Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTYQ097)

• DOT Name: NADPH oxidase 4 (NOX4)
• Synonyms: EC 1.6.3.1; Kidney oxidase-1; KOX-1; Kidney superoxide-producing NADPH oxidase; Renal NAD(P)H-oxidase
• Gene Name: NOX4
• UniProt ID: NOX4_HUMAN
• EC Number: 1.6.3.1
• Pfam ID: PF08022 ; PF01794 ; PF08030
• Sequence:
  MAVSWRSWLANEGVKHLCLFIWLSMNVLLFWKTFLLYNQGPEYHYLHQMLGLGLCLSRAS
  ASVLNLNCSLILLPMCRTLLAYLRGSQKVPSRRTRRLLDKSRTFHITCGVTICIFSGVHV
  AAHLVNALNFSVNYSEDFVELNAARYRDEDPRKLLFTTVPGLTGVCMVVVLFLMITASTY
  AIRVSNYDIFWYTHNLFFVFYMLLTLHVSGGLLKYQTNLDTHPPGCISLNRTSSQNISLP
  EYFSEHFHEPFPEGFSKPAEFTQHKFVKICMEEPRFQANFPQTWLWISGPLCLYCAERLY
  RYIRSNKPVTIISVMSHPSDVMEIRMVKENFKARPGQYITLHCPSVSALENHPFTLTMCP
  TETKATFGVHLKIVGDWTERFRDLLLPPSSQDSEILPFIQSRNYPKLYIDGPFGSPFEES
  LNYEVSLCVAGGIGVTPFASILNTLLDDWKPYKLRRLYFIWVCRDIQSFRWFADLLCMLH
  NKFWQENRPDYVNIQLYLSQTDGIQKIIGEKYHALNSRLFIGRPRWKLLFDEIAKYNRGK
  TVGVFCCGPNSLSKTLHKLSNQNNSYGTRFEYNKESFS
• 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 ; [Isoform 4]: 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 ; [Isoform 3]: Lacks superoxide-generating NADPH oxidase activity.
• 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.
• KEGG Pathway:
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518)
  Signaling by FLT3 fusion proteins (R-HSA-9703465)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of NADPH oxidase 4 (NOX4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of NADPH oxidase 4 (NOX4).	[20]

27 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NADPH oxidase 4 (NOX4).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADPH oxidase 4 (NOX4).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of NADPH oxidase 4 (NOX4).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of NADPH oxidase 4 (NOX4).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of NADPH oxidase 4 (NOX4).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NADPH oxidase 4 (NOX4).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of NADPH oxidase 4 (NOX4).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of NADPH oxidase 4 (NOX4).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of NADPH oxidase 4 (NOX4).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of NADPH oxidase 4 (NOX4).	[11]
Capsaicin	DMGMF6V	Approved	Capsaicin affects the expression of NADPH oxidase 4 (NOX4).	[12]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of NADPH oxidase 4 (NOX4).	[13]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of NADPH oxidase 4 (NOX4).	[14]
Hesperetin	DMKER83	Approved	Hesperetin decreases the expression of NADPH oxidase 4 (NOX4).	[3]
Amsacrine	DMZKYIV	Approved	Amsacrine increases the expression of NADPH oxidase 4 (NOX4).	[15]
Candesartan	DMRK8OT	Approved	Candesartan decreases the expression of NADPH oxidase 4 (NOX4).	[16]
Angiotensin Ii	DMLWQ27	Approved	Angiotensin Ii increases the expression of NADPH oxidase 4 (NOX4).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of NADPH oxidase 4 (NOX4).	[18]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of NADPH oxidase 4 (NOX4).	[19]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of NADPH oxidase 4 (NOX4).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADPH oxidase 4 (NOX4).	[21]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of NADPH oxidase 4 (NOX4).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NADPH oxidase 4 (NOX4).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of NADPH oxidase 4 (NOX4).	[23]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of NADPH oxidase 4 (NOX4).	[24]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone decreases the expression of NADPH oxidase 4 (NOX4).	[25]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the expression of NADPH oxidase 4 (NOX4).	[26]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact. 2019 Aug 1;308:269-278.
• [4] Rhizoma Dioscoreae Nipponicae polysaccharides protect HUVECs from H2O2-induced injury by regulating PPAR factor and the NADPH oxidase/ROS-NF-B signal pathway. Toxicol Lett. 2015 Jan 5;232(1):149-58. doi: 10.1016/j.toxlet.2014.10.006. Epub 2014 Oct 8.
• [5] Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study. J Nutrigenet Nutrigenomics. 2008;1(1-2):30-48. doi: 10.1159/000109873. Epub 2007 Oct 16.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [9] Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF- expression in hydroquinone-treated leukemia cells. Cell Biol Toxicol. 2023 Oct;39(5):2207-2225. doi: 10.1007/s10565-022-09705-5. Epub 2022 Mar 18.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] Capsaicin inhibits cell proliferation by enhancing oxidative stress and apoptosis through SIRT1/NOX4 signaling pathways in HepG2 and HL-7702 cells. J Biochem Mol Toxicol. 2022 Mar;36(3):e22974. doi: 10.1002/jbt.22974. Epub 2021 Dec 23.
• [13] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [14] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [15] Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway. Toxicol Appl Pharmacol. 2023 Sep 1;474:116625. doi: 10.1016/j.taap.2023.116625. Epub 2023 Jul 13.
• [16] Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008 Jul;26(7):1435-45. doi: 10.1097/HJH.0b013e3283013b6e.
• [17] Uncovering the mechanism of Naoxintong capsule against hypertension based on network analysis and in?vitro experiments. Chem Biol Drug Des. 2024 Jan;103(1):e14440. doi: 10.1111/cbdd.14440.
• [18] Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J Physiol Pharmacol. 2009 Oct;60 Suppl 4:111-6.
• [19] Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [23] Suppression of ROS generation by 4,4-diaminodiphenylsulfone in non-phagocytic human diploid fibroblasts. Exp Mol Med. 2010 Mar 31;42(3):223-32. doi: 10.3858/emm.2010.42.3.024.
• [24] FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells. Chem Biol Interact. 2019 Nov 1;313:108818. doi: 10.1016/j.cbi.2019.108818. Epub 2019 Sep 5.
• [25] Overexpression of HIF-1a could partially protect K562 cells from 1,4-benzoquinone induced toxicity by inhibiting ROS, apoptosis and enhancing glycolysis. Toxicol In Vitro. 2019 Mar;55:18-23. doi: 10.1016/j.tiv.2018.11.005. Epub 2018 Nov 15.
• [26] Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med. 2014 Aug;73:201-13. doi: 10.1016/j.freeradbiomed.2014.04.029. Epub 2014 May 14.