{"gene":"PRDX2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1995,"finding":"TDPX1 (PRDX2) encodes an enzyme homologous to yeast thioredoxin-dependent peroxide reductase (thioredoxin peroxidase, TPX) and was mapped to human chromosome 13q12 by fluorescence in situ hybridization and somatic cell hybrid analysis.","method":"PCR amplification of human cDNA, somatic cell hybrid panel analysis, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by FISH and functional homology established by sequence analysis, single lab","pmids":["7607688"],"is_preprint":false},{"year":2003,"finding":"Down-regulation of PRDX2 in SH-SY5Y neuroblastoma cells via stable antisense transfection increased apoptosis under basal conditions and enhanced sensitivity to oxidative cytotoxic agents, demonstrating PRDX2's role in protecting neurons from reactive oxygen species.","method":"Stable antisense transfection, cell viability assays, comparison with SOD1 overexpression","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined phenotypic readout (apoptosis, oxidative stress sensitivity), single lab","pmids":["12943237"],"is_preprint":false},{"year":2004,"finding":"Deletion of the PrxII (PRDX2) gene in mice increases ROS levels in thymocytes, reduces apoptosis (hypodiploid cell formation), enlarges the thymus, and alters the SP/DP thymocyte ratio, establishing PRDX2 as a regulator of thymocyte development and proliferation through ROS control.","method":"PrxII-null mouse model, flow cytometry, dexamethasone and food restriction treatments, concanavalin A stimulation assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple orthogonal phenotypic readouts (apoptosis, proliferation, ROS levels, thymocyte subsets), multiple experimental conditions","pmids":["15259009"],"is_preprint":false},{"year":2011,"finding":"PRDX2 promoter has decreased histone H3 acetylation and DNA hypermethylation in AML, leading to low PRDX2 expression; forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo and reduced ROS generated in response to cytokines, identifying PRDX2 as an epigenetically silenced tumor suppressor in AML that limits ROS-driven myeloid cell growth.","method":"ChIP-on-microarray (H3Ac), bisulfite sequencing (DNA methylation), forced PRDX2 expression with bone marrow transplantation mouse model, ROS measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, methylation analysis, in vivo transplantation model, and functional ROS assay in single study","pmids":["22207736"],"is_preprint":false},{"year":2011,"finding":"In human erythrocytes, PRDX2 forms multiple oligomeric states (decamers and homo-polymers) in the cytosol and associates with catalase (CAT) in a 440 kDa hetero-oligomeric complex; upon oxidative stress (28-day storage), PRDX2 translocates to the membrane and forms cross-linked species with hemoglobin. Both the 440 kDa and 140 kDa complexes exhibit peroxidase activity.","method":"Proteomics, 2D gel electrophoresis, native PAGE, mass spectrometry, peroxidase activity assays on fractionated cytosol and membrane ghosts","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical fractionation and activity assays, single lab","pmids":["21354257"],"is_preprint":false},{"year":2016,"finding":"PRDX2 interacts with HIF-1α and HIF-2α in vitro and in hypoxic HeLa cells; prolonged hypoxia increases nuclear translocation of PRDX2, where it impairs HIF-1 and HIF-2 binding to hypoxia response elements of target genes, inhibiting their transcription. This effect is independent of PRDX2 enzymatic peroxidase activity.","method":"Co-immunoprecipitation, ChIP assay, nuclear fractionation, gene reporter assays, mutagenesis of catalytic site","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP demonstrating impaired HIF binding, nuclear fractionation showing translocation, enzymatic activity mutant ruling out peroxidase mechanism, single lab with multiple orthogonal methods","pmids":["26837221"],"is_preprint":false},{"year":2017,"finding":"PRDX2 knockdown in colon cancer cells reduces PI3K/AKT pathway activation (decreased p-AKT); PRDX2 overexpression increases p-AKT and alters Bcl-2/Bax ratio, placing PRDX2 upstream of the PI3K/AKT survival pathway in 5-FU chemoresistance.","method":"shRNA knockdown, Western blotting, in vivo xenograft model, immunohistochemistry correlation","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function and gain-of-function with defined pathway readout, single lab","pmids":["28432271"],"is_preprint":false},{"year":2017,"finding":"PRDX2 is a direct target of miR-200b-3p (validated by luciferase reporter assay); c-Myc represses miR-200b-3p transcription by binding its promoter (ChIP assay); PRDX2 overexpression rescues the suppressive effects of miR-200b-3p on CRC invasion, EMT, and chemoresistance, establishing a c-Myc/miR-200b-3p/PRDX2 regulatory loop.","method":"Luciferase reporter assay, ChIP assay, Western blotting, invasion assay, metastatic mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of miRNA target, ChIP for c-Myc binding, rescue experiment, single lab","pmids":["29258530"],"is_preprint":false},{"year":2018,"finding":"PRDX2 is a direct substrate/interactor of CDK2 in AML; CDK2 depletion leads to ubiquitin-dependent proteasomal degradation of CDK2 (mediated by E3 ligase KLHL6) and reactivates differentiation; CDK2 maintains its differentiation-blocking function at least in part by maintaining PRDX2 activity, establishing a CDK2-PRDX2 axis that blocks AML differentiation.","method":"Yeast 2-hybrid system, functional analyses, CDK2 knockdown/inhibitor studies, in vivo xenograft and PDX mouse models","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast 2-hybrid interaction plus functional rescue experiments, multiple AML subtypes tested, in vivo validation, single lab","pmids":["29720484"],"is_preprint":false},{"year":2018,"finding":"DNMT3A-R882H/C mutations upregulate PRDX2 expression through promoter hypomethylation, reducing ROS accumulation and impairing apoptosis. Both DNMT3A-WT and R882H/C mutants physically interact with PRDX2. Knockdown of PRDX2 from DNMT3A-mutant myeloid cells increases ROS, drug sensitivity, and apoptosis.","method":"Gene expression profiling, DNA methylation assay, PRDX2 knockdown, ROS measurement, co-immunoprecipitation","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction plus methylation/expression analysis plus functional knockdown, single lab","pmids":["30245403"],"is_preprint":false},{"year":2018,"finding":"Differential kinetics between PRDX1 and PRDX2: the rate of disulfide formation (resolution step) is 11 s⁻¹ for PRDX1 vs 0.2 s⁻¹ for PRDX2, independent of oxidant. This slower resolution in PRDX2 allows its sulfenic acid intermediate to react with other protein thiols (forming mixed disulfides via the peroxidatic cysteine) to relay redox signals, whereas PRDX1 forms an intramolecular disulfide and continues the catalytic cycle.","method":"In vitro kinetic assays with recombinant human PRDX1 and PRDX2, intrinsic fluorescence measurements, rate constant determination for H2O2 and peroxynitrite reactions","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro assay with recombinant proteins, quantitative rate constants determined for multiple reactions, mechanistically distinguishes PRDX1 vs PRDX2 catalytic cycle","pmids":["30284335"],"is_preprint":false},{"year":2019,"finding":"REV7 physically interacts with PRDX2 (validated by immunoprecipitation and immunofluorescence); the REV7-PRDX2 complex is augmented post-irradiation and assembles onto DNA double-strand breaks; REV7 knockdown disrupts nuclear PRDX2 localization post-irradiation, leading to increased oxidative stress and radiosensitization of esophageal cancer cells.","method":"Proteomic analysis of REV7-interacting proteins, co-immunoprecipitation, immunofluorescence, γH2AX focus assay, ROS measurement, xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence colocalization, nuclear localization linked to functional consequence, single lab","pmids":["30657231"],"is_preprint":false},{"year":2019,"finding":"NF-κB-p65 directly binds the PRDX2 promoter (confirmed by luciferase reporter and ChIP assays) and drives PRDX2 upregulation in response to H. pylori infection; PRDX2 knockdown increases ROS, oxidative DNA damage (8-oxoguanine), and double-strand breaks (γ-H2AX), and sensitizes gastric cancer cells to cisplatin.","method":"Luciferase reporter assay, ChIP assay, H2DCFDA ROS assay, 8-oxoguanine immunostaining, γ-H2AX detection, in vitro and in vivo H. pylori infection models","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and luciferase reporter establish direct transcriptional regulation by NF-κB-p65; multiple orthogonal functional assays in vitro and in vivo, single lab","pmids":["31536951"],"is_preprint":false},{"year":1999,"finding":"Silica treatment triggers rapid degradation of PrxII (PRDX2) in Rat2 cells through a Ca²⁺-dependent protease (likely calpain), independent of ROS and proteasomal activity (insensitive to MG132 and lactacystin), thereby aggravating cellular oxidative stress.","method":"Western blotting, protease inhibitor studies (MG132, lactacystin), Ca²⁺ ionophore treatment, NAC and DPI inhibitor experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor dissection of degradation pathway with multiple negative controls, single lab","pmids":["10558905"],"is_preprint":false},{"year":2008,"finding":"In PrxII-null mouse splenocytes and macrophages, TLR4 protein is decreased compared to wild-type, and BAFF expression and BAFF promoter activity are elevated. PrxII-null mice show more severe airway hyper-responsiveness in OVA-induced asthma. This establishes PRDX2 as a regulator of TLR4 and BAFF expression through ROS control.","method":"PrxII-null mouse model, real-time quantitative RT-PCR, BAFF promoter activity assay, airway hyper-responsiveness measurements, eosinophil and IgE quantification","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple immune readouts and promoter activity assay, single lab","pmids":["18442801"],"is_preprint":false},{"year":2021,"finding":"PRDX2 binds RPL4 (ribosomal protein L4), reducing the interaction between RPL4 and MDM2; this leads to increased MDM2-mediated ubiquitination and degradation of p53, thereby promoting colorectal cancer cell proliferation. PRDX2 thus acts as an oncogenic regulator of the RPL4-MDM2-p53 axis.","method":"Co-immunoprecipitation, Western blotting, PRDX2 knockdown and overexpression, proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying RPL4 interaction and competitive displacement of MDM2-RPL4 complex, functional rescue experiment, single lab","pmids":["34117220"],"is_preprint":false},{"year":2021,"finding":"PRDX2 is released by erythroid cells in exosomes; inhibiting exosomal release significantly decreases the osteoclastogenic capacity of erythroid conditioned medium. Recombinant PRDX2 directly induces osteoclast formation from RANKL-primed precursors to levels comparable to continuous RANKL treatment, establishing an extracellular/exosomal function of PRDX2 in promoting osteoclastogenesis.","method":"Immunoblotting, mass spectrometry, exosomal inhibitor treatment, recombinant PRDX2 addition to RAW264.7 and primary bone marrow precursors, phlebotomy-induced anemia mouse model","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein functional assay plus exosomal inhibition experiment plus in vivo correlation, single lab","pmids":["33587325"],"is_preprint":false},{"year":2020,"finding":"PRDX2 removal in colorectal cancer cells inhibits S-phase progression and activates p38 MAPK, leading to autophagy flux disruption. The p38 MAPK activator partially rescues the cell-cycle and autophagy phenotypes of PRDX2 knockdown, placing PRDX2 upstream of p38 MAPK/FOXO signaling in CRC cell-cycle and autophagy regulation.","method":"shRNA knockdown, electron microscopy, immunostaining, Western blotting, p38 activator rescue experiment, xenograft model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with defined cellular phenotypes, pharmacological rescue placing PRDX2 in pathway, single lab","pmids":["32692719"],"is_preprint":false},{"year":2022,"finding":"PRDX2 knockdown in colorectal cancer cells sensitizes them to dihydroartemisinin (DHA) by increasing ROS levels; mechanistically, DHA inhibits PRDX2 expression to elevate ROS, which activates ER stress, STAT3, JNK, and p38 signaling pathways, enhancing the anti-tumor activity of oxaliplatin.","method":"PRDX2 knockdown, ROS measurement, Western blotting, flow cytometry, in vivo mouse xenograft model","journal":"Phytomedicine : international journal of phytotherapy and phytopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with pathway readout, mechanistic link between DHA and PRDX2 established by indirect evidence only, single lab","pmids":["35104762"],"is_preprint":false},{"year":2022,"finding":"Oxiconazole downregulates PRDX2 protein levels, leading to ROS accumulation that inactivates the Akt/mTOR pathway and inhibits RAB7A-mediated autophagosome-lysosome fusion, causing autophagy arrest and CRC cell death. Overexpression of PRDX2 significantly impedes oxiconazole-induced autophagy arrest.","method":"PRDX2 overexpression rescue, Western blotting, flow cytometry, Akt/mTOR pathway analysis, RAB7A colocalization assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PRDX2 overexpression rescue places PRDX2 mechanistically upstream of Akt/mTOR and RAB7A-mediated autophagy, multiple pathway readouts, single lab","pmids":["35813474"],"is_preprint":false},{"year":2023,"finding":"PRDX2 was identified as a downstream target of isorhapontigenin (ISO) in diabetic cardiac microvascular dysfunction; endothelial-specific overexpression of PRDX2 inhibits ferroptosis by suppressing oxidative stress, iron overload, and lipid peroxidation. PRDX2 mediates its anti-ferroptotic effect via MFN2-dependent mitochondrial dynamics, and MFN2 overexpression suppresses mitochondrial translocation of ACSL4, inhibiting mitochondria-associated ferroptosis.","method":"Endothelial-specific PRDX2 overexpression in db/db mice, ACSL4/MFN2 overexpression/knockdown, lipid peroxidation and iron measurements, mitochondrial function assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression with mechanistic pathway dissection (PRDX2-MFN2-ACSL4), in vivo and in vitro, single lab","pmids":["36367849"],"is_preprint":false},{"year":2025,"finding":"PRDX2 activates the PI3K/AKT signaling pathway to enhance SP1 binding to the FN1 promoter (confirmed by dual luciferase reporter assay), driving FN1 expression and promoting TNBC cell migration, invasion, and EMT.","method":"RNA sequencing, Western blotting, dual luciferase reporter assay, PRDX2 knockdown, in vivo xenograft model, Conoidin A PRDX2 inhibitor treatment","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay and RNA-seq mechanistic dissection, in vivo validation, single lab","pmids":["40217291"],"is_preprint":false}],"current_model":"PRDX2 is a cytosolic 2-Cys peroxiredoxin that reduces H2O2 and lipid peroxides using a thioredoxin-dependent catalytic mechanism with an unusually slow resolution (disulfide formation) rate of ~0.2 s⁻¹ that allows its sulfenic acid intermediate to form transient mixed disulfides with partner proteins, enabling redox signal relay; in cells it controls ROS homeostasis to regulate thymocyte development, myeloid differentiation (via a CDK2-PRDX2 axis), HIF-1/2 transcriptional activity (by nuclear translocation and direct binding to HIF-α subunits independent of peroxidase activity), and p53 stability (by binding RPL4 to compete with MDM2), is transcriptionally induced by NF-κB-p65 in response to H. pylori infection and by prolonged hypoxia as a feedback brake, can be released in exosomes to promote osteoclastogenesis, and is epigenetically silenced by histone hypoacetylation and promoter hypermethylation in AML where its loss drives ROS-dependent leukemogenesis."},"narrative":{"mechanistic_narrative":"PRDX2 is a cytosolic thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydrogen peroxide and thereby governs intracellular ROS homeostasis, a role first established by its sequence homology to yeast thioredoxin peroxidase [PMID:7607688] and by loss-of-function studies showing that PRDX2 depletion or knockout raises ROS and sensitizes cells to oxidative apoptosis [PMID:12943237, PMID:15259009]. Its catalytic cycle is distinguished from that of PRDX1 by an unusually slow resolution (disulfide-formation) step (~0.2 s⁻¹ vs 11 s⁻¹), which prolongs the lifetime of the peroxidatic-cysteine sulfenic acid and permits formation of mixed disulfides with partner protein thiols, providing a biochemical basis for redox relay signaling [PMID:30284335]. Through its ROS-buffering activity PRDX2 controls thymocyte development and proliferation [PMID:15259009] and regulates innate/adaptive immune effectors including TLR4 and BAFF [PMID:18442801]. Beyond peroxidase chemistry, PRDX2 acts through direct protein interactions: it binds HIF-1α and HIF-2α and, upon nuclear translocation during prolonged hypoxia, blocks their binding to hypoxia-response elements independently of its enzymatic activity [PMID:26837221], and it binds RPL4 to displace MDM2, accelerating p53 ubiquitination and degradation to promote proliferation [PMID:34117220]. PRDX2 has context-dependent roles in cancer: it is an epigenetically silenced tumor suppressor in AML whose loss drives ROS-dependent myeloid leukemogenesis and which participates in a CDK2-PRDX2 differentiation-blocking axis [PMID:22207736, PMID:29720484], yet in solid tumors it acts as a pro-survival factor supporting PI3K/AKT signaling, EMT, and chemoresistance [PMID:28432271, PMID:40217291]. Its expression is transcriptionally driven by NF-κB-p65 during H. pylori infection [PMID:31536951] and modulated by DNMT3A mutations and the c-Myc/miR-200b-3p axis [PMID:30245403, PMID:29258530]. PRDX2 is also secreted in erythroid exosomes where extracellular PRDX2 promotes osteoclastogenesis [PMID:33587325].","teleology":[{"year":1995,"claim":"Established the molecular identity of PRDX2 as a thioredoxin-dependent peroxide reductase and placed it in the genome, defining the gene as an antioxidant enzyme.","evidence":"PCR cloning of human cDNA with sequence homology to yeast thioredoxin peroxidase, FISH and somatic cell hybrid mapping to 13q12","pmids":["7607688"],"confidence":"Medium","gaps":["No direct enzymatic assay of the human protein in this study","Cellular function not addressed"]},{"year":2003,"claim":"Showed that PRDX2 protects cells against oxidative death, moving from inferred enzymatic identity to a defined cytoprotective cellular role.","evidence":"Stable antisense knockdown in SH-SY5Y neuroblastoma cells with apoptosis and oxidative-stress sensitivity assays","pmids":["12943237"],"confidence":"Medium","gaps":["Antisense specificity limits mechanistic interpretation","Did not identify ROS targets or downstream signaling"]},{"year":2004,"claim":"Demonstrated in vivo that PRDX2 controls developmental and proliferative decisions through ROS, establishing it as a physiological ROS rheostat rather than a passive scavenger.","evidence":"PrxII-null mouse with flow cytometry of thymocyte subsets, apoptosis and proliferation readouts","pmids":["15259009"],"confidence":"High","gaps":["Direct molecular ROS targets in thymocytes not defined","Did not distinguish enzymatic from non-enzymatic contributions"]},{"year":2008,"claim":"Extended PRDX2's ROS-control role to immune effector regulation, linking it to TLR4/BAFF expression and allergic airway pathology.","evidence":"PrxII-null mouse splenocytes/macrophages, qRT-PCR, BAFF promoter assay, OVA-induced asthma model","pmids":["18442801"],"confidence":"Medium","gaps":["Mechanism connecting ROS to TLR4/BAFF transcription unresolved","Single knockout model"]},{"year":2011,"claim":"Resolved PRDX2's tumor-suppressor function in AML and its epigenetic silencing, explaining how its loss enables ROS-driven leukemogenesis.","evidence":"ChIP-on-microarray for H3Ac, bisulfite sequencing, forced expression in bone marrow transplant mouse model with ROS measurement","pmids":["22207736"],"confidence":"High","gaps":["Did not define which ROS-dependent c-Myc effectors are restrained","Did not address PRDX2 protein partners in myeloid cells"]},{"year":2011,"claim":"Defined the native oligomeric and complex states of PRDX2 and its stress-induced redistribution, linking quaternary structure to peroxidase function in erythrocytes.","evidence":"Proteomics, native PAGE, mass spectrometry and peroxidase assays on erythrocyte cytosol and membrane fractions","pmids":["21354257"],"confidence":"Medium","gaps":["Functional consequence of catalase association not tested mechanistically","Membrane translocation trigger not isolated"]},{"year":2016,"claim":"Uncovered a non-enzymatic moonlighting function: PRDX2 directly inhibits HIF transcriptional activity in the nucleus, decoupling a signaling role from peroxidase chemistry.","evidence":"Reciprocal Co-IP, ChIP, nuclear fractionation and catalytic-site mutagenesis in hypoxic HeLa cells","pmids":["26837221"],"confidence":"High","gaps":["Mechanism of nuclear translocation not defined","Structural basis of HIF-α binding unknown"]},{"year":2017,"claim":"Placed PRDX2 upstream of PI3K/AKT survival signaling and within a c-Myc/miR-200b-3p regulatory loop, framing its pro-tumor role in colon cancer.","evidence":"shRNA knockdown/overexpression with Western blotting, xenografts; luciferase miRNA target validation and c-Myc ChIP","pmids":["28432271","29258530"],"confidence":"Medium","gaps":["Direct mechanism linking PRDX2 to AKT activation not defined","Whether AKT effect is enzymatic or via protein interaction untested"]},{"year":2018,"claim":"Established the kinetic basis for redox relay — PRDX2's slow resolution step lets its sulfenic intermediate form mixed disulfides with partner proteins, distinguishing it mechanistically from PRDX1.","evidence":"In vitro kinetics with recombinant PRDX1/PRDX2, intrinsic fluorescence and rate-constant determination for H2O2 and peroxynitrite","pmids":["30284335"],"confidence":"High","gaps":["Specific physiological relay partners not identified in this assay","Cellular validation of mixed-disulfide transfer not shown"]},{"year":2018,"claim":"Connected PRDX2 to CDK2 and DNMT3A in myeloid cells, identifying physical interactions and regulatory inputs that modulate PRDX2 levels/activity to control differentiation and survival.","evidence":"Yeast 2-hybrid and Co-IP, knockdown/inhibitor studies, methylation analysis, xenograft/PDX models","pmids":["29720484","30245403"],"confidence":"Medium","gaps":["Whether CDK2 phosphorylates PRDX2 not shown","Functional consequence of DNMT3A-PRDX2 binding beyond expression unclear"]},{"year":2019,"claim":"Revealed nuclear/DNA-damage roles: PRDX2 is recruited to double-strand breaks via REV7 and its expression is driven by NF-κB-p65 in infection, linking PRDX2 to genome-protective ROS control.","evidence":"Proteomics, reciprocal Co-IP, immunofluorescence, γH2AX foci; luciferase and ChIP for NF-κB-p65 with 8-oxoguanine/γH2AX assays in H. pylori models","pmids":["30657231","31536951"],"confidence":"High","gaps":["Mechanism by which PRDX2 acts at DSBs not defined","Whether PRDX2 enzymatic activity is required at breaks untested"]},{"year":2020,"claim":"Positioned PRDX2 upstream of p38 MAPK/FOXO and autophagy/cell-cycle control in colorectal cancer, broadening its signaling reach.","evidence":"shRNA knockdown, electron microscopy, p38 activator rescue, xenograft model","pmids":["32692719"],"confidence":"Medium","gaps":["Direct molecular link from PRDX2 to p38 activation not defined","Single cancer context"]},{"year":2021,"claim":"Identified a non-enzymatic oncogenic mechanism (RPL4 binding displacing MDM2 to degrade p53) and an extracellular exosomal function promoting osteoclastogenesis, expanding PRDX2 beyond intracellular antioxidant chemistry.","evidence":"Co-IP and competitive displacement assays for RPL4-MDM2-p53; exosome inhibition and recombinant PRDX2 osteoclast assays with anemia mouse model","pmids":["34117220","33587325"],"confidence":"Medium","gaps":["Structural basis of RPL4 binding not resolved","Receptor/mechanism of extracellular PRDX2 osteoclast induction unknown"]},{"year":2023,"claim":"Linked PRDX2 to ferroptosis suppression via MFN2-dependent mitochondrial dynamics, defining a protective role in diabetic vascular dysfunction.","evidence":"Endothelial-specific PRDX2 overexpression in db/db mice with ACSL4/MFN2 manipulation and lipid peroxidation/iron assays","pmids":["36367849"],"confidence":"Medium","gaps":["Direct biochemical interaction of PRDX2 with MFN2 not shown","Whether effect requires peroxidase activity untested"]},{"year":2025,"claim":"Showed PRDX2 drives EMT and metastasis in TNBC through PI3K/AKT-dependent SP1 activation of FN1, reinforcing its pro-metastatic role in solid tumors.","evidence":"RNA-seq, dual luciferase reporter, knockdown, Conoidin A inhibitor, xenograft model","pmids":["40217291"],"confidence":"Medium","gaps":["Mechanism by which PRDX2 activates PI3K/AKT not resolved","Whether redox relay underlies SP1 activation untested"]},{"year":null,"claim":"The physiological redox-relay partners that receive PRDX2's mixed-disulfide signal in cells, and a unifying explanation for its opposing tumor-suppressor (AML) versus pro-tumor (solid cancer) roles, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cellular redox-relay partner identified despite established kinetic capacity","Context-determinants of tumor-suppressor vs oncogenic behavior unknown","Structural models for non-enzymatic HIF-α and RPL4 binding lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,1,2,4,10]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,15,20]}],"complexes":["PRDX2-catalase 440 kDa hetero-oligomer","REV7-PRDX2 complex"],"partners":["CAT","HIF1A","EPAS1","RPL4","MDM2","CDK2","DNMT3A","REV7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P32119","full_name":"Peroxiredoxin-2","aliases":["Natural killer cell-enhancing factor B","NKEF-B","PRP","Thiol-specific antioxidant protein","TSA","Thioredoxin peroxidase 1","Thioredoxin-dependent peroxide reductase 1","Thioredoxin-dependent peroxiredoxin 2"],"length_aa":198,"mass_kda":21.9,"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. 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Promotes Intrahepatic Cholangiocarcinoma Possibly through Inducing PRDX2/PI3K/AKT Axis.","date":"2020","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33017884","citation_count":23,"is_preprint":false},{"pmid":"30814580","id":"PMC_30814580","title":"TSA restores hair follicle-inductive capacity of skin-derived precursors.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30814580","citation_count":23,"is_preprint":false},{"pmid":"9551972","id":"PMC_9551972","title":"Characterization and mapping to human chromosome 8q24.3 of Ly-6-related gene 9804 encoding an apparent homologue of mouse TSA-1.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9551972","citation_count":23,"is_preprint":false},{"pmid":"32130676","id":"PMC_32130676","title":"PRDX2 plays an oncogenic role in esophageal squamous cell carcinoma via Wnt/β-catenin and AKT 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the involvement of Prdx1 and Prdx2 in the severity of beta thalassemia.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30521599","citation_count":20,"is_preprint":false},{"pmid":"24730998","id":"PMC_24730998","title":"Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats.","date":"2014","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24730998","citation_count":19,"is_preprint":false},{"pmid":"18770747","id":"PMC_18770747","title":"Tyramide signal amplification (TSA) systems for the enhancement of ISH signals in cytogenetics.","date":"2001","source":"Current protocols in cytometry","url":"https://pubmed.ncbi.nlm.nih.gov/18770747","citation_count":19,"is_preprint":false},{"pmid":"25363222","id":"PMC_25363222","title":"Prevention of Pulmonary Fibrosis via Trichostatin A (TSA) in Bleomycin Induced Rats.","date":"2014","source":"Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG","url":"https://pubmed.ncbi.nlm.nih.gov/25363222","citation_count":19,"is_preprint":false},{"pmid":"6309870","id":"PMC_6309870","title":"Cell growth and differentiation in vitro in mouse macrophages transformed by a tsA mutant of simian virus 40. I. Cellular response in proliferative and phagocytic activities to the shift of temperature differs depending on the culture state in mouse bone marrow cells transformed by the tsA640 mutant of simian virus 40.","date":"1983","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/6309870","citation_count":19,"is_preprint":false},{"pmid":"33791345","id":"PMC_33791345","title":"PRDX2 Protects Against Atherosclerosis by Regulating the Phenotype and Function of the Vascular Smooth Muscle Cell.","date":"2021","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33791345","citation_count":18,"is_preprint":false},{"pmid":"16455503","id":"PMC_16455503","title":"[Histone-deacetylases inhibitors: from TSA to SAHA].","date":"2006","source":"Bulletin du cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16455503","citation_count":18,"is_preprint":false},{"pmid":"25319599","id":"PMC_25319599","title":"Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant β-blockers in the cardiovascular systems of spontaneously hypertensive rats.","date":"2014","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/25319599","citation_count":18,"is_preprint":false},{"pmid":"17110788","id":"PMC_17110788","title":"TSA-induced cell death in prostate cancer cell lines is caspase-2 dependent and involves the PIDDosome.","date":"2006","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17110788","citation_count":18,"is_preprint":false},{"pmid":"25471491","id":"PMC_25471491","title":"Mapping of single-copy genes by TSA-FISH in the codling moth, Cydia pomonella.","date":"2014","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25471491","citation_count":18,"is_preprint":false},{"pmid":"36819780","id":"PMC_36819780","title":"Overexpression of PRDX2 in Adipose-Derived Mesenchymal Stem Cells Enhances the Therapeutic Effect in a Neurogenic Erectile Dysfunction Rat Model by Inhibiting Ferroptosis.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36819780","citation_count":17,"is_preprint":false},{"pmid":"31807984","id":"PMC_31807984","title":"Prdx2 Upregulation Promotes the Growth and Survival of Gastric Cancer Cells.","date":"2019","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/31807984","citation_count":16,"is_preprint":false},{"pmid":"29036266","id":"PMC_29036266","title":"Alterations in NO/ROS ratio and expression of Trx1 and Prdx2 in isoproterenol-induced cardiac hypertrophy.","date":"2017","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/29036266","citation_count":15,"is_preprint":false},{"pmid":"16631079","id":"PMC_16631079","title":"Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor alpha7 subtype 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(FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by FISH and functional homology established by sequence analysis, single lab\",\n      \"pmids\": [\"7607688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Down-regulation of PRDX2 in SH-SY5Y neuroblastoma cells via stable antisense transfection increased apoptosis under basal conditions and enhanced sensitivity to oxidative cytotoxic agents, demonstrating PRDX2's role in protecting neurons from reactive oxygen species.\",\n      \"method\": \"Stable antisense transfection, cell viability assays, comparison with SOD1 overexpression\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined phenotypic readout (apoptosis, oxidative stress sensitivity), single lab\",\n      \"pmids\": [\"12943237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Deletion of the PrxII (PRDX2) gene in mice increases ROS levels in thymocytes, reduces apoptosis (hypodiploid cell formation), enlarges the thymus, and alters the SP/DP thymocyte ratio, establishing PRDX2 as a regulator of thymocyte development and proliferation through ROS control.\",\n      \"method\": \"PrxII-null mouse model, flow cytometry, dexamethasone and food restriction treatments, concanavalin A stimulation assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple orthogonal phenotypic readouts (apoptosis, proliferation, ROS levels, thymocyte subsets), multiple experimental conditions\",\n      \"pmids\": [\"15259009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PRDX2 promoter has decreased histone H3 acetylation and DNA hypermethylation in AML, leading to low PRDX2 expression; forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo and reduced ROS generated in response to cytokines, identifying PRDX2 as an epigenetically silenced tumor suppressor in AML that limits ROS-driven myeloid cell growth.\",\n      \"method\": \"ChIP-on-microarray (H3Ac), bisulfite sequencing (DNA methylation), forced PRDX2 expression with bone marrow transplantation mouse model, ROS measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, methylation analysis, in vivo transplantation model, and functional ROS assay in single study\",\n      \"pmids\": [\"22207736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In human erythrocytes, PRDX2 forms multiple oligomeric states (decamers and homo-polymers) in the cytosol and associates with catalase (CAT) in a 440 kDa hetero-oligomeric complex; upon oxidative stress (28-day storage), PRDX2 translocates to the membrane and forms cross-linked species with hemoglobin. Both the 440 kDa and 140 kDa complexes exhibit peroxidase activity.\",\n      \"method\": \"Proteomics, 2D gel electrophoresis, native PAGE, mass spectrometry, peroxidase activity assays on fractionated cytosol and membrane ghosts\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical fractionation and activity assays, single lab\",\n      \"pmids\": [\"21354257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRDX2 interacts with HIF-1α and HIF-2α in vitro and in hypoxic HeLa cells; prolonged hypoxia increases nuclear translocation of PRDX2, where it impairs HIF-1 and HIF-2 binding to hypoxia response elements of target genes, inhibiting their transcription. This effect is independent of PRDX2 enzymatic peroxidase activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, nuclear fractionation, gene reporter assays, mutagenesis of catalytic site\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP demonstrating impaired HIF binding, nuclear fractionation showing translocation, enzymatic activity mutant ruling out peroxidase mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26837221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRDX2 knockdown in colon cancer cells reduces PI3K/AKT pathway activation (decreased p-AKT); PRDX2 overexpression increases p-AKT and alters Bcl-2/Bax ratio, placing PRDX2 upstream of the PI3K/AKT survival pathway in 5-FU chemoresistance.\",\n      \"method\": \"shRNA knockdown, Western blotting, in vivo xenograft model, immunohistochemistry correlation\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function and gain-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"28432271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRDX2 is a direct target of miR-200b-3p (validated by luciferase reporter assay); c-Myc represses miR-200b-3p transcription by binding its promoter (ChIP assay); PRDX2 overexpression rescues the suppressive effects of miR-200b-3p on CRC invasion, EMT, and chemoresistance, establishing a c-Myc/miR-200b-3p/PRDX2 regulatory loop.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, Western blotting, invasion assay, metastatic mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of miRNA target, ChIP for c-Myc binding, rescue experiment, single lab\",\n      \"pmids\": [\"29258530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX2 is a direct substrate/interactor of CDK2 in AML; CDK2 depletion leads to ubiquitin-dependent proteasomal degradation of CDK2 (mediated by E3 ligase KLHL6) and reactivates differentiation; CDK2 maintains its differentiation-blocking function at least in part by maintaining PRDX2 activity, establishing a CDK2-PRDX2 axis that blocks AML differentiation.\",\n      \"method\": \"Yeast 2-hybrid system, functional analyses, CDK2 knockdown/inhibitor studies, in vivo xenograft and PDX mouse models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast 2-hybrid interaction plus functional rescue experiments, multiple AML subtypes tested, in vivo validation, single lab\",\n      \"pmids\": [\"29720484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNMT3A-R882H/C mutations upregulate PRDX2 expression through promoter hypomethylation, reducing ROS accumulation and impairing apoptosis. Both DNMT3A-WT and R882H/C mutants physically interact with PRDX2. Knockdown of PRDX2 from DNMT3A-mutant myeloid cells increases ROS, drug sensitivity, and apoptosis.\",\n      \"method\": \"Gene expression profiling, DNA methylation assay, PRDX2 knockdown, ROS measurement, co-immunoprecipitation\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction plus methylation/expression analysis plus functional knockdown, single lab\",\n      \"pmids\": [\"30245403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Differential kinetics between PRDX1 and PRDX2: the rate of disulfide formation (resolution step) is 11 s⁻¹ for PRDX1 vs 0.2 s⁻¹ for PRDX2, independent of oxidant. This slower resolution in PRDX2 allows its sulfenic acid intermediate to react with other protein thiols (forming mixed disulfides via the peroxidatic cysteine) to relay redox signals, whereas PRDX1 forms an intramolecular disulfide and continues the catalytic cycle.\",\n      \"method\": \"In vitro kinetic assays with recombinant human PRDX1 and PRDX2, intrinsic fluorescence measurements, rate constant determination for H2O2 and peroxynitrite reactions\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro assay with recombinant proteins, quantitative rate constants determined for multiple reactions, mechanistically distinguishes PRDX1 vs PRDX2 catalytic cycle\",\n      \"pmids\": [\"30284335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"REV7 physically interacts with PRDX2 (validated by immunoprecipitation and immunofluorescence); the REV7-PRDX2 complex is augmented post-irradiation and assembles onto DNA double-strand breaks; REV7 knockdown disrupts nuclear PRDX2 localization post-irradiation, leading to increased oxidative stress and radiosensitization of esophageal cancer cells.\",\n      \"method\": \"Proteomic analysis of REV7-interacting proteins, co-immunoprecipitation, immunofluorescence, γH2AX focus assay, ROS measurement, xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence colocalization, nuclear localization linked to functional consequence, single lab\",\n      \"pmids\": [\"30657231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF-κB-p65 directly binds the PRDX2 promoter (confirmed by luciferase reporter and ChIP assays) and drives PRDX2 upregulation in response to H. pylori infection; PRDX2 knockdown increases ROS, oxidative DNA damage (8-oxoguanine), and double-strand breaks (γ-H2AX), and sensitizes gastric cancer cells to cisplatin.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, H2DCFDA ROS assay, 8-oxoguanine immunostaining, γ-H2AX detection, in vitro and in vivo H. pylori infection models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and luciferase reporter establish direct transcriptional regulation by NF-κB-p65; multiple orthogonal functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"31536951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Silica treatment triggers rapid degradation of PrxII (PRDX2) in Rat2 cells through a Ca²⁺-dependent protease (likely calpain), independent of ROS and proteasomal activity (insensitive to MG132 and lactacystin), thereby aggravating cellular oxidative stress.\",\n      \"method\": \"Western blotting, protease inhibitor studies (MG132, lactacystin), Ca²⁺ ionophore treatment, NAC and DPI inhibitor experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor dissection of degradation pathway with multiple negative controls, single lab\",\n      \"pmids\": [\"10558905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In PrxII-null mouse splenocytes and macrophages, TLR4 protein is decreased compared to wild-type, and BAFF expression and BAFF promoter activity are elevated. PrxII-null mice show more severe airway hyper-responsiveness in OVA-induced asthma. This establishes PRDX2 as a regulator of TLR4 and BAFF expression through ROS control.\",\n      \"method\": \"PrxII-null mouse model, real-time quantitative RT-PCR, BAFF promoter activity assay, airway hyper-responsiveness measurements, eosinophil and IgE quantification\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple immune readouts and promoter activity assay, single lab\",\n      \"pmids\": [\"18442801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX2 binds RPL4 (ribosomal protein L4), reducing the interaction between RPL4 and MDM2; this leads to increased MDM2-mediated ubiquitination and degradation of p53, thereby promoting colorectal cancer cell proliferation. PRDX2 thus acts as an oncogenic regulator of the RPL4-MDM2-p53 axis.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, PRDX2 knockdown and overexpression, proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying RPL4 interaction and competitive displacement of MDM2-RPL4 complex, functional rescue experiment, single lab\",\n      \"pmids\": [\"34117220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX2 is released by erythroid cells in exosomes; inhibiting exosomal release significantly decreases the osteoclastogenic capacity of erythroid conditioned medium. Recombinant PRDX2 directly induces osteoclast formation from RANKL-primed precursors to levels comparable to continuous RANKL treatment, establishing an extracellular/exosomal function of PRDX2 in promoting osteoclastogenesis.\",\n      \"method\": \"Immunoblotting, mass spectrometry, exosomal inhibitor treatment, recombinant PRDX2 addition to RAW264.7 and primary bone marrow precursors, phlebotomy-induced anemia mouse model\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein functional assay plus exosomal inhibition experiment plus in vivo correlation, single lab\",\n      \"pmids\": [\"33587325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX2 removal in colorectal cancer cells inhibits S-phase progression and activates p38 MAPK, leading to autophagy flux disruption. The p38 MAPK activator partially rescues the cell-cycle and autophagy phenotypes of PRDX2 knockdown, placing PRDX2 upstream of p38 MAPK/FOXO signaling in CRC cell-cycle and autophagy regulation.\",\n      \"method\": \"shRNA knockdown, electron microscopy, immunostaining, Western blotting, p38 activator rescue experiment, xenograft model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with defined cellular phenotypes, pharmacological rescue placing PRDX2 in pathway, single lab\",\n      \"pmids\": [\"32692719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRDX2 knockdown in colorectal cancer cells sensitizes them to dihydroartemisinin (DHA) by increasing ROS levels; mechanistically, DHA inhibits PRDX2 expression to elevate ROS, which activates ER stress, STAT3, JNK, and p38 signaling pathways, enhancing the anti-tumor activity of oxaliplatin.\",\n      \"method\": \"PRDX2 knockdown, ROS measurement, Western blotting, flow cytometry, in vivo mouse xenograft model\",\n      \"journal\": \"Phytomedicine : international journal of phytotherapy and phytopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with pathway readout, mechanistic link between DHA and PRDX2 established by indirect evidence only, single lab\",\n      \"pmids\": [\"35104762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Oxiconazole downregulates PRDX2 protein levels, leading to ROS accumulation that inactivates the Akt/mTOR pathway and inhibits RAB7A-mediated autophagosome-lysosome fusion, causing autophagy arrest and CRC cell death. Overexpression of PRDX2 significantly impedes oxiconazole-induced autophagy arrest.\",\n      \"method\": \"PRDX2 overexpression rescue, Western blotting, flow cytometry, Akt/mTOR pathway analysis, RAB7A colocalization assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PRDX2 overexpression rescue places PRDX2 mechanistically upstream of Akt/mTOR and RAB7A-mediated autophagy, multiple pathway readouts, single lab\",\n      \"pmids\": [\"35813474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRDX2 was identified as a downstream target of isorhapontigenin (ISO) in diabetic cardiac microvascular dysfunction; endothelial-specific overexpression of PRDX2 inhibits ferroptosis by suppressing oxidative stress, iron overload, and lipid peroxidation. PRDX2 mediates its anti-ferroptotic effect via MFN2-dependent mitochondrial dynamics, and MFN2 overexpression suppresses mitochondrial translocation of ACSL4, inhibiting mitochondria-associated ferroptosis.\",\n      \"method\": \"Endothelial-specific PRDX2 overexpression in db/db mice, ACSL4/MFN2 overexpression/knockdown, lipid peroxidation and iron measurements, mitochondrial function assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression with mechanistic pathway dissection (PRDX2-MFN2-ACSL4), in vivo and in vitro, single lab\",\n      \"pmids\": [\"36367849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRDX2 activates the PI3K/AKT signaling pathway to enhance SP1 binding to the FN1 promoter (confirmed by dual luciferase reporter assay), driving FN1 expression and promoting TNBC cell migration, invasion, and EMT.\",\n      \"method\": \"RNA sequencing, Western blotting, dual luciferase reporter assay, PRDX2 knockdown, in vivo xenograft model, Conoidin A PRDX2 inhibitor treatment\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay and RNA-seq mechanistic dissection, in vivo validation, single lab\",\n      \"pmids\": [\"40217291\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX2 is a cytosolic 2-Cys peroxiredoxin that reduces H2O2 and lipid peroxides using a thioredoxin-dependent catalytic mechanism with an unusually slow resolution (disulfide formation) rate of ~0.2 s⁻¹ that allows its sulfenic acid intermediate to form transient mixed disulfides with partner proteins, enabling redox signal relay; in cells it controls ROS homeostasis to regulate thymocyte development, myeloid differentiation (via a CDK2-PRDX2 axis), HIF-1/2 transcriptional activity (by nuclear translocation and direct binding to HIF-α subunits independent of peroxidase activity), and p53 stability (by binding RPL4 to compete with MDM2), is transcriptionally induced by NF-κB-p65 in response to H. pylori infection and by prolonged hypoxia as a feedback brake, can be released in exosomes to promote osteoclastogenesis, and is epigenetically silenced by histone hypoacetylation and promoter hypermethylation in AML where its loss drives ROS-dependent leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRDX2 is a cytosolic thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydrogen peroxide and thereby governs intracellular ROS homeostasis, a role first established by its sequence homology to yeast thioredoxin peroxidase [#0] and by loss-of-function studies showing that PRDX2 depletion or knockout raises ROS and sensitizes cells to oxidative apoptosis [#1, #2]. Its catalytic cycle is distinguished from that of PRDX1 by an unusually slow resolution (disulfide-formation) step (~0.2 s⁻¹ vs 11 s⁻¹), which prolongs the lifetime of the peroxidatic-cysteine sulfenic acid and permits formation of mixed disulfides with partner protein thiols, providing a biochemical basis for redox relay signaling [#10]. Through its ROS-buffering activity PRDX2 controls thymocyte development and proliferation [#2] and regulates innate/adaptive immune effectors including TLR4 and BAFF [#14]. Beyond peroxidase chemistry, PRDX2 acts through direct protein interactions: it binds HIF-1α and HIF-2α and, upon nuclear translocation during prolonged hypoxia, blocks their binding to hypoxia-response elements independently of its enzymatic activity [#5], and it binds RPL4 to displace MDM2, accelerating p53 ubiquitination and degradation to promote proliferation [#15]. PRDX2 has context-dependent roles in cancer: it is an epigenetically silenced tumor suppressor in AML whose loss drives ROS-dependent myeloid leukemogenesis and which participates in a CDK2-PRDX2 differentiation-blocking axis [#3, #8], yet in solid tumors it acts as a pro-survival factor supporting PI3K/AKT signaling, EMT, and chemoresistance [#6, #21]. Its expression is transcriptionally driven by NF-κB-p65 during H. pylori infection [#12] and modulated by DNMT3A mutations and the c-Myc/miR-200b-3p axis [#9, #7]. PRDX2 is also secreted in erythroid exosomes where extracellular PRDX2 promotes osteoclastogenesis [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of PRDX2 as a thioredoxin-dependent peroxide reductase and placed it in the genome, defining the gene as an antioxidant enzyme.\",\n      \"evidence\": \"PCR cloning of human cDNA with sequence homology to yeast thioredoxin peroxidase, FISH and somatic cell hybrid mapping to 13q12\",\n      \"pmids\": [\"7607688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic assay of the human protein in this study\", \"Cellular function not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that PRDX2 protects cells against oxidative death, moving from inferred enzymatic identity to a defined cytoprotective cellular role.\",\n      \"evidence\": \"Stable antisense knockdown in SH-SY5Y neuroblastoma cells with apoptosis and oxidative-stress sensitivity assays\",\n      \"pmids\": [\"12943237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antisense specificity limits mechanistic interpretation\", \"Did not identify ROS targets or downstream signaling\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in vivo that PRDX2 controls developmental and proliferative decisions through ROS, establishing it as a physiological ROS rheostat rather than a passive scavenger.\",\n      \"evidence\": \"PrxII-null mouse with flow cytometry of thymocyte subsets, apoptosis and proliferation readouts\",\n      \"pmids\": [\"15259009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular ROS targets in thymocytes not defined\", \"Did not distinguish enzymatic from non-enzymatic contributions\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended PRDX2's ROS-control role to immune effector regulation, linking it to TLR4/BAFF expression and allergic airway pathology.\",\n      \"evidence\": \"PrxII-null mouse splenocytes/macrophages, qRT-PCR, BAFF promoter assay, OVA-induced asthma model\",\n      \"pmids\": [\"18442801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ROS to TLR4/BAFF transcription unresolved\", \"Single knockout model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved PRDX2's tumor-suppressor function in AML and its epigenetic silencing, explaining how its loss enables ROS-driven leukemogenesis.\",\n      \"evidence\": \"ChIP-on-microarray for H3Ac, bisulfite sequencing, forced expression in bone marrow transplant mouse model with ROS measurement\",\n      \"pmids\": [\"22207736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which ROS-dependent c-Myc effectors are restrained\", \"Did not address PRDX2 protein partners in myeloid cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the native oligomeric and complex states of PRDX2 and its stress-induced redistribution, linking quaternary structure to peroxidase function in erythrocytes.\",\n      \"evidence\": \"Proteomics, native PAGE, mass spectrometry and peroxidase assays on erythrocyte cytosol and membrane fractions\",\n      \"pmids\": [\"21354257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of catalase association not tested mechanistically\", \"Membrane translocation trigger not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a non-enzymatic moonlighting function: PRDX2 directly inhibits HIF transcriptional activity in the nucleus, decoupling a signaling role from peroxidase chemistry.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, nuclear fractionation and catalytic-site mutagenesis in hypoxic HeLa cells\",\n      \"pmids\": [\"26837221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear translocation not defined\", \"Structural basis of HIF-α binding unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed PRDX2 upstream of PI3K/AKT survival signaling and within a c-Myc/miR-200b-3p regulatory loop, framing its pro-tumor role in colon cancer.\",\n      \"evidence\": \"shRNA knockdown/overexpression with Western blotting, xenografts; luciferase miRNA target validation and c-Myc ChIP\",\n      \"pmids\": [\"28432271\", \"29258530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking PRDX2 to AKT activation not defined\", \"Whether AKT effect is enzymatic or via protein interaction untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the kinetic basis for redox relay — PRDX2's slow resolution step lets its sulfenic intermediate form mixed disulfides with partner proteins, distinguishing it mechanistically from PRDX1.\",\n      \"evidence\": \"In vitro kinetics with recombinant PRDX1/PRDX2, intrinsic fluorescence and rate-constant determination for H2O2 and peroxynitrite\",\n      \"pmids\": [\"30284335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific physiological relay partners not identified in this assay\", \"Cellular validation of mixed-disulfide transfer not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected PRDX2 to CDK2 and DNMT3A in myeloid cells, identifying physical interactions and regulatory inputs that modulate PRDX2 levels/activity to control differentiation and survival.\",\n      \"evidence\": \"Yeast 2-hybrid and Co-IP, knockdown/inhibitor studies, methylation analysis, xenograft/PDX models\",\n      \"pmids\": [\"29720484\", \"30245403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDK2 phosphorylates PRDX2 not shown\", \"Functional consequence of DNMT3A-PRDX2 binding beyond expression unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed nuclear/DNA-damage roles: PRDX2 is recruited to double-strand breaks via REV7 and its expression is driven by NF-κB-p65 in infection, linking PRDX2 to genome-protective ROS control.\",\n      \"evidence\": \"Proteomics, reciprocal Co-IP, immunofluorescence, γH2AX foci; luciferase and ChIP for NF-κB-p65 with 8-oxoguanine/γH2AX assays in H. pylori models\",\n      \"pmids\": [\"30657231\", \"31536951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PRDX2 acts at DSBs not defined\", \"Whether PRDX2 enzymatic activity is required at breaks untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned PRDX2 upstream of p38 MAPK/FOXO and autophagy/cell-cycle control in colorectal cancer, broadening its signaling reach.\",\n      \"evidence\": \"shRNA knockdown, electron microscopy, p38 activator rescue, xenograft model\",\n      \"pmids\": [\"32692719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from PRDX2 to p38 activation not defined\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a non-enzymatic oncogenic mechanism (RPL4 binding displacing MDM2 to degrade p53) and an extracellular exosomal function promoting osteoclastogenesis, expanding PRDX2 beyond intracellular antioxidant chemistry.\",\n      \"evidence\": \"Co-IP and competitive displacement assays for RPL4-MDM2-p53; exosome inhibition and recombinant PRDX2 osteoclast assays with anemia mouse model\",\n      \"pmids\": [\"34117220\", \"33587325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of RPL4 binding not resolved\", \"Receptor/mechanism of extracellular PRDX2 osteoclast induction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PRDX2 to ferroptosis suppression via MFN2-dependent mitochondrial dynamics, defining a protective role in diabetic vascular dysfunction.\",\n      \"evidence\": \"Endothelial-specific PRDX2 overexpression in db/db mice with ACSL4/MFN2 manipulation and lipid peroxidation/iron assays\",\n      \"pmids\": [\"36367849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical interaction of PRDX2 with MFN2 not shown\", \"Whether effect requires peroxidase activity untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PRDX2 drives EMT and metastasis in TNBC through PI3K/AKT-dependent SP1 activation of FN1, reinforcing its pro-metastatic role in solid tumors.\",\n      \"evidence\": \"RNA-seq, dual luciferase reporter, knockdown, Conoidin A inhibitor, xenograft model\",\n      \"pmids\": [\"40217291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRDX2 activates PI3K/AKT not resolved\", \"Whether redox relay underlies SP1 activation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological redox-relay partners that receive PRDX2's mixed-disulfide signal in cells, and a unifying explanation for its opposing tumor-suppressor (AML) versus pro-tumor (solid cancer) roles, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cellular redox-relay partner identified despite established kinetic capacity\", \"Context-determinants of tumor-suppressor vs oncogenic behavior unknown\", \"Structural models for non-enzymatic HIF-α and RPL4 binding lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 1, 2, 4, 10]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 15, 20]}\n    ],\n    \"complexes\": [\"PRDX2-catalase 440 kDa hetero-oligomer\", \"REV7-PRDX2 complex\"],\n    \"partners\": [\"CAT\", \"HIF1A\", \"EPAS1\", \"RPL4\", \"MDM2\", \"CDK2\", \"DNMT3A\", \"REV7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}