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Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 6 | 578 | 11q14.3 | NOX4 | NADPH oxidase 4 | |
| Mouse | 6 | 578 | 7 D3 | Nox4 | NADPH oxidase 4 | |
| Rat | 6 | 578 | 1q32 | Nox4 | NADPH oxidase 4 | |
| Gene and Protein Information Comments | ||||||
| The human gene gives rise to multiple transcripts and protein isoforms (a-g). Variant 1/Isoform a is detailed in the table above. Three transcripts and protein isoforms have been identified from the mouse gene, and we include the longest isoform in the table above. | ||||||
| Previous and Unofficial Names |
| KOX | KOX-1 | RENOX |
| Database Links |
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| Alphafold | Q9NPH5 (Hs), Q9JHI8 (Mm), Q924V1 (Rn) |
| ChEMBL Target | CHEMBL1250375 (Hs) |
| Ensembl Gene | ENSG00000086991 (Hs), ENSMUSG00000030562 (Mm), ENSRNOG00000013925 (Rn) |
| Entrez Gene | 50507 (Hs), 50490 (Mm), 85431 (Rn) |
| Human Protein Atlas | ENSG00000086991 (Hs) |
| KEGG Gene | hsa:50507 (Hs), mmu:50490 (Mm), rno:85431 (Rn) |
| OMIM | 605261 (Hs) |
| Pharos | Q9NPH5 (Hs) |
| RefSeq Nucleotide | NM_016931 (Hs), NM_015760 (Mm), NM_053524 (Rn) |
| RefSeq Protein | NP_058627 (Hs), NP_056575 (Mm), NP_445976 (Rn) |
| UniProtKB | Q9NPH5 (Hs), Q9JHI8 (Mm), Q924V1 (Rn) |
| Wikipedia | NOX4 (Hs) |
Download all structure-activity data for this target as a CSV file 
| Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Three potential Nox4 inhibitors are reported by Xu et al. (2018), the most potent of which was compound 25 which exhibited an IC50 of 500 nM in a cell based assay [12]. These novel compounds have not been tested in a direct Nox4 activity assay, nor has selectivity been determined. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| Nox4 is a known driver of the fibrotic process. We have included Nox4 in GToImmunoPdb based on the association between fibrosis and inflammation. |
| Immuno Process Associations | ||
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| General Comments |
| Nox4 influences multiple normal biological processes by constitutively generating hydrogen peroxide (H2O2). It is also implicated in disease development, notably in conditions involving ischemia or fibrosis. Nox4 biosynthesis is reported to be upregulated in hypertension [8], cardiac hypertrophy [6], atherosclerosis [11], diabetic nephropathy [10], pulmonary hypertension [2], and pulmonary fibrosis [4-5,9]. Thus, small-molecule pharmacologic inhibitors of Nox4 offer therapeutic potential for this wide spectrum of diseases. |
1. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C et al.. (2012) Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology, 56 (6): 2316-27. [PMID:22806357]
2. Barman SA, Chen F, Su Y, Dimitropoulou C, Wang Y, Catravas JD, Han W, Orfi L, Szantai-Kis C, Keri G et al.. (2014) NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol, 34 (8): 1704-15. [PMID:24947524]
3. Gaggini F, Laleu B, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, Gradia A, Duboux G, Merlot C, Heitz F et al.. (2011) Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. Bioorg Med Chem, 19 (23): 6989-99. [PMID:22041175]
4. Ghatak S, Hascall VC, Markwald RR, Feghali-Bostwick C, Artlett CM, Gooz M, Bogatkevich GS, Atanelishvili I, Silver RM, Wood J et al.. (2017) Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem, 292 (25): 10490-10519. [PMID:28389561]
5. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med, 15 (9): 1077-81. [PMID:19701206]
6. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J. (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci USA, 107 (35): 15565-70. [PMID:20713697]
7. Laleu B, Gaggini F, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, Gradia A, Duboux G, Merlot C, Heitz F et al.. (2010) First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J Med Chem, 53 (21): 7715-30. [PMID:20942471]
8. Paravicini TM, Chrissobolis S, Drummond GR, Sobey CG. (2004) Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke, 35 (2): 584-9. [PMID:14739416]
9. Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, Saito N, Fujita Y, Kurita Y, Kobayashi K et al.. (2016) Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res, 17 (1): 107. [PMID:27576730]
10. Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H. (2001) A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem, 276 (2): 1417-23. [PMID:11032835]
11. Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD et al.. (2002) Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation, 105 (12): 1429-35. [PMID:11914250]
12. Xu Q, Kulkarni AA, Sajith AM, Hussein D, Brown D, Güner OF, Reddy MD, Watkins EB, Lassègue B, Griendling KK et al.. (2018) Design, synthesis, and biological evaluation of inhibitors of the NADPH oxidase, Nox4. Bioorg Med Chem, 26 (5): 989-998. [PMID:29426628]
target has curated data in GtoImmuPdb
