NADPH oxidase 4

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.

Classification

Family (Pfam)

PF08022 FAD_binding_8, PF01794 Ferric_reduct, PF08030 NAD_binding_6

InterPro

Cyt_b245_heavy_chain, FAD-bd_8, FAD-bd_FR_type, Fe3_Rdtase_TM_dom, Fe_red_NAD-bd_6, FNR_nucleotide-bd, RBOH/FRE, Riboflavin_synthase-like_b-brl

Functional cluster

Membrane Channels & Lipid-Anchored Proteins

Gene Ontology · 35

• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0005925 focal adhesion
• GO:0016020 membrane
• GO:0005739 mitochondrion
• GO:0043020 NADPH oxidase complex
• GO:0005730 nucleolus
• GO:0005634 nucleus
• GO:0097038 perinuclear endoplasmic reticulum
• GO:0048471 perinuclear region of cytoplasm
• GO:0005886 plasma membrane
• GO:0009055 electron transfer activity
• GO:0050660 flavin adenine dinucleotide binding
• GO:0020037 heme binding
• GO:0072341 modified amino acid binding
• GO:0016174 NAD(P)H oxidase H2O2-forming activity
• GO:0000166 nucleotide binding
• GO:0019826 oxygen sensor activity
• GO:1990782 protein tyrosine kinase binding
• GO:0016175 superoxide-generating NAD(P)H oxidase activity
• GO:0106292 superoxide-generating NADPH oxidase activity
• GO:0000902 cell morphogenesis
• GO:0006952 defense response
• GO:0010467 gene expression
• GO:0003015 heart process
• GO:0050667 homocysteine metabolic process
• GO:0006954 inflammatory response
• GO:0035556 intracellular signal transduction
• GO:0008285 negative regulation of cell population proliferation
• GO:2000573 positive regulation of DNA biosynthetic process
• GO:0070374 positive regulation of ERK1 and ERK2 cascade
• GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:1903409 reactive oxygen species biosynthetic process
• GO:0042554 superoxide anion generation
• GO:0006801 superoxide metabolic process

Drugs targeting this protein · 1

• SETANAXIB inhibitor

Related proteins · sequence + function similarity

• NADPH oxidase 4 1.00
• NADPH oxidase 4 0.99
• NADPH oxidase 4 0.99
• NADPH oxidase 3 0.85
• NADPH oxidase 3 0.84
• NADPH oxidase 3 0.84
• NADPH oxidase 2 0.72
• NADPH oxidase 2 0.72
• NADPH oxidase 2 0.71
• NADPH oxidase 2 0.71
• Superoxide-generating NADPH oxidase heavy chain subunit A 0.71
• NADPH oxidase 1 0.70

Co-cited proteins · studied together in the literature

• NADPH oxidase 4 3 shared papers
• NADPH oxidase 5 2 shared papers
• Ubiquitin carboxyl-terminal hydrolase 19 1 shared papers
• NADPH oxidase 4 1 shared papers
• NADPH oxidase 3 1 shared papers
• Protein phosphatase 1 regulatory subunit 15A 1 shared papers
• Cytochrome b-245 light chain 1 shared papers
• Volume-regulated anion channel subunit LRRC8A 1 shared papers
• Toll-like receptor 4 1 shared papers
• Dual oxidase 1 1 shared papers
• Dual oxidase 2 1 shared papers

Literature · 23 cited papers

• NOX4 Regulates NLRP3 by Inhibiting the Ubiquitination of LRRC8A to Promote Ferroptosis in Nucleus Pulposus Cells. Inflammation · 2025
• Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein. J. Alzheimers Dis. · 2024
• Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha-mediated stress signaling. EMBO J. · 2016
• Nox4: a hydrogen peroxide-generating oxygen sensor. Biochemistry · 2014
• A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells. Arterioscler. Thromb. Vasc. Biol. · 2013
• The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J. Biol. Chem. · 2011
• Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature · 2006
• The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells · 2005
• Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res. · 2005
• NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ. Res. · 2005
• NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell. Signal. · 2006
• Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell. Signal. · 2006
• … and 11 more in the literature graph