY5, D9J041, O04955, O15770, O34324, O62768, O89049, P00390, P06715, P0A0E4, P0A0E5, P13110, P16171, P23189, P27456, P28593, P30635, P35484, P39040, P39050, P39051, P39916, P41921, P42770, P43783, P47791, P48638, P48639, P48640, P48641, P48642, P61076, P70619, P78965, P80461, P80647, P85207, P91938

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	411
Likely benign	318
Benign	73

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2580321	GRCh37/hg19 22q11.21(chr22:18893838-20307561)x1	Pathogenic
584158	NC_000022.11:g.(?19722428)(19975757_?)del	Pathogenic
812919	Single allele	Pathogenic

SpliceAI

3755 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19877232:CAC:C	acceptor_gain	1.0000
22:19878361:CTCA:C	donor_loss	1.0000
22:19878362:TCA:T	donor_loss	1.0000
22:19878363:CA:C	donor_loss	1.0000
22:19878364:ACC:A	donor_loss	1.0000
22:19878365:C:G	donor_loss	1.0000
22:19880173:CCTCA:C	donor_loss	1.0000
22:19880174:CTCA:C	donor_loss	1.0000
22:19880175:TCACC:T	donor_loss	1.0000
22:19880176:CA:C	donor_loss	1.0000
22:19880178:C:G	donor_loss	1.0000
22:19880615:AACTC:A	donor_loss	1.0000
22:19880616:ACTC:A	donor_loss	1.0000
22:19880617:CTCA:C	donor_loss	1.0000
22:19880618:TCACA:T	donor_loss	1.0000
22:19880619:CAC:C	donor_loss	1.0000
22:19880620:A:AC	donor_gain	1.0000
22:19880620:ACATT:A	donor_loss	1.0000
22:19880621:C:CA	donor_gain	1.0000
22:19880621:C:CT	donor_loss	1.0000
22:19880621:CA:C	donor_gain	1.0000
22:19880713:CGCCC:C	acceptor_gain	1.0000
22:19880715:CCC:C	acceptor_gain	1.0000
22:19880715:CCCC:C	acceptor_loss	1.0000
22:19880715:CCCCT:C	acceptor_gain	1.0000
22:19880716:CC:C	acceptor_gain	1.0000
22:19880716:CCCT:C	acceptor_gain	1.0000
22:19880717:CC:C	acceptor_gain	1.0000
22:19880717:CCTT:C	acceptor_loss	1.0000
22:19880718:C:CC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000000 (22:19903375 G>A), RS1000039137 (22:19910841 G>A,T), RS1000041198 (22:19880725 A>G), RS1000051672 (22:19940730 C>G,T), RS1000082071 (22:19910612 G>A), RS1000084751 (22:19940073 C>G), RS1000191857 (22:19935877 C>T), RS1000257634 (22:19915690 A>G), RS1000411005 (22:19920562 G>A), RS1000437582 (22:19884527 C>T), RS1000474772 (22:19903558 A>G), RS1000574226 (22:19908511 G>A), RS1000614837 (22:19875278 C>T), RS1000679541 (22:19905409 C>G,T), RS1000693363 (22:19915976 A>C,G)

Disease associations

OMIM: gene MIM:606448 | disease phenotypes: MIM:617825, MIM:192600, MIM:188400

GenCC curated gene-disease

Disease	Classification	Inheritance
glucocorticoid deficiency 5	Strong	Autosomal recessive
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
familial glucocorticoid deficiency	Supportive	Autosomal recessive
dilated cardiomyopathy	Limited	Autosomal dominant

Mondo (8): dilated cardiomyopathy (MONDO:0005021), glucocorticoid deficiency 5 (MONDO:0040502), familial hypertrophic cardiomyopathy (MONDO:0024573), cardiomyopathy (MONDO:0004994), DiGeorge syndrome (MONDO:0008564), ependymoma (MONDO:0016698), (MONDO:0015470), familial glucocorticoid deficiency (MONDO:0008733)

Orphanet (6): Dilated cardiomyopathy (Orphanet:217604), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Rare cardiomyopathy (Orphanet:167848), 22q11.2 deletion syndrome (Orphanet:567), Ependymoma (Orphanet:251636), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000098	Tall stature
HP:0000127	Renal salt wasting
HP:0000407	Sensorineural hearing impairment
HP:0000826	Precocious puberty
HP:0000846	Adrenal insufficiency
HP:0000851	Congenital hypothyroidism
HP:0000953	Hyperpigmentation of the skin
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001325	Hypoglycemic coma
HP:0001508	Failure to thrive
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001727	Thromboembolic stroke
HP:0001824	Weight loss
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002039	Anorexia
HP:0002153	Hyperkalemia
HP:0002173	Hypoglycemic seizures
HP:0002445	Tetraplegia
HP:0002574	Episodic abdominal pain
HP:0002615	Hypotension
HP:0002719	Recurrent infections

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001649_4	Glaucoma (primary angle closure)	2.000000e-07
GCST002440_2	Staphylococcus aureus infection	3.000000e-06
GCST003342_2	Glaucoma (primary open-angle)	4.000000e-11
GCST003342_5	Glaucoma (primary open-angle)	9.000000e-11
GCST006065_45	Glaucoma (primary open-angle)	1.000000e-13
GCST006067_9	Glaucoma (primary open-angle)	8.000000e-09
GCST006394_61	Intraocular pressure	1.000000e-09
GCST006395_27	Glaucoma	3.000000e-09
GCST006412_130	Intraocular pressure	5.000000e-12
GCST008153_17	Lean body mass	4.000000e-06
GCST009722_12	Glaucoma (multi-trait analysis)	9.000000e-12
GCST009725_60	Intraocular pressure	5.000000e-09
GCST009726_23	Glaucoma	1.000000e-06
GCST011438_15	Glaucoma (primary open-angle)	3.000000e-09
GCST011439_5	Glaucoma (primary open-angle)	9.000000e-09
GCST90011766_21	Glaucoma (primary open-angle)	2.000000e-13
GCST90011770_84	Glaucoma (primary open-angle)	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0004995	lean body mass

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
C565974	Familial Glucocorticoid Deficiency 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096978 (PROTEIN FAMILY), CHEMBL2403 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 117,080 (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
CHEMBL140	CURCUMIN	3	93,882
CHEMBL6246	ELLAGIC ACID	2	23,148
CHEMBL2035460	ETHASELEN	1	50

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs933271	Efficacy	3	methadone	Opioid-Related Disorders

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs737865	COMT, TXNRD2		0.00	0
rs737866	COMT, TXNRD2		0.00	0
rs933271	COMT, TXNRD2	3	2.50	1	methadone
rs2020917	COMT, TXNRD2		0.00	0
rs2075507	COMT, TXNRD2		0.00	0
rs7287550	COMT, TXNRD2		0.00	0
rs9606186	COMT, TXNRD2	3	2.25	1	risperidone
rs13306278	COMT, TXNRD2	3	2.50	1	Selective serotonin reuptake inhibitors

ChEMBL bioactivities

70 potent at pChembl≥5 of 103 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.96	IC50	0.11	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
9.92	IC50	0.12	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
8.70	IC50	2	nM	Platinum complex
8.52	IC50	3	nM	2-Mercaptoimidazole Bis[(4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II)] Trinitrate
8.40	Ki	4	nM	Platinum complex
8.40	IC50	4	nM	4-Mercaptopyridine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
8.30	IC50	5	nM	Platinum complex
8.30	Ki	5	nM	4-Mercaptopyridine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
8.22	IC50	6	nM	2-Mercaptopyridine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
8.15	Ki	7	nM	2-Mercaptopyridine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
8.15	IC50	7	nM	2-Mercaptopyrimidine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
7.96	Ki	11	nM	2-Mercaptoimidazole Bis[(4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II)] Trinitrate
7.77	Ki	17	nM	2-Mercaptopyrimidine (4’-chloro-2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
7.75	IC50	18	nM	CHEMBL120147
7.66	Ki	22	nM	4-Mercaptoethanol-(2,2’:6’,4’-chloro,2’’-terpyridine)platinum (II) Nitrate
7.60	IC50	25	nM	Platinum complex
7.52	IC50	30	nM	4-Mercaptoethanol-(2,2’:6’,4’-chloro,2’’-terpyridine)platinum (II) Nitrate
7.46	Ki	35	nM	Platinum complex
7.46	IC50	35	nM	4-Mercaptoethanol-(2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
7.42	IC50	38	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
6.89	IC50	130	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
6.86	Ki	139	nM	Platinum complex
6.84	IC50	145	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
6.70	IC50	200	nM	Platinum complex
6.67	IC50	215	nM	CHEMBL120147
6.58	IC50	260	nM	CHEMBL217200
6.56	Ki	275	nM	2-(2-Amino-ethylamino)-N-(7-{2-[N’-(5-nitro-furan-2-carbonyl)-hydrazino]-2-oxo-ethyl}-naphthalen-2-yl)-acetamide; compound with GENERIC INORGANIC NEUTRAL COMPONENT
6.55	Ki	280	nM	CHEMBL3814977
6.47	Ki	337	nM	Platinum complex
6.46	Ki	348	nM	4-Mercaptoethanol-(2,2’:6’,2’’-terpyridine)platinum (II) Nitrate
6.46	IC50	350	nM	CHEMBL88230
6.30	IC50	500	nM	CHEMBL412348
5.92	IC50	1200	nM	CHEMBL413290
5.91	IC50	1220	nM	CHEMBL4451948
5.85	IC50	1400	nM	CHEMBL3290761
5.83	IC50	1490	nM	CHEMBL4451948
5.80	IC50	1600	nM	CHEMBL440625
5.80	IC50	1600	nM	CHEMBL385299
5.70	IC50	2000	nM	CHEMBL2035489
5.70	IC50	2000	nM	CHEMBL206140
5.70	IC50	1980	nM	CHEMBL4475597
5.68	IC50	2100	nM	CHEMBL89232
5.63	IC50	2360	nM	CHEMBL4475597
5.62	IC50	2400	nM	CHEMBL412348
5.53	IC50	2950	nM	CHEMBL4451948
5.52	IC50	3000	nM	CORULEOELLAGIC ACID
5.51	IC50	3060	nM	CHEMBL4475597
5.47	IC50	3400	nM	CHEMBL217200
5.47	IC50	3400	nM	CHEMBL91078
5.46	IC50	3500	nM	CHEMBL32856

PubChem BioAssay actives

44 with measured affinity, of 211 total; 27 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
N’-(2-naphthalen-2-ylacetyl)-5-nitrofuran-2-carbohydrazide	255063: Inhibitory concentration against wild type human thioredoxin reductase (5 nM) pre-incubated for 10 min at 25 degree C in buffer in the presence of 200 uM NADPH	ic50	0.0180	uM
(1S,3R,6S,8S,11S,13R,16S,18R,21S,23R,26S,28S,31S,33R)-10-[[4-(dimethylamino)phenyl]tellanylmethyl]-5,15,20,25,30,35-hexakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213240: Inhibition of thioredoxin reductase	ic50	0.2600	uM
(1R,5S,8S,15S,18R,21S,22S)-5-methyl-7,16-dioxahexacyclo[13.6.1.01,8.04,21.09,14.018,22]docosa-9(14),11-diene-10,13,17-trione	1306725: Irreversible inhibition of thioredoxin reductase (unknown origin)	ki	0.2800	uM
8’-hydroxyspiro[2,4-dioxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaene-3,4’-naphthalene]-1’-one	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	0.3500	uM
(1S,3R,6S,8R,11S,13R,16S,18R,21S,23S,26S,28R,31S,33S)-5,10,15,20,30,35-hexakis(hydroxymethyl)-25-[[(1S,3S,6S,8S,11S,13R,16S,18R,21S,23R,26S,28R,31S,33R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecahydroxy-5,15,20,25,30,35-hexakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-10-yl]methyltellanylmethyl]-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213241: Inhibition of thioredoxin reductase in the presence of thioredoxinand insulin	ic50	0.5000	uM
(1S,3R,6S,8S,11S,13R,16S,18R,21S,23R,26S,28S,31S,33R)-10-(butyltellanylmethyl)-5,15,20,25,30,35-hexakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213241: Inhibition of thioredoxin reductase in the presence of thioredoxinand insulin	ic50	1.2000	uM
(1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-5-(3,5,6-trimethylpyrazin-2-yl)penta-1,4-dien-3-one	1628168: Inhibition of thioredoxin reductase in human A549/CDDP cells by DTNB dye based microplate spectrophotometry	ic50	1.2200	uM
4-(1,3,2-dithiarsinan-2-yl)aniline	1154308: Inhibition of human TrxR activity in human HeLa cell lysate after 12 hrs by insulin reduction assay	ic50	1.4000	uM
(1S,3R,6S,8S,11S,13R,16S,18R,21S,23S,26S,28R,31S,33R)-5,10,15,20,30,35-hexakis(hydroxymethyl)-25-(phenyltellanylmethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213240: Inhibition of thioredoxin reductase	ic50	1.6000	uM
(1S,3R,6S,8S,11S,13R,16S,18R,21S,23S,26S,28R,31S,33R)-5,10,15,20,30,35-hexakis(hydroxymethyl)-25-[(4-methoxyphenyl)tellanylmethyl]-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213240: Inhibition of thioredoxin reductase	ic50	1.6000	uM
(1E,4E)-1-(3,4,5-trimethoxyphenyl)-5-(3,5,6-trimethylpyrazin-2-yl)penta-1,4-dien-3-one	1628168: Inhibition of thioredoxin reductase in human A549/CDDP cells by DTNB dye based microplate spectrophotometry	ic50	1.9800	uM
4,6-dinitro-2,1,3-benzothiadiazole	263781: Inhibition of human TrxR	ic50	2.0000	uM
5-methoxy-2-[2-(5-methoxy-3-oxo-1,2-benzoselenazol-2-yl)ethyl]-1,2-benzoselenazol-3-one	665478: Inhibition of TrxR in human U87MG cells after 12 hrs by insulin-reducing method	ic50	2.0000	uM
spiro[2,4-dioxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaene-3,8’-3,4-dihydro-2H-naphthalene]-1’,5’-dione	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	2.1000	uM
3,5,6,10,12,13-hexahydroxy-2,9-dioxatetracyclo[6.6.2.04,16.011,15]hexadeca-1(15),3,5,8(16),10,12-hexaene-7,14-dione	580674: Inhibition of human thioredoxin reductase	ic50	3.0000	uM
8’-hydroxyspiro[1,3-dioxolane-2,4’-naphthalene]-1’-one	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	3.4000	uM
(E)-3-(3-nitrophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one	1199613: Inhibition of TrxR in human HeLa cells assessed as depletion of cellular thiol after 48 hrs	ic50	3.5000	uM
4-arsorosoaniline	1154308: Inhibition of human TrxR activity in human HeLa cell lysate after 12 hrs by insulin reduction assay	ic50	4.0000	uM
(1S,3R,6S,8S,11S,13R,16S,18R,21S,23S,26S,28R,31S,33R)-5,10,15,20,30,35-hexakis(hydroxymethyl)-25-[(4-hydroxyphenyl)tellanylmethyl]-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecol	213241: Inhibition of thioredoxin reductase in the presence of thioredoxinand insulin	ic50	4.0000	uM
1-(2,4-dinitrophenyl)sulfanyl-2,4-dinitrobenzene	263781: Inhibition of human TrxR	ic50	4.0000	uM
(1E,4E)-1-(2,4-dimethoxyphenyl)-5-(3,5,6-trimethylpyrazin-2-yl)penta-1,4-dien-3-one	1628167: Inhibition of thioredoxin reductase in human A549 cells by DTNB dye based microplate spectrophotometry	ic50	4.1200	uM
(1E,4E)-1-(3,4-dimethoxyphenyl)-5-(3,5,6-trimethylpyrazin-2-yl)penta-1,4-dien-3-one	1628167: Inhibition of thioredoxin reductase in human A549 cells by DTNB dye based microplate spectrophotometry	ic50	4.1700	uM
(1’S,2’S,3’R,5’R,7’R,11’S)-2’,11’-dihydroxyspiro[2,4-dioxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaene-3,6’-4,12-dioxatetracyclo[5.4.1.01,7.03,5]dodec-9-ene]-8’-one	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	4.5000	uM
(1E,4E)-1-(2-hydroxy-3-methoxyphenyl)-5-(3,5,6-trimethylpyrazin-2-yl)penta-1,4-dien-3-one	1628168: Inhibition of thioredoxin reductase in human A549/CDDP cells by DTNB dye based microplate spectrophotometry	ic50	4.6400	uM
8’-(2-methylprop-2-enoxy)spiro[2,4-dioxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaene-3,4’-naphthalene]-1’-one	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	4.8000	uM
2-[2-(3-oxo-1,2-benzoselenazol-2-yl)ethyl]-1,2-benzoselenazol-3-one	665478: Inhibition of TrxR in human U87MG cells after 12 hrs by insulin-reducing method	ic50	5.0000	uM
(3’S,10’R)-3’,10’-dihydroxyspiro[2,4-dioxatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaene-3,8’-tetracyclo[10.2.1.02,11.04,9]pentadeca-4(9),6,13-triene]-5’-one	213244: Inhibition of thioredoxin-1/thioredoxin reductase system	ic50	8.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
Auranofin	decreases reaction, increases activity, decreases expression, increases reaction, decreases activity	3
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	3
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases expression, decreases methylation	2
Acetaminophen	affects cotreatment, decreases expression	2
Cisplatin	decreases activity, affects cotreatment, decreases expression	2
Selenomethionine	affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
Sodium Selenite	decreases reaction, increases activity, decreases expression, increases reaction, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
juglone	increases reduction	1
lipoamide	increases reduction	1
W 7	decreases reaction, increases expression	1
cobaltous chloride	decreases expression	1
cinnamyl alcohol	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
cerous chloride	decreases expression	1
potassium tellurate(IV)	increases activity	1
aflatoxin B2	decreases methylation, increases methylation	1
nickel sulfate	increases expression	1
cadmium sulfide	decreases expression	1
isoeugenol	increases expression	1
avobenzone	increases expression	1
arsenic trichloride	affects binding, decreases reaction	1
Bandrowski’s base	increases expression	1
hexyl cinnamic aldehyde	increases expression	1

ChEMBL screening assays

91 unique, capped per target: 76 binding, 15 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1694678	Binding	Inhibition of human thioredoxin reductase	Compounds structurally related to ellagic acid show improved antiplasmodial activity. — Antimicrob Agents Chemother
CHEMBL811689	Functional	Percent TrxR activity after exposure to 3x1 uM concentration at regular intervals of 0,24,48 hours for the period of 67 hours	Human thioredoxin reductase is efficiently inhibited by (2,2’:6’,2’ ‘-terpyridine)platinum(II) complexes. Possible implications for a novel antitumor strategy. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KF	Abcam HEK293T TXNRD2 KO	Transformed cell line	Female
CVCL_KU15	HeLa SilenciX TXNRD2	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	PHASE2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	PHASE2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	PHASE2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	PHASE2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	PHASE2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM
NCT03775070	PHASE2	COMPLETED	Simvastatin Therapy in Patients With Dilated Cardiomyopathy.
NCT04405804	PHASE2	UNKNOWN	Early Administration of Ivabradine in Children With Heart Failure
NCT05410873	PHASE2	COMPLETED	Examining the Effects of Mitochondrial Oxidative Stress in DCM
NCT06632834	PHASE2	RECRUITING	Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation
NCT00585546	PHASE1	TERMINATED	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
NCT02293603	PHASE1	UNKNOWN	Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC)
NCT03062956	PHASE1	COMPLETED	A Single Ascending Dose Study Assessing the Safety, Tolerability, PK and PD of MYK-491
NCT03129568	PHASE1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Pediatric Dilated Cardiomyopathy
NCT04982081	PHASE1	UNKNOWN	Treating Congestive HF With hiPSC-CMs Through Endocardial Injection
NCT06381466	PHASE1	TERMINATED	A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.
NCT06464588	PHASE1	RECRUITING	A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
NCT06902896	PHASE1	COMPLETED	Safety and Efficacy of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT07137338	PHASE1	RECRUITING	A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy
NCT07241104	PHASE1	RECRUITING	A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy