Affinage

PRDX4

Peroxiredoxin-4 · UniProt Q13162

Length
271 aa
Mass
30.5 kDa
Annotated
2026-06-10
42 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRDX4 is an endoplasmic reticulum (ER)-resident 2-Cys peroxiredoxin that couples H2O2 catabolism to oxidative protein folding, using lumenal H2O2 as substrate to drive disulfide bond formation in nascent client proteins (PMID:23025503). This oxidative folding activity is supplied by an ERO1-independent, ER-intrinsic H2O2 source, with the ER lumen kept relatively isolated from cytosolic and mitochondrial H2O2 pools (PMID:26504166); in pancreatic ductal adenocarcinoma, NADPH-driven ER-membrane NOX4 provides the H2O2 that PRDX4 metabolizes, making high-NADPH tumor cells dependent on PRDX4 for survival and resistant to oxidative DNA damage (PMID:33962950). Through this function PRDX4 supports the folding and secretion of disulfide-rich clients, including triglyceride-rich lipoprotein (PMID:30050648) and proinsulin [PMID:bio_10.1101_2024.06.26.599433], and protects ER homeostasis, with its loss producing ER stress, CHOP and caspase-3 activation, and exacerbated tissue injury in colitis and diabetic retinopathy models (PMID:30578917, PMID:39706273). Beyond bulk folding, PRDX4 acts as a compartment-specific H2O2 sensor that, via H2O2-driven dimerization, directly oxidizes two cysteines in the ectoenzyme GDE2 to block its trafficking to the plasma membrane, thereby restraining GDE2-dependent neurogenesis (PMID:25943695). PRDX4 additionally limits inflammasome activity by forming a redox-sensitive complex with caspase-1 at Cys397, sequestering and inactivating the protease to dampen IL-1β maturation, such that Prdx4 loss heightens susceptibility to LPS-induced septic shock (PMID:31544965). A non-enzymatic role has also been documented, in which PRDX4 translocates to the nucleus during prolonged hypoxia and interacts with HIF-1α/HIF-2α to impair their binding to hypoxia response elements independently of peroxidase activity (PMID:26837221).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Established the core mechanistic identity of PRDX4 as an ER thiol oxidase that converts H2O2 into a driver of disulfide bond formation, defining it as a redundant pathway alongside ERO1.

    Evidence Compound Prdx4/Ero1 double-knockout mice with sulfenylation and ascorbate biochemistry

    PMID:23025503

    Open questions at the time
    • Identity of the lumenal H2O2 source not resolved here
    • Specific client proteins not defined
    • Summarized in a review/commentary from a single lab
  2. 2015 High

    Resolved where PRDX4's substrate H2O2 comes from, showing the ER lumen is a compartmentally isolated H2O2 pool that PRDX4 exploits independently of cytosolic/mitochondrial sources.

    Evidence ER-targeted catalase, compartment-specific H2O2 tracking, and ERO1/PRDX4 double knockout in cells

    PMID:26504166

    Open questions at the time
    • Did not identify the enzymatic generator of lumenal H2O2
    • Client specificity not addressed
  3. 2015 High

    Showed PRDX4 is not only a bulk folding catalyst but a redox sensor that uses H2O2-driven dimerization to oxidize a specific substrate, linking ER redox state to membrane trafficking and neurogenesis.

    Evidence Prdx4 knockout, GDE2 cysteine mutagenesis, trafficking imaging, and dimer-mediated oxidation biochemistry

    PMID:25943695

    Open questions at the time
    • Generality of substrate-specific oxidation beyond GDE2 unknown
    • Mechanism of selecting GDE2 cysteines over other thiols unresolved
  4. 2016 Medium

    Revealed a peroxidase-independent moonlighting function in which PRDX4 acts in the nucleus to repress HIF transcriptional output.

    Evidence Co-IP, nuclear fractionation, ChIP, and catalytically inactive mutant in hypoxic HeLa cells

    PMID:26837221

    Open questions at the time
    • How an ER-resident protein relocates to the nucleus is unexplained
    • Physiological relevance outside HeLa not established
  5. 2018 Medium

    Connected PRDX4's folding activity to physiological secretory output and ER-stress protection across organs.

    Evidence Prdx4/Sod1 double-KO mouse (lipoprotein secretion, liver steatosis) and Prdx4-KO DSS colitis model (CHOP, caspase-3, ER morphology)

    PMID:30050648 PMID:30578917

    Open questions at the time
    • Direct PRDX4 substrates in these tissues not identified
    • Contribution of folding vs. peroxidase activity not separated
  6. 2019 High

    Defined a direct anti-inflammatory mechanism whereby PRDX4 forms a redox-sensitive complex to inactivate caspase-1 and restrain inflammasome signaling.

    Evidence Reciprocal Co-IP, caspase-1 Cys397 mutagenesis, myeloid-conditional Prdx4 KO with septic shock model and extracellular vesicle transfer assays

    PMID:31544965

    Open questions at the time
    • How an ER enzyme accesses cytosolic caspase-1 mechanistically unclear
    • Structural basis of the redox-sensitive complex undefined
  7. 2021 High

    Identified the enzymatic source of PRDX4's lumenal H2O2 in a disease context and exposed PRDX4 as a metabolic survival dependency.

    Evidence Functional genomics, PRDX4 KD/KO, xenografts, and NOX4/NADPH epistasis rescue in PDAC

    PMID:33962950

    Open questions at the time
    • Whether NOX4 is the lumenal H2O2 source in non-PDAC contexts unknown
    • Link between PRDX4 loss and DNA-PKcs DNA damage response not mechanistically dissected
  8. 2024 Low

    Extended PRDX4's folding role to proinsulin maturation and uncovered post-transcriptional control of PRDX4 abundance.

    Evidence Cnot7-KO β cells, proinsulin/insulin measurement, and CNOT8/MSI2 RNA-binding analysis of Prdx4 mRNA (preprint)

    PMID:bio_10.1101_2024.06.26.599433

    Open questions at the time
    • Preprint; RNA-binding evidence is indirect via an MSI2 intermediary
    • Direct proinsulin disulfide catalysis by PRDX4 not biochemically shown here
  9. 2024 Medium

    Implicated PRDX4 in DPP-4 degradation as a cytoprotective axis in diabetic retinal neurodegeneration.

    Evidence PRDX4-KO STZ-diabetic mice with Müller cell knockdown/overexpression and DPP-4 degradation assays

    PMID:39706273

    Open questions at the time
    • Mechanism by which PRDX4 promotes DPP-4 degradation undefined
    • Whether this depends on peroxidase activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PRDX4's canonical ER thiol-oxidase activity is mechanistically reconciled with its non-ER localizations (nuclear HIF repression, cytosolic caspase-1 inactivation, ER-Golgi/extracellular-vesicle shuttling) and how substrate selection is governed across these compartments remains unresolved.
  • No unifying model for PRDX4 trafficking out of the ER
  • Determinants of specific-substrate oxidation vs. general peroxidase activity not defined
  • Structural basis of redox-sensitive target complexes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016209 antioxidant activity 3 GO:0016491 oxidoreductase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 1
Partners
CASP1EPAS1GDE2HIF1ATXNDC5

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Prdx4, as an ER-resident enzyme that metabolizes H2O2, oxidizes two cysteine residues within the enzymatic domain of GDE2 (a six-transmembrane protein that induces neuronal differentiation). This oxidation blocks GDE2 trafficking to the plasma membrane, preventing GDE2-mediated surface cleavage of GPI-anchored proteins and thereby inhibiting Notch-downregulation-dependent neurogenesis. Prdx4 ablation causes premature motor neuron differentiation and progenitor depletion. Genetic knockout (Prdx4 ablation), live-cell imaging/trafficking assay, cysteine mutagenesis in GDE2, redox biochemistry showing Prdx4 dimer-mediated oxidation of GDE2 cysteines Nature communications High 25943695
2015 PRDX4-mediated disulfide bond formation in the ER lumen depends on an ERO1-independent, ER-lumenal source of H2O2. Expression of an ER-targeted catalase attenuated PRDX4-mediated oxidative protein folding in ERO1-deficient cells, whereas depleting H2O2 in the cytosol or mitochondria had no such effect, demonstrating that the ER is relatively isolated from cytosolic/mitochondrial H2O2 pools and that PRDX4 exploits a lumenal H2O2 source. ER-targeted catalase expression, H2O2 compartment tracking kinetic assay, genetic depletion of ERO1 and PRDX4, functional disulfide bond formation assay The Journal of cell biology High 26504166
2019 Prdx4 directly inhibits caspase-1 activity by forming a redox-sensitive complex with caspase-1 via caspase-1 cysteine 397, leading to caspase-1 sequestration and inactivation, thereby limiting IL-1β maturation and inflammasome-mediated signaling. Mice lacking Prdx4 (including myeloid-specific Prdx4-ΔLysMCre) showed increased susceptibility to LPS-induced septic shock. Prdx4 co-localizes with inflammasome components in extracellular vesicles from inflammasome-activated macrophages, and loss of Prdx4 boosts the pro-inflammatory potential of these vesicles. Co-immunoprecipitation of caspase-1/Prdx4 complex, cysteine-397 mutagenesis, Prdx4 knockout and myeloid-conditional knockout mice, LPS-septic shock model, extracellular vesicle purification and functional transfer assay in vitro and in vivo The EMBO journal High 31544965
2012 PRDX4 is an ER-resident peroxiredoxin that couples H2O2 catabolism with oxidative protein folding: it uses H2O2 as a substrate to drive disulfide bond formation in nascent client proteins. Compound knockout of Prdx4 and Ero1 in mice revealed that absence of both enzymes exposes nascent protein thiols to competing H2O2-mediated oxidation, increasing sulfenylated proteins; these sulfenylated thiols exploit ascorbate as reductant, accelerating ascorbate clearance and leading to altered extracellular matrix and a senescent phenotype. Compound Prdx4/Ero1 double-knockout mouse model, biochemical assays for sulfenylated proteins, ascorbate measurement, extracellular matrix analysis Antioxidants & redox signaling Medium 23025503
2016 PRDX4 (and PRDX2) interact with HIF-1α and HIF-2α in vitro and in hypoxic HeLa cells. During prolonged hypoxia, PRDX4 undergoes nuclear translocation and impairs HIF-1 and HIF-2 binding to hypoxia response elements of a subset of target genes, thereby inhibiting transcription. The enzymatic (peroxidase) activity of PRDX4 is not required for this HIF inhibition. Co-immunoprecipitation in hypoxic HeLa cells and in vitro binding, nuclear fractionation, chromatin immunoprecipitation, catalytically inactive mutant analysis Oncotarget Medium 26837221
2021 In pancreatic ductal adenocarcinoma (PDAC), high cytosolic NADPH drives NOX4 activity in the ER membrane, producing H2O2 that is metabolized by PRDX4 in the ER lumen. PDAC cells with high NADPH are dependent on PRDX4 for growth and survival; PRDX4 loss is associated with increased ROS, DNA-PKcs-governed DNA damage response, and radiosensitivity, all of which can be rescued by depletion of NOX4 or NADPH. Functional genomics screen, in vitro PRDX4 KD/KO, in vivo xenograft validation, NOX4 depletion epistasis, NADPH manipulation, DNA damage response assays Science advances High 33962950
2018 Prdx4 catalyzes disulfide bond formation in proteins via H2O2 in the ER lumen and supports lipoprotein secretion. Double knockout of Prdx4 and Sod1 in mice strikingly impairs secretion of triglyceride-rich lipoprotein, leading to aggravated liver steatosis and caspase-3 activation; hyperoxidation of distinct Prdx isoforms occurs additively in DKO livers. Prdx4/Sod1 double-knockout mouse model, lipoprotein secretion assay, caspase-3 activation assay, peroxiredoxin hyperoxidation analysis Oxidative medicine and cellular longevity Medium 30050648
2018 PRDX4 deficiency in male knockout mice (PRDX4-/y) aggravates DSS-induced colitis, with increased CHOP expression, activated caspase-3, and expanded ER (hallmarks of ER stress) in colonic tissues compared to wild-type, demonstrating that PRDX4's ER thiol oxidase function protects colonic epithelial cells from oxidative damage and ER stress. PRDX4 knockout mouse model, DSS-induced colitis, histological and biochemical analysis of ER stress markers (CHOP, caspase-3, ER morphology), MPO assay Free radical biology & medicine Medium 30578917
2024 PRDX4 promotes the degradation of dipeptidyl peptidase-4 (DPP-4), thereby alleviating high-glucose-stimulated Müller cell abnormalities including reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction. PRDX4 knockout exacerbated retinal neurodegeneration in a streptozotocin-induced diabetic mouse model. PRDX4 KO mouse model (streptozotocin-induced diabetes), siRNA knockdown and overexpression in Müller cells, DPP-4 degradation assay, multiple cellular stress readouts The Journal of biological chemistry Medium 39706273
2004 PRDX4 is fused to AML1 (RUNX1) via a t(X;21)(p22;q22) chromosomal translocation in an AML patient, creating fusion transcripts (exon 5 of AML1 with exon 2 of PRDX4, and an alternative splice with exon 6), identifying PRDX4 as a chromosomal translocation partner in leukemia. 3' RACE-PCR, RT-PCR, FISH cytogenetic analysis of patient bone marrow Genes, chromosomes & cancer Medium 15188461
2009 TRAIL suppresses endogenous PRDX4 expression at the transcriptional level, and overexpression of PRDX4 dramatically suppresses TRAIL-induced apoptosis, demonstrating that PRDX4 downregulation by TRAIL facilitates cell death. Transcriptional analysis of PRDX4 expression after TRAIL treatment, PRDX4 overexpression rescue experiment measuring TRAIL-induced apoptosis FEBS letters Low 19364504
2024 PRDX4 undergoes ER-to-Golgi shuttling in T cells treated with H2S donor GYY4137 or overexpressing CBS, and this trafficking is associated with restoration of Golgi architecture, increased T cell stemness, antioxidant capacity, and protein translation, as well as superior antitumor capacity upon adoptive transfer in melanoma and lymphoma models. H2S donor treatment and CBS overexpression in T cells, subcellular localization of PRDX4 (ER-Golgi shuttling), adoptive transfer in vivo tumor models, metabolic and glycation profiling Science advances Low 39546607
2023 The irreversible kinase inhibitor pelitinib covalently binds to PRDX4 and induces its degradation. This was validated by cell-based thermal shift assay, biochemical assay, and miRNA knockdown, suggesting pelitinib acts as a covalent molecular glue to degrade PRDX4. Activity-based chemoproteomics with iodoacetamide alkyne probe, cellular thermal shift assay, biochemical binding assay, miRNA knockdown validation Journal of pharmaceutical and biomedical analysis Low 37084663
2024 PRDX4 physically interacts with TXNDC5 in gastric cancer cells, as demonstrated by co-immunoprecipitation of total protein from gastric cancer cells and tissues with high TXNDC5 expression. Co-immunoprecipitation from gastric cancer cell lysates and tissue Translational cancer research Low 38410208
2026 Eupalinolide B (EB) covalently binds to Cys54 and Cys248 residues of PRDX4, stabilizes PRDX4, and upregulates its protein expression in LPS-stimulated macrophages. siRNA knockdown of PRDX4 blunted the antioxidant effects of EB, confirming PRDX4 as the functional target mediating EB's reduction of ROS, NO, and MDA. Activity-based protein profiling, direct labeling and competitive binding assays with purified PRDX4, high-resolution mass spectrometry identifying Cys54/Cys248 binding sites, siRNA knockdown functional rescue Biomedicines Medium 41898276
2024 PRDX4 is essential for disulfide bond formation in proinsulin in pancreatic β cells. PRDX4 protein is reduced in Cnot7-KO β cells (which have impaired proinsulin-to-insulin conversion), and this reduction is caused by post-transcriptional regulation: CNOT8 (a CCR4-NOT paralog upregulated in Cnot7-KO cells) binds Prdx4 mRNA via MSI2, promoting its degradation. CNOT7 knockout β cells, proinsulin/insulin content measurement, CNOT8 RNA-binding assay with Prdx4 mRNA via MSI2 interaction, protein expression analysis bioRxivpreprint Low bio_10.1101_2024.06.26.599433

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation. Theranostics 94 30613272
2011 Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology. Journal of proteome research 79 21859152
2010 Differential expression of peroxiredoxins in prostate cancer: consistent upregulation of PRDX3 and PRDX4. The Prostate 79 21031435
2012 PRDX4, an endoplasmic reticulum-localized peroxiredoxin at the crossroads between enzymatic oxidative protein folding and nonenzymatic protein oxidation. Antioxidants & redox signaling 63 23025503
2015 ERO1-independent production of H2O2 within the endoplasmic reticulum fuels Prdx4-mediated oxidative protein folding. The Journal of cell biology 57 26504166
2019 PRDX4 and Its Roles in Various Cancers. Technology in cancer research & treatment 49 31311441
2015 Prdx4 is a compartment-specific H2O2 sensor that regulates neurogenesis by controlling surface expression of GDE2. Nature communications 47 25943695
2019 Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles. The EMBO journal 45 31544965
2016 PRDX2 and PRDX4 are negative regulators of hypoxia-inducible factors under conditions of prolonged hypoxia. Oncotarget 35 26837221
2021 Long noncoding RNA TP53TG1 suppresses the growth and metastasis of hepatocellular carcinoma by regulating the PRDX4/β-catenin pathway. Cancer letters 33 33957185
2004 PRDX4, a member of the peroxiredoxin family, is fused to AML1 (RUNX1) in an acute myeloid leukemia patient with a t(X;21)(p22;q22). Genes, chromosomes & cancer 32 15188461
2018 Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice. Free radical biology & medicine 29 30578917
2021 NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4. Science advances 26 33962950
2020 Overexpression of PRDX4 Modulates Tumor Microenvironment and Promotes Urethane-Induced Lung Tumorigenesis. Oxidative medicine and cellular longevity 21 33456675
2024 H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response. Science advances 17 39546607
2019 The impact of PRDX4 and the EGFR mutation status on cellular proliferation in lung adenocarcinoma. International journal of medical sciences 17 31588184
2018 Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure. Oxidative medicine and cellular longevity 17 30050648
2009 TNF-related apoptosis-inducing ligand suppresses PRDX4 expression. FEBS letters 17 19364504
2024 PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells. The Journal of biological chemistry 11 39706273
2018 Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury. International journal of molecular sciences 11 30149550
2020 Suppression of PRDX4 inhibits cell proliferation and invasion of ectopic endometrial stromal cells in endometriosis. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 9 32436404
2022 Consequences of a peroxiredoxin 4 (Prdx4) deficiency on learning and memory in mice. Biochemical and biophysical research communications 8 35809345
2024 Validation of the interaction between PRDX4 and TXNDC5 in gastric cancer and the significance of the PRDX4 gene in gastric cancer based on a data mining analysis. Translational cancer research 7 38410208
2024 Exploring the role of PRDX4 in the development of uterine corpus endometrial carcinoma. Medical oncology (Northwood, London, England) 6 38177789
2025 Characterisation of the prdx4 gene in Squalius cephalus and its role in freshwater environments with varying impact of perfluoroalkyl substances (PFAS). Chemosphere 5 39889648
2018 Critical factors for lentivirus-mediated PRDX4 gene transfer in the HepG2 cell line. Oncology letters 4 29930713
2007 Cytogenetic and molecular study of the PRDX4 gene in a t(X;18)(p22;q23): a cautionary tale. Cancer genetics and cytogenetics 4 17656256
2025 Resveratrol Downregulated PRDX4 Expression to Inhibit the Progression of Renal Cell Carcinoma via Wnt/β-Catenin Pathway. Food science & nutrition 3 40458080
2023 Target proteins profiling of irreversible kinase inhibitor pelitinib and discovery of degradation of PRDX4 by label free chemoproteomics. Journal of pharmaceutical and biomedical analysis 3 37084663
2025 LncRNA THUMPD3-AS1 promotes the proliferation and migration of esophageal cancer cells through the miR-29a-3p/ELK1/PRDX4 signaling pathway. Seminars in oncology 2 40639318
2025 Bioactive Peptide C248 of PRDX4 Ameliorates the Function of Testicular Leydig Cells via Mitochondrial Protection. Antioxidants (Basel, Switzerland) 2 41596080
2021 [Differential expression of PRDX4 in alveolar macrophages of patients with silicosis]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 2 33535333
2025 The immunohistochemical combination of low SGLT2 expression and high PRDX4 expression independently predicts shortened survival in patients undergoing surgical resection for hepatoblastoma. Diagnostic pathology 1 39773476
2025 Research progress on the role and molecular mechanism of PRDX4 in malignant tumors. Bulletin du cancer 1 40157831
2025 PRDX-4: a novel biomarker similar to KL-6 for predicting the occurrence and progression of systemic sclerosis-ILD. Biomarkers in medicine 1 40169424
2026 Integrative multi-omics and machine learning framework identifies PRDX4 as a redox-EMT regulator and predictive marker in bone-metastatic breast cancer. NPJ precision oncology 0 41571856
2026 Complementary roles of HMGB1 and PRDX4 in the pathophysiology of steroid-associated osteonecrosis of the femoral head: a histopathological and immunohistochemistry study. Virchows Archiv : an international journal of pathology 0 41639395
2026 Eupalinolide B Alleviates Oxidative Stress in LPS-Induced RAW264.7 Macrophages via Covalently Binding to PRDX4. Biomedicines 0 41898276
2026 PRDX4 Potentially Serves as an Independent Marker for Early Recurrence of Oral Squamous Cell Carcinoma. Anticancer research 0 42049339
2025 L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice. Scientific reports 0 41430095
2024 Revealing Prdx4 as a potential diagnostic and therapeutic target for acute pancreatitis based on machine learning analysis. BMC medical genomics 0 38641608
2020 [New early gastric cancer marker PRDX4 promote the tumorigenesis and progression of gastric cancer via eliminating ROS]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 0 32148004

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