NOX4 Gene: NADPH Oxidase 4 - Function, Disease Associations, and Expression
Comprehensive biomedical overview of NOX4, a reactive oxygen species-generating enzyme implicated in fibrosis, cancer, and metabolic disorders.
Gene Information Card
| Symbol | NOX4 |
|---|---|
| Full Name | NADPH oxidase 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 11q14.3 |
| NCBI Gene ID | 50507 ncbi.nlm.nih.gov/gene/50507 |
| Ensembl ID | ENSG00000086991 |
| UniProt ID | Q9NPH5 |
| OMIM ID | 605761 |
| HGNC ID | 7891 |
| Aliases | KOX-1, RENOX, Nox-4, EC 1.6.3.- |
Description
NOX4 (NADPH oxidase 4) encodes a member of the NADPH oxidase family that catalyzes the reduction of molecular oxygen to superoxide or hydrogen peroxide. Unlike other NOX enzymes, NOX4 primarily produces hydrogen peroxide and is constitutively active. It is widely expressed in various tissues, including kidney, vascular endothelium, and liver. NOX4 plays roles in cellular signaling, differentiation, senescence, and apoptosis. Dysregulation of NOX4 is implicated in fibrotic diseases, cardiovascular disorders, and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Fibrosis (pulmonary, hepatic, renal) | NOX4-derived H2O2 promotes fibroblast activation and extracellular matrix deposition | PMID: 26005864; 27174935 |
| Cardiovascular diseases (atherosclerosis, hypertension) | NOX4 modulates endothelial function and vascular tone via ROS signaling | PMID: 23202732 |
| Diabetic nephropathy | Increased NOX4 expression in renal cells contributes to oxidative stress and fibrosis | PMID: 24089245 |
| Cancer (e.g., melanoma, pancreatic cancer) | NOX4 supports tumor growth and metastasis via ROS-mediated signaling pathways | PMID: 25620006; 28302723 |
| Ischemic stroke | NOX4 upregulation in brain tissue exacerbates oxidative damage | PMID: 22387505 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | High | High |
| Liver | High | High |
| Lung | Medium | Medium |
| Heart | Medium | Medium |
| Brain | Low | Low |
| Skeletal Muscle | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (endothelial) | High | Constitutive expression; involved in angiogenesis |
| HK-2 (renal proximal tubular) | High | Upregulated under diabetic conditions |
| HepG2 (hepatocellular carcinoma) | Medium | Expression linked to oxidative stress response |
| A549 (lung carcinoma) | Medium | Induced by TGF-beta; contributes to epithelial-mesenchymal transition |
| MCF7 (breast cancer) | Low | Variable expression; role in proliferation |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.994G>A (p.Asp332Asn) | Missense | Rare (MAF <0.01) | Potential impact on enzyme activity; not well characterized |
| c.1150C>T (p.Arg384Trp) | Missense | Rare | Unknown functional effect |
| c.1369G>A (p.Val457Met) | Missense | Rare | Reported in ClinVar as uncertain significance |
| c.1600C>T (p.Arg534Ter) | Nonsense | Very rare | Predicted to cause loss of function; not observed in healthy populations |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in NOX4 are rare and not well documented. Complete knockout in mice is viable but shows reduced ROS production and protection against fibrosis in some models.
Gain of Function (GOF)
Gain-of-function mutations have not been clearly identified. Overexpression of wild-type NOX4 is common in pathological states, leading to increased H2O2 production.
Dominant Negative (DN)
No dominant-negative mutations have been reported for NOX4.
View complete mutation data：
Gene Ontology (GO)
| • NADPH oxidase activity | • superoxide-generating NADPH oxidase activity |
| • electron transfer activity | • heme binding |
| • FAD binding | • plasma membrane |
| • cytoplasm | • response to oxidative stress |
| • superoxide metabolic process | • hydrogen peroxide biosynthetic process |
| • angiogenesis | • cell proliferation |
| • apoptotic process |
Pathways
• Reactive oxygen species (ROS) metabolism
• VEGF signaling pathway
• TGF-beta signaling pathway
• HIF-1 signaling pathway
• p53 signaling pathway
• AGE-RAGE signaling pathway in diabetic complications
Protein Summary
NOX4 is a 578-amino acid protein with a molecular mass of approximately 67 kDa. It contains six transmembrane domains, a FAD-binding domain, and a NADPH-binding domain. Unlike other NOX family members, NOX4 does not require cytosolic subunits for activation and is constitutively active. It primarily generates hydrogen peroxide (H2O2) rather than superoxide. NOX4 is localized to the plasma membrane, endoplasmic reticulum, and nucleus, depending on cell type. It plays a role in cell differentiation, senescence, and apoptosis. Its expression is regulated by TGF-beta, hypoxia, and growth factors.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NOX4 Knockout HEK293 Cell Line | EDJ-KQ17889 | Human | 50507 | Details Get a Quote |
| NOX4 Knockout HeLa Cell Line | EDJ-KQ20327 | Human | 50507 | Details Get a Quote |
| NOX4 Knockout A-549 Cell Line | EDJ-KQ64656 | Human | 50507 | Details Get a Quote |
| NOX4 Knockout HCT 116 Cell Line | EDJ-KQ73105 | Human | 50507 | Details Get a Quote |
