Affinage

NOX4

NADPH oxidase 4 · UniProt Q9NPH5

Length
578 aa
Mass
66.9 kDa
Annotated
2026-04-29
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOX4 is a constitutively active, p22phox-dependent NADPH oxidase that primarily generates H2O2 and functions as a redox signaling hub controlling cell survival, metabolic adaptation, and tissue homeostasis across diverse organs. Its cytosolic C-terminal domain confers constitutive catalytic activity, while the N-terminal region directs localization predominantly to the endoplasmic reticulum and ER–mitochondria contact sites, where it inhibits PP1 via GADD34-dependent metal-center oxidation to sustain eIF2α phosphorylation and ATF4-mediated survival, and suppresses calcium transfer through Akt-dependent InsP3R phosphorylation to prevent mitochondrial permeability transition (PMID:19061439, PMID:26742780, PMID:33001475). NOX4-derived H2O2 activates the Nrf2/NFE2L2 antioxidant pathway to maintain redox homeostasis in cardiomyocytes, skeletal muscle, and hepatocytes, and also stabilizes HIF-1α/HIF-2α to drive angiogenic and glycolytic programs; it further inactivates protein tyrosine phosphatases to potentiate insulin and growth factor signaling through Akt and ERK (PMID:21554947, PMID:34910515, PMID:25467946, PMID:22328777). NOX4 activity is negatively regulated by FYN-mediated phosphorylation at Y566 and by IP4 competing for the NADPH-binding site, while its expression is induced by TGF-β/Smad, STAT5, ATF4, and E2F pathways, and post-translationally stabilized by ISG15-mediated ISGylation (PMID:27525436, PMID:31081803, PMID:24259511, PMID:26308771, PMID:38354631).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Establishing NOX4 as a functional NADPH oxidase in non-phagocytic cells resolved the question of which oxidase generates angiotensin II-induced ROS in mesangial cells, linking it to Akt/PKB activation and protein synthesis.

    Evidence Antisense oligonucleotide knockdown of Nox4 with dominant-negative Rac1 in mesangial cells

    PMID:12842860

    Open questions at the time
    • Rac1 dependence later contested for NOX4
    • no structural basis for constitutive activity
  2. 2005 High

    Demonstrating that Nox4 is the major renal NADPH oxidase in diabetic kidney established it as a disease-relevant ROS source mediating hypertrophy and fibrosis via Akt and ERK1/2.

    Evidence In vivo and in vitro antisense knockdown in diabetic mouse kidney with functional readouts

    PMID:16135519

    Open questions at the time
    • mechanism of Nox4 transcriptional induction in diabetes not defined
    • specificity of antisense oligonucleotides
  3. 2006 High

    Visualization of the NOX4–p22phox interaction and ER colocalization established that NOX4 forms a heterodimeric oxidase at the endoplasmic reticulum rather than the plasma membrane.

    Evidence Bimolecular fluorescent complementation with ER marker colocalization in endothelial cells

    PMID:16987004

    Open questions at the time
    • stoichiometry of NOX4–p22phox complex unresolved
    • no structural model of the heterodimer
  4. 2009 High

    Domain-swap chimeras between Nox1 and Nox4 revealed that the C-terminal dehydrogenase domain confers constitutive activity and H2O2 (rather than superoxide) production, while the N-terminus dictates subcellular targeting, resolving how NOX4 differs functionally from other NOX isoforms.

    Evidence Chimeric Nox1/Nox4 constructs in HEK293 cells with TIRF microscopy and ROS measurement; separately, mitochondrial localization confirmed by subcellular fractionation and confocal microscopy in mesangial cells

    PMID:19061439 PMID:19706525

    Open questions at the time
    • structural basis for H2O2 vs. superoxide selectivity unclear
    • whether mitochondrial localization reflects outer membrane vs. matrix association
  5. 2011 High

    Identification of NOX4 as an activator of the Nrf2 antioxidant pathway in cardiomyocytes and of FoxO3a via JNK-dependent 14-3-3 phosphorylation in vascular smooth muscle revealed that NOX4-derived ROS engage specific transcription factor circuits rather than causing indiscriminate oxidative damage.

    Evidence Transgenic Nox4 overexpression with Nrf2 KO epistasis in mouse heart; NOX4 siRNA with FoxO3a KO mice and JNK/14-3-3 Co-IP in VSMCs

    PMID:21554947 PMID:21965295

    Open questions at the time
    • direct oxidative target linking NOX4 to Nrf2 activation not identified
    • whether FoxO3a regulation is cell-type-specific
  6. 2015 High

    A series of studies established NOX4's dual role in cancer and vascular biology: NOX4-derived ROS stabilize HIF-1α/HIF-2α to promote tumor angiogenesis and renal carcinoma, inactivate protein tyrosine phosphatases to potentiate insulin signaling in hepatocytes, and confer anti-atherosclerotic protection in endothelial cells, demonstrating context-dependent pro- and anti-pathological functions.

    Evidence Endothelial-specific Nox4 KO in ApoE−/− mice; NOX4 siRNA in VHL-deficient RCC with xenograft; Nox4 KO in carcinogen-induced fibrosarcoma; NOX4 knockdown in hepatocytes with insulin signaling readout; STAT5-driven NOX4 expression in FLT3-ITD AML

    PMID:22328777 PMID:24755467 PMID:26308771 PMID:26385958 PMID:26513738

    Open questions at the time
    • molecular identity of the oxidized PTPs varies by cell context and is incompletely catalogued
    • mechanism of HIF-2α nuclear import regulation by ROS unknown
  7. 2016 High

    Discovery that NOX4 binds GADD34 at the ER and inhibits PP1 via oxidation of the PP1 metal center (not cysteine thiols) provided the first direct enzymatic substrate mechanism for NOX4-derived H2O2, explaining how it sustains eIF2α phosphorylation and ATF4-dependent survival during stress.

    Evidence Co-immunoprecipitation of Nox4–GADD34, PP1 activity assay with metal-center oxidation mechanism, in vivo ischemia-reperfusion models

    PMID:26742780

    Open questions at the time
    • whether metal-center oxidation generalizes to other PP1 holoenzyme contexts
    • no crystal structure of NOX4–GADD34–PP1 ternary complex
  8. 2016 High

    Identification of FYN as a direct NOX4 kinase at Y566 that negatively regulates ROS production, with genetic epistasis in FYN KO/Nox4 KO mice, established the first post-translational negative regulatory mechanism for NOX4 catalytic output.

    Evidence Co-IP, Y566 site-directed mutagenesis, FYN KO and Nox4 KO epistasis in transverse aortic constriction model

    PMID:27525436

    Open questions at the time
    • whether other Src-family kinases also phosphorylate Y566
    • structural consequence of Y566 phosphorylation on dehydrogenase domain
  9. 2017 High

    Demonstration that NOX4 oxidizes NADH to regenerate NAD+ for GAPDH-dependent glycolysis in pancreatic cancer revealed an unexpected metabolic function beyond canonical ROS signaling, with transcriptional regulation through p16-Rb-E2F and p22phox upregulation via KrasG12V–NF-κB.

    Evidence NADH oxidation assay, glycolytic flux measurement, E2F ChIP, p22phox Co-IP in PDAC cell lines and patient specimens

    PMID:28232723

    Open questions at the time
    • relative contribution of NAD+ regeneration vs. H2O2 signaling to PDAC phenotype unclear
    • whether NOX4-mediated NAD+ regeneration operates in non-cancer contexts
  10. 2018 High

    NOX4-derived H2O2 was shown to activate TRPC6-dependent calcium influx in podocytes, defining a non-transcriptional ion-channel regulatory function of NOX4 relevant to diabetic kidney disease.

    Evidence SSNox4−/− rats combined with TRPC6 KO and TRPC5/6 double-KO mice, live calcium imaging, electrophysiology

    PMID:29793963

    Open questions at the time
    • direct molecular target on TRPC6 oxidized by H2O2 not identified
    • whether ENaC regulation (separately shown) involves the same mechanism
  11. 2019 High

    Discovery that IP4 inhibits NOX4 by competing with NADPH for its binding site identified a novel endogenous small-molecule mechanism for NOX4 regulation and explained ITPKB-dependent cisplatin resistance.

    Evidence In vitro competitive binding assay (IP4 vs. NADPH on NOX4), patient-derived xenografts, ITPKB inhibitor

    PMID:31081803

    Open questions at the time
    • structural basis for IP4–NADPH competition not resolved
    • whether other inositol phosphates also regulate NOX4
  12. 2020 High

    Localization of stress-induced NOX4 to ER–mitochondria contact sites (MAMs) and demonstration that it inhibits InsP3R-mediated calcium transfer via Akt-dependent phosphorylation established a cytoprotective mechanism at the ER–mitochondria interface limiting necrotic cell death.

    Evidence MAM fractionation, InsP3R phosphorylation assay, calcium flux measurement, mPT assay, Nox4 KO mice in ischemia-reperfusion

    PMID:33001475

    Open questions at the time
    • how NOX4 is specifically recruited to MAMs under stress is unknown
    • which Akt isoform mediates InsP3R phosphorylation downstream of NOX4
  13. 2021 High

    Tissue-specific knockout studies in skeletal muscle and hepatocytes, combined with CYB5R3 interaction mapping, revealed that NOX4 is a central node in the NFE2L2-mediated antioxidant defense that prevents insulin resistance and NASH, and that CYB5R3 cooperates with NOX4 at the mitochondrial outer membrane via coenzyme Q for optimal H2O2 generation.

    Evidence Muscle-specific and hepatocyte-specific Nox4 KO mice, GPX-1 KO epistasis, NFE2L2 agonist rescue; APEX2-EM, proximity ligation, super-resolution microscopy for CYB5R3–NOX4 interaction, Cyb5r3 KO mice

    PMID:34656824 PMID:34910515 PMID:38060313

    Open questions at the time
    • whether CYB5R3 donates electrons directly to NOX4 or acts indirectly through CoQ pool
    • mechanism by which NOX4-derived H2O2 activates NFE2L2 (direct Keap1 oxidation vs. intermediary)
  14. 2023 Medium

    Identification of IRE-like sequences in the NOX4 locus bound by IRP1, which dissociates upon iron loading to derepress NOX4 transcription, linked NOX4 to iron-responsive gene regulation and ferroptosis in osteoblasts.

    Evidence IRP1 binding assay on NOX4 IRE-like sequences, Hepc1−/− iron overload mice, ferroptosis inhibitor rescue

    PMID:36738798

    Open questions at the time
    • IRE-like elements not validated by reporter mutagenesis in independent labs
    • whether IRP1-NOX4 axis operates in non-bone tissues
  15. 2024 Medium

    ISG15-mediated ISGylation was identified as a post-translational stabilizer of NOX4 protein, with DRD4 activation counteracting this by promoting NOX4 ubiquitination and degradation, revealing a new layer of NOX4 protein turnover control.

    Evidence ISGylation and ubiquitination assays, ISG15 knockdown, DRD4 KO mice in IRI and cisplatin kidney injury models

    PMID:38354631

    Open questions at the time
    • specific ISGylation sites on NOX4 not mapped
    • E3 ligase mediating NOX4 ubiquitination not identified
    • single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive functional characterization, no high-resolution structure of NOX4 (alone or in complex with p22phox, GADD34, or CYB5R3) exists, and the precise molecular mechanism by which the dehydrogenase domain selectively produces H2O2 rather than superoxide remains unresolved.
  • no cryo-EM or crystal structure of NOX4
  • structural basis for H2O2 selectivity unknown
  • complete inventory of direct oxidation substrates of NOX4-derived H2O2 not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
CD44CYB5R3CYBAFYNPPP1R15APRKCATRPC6
Complex memberships
NOX4–p22phox NADPH oxidase

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Nox4-based NADPH oxidase mediates angiotensin II-induced ROS generation and downstream Akt/PKB activation and protein synthesis in mesangial cells, acting downstream of Rac1 and arachidonic acid signaling Antisense oligonucleotide knockdown of Nox4, dominant-negative Rac1, NADPH oxidase activity assay, Akt phosphorylation measurement, protein synthesis assay American journal of physiology. Renal physiology High 12842860
2005 Nox4 is the major source of NADPH-dependent ROS in diabetic kidney, and Nox4-derived ROS mediate renal hypertrophy and fibronectin expression via Akt/PKB and ERK1/2 activation Antisense oligonucleotide knockdown in vivo and in vitro, NADPH oxidase activity assay, glomerular hypertrophy measurement, fibronectin western blot, kinase phosphorylation assays The Journal of biological chemistry High 16135519
2009 Nox4 localizes to mitochondria in mesangial cells and kidney cortex, and mitochondrial Nox4 is a functional source of NADPH oxidase-dependent superoxide generation; siRNA knockdown of Nox4 reduces mitochondrial NADPH oxidase activity and blocks glucose-induced mitochondrial superoxide Subcellular fractionation, immunofluorescence confocal microscopy with MitoTracker, siRNA knockdown, NADPH oxidase activity assay in purified mitochondria Proceedings of the National Academy of Sciences of the United States of America High 19706525
2009 The cytosolic tail of Nox4 confers constitutive activity, while the N-terminal region determines subcellular localization (ER vs. plasma membrane) and the type of ROS released (H2O2 vs. superoxide); Nox4 colocalizes with ER marker proteins Chimeric Nox1/Nox4 constructs expressed in HEK293 cells, TIRF microscopy, ROS measurement, N-terminal signal peptide swap experiments Antioxidants & redox signaling High 19061439
2008 Nox4 acts as a switch from insulin-induced proliferation to differentiation in preadipocytes by controlling MAP kinase phosphatase-1 (MKP-1) expression, which limits ERK1/2 signaling; downregulation of Nox4 promotes ERK1/2-dependent proliferation and inhibits differentiation via IRS-1 phosphorylation at Ser612 siRNA knockdown, Nox4 overexpression, MKP-1 siRNA and overexpression, ERK1/2 inhibition, IRS-1 phosphorylation assays in human and mouse preadipocytes Arteriosclerosis, thrombosis, and vascular biology High 19057021
2006 NOX4 interacts with p22phox (shown by bimolecular fluorescent complementation) and co-localizes with the endoplasmic reticulum marker calreticulin in endothelial cells; NOX4 contributes equally with NOX2 to endothelial ROS production and proliferation Bimolecular fluorescent complementation, colocalization with ER marker, siRNA knockdown, ROS measurement, proliferation assays Antioxidants & redox signaling High 16987004
2016 Nox4 is induced downstream of ATF4, binds to the PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 via oxidation of the PP1 metal center (not thiol oxidation), thereby sustaining eIF2α phosphorylation and ATF4 levels to promote cell survival during stress Co-immunoprecipitation (Nox4–GADD34), PP1 activity assay, eIF2α phosphorylation measurement, mutagenesis, ER fractionation, heart ischemia-reperfusion and kidney injury in vivo models The EMBO journal High 26742780
2020 Stress-induced Nox4 localizes to ER-mitochondria contact sites (MAMs) and inhibits calcium transfer through InsP3 receptors by augmenting Akt-dependent phosphorylation of InsP3R, thereby preventing mitochondrial permeability transition-dependent necrosis; limits infarct size in ischemia-reperfusion MAM fractionation, co-immunoprecipitation, InsP3R phosphorylation assay, calcium flux measurement, mPT assay, Nox4 KO mice, cardiomyocyte and neuron models The EMBO journal High 33001475
2016 FYN tyrosine kinase interacts with the C-terminal domain of NOX4, co-localizes in perinuclear mitochondria/ER/nuclear fractions, and directly phosphorylates NOX4 at tyrosine 566 to negatively regulate NOX4-induced ROS production and apoptosis; FYN KO mice show exaggerated cardiac remodeling rescued by Nox4 deletion Co-immunoprecipitation, site-directed mutagenesis (Y566), ROS measurement, apoptosis assay, FYN KO and Nox4 KO epistasis in mice with transverse aortic constriction The Journal of clinical investigation High 27525436
2011 Nox4 activates the Nrf2-regulated antioxidant pathway in cardiomyocytes, increasing expression of antioxidant/detoxifying genes and elevating GSH levels; these effects are abolished in an Nrf2-null genetic background Transgenic Nox4 overexpression in mouse heart, microarray transcriptomics, Q-PCR, GSH measurement, Nrf2 KO epistasis Free radical biology & medicine High 21554947
2013 TGF-β1-induced podocyte apoptosis is mediated by selective upregulation of Nox4 (localized to mitochondria) via TGF-β receptor I–Smad2/3 signaling, leading to ROS production, mitochondrial membrane potential loss, and caspase-3 activation siRNA knockdown (Nox4, Smad2, Smad3), TGF-β receptor inhibitor, Nox inhibitor DPI, mitochondrial membrane potential assay, caspase-3 activation assay, immunofluorescence American journal of physiology. Renal physiology High 24259511
2015 NOX4 silencing in VHL-deficient renal cell carcinoma cells abrogates invasion, colony formation, and xenograft growth; NOX4 knockdown or superoxide scavenging blocks nuclear accumulation of HIF2α, establishing NOX4 as required for HIF2α nuclear localization and renal tumorigenesis siRNA knockdown, TEMPOL and catalase/MnSOD overexpression, xenograft model, HIF2α nuclear fractionation, cell invasion and colony assays Cancer research High 24755467
2015 NOX4 promotes tumour angiogenesis by stabilizing HIF-1α and inducing VEGF-A, Glut1, and adrenomedullin expression; Nox4 knockout mice show 38% reduced tumour vessel density in fibrosarcoma model Nox4 KO mice (carcinogen-induced fibrosarcoma), CD31 immunostaining, Hif-1α and VEGF expression analysis Acta physiologica (Oxford, England) Medium 26513738
2015 NOX4 in endothelial cells produces H2O2 rather than superoxide, and has anti-atherosclerotic function; endothelial-specific (but not macrophage) Nox4 deletion increases macrophage adhesion and atherosclerosis in ApoE-/- mice Tamoxifen-induced Nox4 KO crossed with ApoE-/- mice, cell-type-specific KO (endothelial vs. macrophage), atherosclerosis measurement, macrophage adhesion assay European heart journal High 26385958
2017 Nox4-derived H2O2 activates Nox2 to increase mitochondrial ROS via p66Shc phosphorylation at Ser36, thereby enhancing VEGFR2 signaling and angiogenesis in endothelial cells (ROS-induced ROS release mechanism) Redox-sensitive RoGFP biosensors (cytosol- and mitochondria-targeted), siRNA knockdown of Nox4/Nox2, Nox4 overexpression, p66Shc(S36A) mutant, VEGFR2 phosphorylation assay, migration/proliferation assays American journal of physiology. Cell physiology High 28424170
2015 NOX4-derived ROS inactivate protein tyrosine phosphatases (PTPs) and are required for all insulin signaling through AKT and ERK in hepatocytes; knockdown or inhibition of NOX4 reproduces the pattern of pathway-selective insulin resistance seen in diabetic db/db mice siRNA knockdown in cultured hepatocytes, pharmacological NOX4 inhibition, AKT Thr308/Ser473 phosphorylation assay, insulin injection in db/db mice Arteriosclerosis, thrombosis, and vascular biology High 22328777
2015 NOX4-driven ROS inactivate the protein tyrosine phosphatase DEP-1/PTPRJ in FLT3ITD-positive AML cells; NOX4 expression is driven by STAT5 transcriptional activation of the NOX4 promoter downstream of FLT3ITD, and NOX4 knockdown restores PTP activity and attenuates FLT3ITD-driven transformation NOX4 mRNA/protein measurement, STAT5 promoter activation assay, NOX4 knockdown, PTP activity assay, Nox4 KO hematopoietic progenitor transformation assay, in vivo mouse leukemia models Leukemia High 26308771
2019 Inositol 1,3,4,5-tetrakisphosphate (IP4), product of ITPKB, inhibits NOX4 by competing with NADPH for binding to NOX4, thereby reducing cisplatin-induced ROS and promoting cisplatin resistance ITPKB RNAi screen, IP4 competition binding assay with NADPH and NOX4, NOX4 activity assay, patient-derived xenografts, ITPKB inhibitor The Journal of clinical investigation High 31081803
2016 TGF-β-induced NOX4 expression is required for SMAD phosphorylation and myofibroblast differentiation in lung fibroblasts; metformin activates AMPK to inhibit TGF-β-induced NOX4 expression, blocking fibrogenesis NOX4 siRNA knockdown, N-acetylcysteine, AMPK activation by metformin, SMAD phosphorylation assay, bleomycin-induced lung fibrosis mouse model Respiratory research High 27576730
2018 NOX4-derived H2O2 stimulates TRPC6-dependent calcium influx in podocytes; genetic ablation of Nox4 reduces basal intracellular Ca2+ and blunts angiotensin II-elicited calcium flux, protecting against diabetic kidney disease SSNox4-/- rats, TRPC6 KO and TRPC5/6 double-KO mice, live calcium imaging in freshly isolated glomeruli, H2O2 stimulation, electrophysiology, electron microscopy Journal of the American Society of Nephrology : JASN High 29793963
2017 In PDAC, NOX4 activity accelerates oxidation of NADH and supports glycolysis by generating NAD+ for GAPDH-mediated glycolytic reactions; NOX4 is transcriptionally induced through p16-Rb-E2F pathway and requires p22phox (upregulated by KrasG12V-NF-κB) for its catalytic activity Gene expression profiling, NOX4 activity assay (NADH oxidation), p22phox Co-IP/expression, NF-κB reporter assay, E2F ChIP, glycolytic flux measurement in PDAC cell lines and patient specimens Nature communications High 28232723
2021 Skeletal muscle NOX4, induced by exercise, generates H2O2 that activates NFE2L2-mediated antioxidant defense; NOX4 deletion in skeletal muscle compromises antioxidant defense and causes insulin resistance in aging and obesity, which is corrected by GPX-1 deletion or NFE2L2 agonist Muscle-specific Nox4 KO mice, exercise testing, ROS measurement, NFE2L2 target gene expression, insulin tolerance, GPX-1 KO epistasis, NFE2L2 agonist treatment Science advances High 34910515
2016 Nox4 promotes smooth muscle cell neointimal hyperplasia by upregulating thrombospondin 1 (TSP1), which drives SMC proliferation and migration; Nox4 dominant-negative mutation or siRNA knockdown reduces TSP1 expression and neointima formation after wire injury SM22α-driven Nox4 dominant-negative (P437H) transgenic mice, wire injury model, siRNA knockdown, TSP1 mRNA/protein, SMC proliferation and migration assays Journal of molecular and cellular cardiology High 26582463
2013 ADAM17 activation by hyperglycemia increases Nox4 expression and NADPH oxidase activity in kidney cortex, establishing Nox4 as downstream of ADAM17 in extracellular matrix accumulation in diabetic nephropathy ADAM17 inhibitor (TMI-005), ADAM17 siRNA, Nox4 expression and NADPH oxidase activity measurement, fibronectin/collagen expression in OVE26 diabetic mice and proximal tubular cells American journal of physiology. Renal physiology Medium 23678045
2016 NOX4-derived ROS suppress Rho GTPase (RhoC) and Cdc42 expression and downstream actomyosin contractility in hepatocellular carcinoma cells, maintaining epithelial characteristics and suppressing amoeboid invasion NOX4 siRNA knockdown and overexpression, Rho/Cdc42 expression, actomyosin contractility assay, 3D invasion assay, Nox4-deficient HCC patient correlation Oncogene Medium 27941881
2011 NOX4 and urotensin-II activate FoxO3a via NOX4-dependent JNK phosphorylation and 14-3-3 phosphorylation, reducing FoxO3a–14-3-3 interaction and enabling MMP-2 transcription to promote vascular smooth muscle cell proliferation and migration NOX4 siRNA, FoxO3a knockdown, FoxO3a-/- mice, MMP2 inhibitor, JNK phosphorylation, 14-3-3 co-immunoprecipitation Molecular biology of the cell High 21965295
2021 NOX4 upregulation by RANKL activates ROS/PERK/eIF-2α/ATF4 pathway to promote autophagy and osteoclastogenesis; Nox4 inhibition or shRNA knockdown attenuates RANKL-induced autophagy and osteoclast formation Nox4 shRNA, 5-O-methyl quercetin Nox4 inhibitor, PERK inhibitor (GSK2606414), ROS scavenger, ATF4/eIF-2α phosphorylation assay, autophagy measurement, osteoclastogenesis assay Frontiers in pharmacology Medium 34650437
2021 NOX4 global or neuronal knockdown in mice reduces pathological tau accumulation and improves macroautophagy flux via the autophagy-lysosomal pathway, preventing cognitive decline in a tauopathy model Global Nox4 KO, neuronal-targeted Nox4 shRNA (AAV-TauP301L model), autophagy flux measurement, tau immunostaining, cognitive behavioral testing Redox biology High 34922273
2019 Tachypacing-induced CD44 signaling directly associates with NOX4 (co-immunoprecipitation documented), increasing NOX4 expression and oxidative stress leading to CaMKII oxidation and ryanodine receptor phosphorylation, contributing to atrial fibrillation Co-immunoprecipitation (CD44–NOX4), HAS/HA/CD44 pathway blockade, CD44-/- mice, Ca2+ spark measurement, ox-CaMKII and p-RyR2 assays Journal of molecular and cellular cardiology Medium 31419440
2021 CYB5R3 interacts with NOX4 at the mitochondrial outer membrane (confirmed by APEX2-EM, proximity ligation, and Co-localization by super-resolution microscopy), and CYB5R3 activity and membrane translocation are required for optimal H2O2 generation by NOX4 via coenzyme Q; endothelial CYB5R3 loss exacerbates NOX4-dependent inflammatory activation APEX2-based electron microscopy, proximity biotinylation, proximity ligation assay, super-resolution confocal microscopy, Cyb5r3 KO mice, siRNA double-knockdown (CYB5R3+NOX4), COQ6 KO cells Redox biology High 34656824
2022 PKCα directly binds NOX4 and mediates TRPM7-dependent chondrocyte ferroptosis; TRPM7 channel inhibition reduces intracellular Ca2+, suppresses PKCα-NOX4 interaction, and attenuates ferroptosis in rheumatoid arthritis chondrocytes Co-immunoprecipitation (PKCα–NOX4), TRPM7 knockdown/pharmacological inhibition, calcium imaging, ferroptosis markers (MDA, lipid ROS), AA-rat model, AAV9-TRPM7 silencing Redox biology Medium 35917680
2023 NOX4 locus contains IRE-like sequences bound and repressed by IRP1; iron loading induces IRP1 dissociation from these sequences, activating NOX4 transcription and increasing lipid peroxidation and ferroptosis in osteoblasts, contributing to osteoporotic bone loss IRE-like sequence identification in NOX4 locus, IRP1 binding/dissociation assay, iron overload mouse model (Hepc1-/-), ferroptosis inhibitor (Ferr-1), iron chelator (DFO), mitochondrial morphology by electron microscopy Free radical biology & medicine Medium 36738798
2020 Mitochondria-derived ROS activate NFE2L2 which induces NOX4 expression; NOX4-derived H2O2 further amplifies NFE2L2 antioxidant defense; hepatocyte-specific NOX4 deletion reduces antioxidant defense and promotes NASH and fibrosis in obese mice Hepatocyte-specific Nox4 KO, Nox4 overexpression, ROS measurement, NFE2L2 target gene expression, NASH scoring, mitochondrial ROS imaging The Journal of clinical investigation High 38060313
2022 NOX4 deletion in HCC leads to Nrf2 activation that upregulates MYC, which drives mitochondrial dynamics and metabolic reprogramming (increased oxidative metabolism, glycolysis, fatty acid use) to promote HCC progression Cell-based NOX4 loss/gain of function, proteomics, transcriptomics, metabolomics, in vivo hepatocarcinogenesis in Nox4-deficient mice, human HCC sample analysis Hepatology (Baltimore, Md.) High 35920301
2021 NOX4 promotes glycolysis in thyroid carcinoma via the mROS–HIF1α axis; NOX4 knockdown and p22phox knockout both abolish mitochondrial ROS increase and destabilize HIF1α in hypoxia, reducing glycolysis and cell growth NOX4 siRNA knockdown, p22phox CRISPR KO, mROS measurement, HIF1α stability assay, glycolytic flux measurement Scientific reports Medium 30367082
2024 ISG15 promotes NOX4 ISGylation to stabilize the protein; DRD4 activation reduces ISG15 expression, enhancing NOX4 ubiquitination and degradation, thereby counteracting oxidative stress-induced acute kidney injury Transcriptome sequencing, ISG15 knockdown, ISGylation and ubiquitination assays for NOX4, DRD4 KO mice (IRI and cisplatin models), HK-2 cell oxidative stress Redox biology Medium 38354631
2020 Nox4 regulates PDGF-induced mesenchymal cell migration by generating H2O2 that activates PKB/Akt (but not Erk1/2) via the PI3-kinase pathway; Nox4 siRNA knockdown reduces PDGF-stimulated H2O2, PKB/Akt phosphorylation, and migration in MSC Nox4 siRNA, real-time H2O2 measurement, PKB/Akt and Erk1/2 phosphorylation assays, migration assay in 3T3 fibroblasts and MSC PloS one Medium 27110716
2018 NOX4-derived ROS activate GLI1 (Hedgehog pathway transcription factor) to promote gastric cancer cell proliferation; DPI (ROS inhibitor) and NOX4 knockdown reduce GLI1 expression, and GLI1 overexpression rescues proliferation in NOX4-knockdown cells NOX4 siRNA, DPI treatment, GLI1 overexpression rescue, proliferation assay, western blot for Cyclin D1/BAX Cellular signalling Medium 29496628
2020 NOX4-derived ROS regulates epithelial Na+ channel (ENaC) activity in the cortical collecting duct; H2O2 upregulates ENaC, and genetic ablation of Nox4 in Dahl salt-sensitive rats attenuates high-salt-induced ENaC activity increase SSNox4-/- rat model, electrophysiology (ENaC patch-clamp), H2O2 stimulation, renal H2O2 production measurement FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 32799394
2021 In cardiomyocytes, Nox4 is activated downstream of mTORC2/Rictor; siRNA knockdown of Rictor decreases Nox4 and NADPH oxidase activity, restoring podocin levels and reducing podocyte apoptosis in diabetic models Rictor siRNA and antisense oligonucleotides, Nox4 expression and NADPH oxidase activity, podocin measurement, apoptosis assay, OVE26 diabetic mouse model Antioxidants & redox signaling Medium 27393154

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. The Journal of biological chemistry 433 16135519
2009 Subcellular localization of Nox4 and regulation in diabetes. Proceedings of the National Academy of Sciences of the United States of America 403 19706525
2005 Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 237 15802177
2003 Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. American journal of physiology. Renal physiology 229 12842860
2008 Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arteriosclerosis, thrombosis, and vascular biology 210 19057021
2006 NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxidants & redox signaling 206 16987004
2017 ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis. American journal of physiology. Cell physiology 203 28424170
2016 Metformin attenuates lung fibrosis development via NOX4 suppression. Respiratory research 181 27576730
2011 Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo. Free radical biology & medicine 150 21554947
2015 The NADPH oxidase Nox4 has anti-atherosclerotic functions. European heart journal 144 26385958
2012 The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. American journal of respiratory cell and molecular biology 132 22904198
2009 Identification of structural elements in Nox1 and Nox4 controlling localization and activity. Antioxidants & redox signaling 125 19061439
2012 Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. Antioxidants & redox signaling 120 22937798
2018 A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease. Journal of the American Society of Nephrology : JASN 116 29793963
2019 miR-590-3p Inhibits Pyroptosis in Diabetic Retinopathy by Targeting NLRP1 and Inactivating the NOX4 Signaling Pathway. Investigative ophthalmology & visual science 105 31618425
2016 Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling. The EMBO journal 101 26742780
2015 The human Nox4: gene, structure, physiological function and pathological significance. Journal of drug targeting 90 25950600
2013 Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes. American journal of physiology. Renal physiology 90 24259511
2022 TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis. Redox biology 87 35917680
2021 Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance. Science advances 81 34910515
2017 Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Nature communications 80 28232723
2014 The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression. Free radical biology & medicine 79 24509161
2020 Nox4 regulates InsP3 receptor-dependent Ca2+ release into mitochondria to promote cell survival. The EMBO journal 76 33001475
2016 Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. The Journal of clinical investigation 74 27525436
2008 Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration. Hypertension (Dallas, Tex. : 1979) 72 18474828
2016 Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 71 27936392
2023 Nox4 as a novel therapeutic target for diabetic vascular complications. Redox biology 68 37321060
2021 Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis. Gut microbes 66 34530693
2013 Role of the NADPH Oxidases DUOX and NOX4 in Thyroid Oxidative Stress. European thyroid journal 64 24847449
2018 Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling. Cardiovascular research 63 29040462
2016 The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination. Oncogene 62 27941881
2018 NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. Cellular signalling 61 29496628
2018 A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. Acta ophthalmologica 60 30178632
2014 NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α. Cancer research 58 24755467
2020 Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice. JCI insight 57 32544088
2022 Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma. Journal of cellular and molecular medicine 56 35023280
2021 Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β. Cellular signalling 55 34438016
2015 NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells. Leukemia 55 26308771
2012 NOX4 pathway as a source of selective insulin resistance and responsiveness. Arteriosclerosis, thrombosis, and vascular biology 55 22328777
2020 Oleic acid-induced NOX4 is dependent on ANGPTL4 expression to promote human colorectal cancer metastasis. Theranostics 54 32641980
2016 mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes. Antioxidants & redox signaling 53 27393154
2015 The NADPH Oxidase Nox4 mediates tumour angiogenesis. Acta physiologica (Oxford, England) 49 26513738
2011 NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II. Molecular biology of the cell 49 21965295
2023 Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts. Free radical biology & medicine 46 36738798
2023 Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy. Redox biology 44 37871532
2016 Pro-atherogenic role of smooth muscle Nox4-based NADPH oxidase. Journal of molecular and cellular cardiology 44 26812119
2013 ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. American journal of physiology. Renal physiology 44 23678045
1993 Duplicated KOX zinc finger gene clusters flank the centromere of human chromosome 10: evidence for a pericentric inversion during primate evolution. Nucleic acids research 42 8464732
2019 Tubular NOX4 expression decreases in chronic kidney disease but does not modify fibrosis evolution. Redox biology 38 31247506
2020 Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. Clinical science (London, England : 1979) 37 32227122
2017 Alternative Splicing of NOX4 in the Failing Human Heart. Frontiers in physiology 37 29204124
2015 Nox-4 and progressive kidney disease. Current opinion in nephrology and hypertension 37 25402870
2015 Nox4 supports proper capillary growth in exercise and retina neo-vascularization. The Journal of physiology 37 25652847
2015 Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia. Journal of molecular and cellular cardiology 37 26582463
2022 NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation. International journal of molecular sciences 36 35269843
2022 Breast cancer chemotherapy induces vascular dysfunction and hypertension through a NOX4-dependent mechanism. The Journal of clinical investigation 35 35617030
2019 Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance. The Journal of clinical investigation 35 31081803
2017 The Role of NOX4 and TRX2 in Angiogenesis and Their Potential Cross-Talk. Antioxidants (Basel, Switzerland) 35 28594389
2023 Topically Administered NOX4 Inhibitor, GLX7013114, Is Efficacious in Treating the Early Pathological Events of Diabetic Retinopathy. Diabetes 34 36821829
2020 Circular RNA NOX4 promotes the development of colorectal cancer via the microRNA‑485‑5p/CKS1B axis. Oncology reports 34 32901890
2018 NADPH oxidase NOX4 is a glycolytic regulator through mROS-HIF1α axis in thyroid carcinomas. Scientific reports 34 30367082
2017 Adventitial Fibroblast Nox4 Expression and ROS Signaling in Pulmonary Arterial Hypertension. Advances in experimental medicine and biology 34 29047077
2023 Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity. The Journal of clinical investigation 33 38060313
2022 The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression. Hepatology (Baltimore, Md.) 33 35920301
2021 Nox4 Promotes RANKL-Induced Autophagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway. Frontiers in pharmacology 33 34650437
2023 Metformin ameliorates ferroptosis in cardiac ischemia and reperfusion by reducing NOX4 expression via promoting AMPKα. Pharmaceutical biology 32 37288723
2020 NOX4-dependent regulation of ENaC in hypertension and diabetic kidney disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 32799394
2011 Nox2 and Nox4 mediate tumour necrosis factor-α-induced ventricular remodelling in mice. Journal of cellular and molecular medicine 32 21251215
2022 NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells. Molecular oncology 31 35203105
2021 Role of Nox4 in High Calcium-Induced Renal Oxidative Stress Damage and Crystal Deposition. Antioxidants & redox signaling 31 34435888
2020 The correlation of IRE1α oxidation with Nox4 activation in aging-associated vascular dysfunction. Redox biology 31 33010578
2022 Forsythiaside A Regulates Activation of Hepatic Stellate Cells by Inhibiting NOX4-Dependent ROS. Oxidative medicine and cellular longevity 30 35035671
2018 NOX4/ROS mediate ethanol‑induced apoptosis via MAPK signal pathway in L‑02 cells. International journal of molecular medicine 30 29336467
2023 Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation. Journal of advanced research 29 37061215
2021 Implication of type 4 NADPH oxidase (NOX4) in tauopathy. Redox biology 29 34922273
2021 NOX4 Signaling Mediates Cancer Development and Therapeutic Resistance through HER3 in Ovarian Cancer Cells. Cells 28 34209278
2019 CSF-1 in Osteocytes Inhibits Nox4-mediated Oxidative Stress and Promotes Normal Bone Homeostasis. JBMR plus 28 32666016
2024 HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis. Cell death & disease 27 38844470
2017 Nox4 genetic inhibition in experimental hypertension and metabolic syndrome. Archives of cardiovascular diseases 27 29113787
2022 AIP1 suppresses neovascularization by inhibiting the NOX4-induced NLRP3/NLRP6 imbalance in a murine corneal alkali burn model. Cell communication and signaling : CCS 26 35524333
2021 NOX4: a potential therapeutic target for pancreatic cancer and its mechanism. Journal of translational medicine 26 34930338
2020 The role of NOX4 in pulmonary diseases. Journal of cellular physiology 26 32780450
2014 Nox4-mediated cell signaling regulates differentiation and survival of neural crest stem cells. Molecules and cells 26 25410908
2021 Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors. Proceedings of the National Academy of Sciences of the United States of America 25 33836590
2020 Chronic Exposure to Fluoride Affects GSH Level and NOX4 Expression in Rat Model of This Element of Neurotoxicity. Biomolecules 25 32182821
2017 Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence. Oncotarget 25 28423654
2016 Nox4 and Duox1/2 Mediate Redox Activation of Mesenchymal Cell Migration by PDGF. PloS one 25 27110716
2024 Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4. Journal of agricultural and food chemistry 24 38483540
2022 Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy. Stem cell reports 24 35090586
2018 Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4-ROS-ADAM17 pathway. Journal of cellular and molecular medicine 24 30953402
2014 Lentivirus-mediated Nox4 shRNA invasion and angiogenesis and enhances radiosensitivity in human glioblastoma. Oxidative medicine and cellular longevity 24 24868315
2019 Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 31661292
2024 DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress. Redox biology 22 38354631
2023 TRIM-containing 44 aggravates cardiac hypertrophy via TLR4/NOX4-induced ferroptosis. Journal of molecular medicine (Berlin, Germany) 22 37119283
2023 NADPH oxidase 4 (NOX4) as a biomarker and therapeutic target in neurodegenerative diseases. Neural regeneration research 22 38227522
2020 NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice. Redox biology 22 33493901
2017 CRISPR-Cas9 Mediated NOX4 Knockout Inhibits Cell Proliferation and Invasion in HeLa Cells. PloS one 22 28099519
1993 Chromosomal localization of 9 KOX zinc finger genes: physical linkages suggest clustering of KOX genes on chromosomes 12, 16, and 19. Human genetics 22 8262519
2021 Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation. Redox biology 21 34656824
2019 Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling. Journal of molecular and cellular cardiology 21 31419440