NOX4

Summary

NOX4 (NADPH oxidase 4, HGNC:7891) is a protein-coding gene on chromosome 11q14.3, encoding NADPH oxidase 4 (Q9NPH5). NADPH oxidase that catalyzes predominantly the reduction of oxygen to H2O2.

This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 50507 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 100 total — 1 likely-pathogenic
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016931

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7891
Approved symbol	NOX4
Name	NADPH oxidase 4
Location	11q14.3
Locus type	gene with protein product
Status	Approved
Aliases	KOX-1, KOX
Ensembl gene	ENSG00000086991
Ensembl biotype	protein_coding
OMIM	605261
Entrez	50507

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000263317, ENST00000343727, ENST00000375979, ENST00000393282, ENST00000424319, ENST00000524473, ENST00000525196, ENST00000525278, ENST00000527626, ENST00000527956, ENST00000528341, ENST00000529343, ENST00000531342, ENST00000532825, ENST00000534731, ENST00000936348, ENST00000942524

RefSeq mRNA: 7 — MANE Select: NM_016931 NM_001143836, NM_001143837, NM_001291926, NM_001291927, NM_001291929, NM_001300995, NM_016931

CCDS: CCDS44695, CCDS44696, CCDS73361, CCDS73362, CCDS8285

Canonical transcript exons

ENST00000263317 — 18 exons

Exon	Start	End
ENSE00000989301	89444135	89444232
ENSE00000989304	89421902	89421982
ENSE00000989305	89402326	89402542
ENSE00000989306	89400215	89400379
ENSE00000995997	89440688	89440715
ENSE00001148056	89400017	89400079
ENSE00003461016	89432784	89432856
ENSE00003468593	89340063	89340171
ENSE00003472960	89373432	89373492
ENSE00003509754	89491190	89491375
ENSE00003536820	89337447	89337515
ENSE00003568488	89449440	89449524
ENSE00003579192	89335845	89335945
ENSE00003585426	89342074	89342193
ENSE00003590323	89354962	89355043
ENSE00003635985	89451785	89451895
ENSE00003641859	89490458	89490553
ENSE00003846189	89324353	89326876

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 98.11.

FANTOM5 (CAGE): breadth broad, TPM avg 7.0762 / max 273.2980, expressed in 741 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121794	4.2264	573
121793	1.0321	217
121798	0.6577	286
121796	0.2656	134
121797	0.1878	102
121791	0.1717	106
206412	0.1562	91
121795	0.1387	68
121792	0.1320	67
121799	0.0586	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.11	gold quality
nephron tubule	UBERON:0001231	96.78	gold quality
renal glomerulus	UBERON:0000074	96.26	gold quality
metanephric glomerulus	UBERON:0004736	96.19	gold quality
kidney epithelium	UBERON:0004819	94.85	gold quality
ascending aorta	UBERON:0001496	94.50	gold quality
thoracic aorta	UBERON:0001515	94.33	gold quality
adult mammalian kidney	UBERON:0000082	93.65	gold quality
descending thoracic aorta	UBERON:0002345	93.48	gold quality
aorta	UBERON:0000947	91.46	gold quality
tendon	UBERON:0000043	91.42	gold quality
kidney	UBERON:0002113	90.46	gold quality
pericardium	UBERON:0002407	90.21	gold quality
cortex of kidney	UBERON:0001225	89.45	gold quality
popliteal artery	UBERON:0002250	89.43	gold quality
tibial artery	UBERON:0007610	89.43	gold quality
right coronary artery	UBERON:0001625	88.71	gold quality
artery	UBERON:0001637	88.67	gold quality
left coronary artery	UBERON:0001626	87.02	gold quality
synovial joint	UBERON:0002217	86.71	gold quality
coronary artery	UBERON:0001621	85.71	gold quality
stromal cell of endometrium	CL:0002255	84.06	gold quality
tendon of biceps brachii	UBERON:0008188	82.87	silver quality
subcutaneous adipose tissue	UBERON:0002190	82.69	gold quality
metanephros	UBERON:0000081	82.17	gold quality
tibial nerve	UBERON:0001323	81.13	gold quality
blood vessel layer	UBERON:0004797	81.06	gold quality
right atrium auricular region	UBERON:0006631	80.26	gold quality
saphenous vein	UBERON:0007318	79.06	gold quality
metanephros cortex	UBERON:0010533	78.45	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	2836.68
E-CURD-119	yes	1781.50
E-ANND-3	yes	18.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ADIPOQ, AP1, CEBPG, E2F1, HIF1A, LRP1, MECP2, MITF, NFE2L2, NFKB1, NFKB, POU2F1, PPARG, RELA, SMAD3, SP1, SP3, STAT1, STAT3, STAT4

miRNA regulators (miRDB)

123 targeting NOX4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861

Literature-anchored findings (GeneRIF, showing 40)

• Nox4 is expressed in aortic media and either not at all or rarely in unaffected intima, while mRNA expression in cells is greatest in fibrofatty lesions. (PMID:12482831)
• Nox4 co-localizes with vinculin in focal adhesions in vascular smooth muscle cells. Its role may be correlated with its (PMID:14670934)
• Data suggest that Nox4 provides a novel link between the insulin receptor and the generation of cellular reactive oxygen species that enhances insulin signal transduction. (PMID:14966267)
• Cells expressed gp91phox homologs Nox1, Nox2, and Nox4. Keratinocytes expressed Nox distinct from phox isoform of phagocytes. Source of superoxide that may regulate cell proliferation and host defense in skin and oral mucosa. (PMID:15102091)
• NOX4 has a role in inhibiting apoptosis with reactive oxygen species in pancreatic cancer cells (PMID:15155719)
• A nox4-based oxidase appears proportionately more important in mammary arteries than in saphenous veins. (PMID:15256399)
• p22phox directly interacts with Nox1 and Nox4, to form an superoxide-generating NADPH oxidase. (PMID:15322091)
• Direct interaction of NADPH oxidase 4 with toll-like receptor 4 is involved in lipopolysaccharide-mediated generation of reactive oxygen species and NF-kappa B activation in HEK293T cells. (PMID:15356101)
• NOX4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in aortic smooth muscle cells. (PMID:15572675)
• Urotensin-II is a potent activator of reactive oxygen species generation by NADPH oxidase in pulmonary artery smooth muscle cells (PMID:15618545)
• mRNA expression and localization of NOX4 in human umbilical vein endothelial cells. (PMID:15706079)
• Nox4 exists as several isoforms that may have different functions in ROS-related cell signaling (PMID:15721269)
• NOX2 and NOX4 have roles as redox messengers in the activation of intracellular signaling pathways leading (or contributing) to mitochondriogenesis, cell survival, and differentiation in hematopoietic stem cells (PMID:15883163)
• The Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. (PMID:15927447)
• Downregulation of Nox4, which results in the reduction of ROS generation, is reported in the skin fibroblasts of patients wtih leprechaunism. (PMID:16249442)
• Thus Nox4 appears to produce superoxide in the nucleus of HUVECs, thereby regulating gene expression via a mechanism for oxidative stress response. (PMID:16324151)
• reactive oxygen species generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis. (PMID:16532036)
• We suggest that Nox4 may be involved in increased superoxide generation in vascular smooth muscle cells under proinflammatory conditions. (PMID:16563235)
• The results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22(phox) expression, may be a novel and highly selective treatment for leukemia. (PMID:16754784)
• In endothelial cells, NOX2 and NOX4, but not NOX1, equally contributed to ROS generation and proliferation under basal conditions, indicating that a complex relation between NOX homologues controls endothelial function. (PMID:16987004)
• VHL protein exerts its tumor suppressor action, at least partially, via inhibition of p22phox-based Nox4/Nox1 NADPH oxidase-dependent reactive oxygen species generation (PMID:17200123)
• Nox4 influences the pathobiochemistry of asthma by generating reactive oxygen species that promote TGF-beta1-induced proliferation and hypertrophy of human airway smooth muscle (PMID:17369289)
• Reactive oxygen species production evolves in parallel with the catalytic activity of NOX and is suppressed by siNOX 4 (small interference oligonucleotide RNA directed against NOX 4) silencing. (PMID:17472580)
• Upregulation of eNOS and a parallel downregulation of Nox4 lead to an increase in bioactive nitric oxide, which in turn could mediate some of the beneficial effects of danshen (PMID:17481637)
• The close correlation between NOX4 mRNA and reactive oxygen species generation might hint towards a function as an inducible NOX isoform. (PMID:17501721)
• Data suggest that decreased NOX4 mRNA content is a hallmark of adipocyte differentiation and that NOX4 expression measured in whole adipose tissue is not an unequivocal indicator of intact or impaired insulin action. (PMID:17553579)
• In lungs from patients with idiopathic pulmonary arterial hypertension, NOX4 expression in the tunica media was 2.5-fold upregulated, supporting an important role for NOX4 in the vascular remodeling associated with pulmonary hypertension. (PMID:17585072)
• Nox4 type NADPH oxidase promotes endothelial angiogenic responses in human microvascular endothelial cells in vitro. (PMID:17717289)
• study shows HIV-1 Tat signaling, leading to concurrent but separate Nox4-dependent Ras/ERK activation, and Nox2-dependent JNK activation; Tat signaling, therefore, provides an example of Nox-specific differential control of MAP kinase pathways (PMID:17940286)
• A novel signaling pathway, in which NADPH oxidase activation results in inhibition of protein tyrosine phosphatases, leading to enhanced and sustained phosphorylation of kinases (JAK2), and suppression of apoptosis is suggested in pancreatic neoplasms. (PMID:17983808)
• Nox2 and Nox4-generated ROS modulate glucose uptake in a leukaemic cell line (PMID:18473264)
• Enhanced expression of Nox4 appears to be involved in cell proliferation and survival in glioma cells. (PMID:18508317)
• Nox4, a subtype of nonphagocytic NADPH oxidase, was found to play a key role in intracellular ROS generation and exogenous H(2)O(2)-induced MUC5AC gene expression in NHNE cells (PMID:18539955)
• These data indicate that the specificity of intracellular reactive oxygen species-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments. (PMID:18573911)
• In hypoxia, NOX4 was significantly upregulated at mRNA & protein levels. A significant increase of NOX4 mRNA expression was seen under hypoxic conditions in pulmonary artery adventitial fibroblasts from idiopathic pulmonary arterial hypertension patients. (PMID:18593227)
• results indicate that Nox4 and Nox2 play a physiological role in hyperoxia-induced ROS production and migration of ECs (PMID:18783311)
• Upregulation of NOX4 by TGF-beta is required for its pro-apoptotic activity in hepatocytes (PMID:18845355)
• analysis of distinct features of the Nox4-p22 phox complex (PMID:18849343)
• hypoxia increases pulmonary artery smooth muscle cell proliferation in vitro, accompanied by increased reactive oxygen species generation and NOX4 gene expression (PMID:19036873)
• Nox4 acts as a switch between differentiation and proliferation in preadipocytes. (PMID:19057021)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	NOX4	ENSDARG00000114937
mus_musculus	Nox4	ENSMUSG00000030562
rattus_norvegicus	Nox4	ENSRNOG00000013925

Paralogs (6): NOX1 (ENSG00000007952), NOX3 (ENSG00000074771), DUOX1 (ENSG00000137857), DUOX2 (ENSG00000140279), CYBB (ENSG00000165168), NOX5 (ENSG00000255346)

Protein

Protein identifiers

NADPH oxidase 4 — Q9NPH5 (reviewed: Q9NPH5)

Alternative names: Kidney oxidase-1, Kidney superoxide-producing NADPH oxidase, Renal NAD(P)H-oxidase

All UniProt accessions (4): Q9NPH5, E9PI95, E9PPP2, E9PR43

UniProt curated annotations — full annotation on UniProt →

Function. NADPH oxidase that catalyzes predominantly the reduction of oxygen to H2O2. Can also catalyze to a smaller extent, the reduction of oxygen to superoxide. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Promotes ferroptosis, reactive oxygen species production and reduced glutathione (GSH) levels by activating NLRP3 inflammasome activation and cytokine release. NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. Involved in redox signaling in vascular cells. Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Lacks superoxide-generating NADPH oxidase activity.

Subunit / interactions. Interacts with protein disulfide isomerase. Interacts with, relocalizes and stabilizes CYBA/p22phox. Interacts with TLR4. Interacts with PPP1R15A. Interacts with LRRC8A; this interaction prevents the ubiquitin-mediated degradation of LRRC8A.

Subcellular location. Cytoplasm. Endoplasmic reticulum membrane. Cell membrane. Cell junction. Focal adhesion. Nucleus Nucleus. Nucleus. Nucleolus. Perinuclear region Cytoplasm. Perinuclear region.

Tissue specificity. Expressed by distal tubular cells in kidney cortex and in endothelial cells (at protein level). Widely expressed. Strongly expressed in kidney and to a lower extent in heart, adipocytes, hepatoma, endothelial cells, skeletal muscle, brain, several brain tumor cell lines and airway epithelial cells.

Post-translational modifications. Deubiquitinated by USP19. N-glycosylated and glycosylation is required for its proper function. N-glycosylated.

Activity regulation. Inhibited by plumbagin. Activated by phorbol 12-myristate 13-acetate (PMA). Activated by insulin. Inhibited by diphenylene iodonium.

Induction. By 7-ketocholesterol (at protein level).

Isoforms (9)

UniProt ID	Names	Canonical?
Q9NPH5-1	1	yes
Q9NPH5-2	2, Nox4A
Q9NPH5-3	3, Nox4E
Q9NPH5-4	4, 28 kDa, Nox4D
Q9NPH5-5	5, Nox4C
Q9NPH5-6	6, Nox4B
Q9NPH5-7	7
Q9NPH5-8	8
Q9NPH5-9	9

RefSeq proteins (7): NP_001137308, NP_001137309, NP_001278855, NP_001278856, NP_001278858, NP_001287924, NP_058627* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000778	Cyt_b245_heavy_chain	Family
IPR013112	FAD-bd_8	Domain
IPR013121	Fe_red_NAD-bd_6	Domain
IPR013130	Fe3_Rdtase_TM_dom	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR050369	RBOH/FRE	Family

Pfam: PF01794, PF08022, PF08030

Catalyzed reactions (Rhea), 2 shown:

• NADPH + O2 + H(+) = H2O2 + NADP(+) (RHEA:11260)
• NADPH + 2 O2 = 2 superoxide + NADP(+) + H(+) (RHEA:63180)

UniProt features (41 total): mutagenesis site 11, splice variant 8, topological domain 7, transmembrane region 6, domain 2, region of interest 2, glycosylation site 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPH5-F1	86.98	0.68

Functional residue map

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

Glycosylation sites (2): 133, 230

Mutagenesis-validated functional residues (11):

Position	Phenotype
16	50% reduction in h2o2 generation, without any effect on superoxide generation.
47	no effect on h2o2 or superoxide generation.
218–235	loss of h2o2 generation with predominant generation of superoxide. no effect on localization to the endoplasmic reticulu
222	loss of h2o2 generation with predominant generation of superoxide.
226	loss of h2o2 generation with predominant generation of superoxide.
246	no effect on h2o2 or superoxide generation.
248	no effect on h2o2 or superoxide generation.
264–273	loss of h2o2 generation with predominant generation of superoxide. no effect on localization to the endoplasmic reticulu
270	loss of h2o2 generation with predominant generation of superoxide.
304	partial loss of catalytic activity. no effect on cyba localization.
575–578	partial loss of catalytic activity. no effect on cyba localization.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-9702518	STAT5 activation downstream of FLT3 ITD mutants
R-HSA-9703465	Signaling by FLT3 fusion proteins

MSigDB gene sets: 202 (showing top): MODULE_97, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_SUPEROXIDE_METABOLIC_PROCESS, MODULE_182, GOBP_HOMOCYSTEINE_METABOLIC_PROCESS, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, GOBP_CARDIAC_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (18): cell morphogenesis (GO:0000902), heart process (GO:0003015), superoxide metabolic process (GO:0006801), defense response (GO:0006952), inflammatory response (GO:0006954), negative regulation of cell population proliferation (GO:0008285), gene expression (GO:0010467), intracellular signal transduction (GO:0035556), superoxide anion generation (GO:0042554), bone resorption (GO:0045453), homocysteine metabolic process (GO:0050667), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cardiac muscle cell differentiation (GO:0055007), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to glucose stimulus (GO:0071333), reactive oxygen species biosynthetic process (GO:1903409), positive regulation of DNA biosynthetic process (GO:2000573), reactive oxygen species metabolic process (GO:0072593)

GO Molecular Function (13): nucleotide binding (GO:0000166), electron transfer activity (GO:0009055), NAD(P)H oxidase H2O2-forming activity (GO:0016174), superoxide-generating NAD(P)H oxidase activity (GO:0016175), oxygen sensor activity (GO:0019826), heme binding (GO:0020037), flavin adenine dinucleotide binding (GO:0050660), modified amino acid binding (GO:0072341), superoxide-generating NADPH oxidase activity (GO:0106292), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor (GO:0050664)

GO Cellular Component (14): nucleus (GO:0005634), nucleolus (GO:0005730), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), focal adhesion (GO:0005925), membrane (GO:0016020), NADPH oxidase complex (GO:0043020), perinuclear region of cytoplasm (GO:0048471), perinuclear endoplasmic reticulum (GO:0097038), cytoplasm (GO:0005737), anchoring junction (GO:0070161), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to chemical stress	1
Signaling by FLT3 ITD and TKD mutants	1
FLT3 signaling in disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular membrane-bounded organelle	3
cytoplasm	3
reactive oxygen species metabolic process	2
intracellular anatomical structure	2
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	2
binding	2
anatomical structure morphogenesis	1
circulatory system process	1
response to stress	1
defense response	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
macromolecule biosynthetic process	1
signal transduction	1
superoxide metabolic process	1
tissue homeostasis	1
bone remodeling	1
sulfur amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	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
cardiocyte differentiation	1
cardiac muscle tissue development	1
striated muscle cell differentiation	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
positive regulation of DNA metabolic process	1
DNA biosynthetic process	1
regulation of DNA biosynthetic process	1
metabolic process	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOX4	CYBA	P13498	998
NOX4	NCF1	P14598	997
NOX4	NCF2	P19878	996
NOX4	TLR4	O00206	993
NOX4	NOX5	Q96PH1	989
NOX4	DUOX1	Q9NRD9	985
NOX4	CYBB	P04839	984
NOX4	NOX1	Q9Y5S8	984
NOX4	NOX3	Q9HBY0	982
NOX4	NCF4	Q15080	971
NOX4	POLDIP2	Q9Y2S7	960
NOX4	DUOX2	Q9NRD8	842
NOX4	NOXA1	Q86UR1	837
NOX4	ZKSCAN1	P17029	826
NOX4	SMAD3	P84022	804

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TLR4	NOX4	psi-mi:“MI:0915”(physical association)	0.680
NOX4	HP	psi-mi:“MI:0914”(association)	0.350
SPOP	NOX4	psi-mi:“MI:2364”(proximity)	0.270
PTEN	NOX4	psi-mi:“MI:2364”(proximity)	0.270
NOX4	EGFR	psi-mi:“MI:2364”(proximity)	0.270
NOX4	AKT1	psi-mi:“MI:2364”(proximity)	0.270
NOX4	BRAF	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (17): ACTBL2 (Affinity Capture-MS), MYO18A (Affinity Capture-MS), NOX4 (Affinity Capture-Western), NOX4 (Reconstituted Complex), NOX4 (Affinity Capture-Western), NOX4 (Reconstituted Complex), PTPN11 (Reconstituted Complex), IGJ (Affinity Capture-MS), BPIFB1 (Affinity Capture-MS), MUC5B (Affinity Capture-MS), PIGR (Affinity Capture-MS), HP (Affinity Capture-MS), CYBA (Affinity Capture-Western), CALCOCO2 (Affinity Capture-Western), NOX4 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K1Q8, A2VE04, A4QP81, G5ECB2, O08680, O13146, O62714, O75899, O88871, O88917, O88923, O94910, O95490, O97817, O97827, O97831, P29319, P35384, P48442, P54755, P54757, P54758, Q07497, Q21540, Q5TZ24, Q5U9X3, Q61703, Q62413, Q6INU7, Q6ZNA5, Q7TT41, Q80T41, Q80TR1, Q80TS3, Q8BG22, Q8BXJ9, Q8C7U7, Q8JZZ7, Q8K385, Q8MSU3

Diamond homologs: O46522, O48538, O81210, O81211, P04839, P52649, Q2HXK9, Q2HXL0, Q5R5C5, Q5ZAJ0, Q61093, Q672J9, Q672K1, Q6J2K5, Q86GL4, Q8CIZ9, Q924V1, Q948T9, Q95L74, Q9FIJ0, Q9HBY0, Q9JHI8, Q9NPH5, Q9SBI0, Q9SW17, Q9WV87, Q9XYS3, Q9Y5S8, Q948U0, Q9NRD8, A3KP77, A4IHY0, F4I4K7, O81209, P92949, Q3KTM0, Q7T0X7, Q8RWS6, Q8VE38, Q8VY13

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NOX4	up-regulates	ROS
NOX4	“up-regulates quantity”	superoxide	“chemical modification”
E2F1	“up-regulates quantity by expression”	NOX4	“transcriptional regulation”
FYN	“down-regulates activity”	NOX4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	74
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3338042	NC_000011.9:g.89110945_89175769del	Likely pathogenic

SpliceAI

3741 predictions. Top by Δscore:

Variant	Effect	Δscore
11:89335843:AC:A	donor_gain	1.0000
11:89335844:CC:C	donor_gain	1.0000
11:89335844:CCCT:C	donor_gain	1.0000
11:89335943:CTT:C	acceptor_gain	1.0000
11:89335950:C:CT	acceptor_gain	1.0000
11:89335951:A:T	acceptor_gain	1.0000
11:89337442:CATA:C	donor_loss	1.0000
11:89337443:ATAC:A	donor_loss	1.0000
11:89337444:TACC:T	donor_loss	1.0000
11:89337445:A:T	donor_loss	1.0000
11:89337446:C:T	donor_loss	1.0000
11:89337511:CAAAA:C	acceptor_gain	1.0000
11:89337512:AAAA:A	acceptor_gain	1.0000
11:89337513:AAA:A	acceptor_gain	1.0000
11:89337514:AA:A	acceptor_gain	1.0000
11:89337515:AC:A	acceptor_loss	1.0000
11:89337516:C:CC	acceptor_gain	1.0000
11:89337517:T:C	acceptor_loss	1.0000
11:89337525:C:CT	acceptor_gain	1.0000
11:89337526:A:T	acceptor_gain	1.0000
11:89337964:T:A	donor_gain	1.0000
11:89342072:A:AC	donor_gain	1.0000
11:89342073:C:CC	donor_gain	1.0000
11:89342073:CAA:C	donor_gain	1.0000
11:89342206:C:CT	acceptor_gain	1.0000
11:89354960:A:AC	donor_gain	1.0000
11:89354961:C:CC	donor_gain	1.0000
11:89373491:CA:C	acceptor_gain	1.0000
11:89373493:C:CC	acceptor_gain	1.0000
11:89400080:C:CC	acceptor_gain	1.0000

AlphaMissense

3791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:89373438:A:G	W377R	0.997
11:89373438:A:T	W377R	0.997
11:89340128:A:G	W461R	0.996
11:89340128:A:T	W461R	0.996
11:89451878:G:C	S57R	0.996
11:89451878:G:T	S57R	0.996
11:89451880:T:G	S57R	0.996
11:89326858:G:C	F545L	0.995
11:89326858:G:T	F545L	0.995
11:89326860:A:G	F545L	0.995
11:89342133:G:C	S426R	0.995
11:89342133:G:T	S426R	0.995
11:89342135:T:G	S426R	0.995
11:89373436:C:A	W377C	0.995
11:89373436:C:G	W377C	0.995
11:89400037:G:C	H352D	0.995
11:89342122:G:T	A430D	0.994
11:89342179:C:T	G411D	0.994
11:89451848:G:C	N67K	0.994
11:89451848:G:T	N67K	0.994
11:89342131:A:G	L427P	0.993
11:89400029:A:C	F354L	0.993
11:89400029:A:T	F354L	0.993
11:89400031:A:G	F354L	0.993
11:89402345:A:G	F276S	0.993
11:89490547:A:G	W22R	0.993
11:89490547:A:T	W22R	0.993
11:89326862:A:T	V544D	0.992
11:89340098:A:G	W471R	0.992
11:89340098:A:T	W471R	0.992

dbSNP variants (sampled 300 via entrez): RS1000021612 (11:89540548 G>A,C), RS1000025044 (11:89331595 G>A), RS1000027210 (11:89462550 C>T), RS1000033787 (11:89366234 AAAAT>A), RS1000045461 (11:89348394 AACAGAGTAAG>A), RS1000051441 (11:89540767 G>A), RS1000052249 (11:89474058 A>C), RS1000058366 (11:89462688 C>T), RS1000075437 (11:89402984 C>A,G), RS1000077356 (11:89331805 T>A), RS1000085696 (11:89366052 C>T), RS1000119322 (11:89360261 T>C), RS1000151272 (11:89518959 G>T), RS1000173041 (11:89445512 A>G), RS1000173951 (11:89564248 G>T)

Disease associations

OMIM: gene MIM:605261 | disease phenotypes: MIM:203100

GenCC curated gene-disease

Mondo (1): oculocutaneous albinism type 1A (MONDO:0008745)

Orphanet (2): Oculocutaneous albinism type 1 (Orphanet:352731), Oculocutaneous albinism type 1A (Orphanet:79431)

HPO phenotypes

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

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST001762_516	Obesity-related traits	8.000000e-06
GCST002087_16	Homocysteine levels	2.000000e-08
GCST002087_5	Homocysteine levels	2.000000e-20
GCST004278_52	Pulse pressure	9.000000e-22
GCST004775_10	Pulse pressure	3.000000e-09
GCST004775_43	Pulse pressure	9.000000e-16
GCST006009_8	Pulse pressure	5.000000e-12
GCST006424_1	Severe diabetic retinopathy in type 2 diabetes	4.000000e-09
GCST006424_2	Severe diabetic retinopathy in type 2 diabetes	1.000000e-08
GCST007096_102	Pulse pressure	2.000000e-30
GCST007097_139	Pulse pressure	1.000000e-10
GCST007097_140	Pulse pressure	1.000000e-14
GCST007099_87	Systolic blood pressure	2.000000e-09
GCST007267_303	Systolic blood pressure	1.000000e-09
GCST007268_41	Diastolic blood pressure	2.000000e-11
GCST007269_307	Pulse pressure	1.000000e-28
GCST007270_12	Systolic blood pressure	9.000000e-08
GCST007272_3	Pulse pressure	1.000000e-16
GCST007703_105	Systolic blood pressure	4.000000e-06
GCST007705_56	Pulse pressure	2.000000e-11
GCST008513_24	Health literacy	5.000000e-06
GCST008839_5	Height	2.000000e-16
GCST009507_3	Triglyceride levels	8.000000e-07
GCST009600_142	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-09
GCST010142_73	Fish- and plant-related diet	9.000000e-09
GCST012048_14	Triglyceride levels	3.000000e-07
GCST90006991_4	Gut microbiota relative abundance (Streptococcus)	8.000000e-06
GCST90011899_23	Aspartate aminotransferase levels	2.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004578	homocysteine measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0010104	health literacy measurement
EFO:0004530	triglyceride measurement
EFO:0008111	diet measurement
EFO:0007874	gut microbiome measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250375 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 124,926 (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
CHEMBL50	QUERCETIN	3	74,559
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL4303187	SETANAXIB	2	811
CHEMBL4650894	ISUZINAXIB	2	93
CHEMBL150	KAEMPFEROL	1	25,940

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — NADPH oxidases

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
compound 87 [PMID: 20942471]	Inhibition	7.33	pKi
compound 7c [PMID: 22041175]	Inhibition	7.14	pKi
setanaxib	Inhibition	6.96	pKi
GKT136901	Inhibition	6.78	pKi
GLX351322	Inhibition	5.3	pIC50

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-N-(3,4-dimethylphenyl)-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	1680 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
6-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-2-N-(3,4-dimethylphenyl)-1,3,5-triazine-2,4-diamine	IC50	15000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
2-N-(3,4-dimethylphenyl)-6-[[4-(4-methylphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	16000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
2-N-(3-chloro-4-methylphenyl)-6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	17000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine
2-N-(3,4-dimethylphenyl)-6-[[4-(3-methylphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	IC50	59000 nM	US-10173988: N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine

ChEMBL bioactivities

161 potent at pChembl≥5 of 176 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.97	IC50	10.71	nM	CHEMBL4859206
7.97	IC50	10.72	nM	CHEMBL4859206
7.79	IC50	16.4	nM	CHEMBL1876217
7.79	IC50	16.41	nM	CHEMBL1876217
7.66	IC50	21.94	nM	CHEMBL4849098
7.66	IC50	21.98	nM	CHEMBL4849098
7.33	Ki	47	nM	CHEMBL1277852
7.19	Ki	65	nM	CHEMBL1277767
7.17	Ki	67	nM	CHEMBL1927157
7.15	IC50	70.77	nM	STAUROSPORINE
7.14	Ki	72	nM	CHEMBL1927147
7.12	Ki	76	nM	CHEMBL1927149
7.09	Ki	82	nM	CHEMBL1277933
7.06	Ki	87	nM	CHEMBL1927146
7.05	IC50	90	nM	DIPHENYLENEIODONIUM CHLORIDE
7.03	Ki	94	nM	CHEMBL1927156
7.03	Ki	93	nM	CHEMBL1927158
7.02	Ki	95	nM	CHEMBL1277853
7.00	Ki	101	nM	CHEMBL1927150
6.99	Ki	103	nM	CHEMBL1927145
6.99	Ki	103	nM	CHEMBL1927151
6.96	Ki	110	nM	SETANAXIB
6.96	Ki	111	nM	CHEMBL1927152
6.96	Ki	111	nM	CHEMBL1927155
6.95	Ki	112	nM	CHEMBL1927153
6.94	Ki	114	nM	CHEMBL1277676
6.94	Ki	114	nM	CHEMBL1277934
6.94	Ki	116	nM	CHEMBL1927154
6.89	Ki	128	nM	CHEMBL1278018
6.88	Ki	131	nM	CHEMBL1927159
6.85	Ki	142	nM	CHEMBL1926690
6.84	Ki	144	nM	CHEMBL1927148
6.82	Ki	153	nM	CHEMBL1277583
6.82	Ki	151	nM	CHEMBL1277677
6.81	Ki	156	nM	CHEMBL1927160
6.80	Ki	158	nM	CHEMBL1278200
6.78	Ki	165	nM	CHEMBL1276946
6.78	Ki	165	nM	CHEMBL1277582
6.77	IC50	170	nM	CHEMBL1242941
6.76	Ki	173	nM	CHEMBL1277489
6.76	Ki	172	nM	CHEMBL1277768
6.67	Ki	215	nM	CHEMBL1276162
6.67	Ki	213	nM	CHEMBL1277932
6.66	Ki	218	nM	CHEMBL1276857
6.66	Ki	218	nM	CHEMBL1277215
6.63	Ki	235	nM	CHEMBL1278111
6.63	Ki	236	nM	CHEMBL1277032
6.63	Ki	235	nM	CHEMBL1277399
6.62	IC50	240	nM	CHEMBL1243033
6.62	Ki	240	nM	CHEMBL1277850

PubChem BioAssay actives

151 with measured affinity, of 318 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
2-[3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]phenol	1778250: Inhibition of human NADPH oxidase 4 by quantitative sandwich enzyme immunoassay technique	ic50	0.0107	uM
2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenol	1778250: Inhibition of human NADPH oxidase 4 by quantitative sandwich enzyme immunoassay technique	ic50	0.0164	uM
2-(3-benzyl-1,2,4-oxadiazol-5-yl)phenol	1778250: Inhibition of human NADPH oxidase 4 by quantitative sandwich enzyme immunoassay technique	ic50	0.0219	uM
4-[[benzyl(methyl)amino]methyl]-2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.0470	uM
2-(2-chlorophenyl)-4-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.0650	uM
4-(2-chlorophenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0670	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1778250: Inhibition of human NADPH oxidase 4 by quantitative sandwich enzyme immunoassay technique	ic50	0.0708	uM
13-benzyl-4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0720	uM
4-(2-chlorophenyl)-13-[(2-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0760	uM
2-(2-chlorophenyl)-4-[(2-chlorophenyl)methoxymethyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.0820	uM
4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0870	uM
8-iodoniatricyclo[7.4.0.02,7]trideca-1(13),2,4,6,9,11-hexaene chloride	2013275: Inhibition of human NOX4 expressed in HEK293T cells assessed as inhibition of teracycline-induced hydrogen peroxide production pretreated for 18 hrs with tetracycline and treated with compound for 15 mins and measured at 10 mins post-compound treatment by Amplex Red based fluorescence analysis	ic50	0.0900	uM
4-(2-methoxyphenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0930	uM
4-(2-chlorophenyl)-13-(pyridin-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.0940	uM
2-(2-chlorophenyl)-4-(phenylmethoxymethyl)-5-(pyrazin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.0950	uM
4-(2-chlorophenyl)-13-[(3-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1010	uM
tert-butyl 4-(2-chlorophenyl)-3,8-dioxo-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-13-carboxylate	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1030	uM
4-(2-chlorophenyl)-13-[(4-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1030	uM
2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	2013293: Binding affinity to human NOX4 assessed as inhibition constant	ki	0.1100	uM
4-(2-chlorophenyl)-13-[(2-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1110	uM
4-(2-chlorophenyl)-13-(furan-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1110	uM
4-(2-chlorophenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1120	uM
2-(2-chloro-4-fluorophenyl)-5-(2-pyridin-2-ylethyl)-4-(pyrrolidin-1-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1140	uM
2-(2-chlorophenyl)-4-[(4-fluorophenoxy)methyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1140	uM
4-(2-chlorophenyl)-13-[(4-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1160	uM
2-(2-chlorophenyl)-4-(2-fluorophenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1280	uM
4-(2-methoxyphenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1310	uM
12-benzyl-4-(2-chlorophenyl)-4,5,9,12-tetrazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1420	uM
13-benzyl-4-(2-methoxyphenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1440	uM
2-(2-chlorophenyl)-4-[(N-methylanilino)methyl]-5-(pyridin-4-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1510	uM
4-[(4-fluorophenoxy)methyl]-5-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1530	uM
4-(2-chlorophenyl)-12-oxa-4,5,9-triazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione	635431: Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.1560	uM
2-(2-chlorophenyl)-4-methyl-5-(3-phenylprop-2-ynyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1580	uM
2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1650	uM
4-[[benzyl(methyl)amino]methyl]-2-(2-chloro-4-fluorophenyl)-5-(3-methoxypropyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1650	uM
2,3,8,9-tetrahydroxy-5-[(2-hydroxy-5-nitrophenyl)methyl]phenanthridin-6-one	510244: Inhibition of NOX4 expressed in HEK293 FS cells assessed as H2O2 production by H2O2/Tyr/LPO assay	ic50	0.1700	uM
2-(2-chlorophenyl)-4-[(N-methylanilino)methyl]-5-(2-pyridin-2-ylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1720	uM
4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.1730	uM
2-(2-chloro-4-fluorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2130	uM
2-(2-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2150	uM
2-[(2,5-dichlorophenyl)methyl]-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2180	uM
N-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1H-pyrazolo[4,3-c]pyridin-5-yl]-2-(4-fluorophenoxy)acetamide	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2180	uM
2-(2-chloro-4-fluorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2350	uM
2-(2-chlorophenyl)-5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2350	uM
2-(2-chlorophenyl)-4-methyl-5-[(6-morpholin-4-yl-2-pyridinyl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2360	uM
4-N-(3-aminophenyl)-[1]benzothiolo[3,2-d]pyrimidine-4,8-diamine	510244: Inhibition of NOX4 expressed in HEK293 FS cells assessed as H2O2 production by H2O2/Tyr/LPO assay	ic50	0.2400	uM
1-acetyl-2-(2-chlorophenyl)-4-methyl-5-(pyridin-3-ylmethyl)pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2400	uM
2-[(4-chlorophenyl)methyl]-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6-dione	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2590	uM
4-[[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1H-pyrazolo[4,3-c]pyridin-5-yl]methyl]benzenesulfonamide	537262: Inhibition of human NOX4 overexpressed in human PMN cell membrane assessed as ROS production by cell free assay in presence of NADPH	ki	0.2590	uM
2,3,8,9-tetrahydroxy-5-[(3-nitrophenyl)methyl]phenanthridin-6-one	510244: Inhibition of NOX4 expressed in HEK293 FS cells assessed as H2O2 production by H2O2/Tyr/LPO assay	ic50	0.2600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases reaction, increases expression, increases abundance, affects binding, affects reaction (+4 more)	8
Oxygen	increases activity, increases reaction, decreases reaction, increases expression	5
sodium arsenite	increases expression, increases reaction, increases abundance, increases activity, increases phosphorylation (+1 more)	3
Vehicle Emissions	affects binding, affects reaction, increases activity, decreases reaction, increases expression (+3 more)	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
hydroquinone	increases degradation, decreases degradation, affects cotreatment, increases expression, decreases expression (+1 more)	2
perfluorooctane sulfonic acid	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Rosiglitazone	decreases reaction, increases expression, decreases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Acetylcysteine	decreases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression, increases reaction	2
Glucose	decreases reaction, increases expression, affects cotreatment	2
Paraquat	decreases reaction, increases expression	2
Plant Extracts	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	decreases methylation, increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
Reactive Oxygen Species	decreases reaction, increases abundance, increases chemical synthesis	2
aristolochic acid I	increases reaction, increases expression, increases response to substance	1
1-(3,4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one	increases expression, affects binding, decreases reaction, increases reaction	1
methyl vanillate	decreases expression	1
WEHI-539	affects cotreatment, increases expression	1
urushiol	decreases expression	1
quinone	decreases expression	1
naringin	decreases reaction, increases expression	1
kaempferol	increases expression, decreases reaction	1
aucubin	affects cotreatment, decreases reaction, increases expression	1
bisphenol A	increases expression, decreases reaction	1
diphenyleneiodonium	decreases reaction, increases expression	1
titanium dioxide	decreases expression	1

ChEMBL screening assays

29 unique, capped per target: 27 binding, 1 unclassified, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1249157	Binding	Inhibition of NOX4 expressed in HEK293 FS cells at 10 uM assessed as H2O2 production by H2O2/Tyr/LPO assay	Small-molecule inhibitors of NADPH oxidase 4. — J Med Chem
CHEMBL1738359	Unclassified	PUBCHEM_BIOASSAY: Late stage results from the probe development effort to identify inhibitors of (NADPH oxidase 1) NOX1: Family selectivity: Set 2. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1792, AID1796,	PubChem BioAssay data set
CHEMBL1931064	Functional	Antagonist activity at human NOX4 expressed in CHO cell membrane coexpressing tetracylin repressor assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9LK	Ubigene HEK293 NOX4 KO	Transformed cell line	Female
CVCL_ZL51	NOX4-HEK293	Transformed cell line	Female

Clinical trials (associated diseases)

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