{"gene":"PRDX4","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2015,"finding":"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.","method":"Genetic knockout (Prdx4 ablation), live-cell imaging/trafficking assay, cysteine mutagenesis in GDE2, redox biochemistry showing Prdx4 dimer-mediated oxidation of GDE2 cysteines","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including KO mouse phenotype, cysteine mutagenesis, biochemical oxidation assay, and trafficking experiments in a single rigorous study","pmids":["25943695"],"is_preprint":false},{"year":2015,"finding":"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.","method":"ER-targeted catalase expression, H2O2 compartment tracking kinetic assay, genetic depletion of ERO1 and PRDX4, functional disulfide bond formation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches (targeted catalase, kinetic H2O2 tracking, double KO cells) with rigorous controls in a single study","pmids":["26504166"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, site-directed mutagenesis, conditional KO with defined phenotype, multiple in vivo and in vitro models in one study","pmids":["31544965"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Compound Prdx4/Ero1 double-knockout mouse model, biochemical assays for sulfenylated proteins, ascorbate measurement, extracellular matrix analysis","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — compound KO mouse model with multiple biochemical readouts, but review/commentary article summarizing compound-KO findings; single lab","pmids":["23025503"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation in hypoxic HeLa cells and in vitro binding, nuclear fractionation, chromatin immunoprecipitation, catalytically inactive mutant analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, nuclear fractionation, ChIP, and enzymatic mutant, single lab with multiple orthogonal methods","pmids":["26837221"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Functional genomics screen, in vitro PRDX4 KD/KO, in vivo xenograft validation, NOX4 depletion epistasis, NADPH manipulation, DNA damage response assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional genomics plus in vitro and in vivo validation, epistasis experiments with NOX4 and NADPH rescue, multiple orthogonal methods in one study","pmids":["33962950"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Prdx4/Sod1 double-knockout mouse model, lipoprotein secretion assay, caspase-3 activation assay, peroxiredoxin hyperoxidation analysis","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-KO mouse model with defined biochemical and cellular phenotypes, single lab","pmids":["30050648"],"is_preprint":false},{"year":2018,"finding":"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.","method":"PRDX4 knockout mouse model, DSS-induced colitis, histological and biochemical analysis of ER stress markers (CHOP, caspase-3, ER morphology), MPO assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse model with defined cellular phenotype and multiple ER stress readouts, single lab","pmids":["30578917"],"is_preprint":false},{"year":2024,"finding":"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.","method":"PRDX4 KO mouse model (streptozotocin-induced diabetes), siRNA knockdown and overexpression in Müller cells, DPP-4 degradation assay, multiple cellular stress readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus in vitro gain/loss-of-function with mechanistic DPP-4 degradation assay, single lab","pmids":["39706273"],"is_preprint":false},{"year":2004,"finding":"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.","method":"3' RACE-PCR, RT-PCR, FISH cytogenetic analysis of patient bone marrow","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning from patient material with FISH confirmation, single patient case","pmids":["15188461"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Transcriptional analysis of PRDX4 expression after TRAIL treatment, PRDX4 overexpression rescue experiment measuring TRAIL-induced apoptosis","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single methods per finding, no mechanistic dissection of the transcriptional regulation pathway","pmids":["19364504"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Science advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization observation linked to functional outcome but mechanistic dissection of PRDX4's specific role is indirect; single lab","pmids":["39546607"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Activity-based chemoproteomics with iodoacetamide alkyne probe, cellular thermal shift assay, biochemical binding assay, miRNA knockdown validation","journal":"Journal of pharmaceutical and biomedical analysis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction confirmed by CETSA and biochemical assay but degradation mechanism not fully resolved","pmids":["37084663"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation from gastric cancer cell lysates and tissue","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, single lab, no functional follow-up of the interaction","pmids":["38410208"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS-level cysteine identification on purified protein plus siRNA functional validation, single lab with multiple orthogonal methods","pmids":["41898276"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CNOT7 knockout β cells, proinsulin/insulin content measurement, CNOT8 RNA-binding assay with Prdx4 mRNA via MSI2 interaction, protein expression analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, RNA-binding evidence is indirect (via MSI2 intermediary), functional connection to proinsulin folding is correlative","pmids":["bio_10.1101_2024.06.26.599433"],"is_preprint":true}],"current_model":"PRDX4 is an ER-resident 2-Cys peroxiredoxin that couples H2O2 catabolism with oxidative protein folding by using lumenal H2O2 (derived from an ERO1-independent, ER-intrinsic source, supplied in part by ER-membrane NOX4) to drive disulfide bond formation in nascent client proteins including proinsulin; it also acts as a compartment-specific H2O2 sensor that, via H2O2-driven dimerization, directly oxidizes target proteins such as GDE2 cysteines to control their ER-to-plasma-membrane trafficking and thereby regulate neurogenesis, and it inhibits caspase-1 by forming a redox-sensitive complex at caspase-1 Cys397, limiting inflammasome activity and IL-1β production."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2012,"claim":"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","pmids":["23025503"],"confidence":"Medium","gaps":["Identity of the lumenal H2O2 source not resolved here","Specific client proteins not defined","Summarized in a review/commentary from a single lab"]},{"year":2015,"claim":"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","pmids":["26504166"],"confidence":"High","gaps":["Did not identify the enzymatic generator of lumenal H2O2","Client specificity not addressed"]},{"year":2015,"claim":"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","pmids":["25943695"],"confidence":"High","gaps":["Generality of substrate-specific oxidation beyond GDE2 unknown","Mechanism of selecting GDE2 cysteines over other thiols unresolved"]},{"year":2016,"claim":"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","pmids":["26837221"],"confidence":"Medium","gaps":["How an ER-resident protein relocates to the nucleus is unexplained","Physiological relevance outside HeLa not established"]},{"year":2018,"claim":"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)","pmids":["30050648","30578917"],"confidence":"Medium","gaps":["Direct PRDX4 substrates in these tissues not identified","Contribution of folding vs. peroxidase activity not separated"]},{"year":2019,"claim":"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","pmids":["31544965"],"confidence":"High","gaps":["How an ER enzyme accesses cytosolic caspase-1 mechanistically unclear","Structural basis of the redox-sensitive complex undefined"]},{"year":2021,"claim":"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","pmids":["33962950"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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)","pmids":["bio_10.1101_2024.06.26.599433"],"confidence":"Low","gaps":["Preprint; RNA-binding evidence is indirect via an MSI2 intermediary","Direct proinsulin disulfide catalysis by PRDX4 not biochemically shown here"]},{"year":2024,"claim":"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","pmids":["39706273"],"confidence":"Medium","gaps":["Mechanism by which PRDX4 promotes DPP-4 degradation undefined","Whether this depends on peroxidase activity unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,6,15]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["GDE2","CASP1","HIF1A","EPAS1","TXNDC5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13162","full_name":"Peroxiredoxin-4","aliases":["Antioxidant enzyme AOE372","AOE37-2","Peroxiredoxin IV","Prx-IV","Thioredoxin peroxidase AO372","Thioredoxin-dependent peroxide reductase A0372","Thioredoxin-dependent peroxiredoxin 4"],"length_aa":271,"mass_kda":30.5,"function":"Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Regulates the activation of NF-kappa-B in the cytosol by a modulation of I-kappa-B-alpha phosphorylation","subcellular_location":"Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q13162/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRDX4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRDX4","total_profiled":1310},"omim":[{"mim_id":"300927","title":"PEROXIREDOXIN 4; PRDX4","url":"https://www.omim.org/entry/300927"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"pancreas","ntpm":1142.7}],"url":"https://www.proteinatlas.org/search/PRDX4"},"hgnc":{"alias_symbol":["AOE37-2"],"prev_symbol":[]},"alphafold":{"accession":"Q13162","domains":[{"cath_id":"3.40.30.10","chopping":"82-222","consensus_level":"high","plddt":97.6999,"start":82,"end":222},{"cath_id":"-","chopping":"224-271","consensus_level":"medium","plddt":97.545,"start":224,"end":271}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13162","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13162-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13162-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRDX4","jax_strain_url":"https://www.jax.org/strain/search?query=PRDX4"},"sequence":{"accession":"Q13162","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13162.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13162/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13162"}},"corpus_meta":[{"pmid":"30613272","id":"PMC_30613272","title":"Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30613272","citation_count":94,"is_preprint":false},{"pmid":"21031435","id":"PMC_21031435","title":"Differential expression of peroxiredoxins in prostate cancer: consistent upregulation of PRDX3 and PRDX4.","date":"2010","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/21031435","citation_count":79,"is_preprint":false},{"pmid":"21859152","id":"PMC_21859152","title":"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.","date":"2011","source":"Journal of proteome 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Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32436404","citation_count":9,"is_preprint":false},{"pmid":"35809345","id":"PMC_35809345","title":"Consequences of a peroxiredoxin 4 (Prdx4) deficiency on learning and memory in mice.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35809345","citation_count":8,"is_preprint":false},{"pmid":"38410208","id":"PMC_38410208","title":"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.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38410208","citation_count":7,"is_preprint":false},{"pmid":"38177789","id":"PMC_38177789","title":"Exploring the role of PRDX4 in the development of uterine corpus endometrial carcinoma.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38177789","citation_count":6,"is_preprint":false},{"pmid":"39889648","id":"PMC_39889648","title":"Characterisation of the prdx4 gene in Squalius cephalus and its role in freshwater environments with varying impact of perfluoroalkyl substances (PFAS).","date":"2025","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/39889648","citation_count":5,"is_preprint":false},{"pmid":"29930713","id":"PMC_29930713","title":"Critical factors for lentivirus-mediated PRDX4 gene transfer in the HepG2 cell line.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29930713","citation_count":4,"is_preprint":false},{"pmid":"17656256","id":"PMC_17656256","title":"Cytogenetic and molecular study of the PRDX4 gene in a t(X;18)(p22;q23): a cautionary tale.","date":"2007","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17656256","citation_count":4,"is_preprint":false},{"pmid":"37084663","id":"PMC_37084663","title":"Target proteins profiling of irreversible kinase inhibitor pelitinib and discovery of degradation of PRDX4 by label free chemoproteomics.","date":"2023","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/37084663","citation_count":3,"is_preprint":false},{"pmid":"40458080","id":"PMC_40458080","title":"Resveratrol Downregulated PRDX4 Expression to Inhibit the Progression of Renal Cell Carcinoma via Wnt/β-Catenin Pathway.","date":"2025","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/40458080","citation_count":3,"is_preprint":false},{"pmid":"40639318","id":"PMC_40639318","title":"LncRNA THUMPD3-AS1 promotes the proliferation and migration of esophageal cancer cells through the miR-29a-3p/ELK1/PRDX4 signaling pathway.","date":"2025","source":"Seminars in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40639318","citation_count":2,"is_preprint":false},{"pmid":"33535333","id":"PMC_33535333","title":"[Differential expression of PRDX4 in alveolar macrophages of patients with silicosis].","date":"2021","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33535333","citation_count":2,"is_preprint":false},{"pmid":"41596080","id":"PMC_41596080","title":"Bioactive Peptide C248 of PRDX4 Ameliorates the Function of Testicular Leydig Cells via Mitochondrial Protection.","date":"2025","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41596080","citation_count":2,"is_preprint":false},{"pmid":"40157831","id":"PMC_40157831","title":"Research progress on the role and molecular mechanism of PRDX4 in malignant tumors.","date":"2025","source":"Bulletin du cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40157831","citation_count":1,"is_preprint":false},{"pmid":"39773476","id":"PMC_39773476","title":"The immunohistochemical combination of low SGLT2 expression and high PRDX4 expression independently predicts shortened survival in patients undergoing surgical resection for hepatoblastoma.","date":"2025","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39773476","citation_count":1,"is_preprint":false},{"pmid":"40169424","id":"PMC_40169424","title":"PRDX-4: a novel biomarker similar to KL-6 for predicting the occurrence and progression of systemic sclerosis-ILD.","date":"2025","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40169424","citation_count":1,"is_preprint":false},{"pmid":"41430095","id":"PMC_41430095","title":"L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice.","date":"2025","source":"Scientific 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Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41639395","citation_count":0,"is_preprint":false},{"pmid":"42049339","id":"PMC_42049339","title":"PRDX4 Potentially Serves as an Independent Marker for Early Recurrence of Oral Squamous Cell Carcinoma.","date":"2026","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/42049339","citation_count":0,"is_preprint":false},{"pmid":"41898276","id":"PMC_41898276","title":"Eupalinolide B Alleviates Oxidative Stress in LPS-Induced RAW264.7 Macrophages via Covalently Binding to PRDX4.","date":"2026","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41898276","citation_count":0,"is_preprint":false},{"pmid":"32148004","id":"PMC_32148004","title":"[New early gastric cancer marker PRDX4 promote the tumorigenesis and progression of gastric cancer via eliminating ROS].","date":"2020","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32148004","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.26.599433","title":"Post-transcriptional regulation by the CCR4-NOT deadenylase complex maintains redox homeostasis in insulin biosynthesis in mouse pancreatic β cells","date":"2024-06-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.26.599433","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.06.680703","title":"ER oxidoreductin-1  <sub>α</sub>  and unfolded protein response as sex-dependent drivers of cardiorenal dysfunction in experimental autoimmune encephalomyelitis","date":"2025-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.680703","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24490,"output_tokens":4558,"usd":0.07092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12548,"output_tokens":3532,"usd":0.07552,"stage2_stop_reason":"end_turn"},"total_usd":0.14644,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockout (Prdx4 ablation), live-cell imaging/trafficking assay, cysteine mutagenesis in GDE2, redox biochemistry showing Prdx4 dimer-mediated oxidation of GDE2 cysteines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including KO mouse phenotype, cysteine mutagenesis, biochemical oxidation assay, and trafficking experiments in a single rigorous study\",\n      \"pmids\": [\"25943695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"ER-targeted catalase expression, H2O2 compartment tracking kinetic assay, genetic depletion of ERO1 and PRDX4, functional disulfide bond formation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches (targeted catalase, kinetic H2O2 tracking, double KO cells) with rigorous controls in a single study\",\n      \"pmids\": [\"26504166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, site-directed mutagenesis, conditional KO with defined phenotype, multiple in vivo and in vitro models in one study\",\n      \"pmids\": [\"31544965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Compound Prdx4/Ero1 double-knockout mouse model, biochemical assays for sulfenylated proteins, ascorbate measurement, extracellular matrix analysis\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — compound KO mouse model with multiple biochemical readouts, but review/commentary article summarizing compound-KO findings; single lab\",\n      \"pmids\": [\"23025503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation in hypoxic HeLa cells and in vitro binding, nuclear fractionation, chromatin immunoprecipitation, catalytically inactive mutant analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, nuclear fractionation, ChIP, and enzymatic mutant, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26837221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Functional genomics screen, in vitro PRDX4 KD/KO, in vivo xenograft validation, NOX4 depletion epistasis, NADPH manipulation, DNA damage response assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional genomics plus in vitro and in vivo validation, epistasis experiments with NOX4 and NADPH rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33962950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Prdx4/Sod1 double-knockout mouse model, lipoprotein secretion assay, caspase-3 activation assay, peroxiredoxin hyperoxidation analysis\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-KO mouse model with defined biochemical and cellular phenotypes, single lab\",\n      \"pmids\": [\"30050648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"PRDX4 knockout mouse model, DSS-induced colitis, histological and biochemical analysis of ER stress markers (CHOP, caspase-3, ER morphology), MPO assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse model with defined cellular phenotype and multiple ER stress readouts, single lab\",\n      \"pmids\": [\"30578917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"PRDX4 KO mouse model (streptozotocin-induced diabetes), siRNA knockdown and overexpression in Müller cells, DPP-4 degradation assay, multiple cellular stress readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus in vitro gain/loss-of-function with mechanistic DPP-4 degradation assay, single lab\",\n      \"pmids\": [\"39706273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"3' RACE-PCR, RT-PCR, FISH cytogenetic analysis of patient bone marrow\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning from patient material with FISH confirmation, single patient case\",\n      \"pmids\": [\"15188461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptional analysis of PRDX4 expression after TRAIL treatment, PRDX4 overexpression rescue experiment measuring TRAIL-induced apoptosis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single methods per finding, no mechanistic dissection of the transcriptional regulation pathway\",\n      \"pmids\": [\"19364504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization observation linked to functional outcome but mechanistic dissection of PRDX4's specific role is indirect; single lab\",\n      \"pmids\": [\"39546607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Activity-based chemoproteomics with iodoacetamide alkyne probe, cellular thermal shift assay, biochemical binding assay, miRNA knockdown validation\",\n      \"journal\": \"Journal of pharmaceutical and biomedical analysis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction confirmed by CETSA and biochemical assay but degradation mechanism not fully resolved\",\n      \"pmids\": [\"37084663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from gastric cancer cell lysates and tissue\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, single lab, no functional follow-up of the interaction\",\n      \"pmids\": [\"38410208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS-level cysteine identification on purified protein plus siRNA functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41898276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CNOT7 knockout β cells, proinsulin/insulin content measurement, CNOT8 RNA-binding assay with Prdx4 mRNA via MSI2 interaction, protein expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, RNA-binding evidence is indirect (via MSI2 intermediary), functional connection to proinsulin folding is correlative\",\n      \"pmids\": [\"bio_10.1101_2024.06.26.599433\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRDX4 is an ER-resident 2-Cys peroxiredoxin that couples H2O2 catabolism with oxidative protein folding by using lumenal H2O2 (derived from an ERO1-independent, ER-intrinsic source, supplied in part by ER-membrane NOX4) to drive disulfide bond formation in nascent client proteins including proinsulin; it also acts as a compartment-specific H2O2 sensor that, via H2O2-driven dimerization, directly oxidizes target proteins such as GDE2 cysteines to control their ER-to-plasma-membrane trafficking and thereby regulate neurogenesis, and it inhibits caspase-1 by forming a redox-sensitive complex at caspase-1 Cys397, limiting inflammasome activity and IL-1β production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3]. 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 [#1]; 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 [#5]. Through this function PRDX4 supports the folding and secretion of disulfide-rich clients, including triglyceride-rich lipoprotein [#6] and proinsulin [#15], 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 [#7, #8]. 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 [#0]. PRDX4 additionally limits inflammasome activity by forming a redox-sensitive complex with caspase-1 at Cys397, sequestering and inactivating the protease to dampen IL-1\\u03b2 maturation, such that Prdx4 loss heightens susceptibility to LPS-induced septic shock [#2]. A non-enzymatic role has also been documented, in which PRDX4 translocates to the nucleus during prolonged hypoxia and interacts with HIF-1\\u03b1/HIF-2\\u03b1 to impair their binding to hypoxia response elements independently of peroxidase activity [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Compound Prdx4/Ero1 double-knockout mice with sulfenylation and ascorbate biochemistry\",\n      \"pmids\": [\"23025503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the lumenal H2O2 source not resolved here\", \"Specific client proteins not defined\", \"Summarized in a review/commentary from a single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"ER-targeted catalase, compartment-specific H2O2 tracking, and ERO1/PRDX4 double knockout in cells\",\n      \"pmids\": [\"26504166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the enzymatic generator of lumenal H2O2\", \"Client specificity not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Prdx4 knockout, GDE2 cysteine mutagenesis, trafficking imaging, and dimer-mediated oxidation biochemistry\",\n      \"pmids\": [\"25943695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of substrate-specific oxidation beyond GDE2 unknown\", \"Mechanism of selecting GDE2 cysteines over other thiols unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a peroxidase-independent moonlighting function in which PRDX4 acts in the nucleus to repress HIF transcriptional output.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, ChIP, and catalytically inactive mutant in hypoxic HeLa cells\",\n      \"pmids\": [\"26837221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an ER-resident protein relocates to the nucleus is unexplained\", \"Physiological relevance outside HeLa not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected PRDX4's folding activity to physiological secretory output and ER-stress protection across organs.\",\n      \"evidence\": \"Prdx4/Sod1 double-KO mouse (lipoprotein secretion, liver steatosis) and Prdx4-KO DSS colitis model (CHOP, caspase-3, ER morphology)\",\n      \"pmids\": [\"30050648\", \"30578917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRDX4 substrates in these tissues not identified\", \"Contribution of folding vs. peroxidase activity not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a direct anti-inflammatory mechanism whereby PRDX4 forms a redox-sensitive complex to inactivate caspase-1 and restrain inflammasome signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, caspase-1 Cys397 mutagenesis, myeloid-conditional Prdx4 KO with septic shock model and extracellular vesicle transfer assays\",\n      \"pmids\": [\"31544965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER enzyme accesses cytosolic caspase-1 mechanistically unclear\", \"Structural basis of the redox-sensitive complex undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the enzymatic source of PRDX4's lumenal H2O2 in a disease context and exposed PRDX4 as a metabolic survival dependency.\",\n      \"evidence\": \"Functional genomics, PRDX4 KD/KO, xenografts, and NOX4/NADPH epistasis rescue in PDAC\",\n      \"pmids\": [\"33962950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended PRDX4's folding role to proinsulin maturation and uncovered post-transcriptional control of PRDX4 abundance.\",\n      \"evidence\": \"Cnot7-KO \\u03b2 cells, proinsulin/insulin measurement, and CNOT8/MSI2 RNA-binding analysis of Prdx4 mRNA (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.26.599433\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; RNA-binding evidence is indirect via an MSI2 intermediary\", \"Direct proinsulin disulfide catalysis by PRDX4 not biochemically shown here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PRDX4 in DPP-4 degradation as a cytoprotective axis in diabetic retinal neurodegeneration.\",\n      \"evidence\": \"PRDX4-KO STZ-diabetic mice with M\\u00fcller cell knockdown/overexpression and DPP-4 degradation assays\",\n      \"pmids\": [\"39706273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRDX4 promotes DPP-4 degradation undefined\", \"Whether this depends on peroxidase activity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 6, 15]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GDE2\", \"CASP1\", \"HIF1A\", \"EPAS1\", \"TXNDC5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}