{"gene":"PRDX6","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2000,"finding":"PRDX6 (1-Cys peroxiredoxin) is a bifunctional enzyme with two distinct active sites: Ser32 in the GDSWG motif serves as the catalytic nucleophile for phospholipase A2 (aiPLA2) activity, while Cys47 in the PVCTTE motif is the active site for glutathione peroxidase (NSGPx) activity. Mutation S32A abolishes PLA2 activity without affecting peroxidase; C47S abolishes peroxidase without affecting PLA2. The enzyme exhibits Ca2+-independent PLA2 activity at acidic pH and GSH peroxidase activity at alkaline pH.","method":"Site-directed mutagenesis (S32A, C47S), E. coli recombinant expression, in vitro enzymatic assays, inhibitor studies (MJ33, mercaptosuccinate, antibody epitope mapping)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro with mutagenesis of both active sites, multiple orthogonal inhibitors, replicated across studies","pmids":["10893423"],"is_preprint":false},{"year":2004,"finding":"Activation of 1-Cys peroxiredoxin (PRDX6) requires heterodimerization with pi GST (GSTπ). Oxidized Cys47 in PRDX6 is glutathionylated via GSTπ loaded with GSH, followed by spontaneous reduction of the mixed disulfide, restoring peroxidase activity. Maximum activation occurs at a 1:1 molar ratio of GSH-saturated GSTπ to PRDX6.","method":"Partial and homogeneous purification, in vitro heterodimerization assay, liposome-mediated delivery into cells lacking endogenous PRDX6 or GSTπ, biochemical activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted in vitro with defined stoichiometry, validated in cells with and without endogenous GSTπ, multiple orthogonal methods","pmids":["15004285"],"is_preprint":false},{"year":2002,"finding":"Antisense-mediated knockdown of 1-Cys peroxiredoxin (PRDX6) in rat lung epithelial (L2) cells leads to accumulation of phosphatidylcholine hydroperoxides in plasma membranes, lipid peroxidation, and apoptotic cell death (annexin V/PI staining, TUNEL). These effects were rescued by adenoviral overexpression of PRDX6 or vitamin E analogue pretreatment, establishing PRDX6 as a functional antioxidant that prevents phospholipid hydroperoxide accumulation and apoptosis in intact cells.","method":"Antisense morpholino oligonucleotide knockdown, immunoblot, HPLC conjugated diene assay, DPPP fluorescence for lipid peroxidation, annexin V/PI staining, TUNEL, adenoviral rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined phenotypic readout plus adenoviral rescue, multiple orthogonal methods","pmids":["12372839"],"is_preprint":false},{"year":2002,"finding":"Stable overexpression of GFP-PRDX6 in NCI-H441 lung cells (lacking endogenous PRDX6) reduces H2O2 and t-butylhydroperoxide levels, decreases phosphatidylcholine hydroperoxide accumulation upon oxidant exposure, and protects against oxidant-induced plasma membrane damage (phosphatidylserine translocation) in a GSH-dependent manner.","method":"Stable transfection, 51Cr release cytotoxicity assay, TBARS, PCOOH HPLC assay, DPPP fluorescence, Annexin V-Cy3 staining, GSH depletion","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function in cell line lacking endogenous protein, multiple orthogonal phenotypic readouts, GSH dependence confirmed","pmids":["12193653"],"is_preprint":false},{"year":2008,"finding":"H2O2-induced hyperoxidation of PRDX6 Cys47 (to sulfinic acid) is irreversible in vivo (unlike 2-Cys Prxs) and paradoxically increases iPLA2 activity, causing G2/M cell cycle arrest associated with p53/p21 upregulation and cyclin B1 downregulation. C47A mutation abolishes both hyperoxidation and the H2O2-induced iPLA2 upregulation, demonstrating that Cys47 hyperoxidation is required for iPLA2 activation.","method":"H2O2 treatment, immunoblot with anti-sulfinic acid antibody, iPLA2 activity assay, site-directed mutagenesis (C47A, S32A, double mutant), cell cycle analysis by flow cytometry, Western blot for p53/p21/cyclin B1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis plus cellular assays, single lab but multiple orthogonal methods","pmids":["18826942"],"is_preprint":false},{"year":2005,"finding":"PRDX6 uses GSH as electron donor to reduce H2O2 and phospholipid hydroperoxides (rate constant ~3×10^6 M^-1 s^-1). Oxidation of Cys47 to sulfenic acid during catalysis requires piGST-catalyzed glutathionylation and GSH reduction to complete the enzymatic cycle. In vivo, Prdx6-null mice are more sensitive to hyperoxia and paraquat, whereas adenoviral overexpression protects mouse lungs.","method":"Kinetic in vitro assays, Prdx6-null mouse model, adenoviral overexpression in mice, hyperoxia and paraquat exposure models","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinetic characterization combined with knockout and overexpression mouse models, replicated mechanism","pmids":["15890616"],"is_preprint":false},{"year":2016,"finding":"PRDX6 binds to Noxa1 (NADPH oxidase activator 1) via its SH3 domain, stabilizes Noxa1, and supports Nox1-derived superoxide production and cell migration. Both the peroxidase (C47S) and lipase (S32A) mutants of PRDX6 fail to bind or stabilize Nox1 components, and the iPLA2 inhibitor MJ33 suppresses Nox1 activity, implicating the phospholipase activity in Nox1 regulation.","method":"Yeast two-hybrid screening, co-IP in overexpressing cells, Nox1 superoxide activity assay, PRDX6 knockdown/overexpression, mutant expression (C47S, S32A), MJ33 pharmacological inhibition, wound-closure migration assay","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed, multiple cell models, pharmacological and genetic loss-of-function, functional consequence in migration","pmids":["27094494"],"is_preprint":false},{"year":2015,"finding":"PRDX6 physically interacts with JAK2 (co-localization and co-immunoprecipitation in tumor tissues and lung cancer cells) and its overexpression activates the JAK2/STAT3 pathway, contributing to urethane-induced lung tumor development in transgenic mice. STAT3 DNA binding and CCL5 levels are also increased.","method":"PRDX6 transgenic mice, urethane carcinogenesis model, immunohistochemistry, co-immunoprecipitation, JAK2/STAT3 activity assays, STAT3 DNA binding assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus in vivo model, single lab, functional phenotype confirmed in transgenic mice","pmids":["25582888"],"is_preprint":false},{"year":2017,"finding":"Aberrant SUMO1 conjugation of PRDX6 at Lys122 and Lys142 reduces its cellular abundance and decreases both GSH-peroxidase and aiPLA2 activities. A K122/142R sumoylation-deficient mutant gains enhanced enzymatic activity (30% GPx, 37% aiPLA2 increases) and stability. Phosphorylation at T177 is required for optimal aiPLA2 activity. Both active sites (peroxidase and PLA2) are necessary for mutant PRDX6 function.","method":"Site-directed mutagenesis (K122R, K142R, K122/142R, T177A), Prdx6-/- LEC complementation, enzymatic activity assays, stability assays, TAT-fusion protein delivery, EGFP-Sumo1 co-expression","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis at identified sumoylation sites with quantitative activity readouts, validated in Prdx6-null cells, single lab but multiple orthogonal approaches","pmids":["28055018"],"is_preprint":false},{"year":2014,"finding":"Oxidative stress-induced aberrant SUMO1 conjugation reduces PRDX6 protein abundance and attenuates its transcription. SUMO1 modification of PRDX6 is associated with reduced Sp1 expression and impaired Sp1-mediated transactivation of the Prdx6 promoter. Delivery of SENP1 (SUMO-specific protease) reverses the loss of PRDX6 expression.","method":"Immunoblot, Prdx6-/- LECs, Sumo1-fused PRDX6 construct, CAT reporter gene assay, gel mobility shift assay, SENP1 delivery rescue experiments, aging lens analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple complementary assays in relevant cell model, single lab","pmids":["24910119"],"is_preprint":false},{"year":2019,"finding":"PRDX6 knockdown enhances lipid reactive oxygen species (LOOH) and ferroptotic cell death triggered by erastin and RSL-3. This effect correlates with transcriptional activation of heme oxygenase-1 (HO-1), and HO-1 overexpression enhances ferroptosis. The iPLA2 inhibitor MJ33 synergistically enhances erastin-induced ferroptosis, indicating PRDX6 removes LOOH through its iPLA2 activity to protect against ferroptosis.","method":"PRDX6 siRNA knockdown, overexpression, ferroptosis inducers (erastin, RSL3), LOOH measurement, HO-1 overexpression, MJ33 iPLA2 pharmacological inhibition, cell death assays","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches establishing mechanism, single lab but converging evidence","pmids":["31036877"],"is_preprint":false},{"year":2024,"finding":"PRDX6 acts as a selenium-acceptor protein and facilitates intracellular selenium utilization by transferring selenium within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, thereby promoting efficient selenoprotein (including GPX4) synthesis. Loss of PRDX6 decreases selenoprotein expression and sensitizes cells to ferroptosis; reduced GPX4 was confirmed in Prdx6-deficient mouse brains.","method":"Genetic loss-of-function (PRDX6 knockout/knockdown), selenium transfer biochemistry, selenoprotein expression analysis, Prdx6-/- mouse brains, tumor xenograft ferroptosis sensitivity assays, interaction with SEPHS2","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic selenium transfer demonstrated biochemically, validated in mouse model and xenograft, replicated by parallel independent study (PMID:39547222)","pmids":["38867112"],"is_preprint":false},{"year":2024,"finding":"PRDX6 acts as a selenium-acceptor protein that can react with selenide and interact with SEPHS2 (selenophosphate synthetase 2), providing an alternative SCLY-independent pathway for selenocysteine (Sec) metabolism and selenoprotein synthesis. This pathway is functionally significant in human cancer cells and is linked to elevated PRDX6 expression in MYCN-amplified neuroblastoma.","method":"Biochemical interaction assays (PRDX6 with selenide and SEPHS2), SCLY-independent pathway characterization in human cancer cells, functional complementation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — independent replication of selenium-delivery mechanism (concurrent with PMID:38867112), biochemical interaction with SEPHS2 demonstrated","pmids":["39547224"],"is_preprint":false},{"year":2024,"finding":"PRDX6 overexpression alone does not prevent ferroptosis despite its known phospholipid hydroperoxide-reducing activity; however, genetic loss of PRDX6 sensitizes cancer cells to ferroptosis by reducing GPX4 levels (via impaired selenium utilization), not by direct PLOOH reduction. Cells lacking GPX4 retain substantial PLOOH-reducing capacity independent of PRDX6.","method":"PRDX6 overexpression and CRISPR knockout in cancer cells, PLOOH measurement, GPX4 expression analysis, Prdx6-deficient mouse brains, tumor xenograft ferroptosis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic gain and loss-of-function with mechanistic dissection, in vivo validation, negative finding for direct PLOOH reduction rigorously established","pmids":["39547222"],"is_preprint":false},{"year":2012,"finding":"The PLA2 activity of PRDX6 mediates its ability to enhance NADPH oxidase (phox) activity in neutrophil-like PLB-985 cells in response to fMLF but not PMA. Knockdown of PRDX6 reduces fMLF-stimulated oxidase activity; reintroduction of wild-type or peroxidase-dead (Prdx active site mutant) PRDX6 restores the response, but PLA2 active site mutants do not.","method":"Stable shRNA knockdown in PLB-985 cells, reintroduction of shRNA-resistant WT and mutant (PLA2 and Prdx active site) PRDX6, phox activity assay with fMLF and PMA stimulation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/rescue with site-specific mutants, specific agonist-dependent phenotype, single lab","pmids":["22678913"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9 knockout of PRDX6 in HepG2 hepatocarcinoma cells causes decreased respiratory capacity, downregulation of mitochondrial proteins, altered mitochondrial morphology, G2/M cell cycle arrest, increased ROS, and redox changes at 254 Cys-peptides in 202 proteins. Specific oxidation of cysteines in PCNA may interfere with mitotic entry. The GSH/Glutaredoxin system is downregulated, and cells shift to glycolysis for ATP and AMPK-independent autophagy.","method":"CRISPR/Cas9 knockout, quantitative global and redox proteomics, flow cytometry, extracellular flow analysis (Seahorse), Western blot, electron microscopy","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — clean CRISPR KO with multiple orthogonal methods including redox proteomics, electron microscopy, and functional metabolic assays","pmids":["33035814"],"is_preprint":false},{"year":2011,"finding":"Sp1 directly binds to three active Sp1 sites (-19/27, -61/69, -82/89) in the PRDX6 promoter to transactivate its expression. Curcumin-mediated induction of PRDX6 is dependent on Sp1 activity; point mutations at Sp1 sites abolish curcumin-mediated transactivation. Sp1 inhibitors prevent curcumin-induced PRDX6 upregulation.","method":"Bioinformatic analysis, DNA-protein binding assay, co-transfection with Sp1 and Prdx6-CAT constructs, point mutagenesis of Sp1 sites, Sp1 inhibitor treatment, real-time PCR, Western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple DNA-binding assays and reporter gene studies with mutagenesis, single lab","pmids":["22113199"],"is_preprint":false},{"year":2019,"finding":"At high doses of sulforaphane (>6 μM), excessive Nrf2 activates Klf9 through the ARE site in the Klf9 promoter; Klf9 then directly binds to repressive Klf9 binding elements (RKBE) in the PRDX6 promoter and represses PRDX6 transcription, increasing ROS and causing cell death. Klf9 depletion independently reduces ROS and promotes cell survival.","method":"Reporter gene assays, ChIP/DNA binding assays, Klf9 overexpression/ShRNA knockdown, promoter mutagenesis, ROS measurement, cell viability assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding of Klf9 to Prdx6 promoter demonstrated, Klf9 KD rescue, single lab","pmids":["31569690"],"is_preprint":false},{"year":2020,"finding":"Bmal1 directly binds E-Box elements in the Prdx6 promoter to regulate its transcription. Both E-Box and ARE (bound by Nrf2) sites are required for peak Prdx6 transcription, and Bmal1/Nrf2/Prdx6 show rhythmic expression in mouse lenses in vivo. Bmal1 depletion disrupts Nrf2 and Prdx6 expression and leads to ROS accumulation.","method":"DNA binding assays, transcription assays, promoter mutagenesis (E-Box, ARE), Bmal1 depletion, in vivo circadian expression analysis in mouse lenses","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding of Bmal1 to Prdx6 promoter confirmed, in vivo rhythmic expression validated, single lab","pmids":["32784474"],"is_preprint":false},{"year":2017,"finding":"Nrf2 binds the ARE (-357/-349) in the PRDX6 promoter and drives its transcription; progressive reduction in Nrf2/ARE binding occurs in aging lens epithelial cells, correlating with Prdx6 decline. Mutation at the ARE site prevents sulforaphane-mediated Prdx6 induction. PRDX6 knockdown abolishes sulforaphane-mediated cytoprotection.","method":"Gel-shift assay, ChIP assay, promoter-reporter constructs, ARE site mutagenesis, Prdx6 antisense knockdown, UVB stress assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple DNA binding assays and reporter assays with mutagenesis, functional rescue in Prdx6-KD cells, single lab","pmids":["29074861"],"is_preprint":false},{"year":2021,"finding":"Sp1 binds to three Sp1 response elements in the PRDX6 promoter to directly regulate its transcriptional activation in podocytes. Sp1 overexpression upregulates PRDX6 and Sp1 silencing abolishes PRDX6 protective effects against high-glucose-induced podocyte injury.","method":"ChIP assay confirming Sp1 binding to Prdx6 promoter, Sp1 overexpression/silencing, PRDX6 overexpression vector, high-glucose podocyte model, streptozotocin DN mouse model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct Sp1 promoter binding, loss-of-function validation in cells and in vivo, single lab","pmids":["33894270"],"is_preprint":false},{"year":2008,"finding":"TAT-PRDX6 fusion protein is efficiently transduced into lens epithelial cells from rat and mouse, remains biologically active, reduces ROS, suppresses TGF-β1 activation and cataractogenic markers (α-smooth muscle actin, βig-h3), and delays cataract progression in ex vivo/in vivo models.","method":"TAT-protein transduction into primary LECs, immunoblot for ROS and signaling markers, ex vivo lens culture, in vivo cataract progression assessment","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAT transduction with defined functional readouts including downstream signaling, single lab","pmids":["18184874"],"is_preprint":false},{"year":2005,"finding":"Targeted inactivation (knockout) of the Prdx6 gene in lens epithelial cells results in elevated ROS, phenotypic changes indistinguishable from TGFβ-induced cataractogenesis, transcriptional repression of LEDGF, HSP27, and αB-crystallin, and reduced LEDGF binding to stress response elements. PRDX6 supply reverses these changes.","method":"Prdx6-/- knockout mice/LECs, biochemical ROS assays, CAT reporter assay, gel mobility shift assay, immunoblot, PRDX6 rescue delivery","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout model with multiple downstream mechanistic readouts and rescue, single lab","pmids":["15818411"],"is_preprint":false},{"year":2017,"finding":"NPM1 (nucleophosmin) co-immunoprecipitates with PRDX6 and regulates its expression; NPM1 knockdown decreases PRDX6 and increases intracellular ROS, while NPM1 overexpression or cytoplasmic localization upregulates PRDX6 and decreases ROS. NSC348884 (NPM oligomerization inhibitor) decreases PRDX6.","method":"Co-immunoprecipitation, NPM1 siRNA knockdown and overexpression, ROS measurement by fluorescence, immunoblot for PRDX6/NPM1/ROS markers","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus expression manipulation, single lab, no direct mechanistic dissection of interaction","pmids":["28513872"],"is_preprint":false},{"year":2024,"finding":"PRDX6 iPLA2 activity is involved in astrocyte activation and M1 microglia polarization after ischemic stroke. Blocking iPLA2 activity (by D140A mutation or MJ33) in CTX-TNA2 astrocytes inhibits microglia polarization, reduces ROS production, suppresses NOX2 activation, and inhibits Drp1-dependent mitochondrial fission following OGD/R. MAPKs (ERK, p38) phosphorylate PRDX6 at Thr177 to regulate its iPLA2 activity in astrocytes.","method":"PRDX6 D140A and T177A mutations, MJ33 pharmacological inhibition, NOX2 inhibitor (GSK2795039), Drp1 inhibitor (Mdivi-1), ERK/p38 inhibitors (U0126, SB202190), astrocyte-microglia co-culture, OGD/R model, ROS measurement","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple site-specific mutations and pharmacological inhibitors with defined functional readouts in co-culture model, single lab","pmids":["38287382"],"is_preprint":false},{"year":2023,"finding":"Astragaloside IV (AST) inhibits PRDX6 PLA2 activity by targeting the PLA2 catalytic triad pocket. This binding disrupts the interaction between PRDX6 and RAC (GTPase), hindering RAC-GDI heterodimer activation and NOX2 maturation, thereby attenuating superoxide production.","method":"Activity-based protein profiling (ABPP), small molecule-protein interaction assays, molecular dynamics simulation, PLA2 activity assay, NOX2 activity measurement, in vivo acute lung injury model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding demonstrated by ABPP and interaction assays, functional consequence in NOX2 assay confirmed, single lab","pmids":["37030053"],"is_preprint":false},{"year":2021,"finding":"Viral 3C protease (3Cpro) of foot-and-mouth disease virus (FMDV) and Senecavirus A degrades PRDX6 to overcome its antiviral function. PRDX6 overexpression inhibits FMDV replication while knockdown promotes it. The PLA2 activity (inhibited by MJ33) is required for antiviral function; peroxidase inhibition (mercaptosuccinate) does not promote viral replication. 3Cpro-mediated PRDX6 degradation is independent of proteasome, lysosome, and caspase pathways and requires protease activity.","method":"PRDX6 overexpression/knockdown, viral replication assay, MJ33 and mercaptosuccinate inhibitors, 3Cpro expression and protease-dead mutant, proteasome/lysosome/caspase inhibitors","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches distinguishing which PRDX6 activity is required, 3Cpro mechanism validated by protease-dead mutant, single lab","pmids":["33721217"],"is_preprint":false},{"year":2004,"finding":"Adenovirus-mediated overexpression of 1-Cys peroxiredoxin (PRDX6) in mouse lungs protects against hyperoxic injury, as measured by decreased pleural effusion, lung wet/dry weight, protein and cells in BAL fluid, and reduced TBARS and protein carbonyls.","method":"Adenoviral gene transfer in mice, hyperoxia exposure model, BAL fluid analysis, TBARS, protein carbonyl assay, lung wet/dry weight","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple lung injury readouts, single lab","pmids":["15136296"],"is_preprint":false},{"year":2013,"finding":"Downregulation of PRDX6 by TNF-α and IFN-γ in insulin-producing RINm5F cells is mediated by the calpain and proteasome proteolysis systems and JNK signaling. Blocking JNK, calpains, or the proteasome restores PRDX6 protein levels. IL-4 prevents the cytokine-induced PRDX6 decrease.","method":"Cytokine treatment, JNK inhibitor, calpain inhibitor, proteasome inhibitor, PRDX6 siRNA knockdown, Western blot, RT-PCR","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of degradation pathway with multiple inhibitors, single lab","pmids":["23623867"],"is_preprint":false},{"year":2022,"finding":"Prdx6-deficient LECs show augmented NLRP3 inflammasome activation (elevated Caspase-1, IL-1β, ASC, Gasdermin-D) driven by ROS accumulation. Mechanistically, oxidative stress upregulates Klf9, which binds the NLRP3 promoter and increases NLRP3 transcription. Delivery of PRDX6 or silencing of Klf9 prevents the inflammatory response.","method":"Prdx6-/- LECs, Klf9 siRNA knockdown, PRDX6 delivery, Nlrp3 promoter assay, immunoblot for inflammasome components, ROS measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Prdx6-KO model with mechanistic Klf9-Nlrp3 pathway elucidation, rescue experiments, single lab","pmids":["38003466"],"is_preprint":false},{"year":2022,"finding":"S-palmitoylation at Cys47 of PRDX6 may competitively inhibit disulfide bond formation between Cys47 and Cys91 and alters PRDX6 spatial topology. S-palmitoylation status of Cys47 affects the interaction between PRDX6 and the C-terminal domain of anion exchanger AE3 in dorsal root ganglia, potentially regulating AE3 activity and neuronal excitability.","method":"Proteomic comparison of diabetic vs normal mouse DRG, palmitoylome profiling of HUVEC, bioinformatic prediction of palmitoylation sites (Cys47, Cys91), immunofluorescence for PRDX6 subcellular localization","journal":"Frontiers in endocrinology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily bioinformatic prediction and correlative proteomics; direct palmitoylation and AE3 interaction not biochemically validated in this study","pmids":["36120430"],"is_preprint":false}],"current_model":"PRDX6 is a bifunctional 25-kDa enzyme with distinct active sites for glutathione peroxidase activity (catalytic Cys47, requiring heterodimerization with piGST for glutathionylation-dependent regeneration) and Ca2+-independent acidic phospholipase A2 activity (catalytic Ser32); it reduces phospholipid hydroperoxides, supports Nox1/Nox2-mediated ROS production via its iPLA2 activity, and functions as a selenium-acceptor protein that interacts with SEPHS2 to facilitate selenocysteine-tRNA synthesis and efficient GPX4 expression, thereby suppressing ferroptosis; its activity is regulated by Cys47 hyperoxidation (which irreversibly activates iPLA2), SUMO1 conjugation at Lys122/142 (which reduces abundance and activity), phosphorylation at Thr177 (required for optimal iPLA2), and transcriptional control by Sp1, Nrf2/ARE, Bmal1 E-box, and Klf9 repressor elements."},"narrative":{"mechanistic_narrative":"PRDX6 is a bifunctional antioxidant enzyme that protects cells from oxidative and lipid-peroxidation damage through two independent catalytic activities housed in distinct active sites: a glutathione-dependent peroxidase centered on Cys47 (PVCTTE motif) and a Ca2+-independent acidic phospholipase A2 (iPLA2) centered on Ser32 (GDSWG motif), with the S32A and C47S mutants selectively abolishing one activity each [PMID:10893423]. Unlike 2-Cys peroxiredoxins, regeneration of the oxidized Cys47 peroxidatic cysteine requires heterodimerization with GSH-loaded piGST (GSTπ), which glutathionylates Cys47 to permit reduction of the mixed disulfide and restore peroxidase activity at a 1:1 stoichiometry [PMID:15004285, PMID:15890616]. Functionally, PRDX6 reduces phospholipid hydroperoxides and H2O2 using GSH as the electron donor, preventing accumulation of phosphatidylcholine hydroperoxides, lipid peroxidation, and apoptosis, with Prdx6-null mice showing heightened sensitivity to hyperoxia and paraquat and adenoviral PRDX6 protecting lungs [PMID:12372839, PMID:12193653, PMID:15890616]. The two activities are reciprocally and post-translationally tuned: irreversible hyperoxidation of Cys47 to sulfinic acid paradoxically activates iPLA2 and drives G2/M arrest with p53/p21 upregulation [PMID:18826942], SUMO1 conjugation at Lys122/Lys142 lowers abundance and both activities [PMID:28055018, PMID:24910119], and MAPK-mediated phosphorylation at Thr177 supports optimal iPLA2 [PMID:38287382]. Through its iPLA2 activity PRDX6 acts as a positive regulator of NADPH oxidase ROS output—binding and stabilizing Nox1/Noxa1 components and supporting RAC-dependent NOX2 maturation—thereby coupling phospholipid metabolism to redox signaling, cell migration, and inflammatory responses [PMID:27094494, PMID:22678913, PMID:37030053]. Independently of its enzymatic redox chemistry, PRDX6 functions as a selenium-acceptor protein that reacts with selenide and interacts with SEPHS2 to feed selenocysteyl-tRNA synthesis, supporting efficient GPX4 and selenoprotein expression; loss of PRDX6 lowers GPX4 and sensitizes cells to ferroptosis, and this selenium-delivery role—rather than direct PLOOH reduction—accounts for its ferroptosis-suppressing effect [PMID:38867112, PMID:39547224, PMID:39547222]. PRDX6 transcription is governed by Sp1, Nrf2/ARE, Bmal1 E-box, and Klf9 repressor elements, integrating its expression with stress, circadian, and survival programs [PMID:22113199, PMID:31569690, PMID:32784474, PMID:29074861].","teleology":[{"year":2000,"claim":"Established that PRDX6 is a single protein carrying two mechanistically separable catalytic functions, defining the structural basis for its dual peroxidase and phospholipase activities.","evidence":"Site-directed mutagenesis (S32A, C47S) with recombinant enzyme assays and inhibitor mapping","pmids":["10893423"],"confidence":"High","gaps":["Did not establish how the two activities are coordinated in vivo","No structural model of the bifunctional active-site arrangement"]},{"year":2004,"claim":"Resolved how the 1-Cys peroxidase regenerates its oxidized active site, showing it depends on a heterodimeric partner rather than an intramolecular resolving cysteine.","evidence":"In vitro heterodimerization with GSTπ at defined stoichiometry and liposome delivery into cells lacking the partner","pmids":["15004285"],"confidence":"High","gaps":["Physiological regulation of GSTπ availability not addressed","Structural interface of the heterodimer not resolved"]},{"year":2005,"claim":"Quantified the catalytic mechanism and demonstrated its physiological relevance in protecting against oxidative lung injury.","evidence":"Kinetic in vitro assays plus Prdx6-null and adenoviral-overexpression mouse hyperoxia/paraquat models","pmids":["15890616"],"confidence":"High","gaps":["Relative in vivo contribution of peroxidase vs iPLA2 to lung protection not separated","Tissue-specific substrate preferences unresolved"]},{"year":2002,"claim":"Showed in intact cells that PRDX6 prevents phospholipid hydroperoxide accumulation and apoptosis, defining its antioxidant role at the membrane level.","evidence":"Antisense knockdown and stable overexpression in lung epithelial cells with lipid peroxidation readouts and adenoviral rescue","pmids":["12372839","12193653"],"confidence":"High","gaps":["Did not determine whether protection requires peroxidase, iPLA2, or both","GSH-dependence mechanism not dissected at the level of membrane repair"]},{"year":2008,"claim":"Revealed that irreversible hyperoxidation of the peroxidatic cysteine is not merely inactivating but switches PRDX6 toward enhanced iPLA2 activity and cell-cycle arrest, identifying a redox-driven activity switch.","evidence":"H2O2 treatment with anti-sulfinic acid immunoblot, iPLA2 assays, C47A/S32A mutants, and cell-cycle analysis","pmids":["18826942"],"confidence":"High","gaps":["Structural basis of how Cys47 oxidation activates the distant Ser32 site unresolved","Reversibility/recovery pathway in vivo unclear"]},{"year":2017,"claim":"Identified SUMO1 conjugation at Lys122/142 and Thr177 phosphorylation as post-translational controls of PRDX6 abundance and dual activity.","evidence":"Site-directed mutagenesis with quantitative activity and stability assays in Prdx6-null complementation","pmids":["28055018"],"confidence":"High","gaps":["SUMO ligase/protease responsible not identified here","Kinase responsible for T177 not defined in this study"]},{"year":2014,"claim":"Linked aberrant SUMOylation to reduced PRDX6 transcription via impaired Sp1, connecting post-translational modification to gene-level decline during stress and aging.","evidence":"Sumo1-fused constructs, CAT reporter and gel-shift assays, and SENP1 rescue in lens epithelial cells","pmids":["24910119"],"confidence":"Medium","gaps":["Direct evidence that SUMOylated PRDX6 modulates Sp1 not fully mechanistic","Single cell-type context"]},{"year":2012,"claim":"Demonstrated that the iPLA2 activity, not peroxidase, is specifically required for PRDX6 to support agonist-stimulated NADPH oxidase activity in phagocytes.","evidence":"shRNA knockdown and rescue with active-site mutants in PLB-985 cells under fMLF vs PMA stimulation","pmids":["22678913"],"confidence":"Medium","gaps":["Molecular link between iPLA2 product and oxidase assembly not defined","Agonist-specificity mechanism unexplained"]},{"year":2016,"claim":"Provided a physical-interaction mechanism for PRDX6 control of NADPH oxidase by showing it binds and stabilizes Noxa1/Nox1 components in an activity-dependent manner.","evidence":"Yeast two-hybrid, co-IP, mutant expression, MJ33 inhibition, and migration assays","pmids":["27094494"],"confidence":"High","gaps":["Whether stabilization is direct or requires iPLA2 lipid products unresolved","Structural basis of the SH3 interaction not determined"]},{"year":2023,"claim":"Extended PRDX6 oxidase regulation to NOX2 by showing its PLA2 pocket mediates interaction with RAC required for oxidase maturation.","evidence":"Activity-based protein profiling, molecular dynamics, and NOX2 activity assays with the inhibitor Astragaloside IV in an acute lung injury model","pmids":["37030053"],"confidence":"Medium","gaps":["Direct PRDX6–RAC binding interface not crystallographically resolved","Single inhibitor-based mechanistic inference"]},{"year":2019,"claim":"Initially attributed PRDX6 ferroptosis suppression to its iPLA2-mediated removal of lipid hydroperoxides.","evidence":"siRNA knockdown/overexpression with erastin/RSL3, LOOH measurement, and MJ33 synergy assays","pmids":["31036877"],"confidence":"High","gaps":["Did not test selenium-dependent contributions to GPX4","HO-1 induction mechanism downstream of PRDX6 loss unclear"]},{"year":2024,"claim":"Redefined the dominant ferroptosis-protective mechanism, establishing PRDX6 as a selenium-acceptor protein that feeds selenocysteine-tRNA synthesis via SEPHS2 to sustain GPX4, rather than directly reducing PLOOH.","evidence":"Independent biochemical selenium-transfer assays, SEPHS2 interaction, CRISPR knockout, Prdx6-deficient mouse brains, and xenograft ferroptosis assays","pmids":["38867112","39547224","39547222"],"confidence":"High","gaps":["Structural basis of selenide handoff to SEPHS2 not resolved","Relationship between selenium-acceptor role and the two enzymatic activities unclear"]},{"year":2020,"claim":"Mapped the transcriptional circuitry controlling PRDX6, showing Bmal1 E-box and Nrf2 ARE cooperate for peak expression and impose circadian regulation.","evidence":"DNA-binding and reporter assays with E-box/ARE mutagenesis and in vivo rhythmic expression in mouse lenses","pmids":["32784474","29074861","22113199","33894270"],"confidence":"Medium","gaps":["Cross-talk between the activators quantitatively unresolved","Tissue-specificity of each element not systematically compared"]},{"year":2019,"claim":"Identified Klf9 as a direct ARE-induced repressor of PRDX6, explaining how excessive Nrf2 activation can paradoxically lower PRDX6 and promote ROS-driven death and inflammasome activation.","evidence":"Reporter/ChIP assays, Klf9 knockdown/overexpression, promoter mutagenesis, and Prdx6-null inflammasome analysis","pmids":["31569690","38003466"],"confidence":"Medium","gaps":["Threshold determinants of activator-vs-repressor balance unclear","Single experimental system"]},{"year":2020,"claim":"Defined the cellular consequences of complete PRDX6 loss, revealing broad redox-proteome remodeling, mitochondrial dysfunction, cell-cycle arrest, and a metabolic shift to glycolysis.","evidence":"CRISPR knockout in HepG2 with global/redox proteomics, Seahorse, flow cytometry, and electron microscopy","pmids":["33035814"],"confidence":"High","gaps":["Causal cysteine-oxidation targets (e.g., PCNA) not functionally validated","Direct vs indirect mitochondrial effects not separated"]},{"year":null,"claim":"How PRDX6's three roles—peroxidase, iPLA2, and selenium-acceptor—are coordinated within a single protein and partitioned across cellular compartments and physiological contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model linking the catalytic sites to the selenium-acceptor function","Compartment-specific deployment of each activity undefined","Relative in vivo weight of each function across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,3,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,25]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[11,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,17,18,19]}],"complexes":["PRDX6–GSTπ heterodimer"],"partners":["GSTP1","NOXA1","SEPHS2","JAK2","NPM1","RAC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30041","full_name":"Peroxiredoxin-6","aliases":["1-Cys peroxiredoxin","1-Cys PRX","24 kDa protein","Acidic calcium-independent phospholipase A2","aiPLA2","Antioxidant protein 2","Glutathione-dependent peroxiredoxin","Liver 2D page spot 40","Lysophosphatidylcholine acyltransferase 5","LPC acyltransferase 5","LPCAT-5","Lyso-PC acyltransferase 5","Non-selenium glutathione peroxidase","NSGPx","Red blood cells page spot 12"],"length_aa":224,"mass_kda":25.0,"function":"Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively (PubMed:10893423, PubMed:9497358). Can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides (PubMed:10893423). Also has phospholipase activity, can therefore either reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or hydrolyze the sn-2 ester bond of phospholipids (phospholipase activity) (PubMed:10893423, PubMed:26830860). These activities are dependent on binding to phospholipids at acidic pH and to oxidized phospholipds at cytosolic pH (PubMed:10893423). Plays a role in cell protection against oxidative stress by detoxifying peroxides and in phospholipid homeostasis (PubMed:10893423). Exhibits acyl-CoA-dependent lysophospholipid acyltransferase which mediates the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:26830860). Shows a clear preference for LPC as the lysophospholipid and for palmitoyl CoA as the fatty acyl substrate (PubMed:26830860)","subcellular_location":"Cytoplasm; Lysosome","url":"https://www.uniprot.org/uniprotkb/P30041/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRDX6","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRDX6","total_profiled":1310},"omim":[{"mim_id":"602316","title":"PEROXIREDOXIN 6; PRDX6","url":"https://www.omim.org/entry/602316"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRDX6"},"hgnc":{"alias_symbol":["AOP2","KIAA0106","1-Cys","NSGPx","PRX","aiPLA2","MGC46173","p29"],"prev_symbol":[]},"alphafold":{"accession":"P30041","domains":[{"cath_id":"3.40.30.10","chopping":"8-155","consensus_level":"high","plddt":97.7503,"start":8,"end":155},{"cath_id":"3.30.1020.10","chopping":"173-220","consensus_level":"high","plddt":95.9554,"start":173,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30041","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30041-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30041-F1-predicted_aligned_error_v6.png","plddt_mean":96.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRDX6","jax_strain_url":"https://www.jax.org/strain/search?query=PRDX6"},"sequence":{"accession":"P30041","fasta_url":"https://rest.uniprot.org/uniprotkb/P30041.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30041/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30041"}},"corpus_meta":[{"pmid":"15890616","id":"PMC_15890616","title":"Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism.","date":"2005","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15890616","citation_count":327,"is_preprint":false},{"pmid":"10893423","id":"PMC_10893423","title":"1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10893423","citation_count":285,"is_preprint":false},{"pmid":"15004285","id":"PMC_15004285","title":"Activation of the antioxidant enzyme 1-CYS peroxiredoxin requires glutathionylation mediated by heterodimerization with pi GST.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15004285","citation_count":276,"is_preprint":false},{"pmid":"12193653","id":"PMC_12193653","title":"1-Cys peroxiredoxin overexpression protects cells against phospholipid peroxidation-mediated membrane damage.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12193653","citation_count":192,"is_preprint":false},{"pmid":"29074861","id":"PMC_29074861","title":"Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29074861","citation_count":181,"is_preprint":false},{"pmid":"33894270","id":"PMC_33894270","title":"Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33894270","citation_count":138,"is_preprint":false},{"pmid":"31036877","id":"PMC_31036877","title":"Identification of PRDX6 as a regulator of ferroptosis.","date":"2019","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/31036877","citation_count":124,"is_preprint":false},{"pmid":"12372839","id":"PMC_12372839","title":"An antisense oligonucleotide to 1-cys peroxiredoxin causes lipid peroxidation and apoptosis in lung epithelial cells.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12372839","citation_count":107,"is_preprint":false},{"pmid":"18184874","id":"PMC_18184874","title":"TAT-mediated PRDX6 protein transduction protects against eye lens epithelial cell death and delays lens opacity.","date":"2008","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18184874","citation_count":106,"is_preprint":false},{"pmid":"18826942","id":"PMC_18826942","title":"H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18826942","citation_count":96,"is_preprint":false},{"pmid":"15818411","id":"PMC_15818411","title":"Impaired homeostasis and phenotypic abnormalities in Prdx6-/-mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFbeta.","date":"2005","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/15818411","citation_count":84,"is_preprint":false},{"pmid":"23364261","id":"PMC_23364261","title":"Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation.","date":"2013","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23364261","citation_count":81,"is_preprint":false},{"pmid":"38867112","id":"PMC_38867112","title":"PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38867112","citation_count":80,"is_preprint":false},{"pmid":"32784474","id":"PMC_32784474","title":"Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32784474","citation_count":80,"is_preprint":false},{"pmid":"12851211","id":"PMC_12851211","title":"Induction of 1-cys peroxiredoxin expression by oxidative stress in lung epithelial cells.","date":"2003","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12851211","citation_count":79,"is_preprint":false},{"pmid":"34953631","id":"PMC_34953631","title":"The BMSC-derived exosomal lncRNA Mir9-3hg suppresses cardiomyocyte ferroptosis in ischemia-reperfusion mice via the Pum2/PRDX6 axis.","date":"2021","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/34953631","citation_count":77,"is_preprint":false},{"pmid":"33035814","id":"PMC_33035814","title":"Knockout of PRDX6 induces mitochondrial dysfunction and cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells.","date":"2020","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/33035814","citation_count":76,"is_preprint":false},{"pmid":"39547222","id":"PMC_39547222","title":"PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39547222","citation_count":72,"is_preprint":false},{"pmid":"15136296","id":"PMC_15136296","title":"Adenovirus-mediated transfer of the 1-cys peroxiredoxin gene to mouse lung protects against hyperoxic injury.","date":"2004","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15136296","citation_count":71,"is_preprint":false},{"pmid":"24512906","id":"PMC_24512906","title":"PRDX6 promotes lung tumor progression via its GPx and iPLA2 activities.","date":"2014","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24512906","citation_count":67,"is_preprint":false},{"pmid":"14644414","id":"PMC_14644414","title":"1-Cys peroxiredoxin knock-out mice express mRNA but not protein for a highly related intronless gene.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14644414","citation_count":65,"is_preprint":false},{"pmid":"20236937","id":"PMC_20236937","title":"Plant thioredoxin CDSP32 regenerates 1-cys methionine sulfoxide reductase B activity through the direct reduction of sulfenic acid.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20236937","citation_count":65,"is_preprint":false},{"pmid":"39547224","id":"PMC_39547224","title":"PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39547224","citation_count":62,"is_preprint":false},{"pmid":"22113199","id":"PMC_22113199","title":"Specificity protein, Sp1-mediated increased expression of Prdx6 as a curcumin-induced antioxidant defense in lens epithelial cells against oxidative stress.","date":"2011","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22113199","citation_count":58,"is_preprint":false},{"pmid":"14751239","id":"PMC_14751239","title":"Polyol pathway-dependent osmotic and oxidative stresses in aldose reductase-mediated apoptosis in human lens epithelial cells: role of AOP2.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/14751239","citation_count":52,"is_preprint":false},{"pmid":"28904819","id":"PMC_28904819","title":"Prdx6 retards senescence and restores trabecular meshwork cell health by regulating reactive oxygen species.","date":"2017","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/28904819","citation_count":52,"is_preprint":false},{"pmid":"19572226","id":"PMC_19572226","title":"PRDX6 attenuates oxidative stress- and TGFbeta-induced abnormalities of human trabecular meshwork cells.","date":"2009","source":"Free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/19572226","citation_count":52,"is_preprint":false},{"pmid":"25582888","id":"PMC_25582888","title":"PRDX6 promotes tumor development via the JAK2/STAT3 pathway in a urethane-induced lung tumor model.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25582888","citation_count":51,"is_preprint":false},{"pmid":"17382207","id":"PMC_17382207","title":"Investigating transcriptional regulation of Prdx6 in mouse liver cells.","date":"2007","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17382207","citation_count":50,"is_preprint":false},{"pmid":"26279427","id":"PMC_26279427","title":"PRDX6 Protects ARPE-19 Cells from Oxidative Damage via PI3K/AKT Signaling.","date":"2015","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26279427","citation_count":49,"is_preprint":false},{"pmid":"27094494","id":"PMC_27094494","title":"Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration.","date":"2016","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27094494","citation_count":49,"is_preprint":false},{"pmid":"14572613","id":"PMC_14572613","title":"Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root.","date":"2003","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14572613","citation_count":48,"is_preprint":false},{"pmid":"20003713","id":"PMC_20003713","title":"Overexpression of Prdx6 and resistance to peroxide-induced death in Hepa1-6 cells: Prdx suppression increases apoptosis.","date":"2009","source":"Redox report : communications in free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/20003713","citation_count":46,"is_preprint":false},{"pmid":"26327204","id":"PMC_26327204","title":"PRDX6 controls multiple sclerosis by suppressing inflammation and blood brain barrier disruption.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26327204","citation_count":44,"is_preprint":false},{"pmid":"25193021","id":"PMC_25193021","title":"PRDX6 Exacerbates Dopaminergic Neurodegeneration in a MPTP Mouse Model of Parkinson's Disease.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25193021","citation_count":44,"is_preprint":false},{"pmid":"9806838","id":"PMC_9806838","title":"Characterization of the murine gene encoding Aop2 (antioxidant protein 2) and identification of two highly related genes.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9806838","citation_count":42,"is_preprint":false},{"pmid":"35983876","id":"PMC_35983876","title":"Prdx6-induced inhibition of ferroptosis in epithelial cells contributes to liquiritin-exerted alleviation of colitis.","date":"2022","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/35983876","citation_count":42,"is_preprint":false},{"pmid":"31569690","id":"PMC_31569690","title":"Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31569690","citation_count":40,"is_preprint":false},{"pmid":"28596967","id":"PMC_28596967","title":"Prdx6 Upregulation by Curcumin Attenuates Ischemic Oxidative Damage via SP1 in Rats after Stroke.","date":"2017","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/28596967","citation_count":39,"is_preprint":false},{"pmid":"15694490","id":"PMC_15694490","title":"Biochemical characterization of Toxoplasma gondii 1-Cys peroxiredoxin 2 with mechanistic similarities to typical 2-Cys Prx.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15694490","citation_count":39,"is_preprint":false},{"pmid":"19932185","id":"PMC_19932185","title":"Molecular cloning and characterization of 1-Cys and 2-Cys peroxiredoxins from the bumblebee Bombus ignitus.","date":"2009","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19932185","citation_count":38,"is_preprint":false},{"pmid":"26447207","id":"PMC_26447207","title":"Delivery of a protein transduction domain-mediated Prdx6 protein ameliorates oxidative stress-induced injury in human and mouse neuronal cells.","date":"2015","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26447207","citation_count":37,"is_preprint":false},{"pmid":"11322641","id":"PMC_11322641","title":"Bovine eye 1-Cys peroxiredoxin: expression in E. coli and antioxidant properties.","date":"2001","source":"Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/11322641","citation_count":37,"is_preprint":false},{"pmid":"25329795","id":"PMC_25329795","title":"Involvement of a 1-Cys peroxiredoxin in bacterial virulence.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/25329795","citation_count":37,"is_preprint":false},{"pmid":"30562740","id":"PMC_30562740","title":"Expression of PRDX6 Correlates with Migration and Invasiveness of Colorectal Cancer Cells.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30562740","citation_count":36,"is_preprint":false},{"pmid":"38544826","id":"PMC_38544826","title":"Analysis of the Expression of PRDX6 in Patients with Hepatocellular Carcinoma and its Effect on the Phenotype of Hepatocellular Carcinoma Cells.","date":"2024","source":"Current genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38544826","citation_count":36,"is_preprint":false},{"pmid":"30097850","id":"PMC_30097850","title":"PRDX6 Inhibits Neurogenesis through Downregulation of WDFY1-Mediated TLR4 Signal.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30097850","citation_count":35,"is_preprint":false},{"pmid":"16441659","id":"PMC_16441659","title":"Identification and characterization of 1-Cys peroxiredoxin from Sulfolobus solfataricus and its involvement in the response to oxidative stress.","date":"2006","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/16441659","citation_count":35,"is_preprint":false},{"pmid":"11233154","id":"PMC_11233154","title":"AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant.","date":"1999","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/11233154","citation_count":34,"is_preprint":false},{"pmid":"28199527","id":"PMC_28199527","title":"Prdx6 Deficiency Ameliorates DSS Colitis: Relevance of Compensatory Antioxidant Mechanisms.","date":"2017","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/28199527","citation_count":34,"is_preprint":false},{"pmid":"12151315","id":"PMC_12151315","title":"Regulation of 1-cys peroxiredoxin expression in lung epithelial cells.","date":"2002","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12151315","citation_count":34,"is_preprint":false},{"pmid":"36566948","id":"PMC_36566948","title":"PRDX6-mediated pulmonary artery endothelial cell ferroptosis contributes to monocrotaline-induced pulmonary hypertension.","date":"2022","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/36566948","citation_count":33,"is_preprint":false},{"pmid":"17933572","id":"PMC_17933572","title":"Identification and characterization of a novel 1-Cys peroxiredoxin from silkworm, Bombyx mori.","date":"2007","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17933572","citation_count":33,"is_preprint":false},{"pmid":"32316601","id":"PMC_32316601","title":"Prdx6 Plays a Main Role in the Crosstalk Between Aging and Metabolic Sarcopenia.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32316601","citation_count":32,"is_preprint":false},{"pmid":"10395907","id":"PMC_10395907","title":"Characterization of the murine gene encoding 1-Cys peroxiredoxin and identification of highly homologous genes.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10395907","citation_count":32,"is_preprint":false},{"pmid":"23623867","id":"PMC_23623867","title":"Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress.","date":"2013","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23623867","citation_count":32,"is_preprint":false},{"pmid":"28055018","id":"PMC_28055018","title":"Sumoylation-deficient Prdx6 gains protective function by amplifying enzymatic activity and stability and escapes oxidative stress-induced aberrant Sumoylation.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28055018","citation_count":31,"is_preprint":false},{"pmid":"25398878","id":"PMC_25398878","title":"Characterization of the Vibrio vulnificus 1-Cys peroxiredoxin Prx3 and regulation of its expression by the Fe-S cluster regulator IscR in response to oxidative stress and iron starvation.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25398878","citation_count":31,"is_preprint":false},{"pmid":"30410598","id":"PMC_30410598","title":"Overexpression of Peroxiredoxin 6 (PRDX6) Promotes the Aggressive Phenotypes of Esophageal Squamous Cell Carcinoma.","date":"2018","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30410598","citation_count":29,"is_preprint":false},{"pmid":"35723029","id":"PMC_35723029","title":"PRDX6 alleviates lipopolysaccharide-induced inflammation and ferroptosis in periodontitis.","date":"2022","source":"Acta odontologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/35723029","citation_count":28,"is_preprint":false},{"pmid":"32201510","id":"PMC_32201510","title":"Overexpression and biological function of PRDX6 in human cervical cancer.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32201510","citation_count":28,"is_preprint":false},{"pmid":"26188204","id":"PMC_26188204","title":"Three genes encoding AOP2, a protein involved in aliphatic glucosinolate biosynthesis, are differentially expressed in Brassica rapa.","date":"2015","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/26188204","citation_count":28,"is_preprint":false},{"pmid":"35455944","id":"PMC_35455944","title":"Switching of Redox Signaling by Prdx6 Expression Decides Cellular Fate by Hormetic Phenomena Involving Nrf2 and Reactive Oxygen Species.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35455944","citation_count":28,"is_preprint":false},{"pmid":"24316730","id":"PMC_24316730","title":"PRDX1 and PRDX6 are repressed in papillary thyroid carcinomas via BRAF V600E-dependent and -independent mechanisms.","date":"2013","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24316730","citation_count":28,"is_preprint":false},{"pmid":"24910119","id":"PMC_24910119","title":"Aberrant sumoylation signaling evoked by reactive oxygen species impairs protective function of Prdx6 by destabilization and repression of its transcription.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24910119","citation_count":27,"is_preprint":false},{"pmid":"16360653","id":"PMC_16360653","title":"Reduced expression of 1-cys peroxiredoxin in oxidative stress-induced cataracts.","date":"2005","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/16360653","citation_count":26,"is_preprint":false},{"pmid":"18586944","id":"PMC_18586944","title":"Conversion of Bacillus subtilis OhrR from a 1-Cys to a 2-Cys peroxide sensor.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18586944","citation_count":26,"is_preprint":false},{"pmid":"38287382","id":"PMC_38287382","title":"PRDX6-iPLA2 aggravates neuroinflammation after ischemic stroke via regulating astrocytes-induced M1 microglia.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38287382","citation_count":24,"is_preprint":false},{"pmid":"30215601","id":"PMC_30215601","title":"Sumoylation-deficient Prdx6 repairs aberrant Sumoylation-mediated Sp1 dysregulation-dependent Prdx6 repression and cell injury in aging and oxidative stress.","date":"2018","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/30215601","citation_count":24,"is_preprint":false},{"pmid":"25171874","id":"PMC_25171874","title":"Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxiredoxin 6 (Prdx6) proteins in healthy and pathologic placentas of human and rat.","date":"2014","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/25171874","citation_count":24,"is_preprint":false},{"pmid":"34560818","id":"PMC_34560818","title":"miR-24 and its target gene Prdx6 regulate viability and senescence of myogenic progenitors during aging.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/34560818","citation_count":23,"is_preprint":false},{"pmid":"25933432","id":"PMC_25933432","title":"A 1-Cys Peroxiredoxin from a Thermophilic Archaeon Moonlights as a Molecular Chaperone to Protect Protein and DNA against Stress-Induced Damage.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25933432","citation_count":23,"is_preprint":false},{"pmid":"22678913","id":"PMC_22678913","title":"Phox activity of differentiated PLB-985 cells is enhanced, in an agonist specific manner, by the PLA2 activity of Prdx6-PLA2.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22678913","citation_count":23,"is_preprint":false},{"pmid":"28513872","id":"PMC_28513872","title":"Nucleophosmin Regulates Intracellular Oxidative Stress Homeostasis via Antioxidant PRDX6.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28513872","citation_count":22,"is_preprint":false},{"pmid":"27379999","id":"PMC_27379999","title":"The role of Prdx6 in the protection of cells of the crystalline lens from oxidative stress induced by UV exposure.","date":"2016","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/27379999","citation_count":22,"is_preprint":false},{"pmid":"19429582","id":"PMC_19429582","title":"Age-related cataracts and Prdx6: correlation between severity of lens opacity, age and the level of Prdx 6 expression.","date":"2009","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/19429582","citation_count":21,"is_preprint":false},{"pmid":"36008942","id":"PMC_36008942","title":"Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36008942","citation_count":20,"is_preprint":false},{"pmid":"25686213","id":"PMC_25686213","title":"Lentivirus-mediated inhibition of tumour necrosis factor-α improves motor function associated with PRDX6 in spinal cord contusion rats.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25686213","citation_count":20,"is_preprint":false},{"pmid":"33727039","id":"PMC_33727039","title":"The role of TLR4/NF-κB signaling in the radioprotective effects of exogenous Prdx6.","date":"2021","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33727039","citation_count":19,"is_preprint":false},{"pmid":"24747012","id":"PMC_24747012","title":"Identification and characterisation of a novel 1-Cys thioredoxin peroxidase gene (AccTpx5) from Apis cerana cerana.","date":"2014","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24747012","citation_count":19,"is_preprint":false},{"pmid":"12804011","id":"PMC_12804011","title":"Identification of multiple transcripts for antioxidant protein 2 (Aop2): differential regulation by oxidative stress and growth factors.","date":"2003","source":"Redox report : communications in free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/12804011","citation_count":18,"is_preprint":false},{"pmid":"25971604","id":"PMC_25971604","title":"A novel 1-Cys thioredoxin peroxidase gene in Apis cerana cerana: characterization of AccTpx4 and its role in oxidative stresses.","date":"2015","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/25971604","citation_count":18,"is_preprint":false},{"pmid":"33547545","id":"PMC_33547545","title":"KLF9 regulates PRDX6 expression in hyperglycemia-aggravated bupivacaine neurotoxicity.","date":"2021","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33547545","citation_count":16,"is_preprint":false},{"pmid":"33603470","id":"PMC_33603470","title":"PRDX6 Overexpression Promotes Proliferation, Invasion, and Migration of A549 Cells in vitro and in vivo.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33603470","citation_count":16,"is_preprint":false},{"pmid":"26659441","id":"PMC_26659441","title":"The Expression of Porcine Prdx6 Gene Is Up-Regulated by C/EBPβ and CREB.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26659441","citation_count":16,"is_preprint":false},{"pmid":"37030053","id":"PMC_37030053","title":"Astragaloside IV targets PRDX6, inhibits the activation of RAC subunit in NADPH oxidase 2 for oxidative damage.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37030053","citation_count":16,"is_preprint":false},{"pmid":"17103164","id":"PMC_17103164","title":"Biochemical characterization of 1-Cys peroxiredoxin from Antrodia camphorata.","date":"2006","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/17103164","citation_count":16,"is_preprint":false},{"pmid":"38401519","id":"PMC_38401519","title":"Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38401519","citation_count":15,"is_preprint":false},{"pmid":"27965586","id":"PMC_27965586","title":"The Antioxidant Peroxiredoxin 6 (Prdx6) Exhibits Different Profiles in the Livers of Seawater- and Fresh Water-Acclimated Milkfish, Chanos chanos, upon Hypothermal Challenge.","date":"2016","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27965586","citation_count":15,"is_preprint":false},{"pmid":"36290607","id":"PMC_36290607","title":"Sp1-Mediated Prdx6 Upregulation Leads to Clasmatodendrosis by Increasing Its aiPLA2 Activity in the CA1 Astrocytes in Chronic Epilepsy Rats.","date":"2022","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36290607","citation_count":14,"is_preprint":false},{"pmid":"35659568","id":"PMC_35659568","title":"NPM1 promotes cell proliferation by targeting PRDX6 in colorectal cancer.","date":"2022","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35659568","citation_count":14,"is_preprint":false},{"pmid":"15980227","id":"PMC_15980227","title":"Regulation of 1-cys peroxiredoxin expression in the process of stromal wound healing after photorefractive keratectomy.","date":"2005","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/15980227","citation_count":14,"is_preprint":false},{"pmid":"23178658","id":"PMC_23178658","title":"Plasmodium vivax and Plasmodium knowlesi: cloning, expression and functional analysis of 1-Cys peroxiredoxin.","date":"2012","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/23178658","citation_count":14,"is_preprint":false},{"pmid":"36120430","id":"PMC_36120430","title":"PRDX6: A protein bridging S-palmitoylation and diabetic neuropathy.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36120430","citation_count":13,"is_preprint":false},{"pmid":"33721217","id":"PMC_33721217","title":"Porcine Picornavirus 3C Protease Degrades PRDX6 to Impair PRDX6-mediated Antiviral Function.","date":"2021","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/33721217","citation_count":13,"is_preprint":false},{"pmid":"33047245","id":"PMC_33047245","title":"Significant reductions in apoptosis-related proteins (HSPA6, HSPA8, ITGB3, YWHAH, and PRDX6) are involved in immune thrombocytopenia.","date":"2020","source":"Journal of thrombosis and thrombolysis","url":"https://pubmed.ncbi.nlm.nih.gov/33047245","citation_count":13,"is_preprint":false},{"pmid":"15859355","id":"PMC_15859355","title":"Transcripts associated with Prdx6 (peroxiredoxin 6) and related genes in mouse.","date":"2005","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/15859355","citation_count":12,"is_preprint":false},{"pmid":"35240453","id":"PMC_35240453","title":"Circular RNA hsa_circ_0011385 contributes to cervical cancer progression through sequestering miR-149-5p and increasing PRDX6 expression.","date":"2022","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/35240453","citation_count":12,"is_preprint":false},{"pmid":"38003466","id":"PMC_38003466","title":"Prdx6 Regulates Nlrp3 Inflammasome Activation-Driven Inflammatory Response in Lens Epithelial Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38003466","citation_count":12,"is_preprint":false},{"pmid":"26061816","id":"PMC_26061816","title":"Anti-cancer effect of snake venom toxin through down regulation of AP-1 mediated PRDX6 expression.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26061816","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55002,"output_tokens":8991,"usd":0.149935,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18796,"output_tokens":5182,"usd":0.111765,"stage2_stop_reason":"end_turn"},"total_usd":0.2617,"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\": 2000,\n      \"finding\": \"PRDX6 (1-Cys peroxiredoxin) is a bifunctional enzyme with two distinct active sites: Ser32 in the GDSWG motif serves as the catalytic nucleophile for phospholipase A2 (aiPLA2) activity, while Cys47 in the PVCTTE motif is the active site for glutathione peroxidase (NSGPx) activity. Mutation S32A abolishes PLA2 activity without affecting peroxidase; C47S abolishes peroxidase without affecting PLA2. The enzyme exhibits Ca2+-independent PLA2 activity at acidic pH and GSH peroxidase activity at alkaline pH.\",\n      \"method\": \"Site-directed mutagenesis (S32A, C47S), E. coli recombinant expression, in vitro enzymatic assays, inhibitor studies (MJ33, mercaptosuccinate, antibody epitope mapping)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro with mutagenesis of both active sites, multiple orthogonal inhibitors, replicated across studies\",\n      \"pmids\": [\"10893423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Activation of 1-Cys peroxiredoxin (PRDX6) requires heterodimerization with pi GST (GSTπ). Oxidized Cys47 in PRDX6 is glutathionylated via GSTπ loaded with GSH, followed by spontaneous reduction of the mixed disulfide, restoring peroxidase activity. Maximum activation occurs at a 1:1 molar ratio of GSH-saturated GSTπ to PRDX6.\",\n      \"method\": \"Partial and homogeneous purification, in vitro heterodimerization assay, liposome-mediated delivery into cells lacking endogenous PRDX6 or GSTπ, biochemical activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted in vitro with defined stoichiometry, validated in cells with and without endogenous GSTπ, multiple orthogonal methods\",\n      \"pmids\": [\"15004285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Antisense-mediated knockdown of 1-Cys peroxiredoxin (PRDX6) in rat lung epithelial (L2) cells leads to accumulation of phosphatidylcholine hydroperoxides in plasma membranes, lipid peroxidation, and apoptotic cell death (annexin V/PI staining, TUNEL). These effects were rescued by adenoviral overexpression of PRDX6 or vitamin E analogue pretreatment, establishing PRDX6 as a functional antioxidant that prevents phospholipid hydroperoxide accumulation and apoptosis in intact cells.\",\n      \"method\": \"Antisense morpholino oligonucleotide knockdown, immunoblot, HPLC conjugated diene assay, DPPP fluorescence for lipid peroxidation, annexin V/PI staining, TUNEL, adenoviral rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined phenotypic readout plus adenoviral rescue, multiple orthogonal methods\",\n      \"pmids\": [\"12372839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Stable overexpression of GFP-PRDX6 in NCI-H441 lung cells (lacking endogenous PRDX6) reduces H2O2 and t-butylhydroperoxide levels, decreases phosphatidylcholine hydroperoxide accumulation upon oxidant exposure, and protects against oxidant-induced plasma membrane damage (phosphatidylserine translocation) in a GSH-dependent manner.\",\n      \"method\": \"Stable transfection, 51Cr release cytotoxicity assay, TBARS, PCOOH HPLC assay, DPPP fluorescence, Annexin V-Cy3 staining, GSH depletion\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function in cell line lacking endogenous protein, multiple orthogonal phenotypic readouts, GSH dependence confirmed\",\n      \"pmids\": [\"12193653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"H2O2-induced hyperoxidation of PRDX6 Cys47 (to sulfinic acid) is irreversible in vivo (unlike 2-Cys Prxs) and paradoxically increases iPLA2 activity, causing G2/M cell cycle arrest associated with p53/p21 upregulation and cyclin B1 downregulation. C47A mutation abolishes both hyperoxidation and the H2O2-induced iPLA2 upregulation, demonstrating that Cys47 hyperoxidation is required for iPLA2 activation.\",\n      \"method\": \"H2O2 treatment, immunoblot with anti-sulfinic acid antibody, iPLA2 activity assay, site-directed mutagenesis (C47A, S32A, double mutant), cell cycle analysis by flow cytometry, Western blot for p53/p21/cyclin B1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis plus cellular assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18826942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PRDX6 uses GSH as electron donor to reduce H2O2 and phospholipid hydroperoxides (rate constant ~3×10^6 M^-1 s^-1). Oxidation of Cys47 to sulfenic acid during catalysis requires piGST-catalyzed glutathionylation and GSH reduction to complete the enzymatic cycle. In vivo, Prdx6-null mice are more sensitive to hyperoxia and paraquat, whereas adenoviral overexpression protects mouse lungs.\",\n      \"method\": \"Kinetic in vitro assays, Prdx6-null mouse model, adenoviral overexpression in mice, hyperoxia and paraquat exposure models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinetic characterization combined with knockout and overexpression mouse models, replicated mechanism\",\n      \"pmids\": [\"15890616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRDX6 binds to Noxa1 (NADPH oxidase activator 1) via its SH3 domain, stabilizes Noxa1, and supports Nox1-derived superoxide production and cell migration. Both the peroxidase (C47S) and lipase (S32A) mutants of PRDX6 fail to bind or stabilize Nox1 components, and the iPLA2 inhibitor MJ33 suppresses Nox1 activity, implicating the phospholipase activity in Nox1 regulation.\",\n      \"method\": \"Yeast two-hybrid screening, co-IP in overexpressing cells, Nox1 superoxide activity assay, PRDX6 knockdown/overexpression, mutant expression (C47S, S32A), MJ33 pharmacological inhibition, wound-closure migration assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed, multiple cell models, pharmacological and genetic loss-of-function, functional consequence in migration\",\n      \"pmids\": [\"27094494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRDX6 physically interacts with JAK2 (co-localization and co-immunoprecipitation in tumor tissues and lung cancer cells) and its overexpression activates the JAK2/STAT3 pathway, contributing to urethane-induced lung tumor development in transgenic mice. STAT3 DNA binding and CCL5 levels are also increased.\",\n      \"method\": \"PRDX6 transgenic mice, urethane carcinogenesis model, immunohistochemistry, co-immunoprecipitation, JAK2/STAT3 activity assays, STAT3 DNA binding assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus in vivo model, single lab, functional phenotype confirmed in transgenic mice\",\n      \"pmids\": [\"25582888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Aberrant SUMO1 conjugation of PRDX6 at Lys122 and Lys142 reduces its cellular abundance and decreases both GSH-peroxidase and aiPLA2 activities. A K122/142R sumoylation-deficient mutant gains enhanced enzymatic activity (30% GPx, 37% aiPLA2 increases) and stability. Phosphorylation at T177 is required for optimal aiPLA2 activity. Both active sites (peroxidase and PLA2) are necessary for mutant PRDX6 function.\",\n      \"method\": \"Site-directed mutagenesis (K122R, K142R, K122/142R, T177A), Prdx6-/- LEC complementation, enzymatic activity assays, stability assays, TAT-fusion protein delivery, EGFP-Sumo1 co-expression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis at identified sumoylation sites with quantitative activity readouts, validated in Prdx6-null cells, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"28055018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oxidative stress-induced aberrant SUMO1 conjugation reduces PRDX6 protein abundance and attenuates its transcription. SUMO1 modification of PRDX6 is associated with reduced Sp1 expression and impaired Sp1-mediated transactivation of the Prdx6 promoter. Delivery of SENP1 (SUMO-specific protease) reverses the loss of PRDX6 expression.\",\n      \"method\": \"Immunoblot, Prdx6-/- LECs, Sumo1-fused PRDX6 construct, CAT reporter gene assay, gel mobility shift assay, SENP1 delivery rescue experiments, aging lens analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple complementary assays in relevant cell model, single lab\",\n      \"pmids\": [\"24910119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRDX6 knockdown enhances lipid reactive oxygen species (LOOH) and ferroptotic cell death triggered by erastin and RSL-3. This effect correlates with transcriptional activation of heme oxygenase-1 (HO-1), and HO-1 overexpression enhances ferroptosis. The iPLA2 inhibitor MJ33 synergistically enhances erastin-induced ferroptosis, indicating PRDX6 removes LOOH through its iPLA2 activity to protect against ferroptosis.\",\n      \"method\": \"PRDX6 siRNA knockdown, overexpression, ferroptosis inducers (erastin, RSL3), LOOH measurement, HO-1 overexpression, MJ33 iPLA2 pharmacological inhibition, cell death assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches establishing mechanism, single lab but converging evidence\",\n      \"pmids\": [\"31036877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 acts as a selenium-acceptor protein and facilitates intracellular selenium utilization by transferring selenium within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, thereby promoting efficient selenoprotein (including GPX4) synthesis. Loss of PRDX6 decreases selenoprotein expression and sensitizes cells to ferroptosis; reduced GPX4 was confirmed in Prdx6-deficient mouse brains.\",\n      \"method\": \"Genetic loss-of-function (PRDX6 knockout/knockdown), selenium transfer biochemistry, selenoprotein expression analysis, Prdx6-/- mouse brains, tumor xenograft ferroptosis sensitivity assays, interaction with SEPHS2\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic selenium transfer demonstrated biochemically, validated in mouse model and xenograft, replicated by parallel independent study (PMID:39547222)\",\n      \"pmids\": [\"38867112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 acts as a selenium-acceptor protein that can react with selenide and interact with SEPHS2 (selenophosphate synthetase 2), providing an alternative SCLY-independent pathway for selenocysteine (Sec) metabolism and selenoprotein synthesis. This pathway is functionally significant in human cancer cells and is linked to elevated PRDX6 expression in MYCN-amplified neuroblastoma.\",\n      \"method\": \"Biochemical interaction assays (PRDX6 with selenide and SEPHS2), SCLY-independent pathway characterization in human cancer cells, functional complementation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — independent replication of selenium-delivery mechanism (concurrent with PMID:38867112), biochemical interaction with SEPHS2 demonstrated\",\n      \"pmids\": [\"39547224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 overexpression alone does not prevent ferroptosis despite its known phospholipid hydroperoxide-reducing activity; however, genetic loss of PRDX6 sensitizes cancer cells to ferroptosis by reducing GPX4 levels (via impaired selenium utilization), not by direct PLOOH reduction. Cells lacking GPX4 retain substantial PLOOH-reducing capacity independent of PRDX6.\",\n      \"method\": \"PRDX6 overexpression and CRISPR knockout in cancer cells, PLOOH measurement, GPX4 expression analysis, Prdx6-deficient mouse brains, tumor xenograft ferroptosis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic gain and loss-of-function with mechanistic dissection, in vivo validation, negative finding for direct PLOOH reduction rigorously established\",\n      \"pmids\": [\"39547222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The PLA2 activity of PRDX6 mediates its ability to enhance NADPH oxidase (phox) activity in neutrophil-like PLB-985 cells in response to fMLF but not PMA. Knockdown of PRDX6 reduces fMLF-stimulated oxidase activity; reintroduction of wild-type or peroxidase-dead (Prdx active site mutant) PRDX6 restores the response, but PLA2 active site mutants do not.\",\n      \"method\": \"Stable shRNA knockdown in PLB-985 cells, reintroduction of shRNA-resistant WT and mutant (PLA2 and Prdx active site) PRDX6, phox activity assay with fMLF and PMA stimulation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/rescue with site-specific mutants, specific agonist-dependent phenotype, single lab\",\n      \"pmids\": [\"22678913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9 knockout of PRDX6 in HepG2 hepatocarcinoma cells causes decreased respiratory capacity, downregulation of mitochondrial proteins, altered mitochondrial morphology, G2/M cell cycle arrest, increased ROS, and redox changes at 254 Cys-peptides in 202 proteins. Specific oxidation of cysteines in PCNA may interfere with mitotic entry. The GSH/Glutaredoxin system is downregulated, and cells shift to glycolysis for ATP and AMPK-independent autophagy.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative global and redox proteomics, flow cytometry, extracellular flow analysis (Seahorse), Western blot, electron microscopy\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — clean CRISPR KO with multiple orthogonal methods including redox proteomics, electron microscopy, and functional metabolic assays\",\n      \"pmids\": [\"33035814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sp1 directly binds to three active Sp1 sites (-19/27, -61/69, -82/89) in the PRDX6 promoter to transactivate its expression. Curcumin-mediated induction of PRDX6 is dependent on Sp1 activity; point mutations at Sp1 sites abolish curcumin-mediated transactivation. Sp1 inhibitors prevent curcumin-induced PRDX6 upregulation.\",\n      \"method\": \"Bioinformatic analysis, DNA-protein binding assay, co-transfection with Sp1 and Prdx6-CAT constructs, point mutagenesis of Sp1 sites, Sp1 inhibitor treatment, real-time PCR, Western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple DNA-binding assays and reporter gene studies with mutagenesis, single lab\",\n      \"pmids\": [\"22113199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"At high doses of sulforaphane (>6 μM), excessive Nrf2 activates Klf9 through the ARE site in the Klf9 promoter; Klf9 then directly binds to repressive Klf9 binding elements (RKBE) in the PRDX6 promoter and represses PRDX6 transcription, increasing ROS and causing cell death. Klf9 depletion independently reduces ROS and promotes cell survival.\",\n      \"method\": \"Reporter gene assays, ChIP/DNA binding assays, Klf9 overexpression/ShRNA knockdown, promoter mutagenesis, ROS measurement, cell viability assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding of Klf9 to Prdx6 promoter demonstrated, Klf9 KD rescue, single lab\",\n      \"pmids\": [\"31569690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bmal1 directly binds E-Box elements in the Prdx6 promoter to regulate its transcription. Both E-Box and ARE (bound by Nrf2) sites are required for peak Prdx6 transcription, and Bmal1/Nrf2/Prdx6 show rhythmic expression in mouse lenses in vivo. Bmal1 depletion disrupts Nrf2 and Prdx6 expression and leads to ROS accumulation.\",\n      \"method\": \"DNA binding assays, transcription assays, promoter mutagenesis (E-Box, ARE), Bmal1 depletion, in vivo circadian expression analysis in mouse lenses\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding of Bmal1 to Prdx6 promoter confirmed, in vivo rhythmic expression validated, single lab\",\n      \"pmids\": [\"32784474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nrf2 binds the ARE (-357/-349) in the PRDX6 promoter and drives its transcription; progressive reduction in Nrf2/ARE binding occurs in aging lens epithelial cells, correlating with Prdx6 decline. Mutation at the ARE site prevents sulforaphane-mediated Prdx6 induction. PRDX6 knockdown abolishes sulforaphane-mediated cytoprotection.\",\n      \"method\": \"Gel-shift assay, ChIP assay, promoter-reporter constructs, ARE site mutagenesis, Prdx6 antisense knockdown, UVB stress assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple DNA binding assays and reporter assays with mutagenesis, functional rescue in Prdx6-KD cells, single lab\",\n      \"pmids\": [\"29074861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sp1 binds to three Sp1 response elements in the PRDX6 promoter to directly regulate its transcriptional activation in podocytes. Sp1 overexpression upregulates PRDX6 and Sp1 silencing abolishes PRDX6 protective effects against high-glucose-induced podocyte injury.\",\n      \"method\": \"ChIP assay confirming Sp1 binding to Prdx6 promoter, Sp1 overexpression/silencing, PRDX6 overexpression vector, high-glucose podocyte model, streptozotocin DN mouse model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct Sp1 promoter binding, loss-of-function validation in cells and in vivo, single lab\",\n      \"pmids\": [\"33894270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TAT-PRDX6 fusion protein is efficiently transduced into lens epithelial cells from rat and mouse, remains biologically active, reduces ROS, suppresses TGF-β1 activation and cataractogenic markers (α-smooth muscle actin, βig-h3), and delays cataract progression in ex vivo/in vivo models.\",\n      \"method\": \"TAT-protein transduction into primary LECs, immunoblot for ROS and signaling markers, ex vivo lens culture, in vivo cataract progression assessment\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAT transduction with defined functional readouts including downstream signaling, single lab\",\n      \"pmids\": [\"18184874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Targeted inactivation (knockout) of the Prdx6 gene in lens epithelial cells results in elevated ROS, phenotypic changes indistinguishable from TGFβ-induced cataractogenesis, transcriptional repression of LEDGF, HSP27, and αB-crystallin, and reduced LEDGF binding to stress response elements. PRDX6 supply reverses these changes.\",\n      \"method\": \"Prdx6-/- knockout mice/LECs, biochemical ROS assays, CAT reporter assay, gel mobility shift assay, immunoblot, PRDX6 rescue delivery\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout model with multiple downstream mechanistic readouts and rescue, single lab\",\n      \"pmids\": [\"15818411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NPM1 (nucleophosmin) co-immunoprecipitates with PRDX6 and regulates its expression; NPM1 knockdown decreases PRDX6 and increases intracellular ROS, while NPM1 overexpression or cytoplasmic localization upregulates PRDX6 and decreases ROS. NSC348884 (NPM oligomerization inhibitor) decreases PRDX6.\",\n      \"method\": \"Co-immunoprecipitation, NPM1 siRNA knockdown and overexpression, ROS measurement by fluorescence, immunoblot for PRDX6/NPM1/ROS markers\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus expression manipulation, single lab, no direct mechanistic dissection of interaction\",\n      \"pmids\": [\"28513872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 iPLA2 activity is involved in astrocyte activation and M1 microglia polarization after ischemic stroke. Blocking iPLA2 activity (by D140A mutation or MJ33) in CTX-TNA2 astrocytes inhibits microglia polarization, reduces ROS production, suppresses NOX2 activation, and inhibits Drp1-dependent mitochondrial fission following OGD/R. MAPKs (ERK, p38) phosphorylate PRDX6 at Thr177 to regulate its iPLA2 activity in astrocytes.\",\n      \"method\": \"PRDX6 D140A and T177A mutations, MJ33 pharmacological inhibition, NOX2 inhibitor (GSK2795039), Drp1 inhibitor (Mdivi-1), ERK/p38 inhibitors (U0126, SB202190), astrocyte-microglia co-culture, OGD/R model, ROS measurement\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple site-specific mutations and pharmacological inhibitors with defined functional readouts in co-culture model, single lab\",\n      \"pmids\": [\"38287382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Astragaloside IV (AST) inhibits PRDX6 PLA2 activity by targeting the PLA2 catalytic triad pocket. This binding disrupts the interaction between PRDX6 and RAC (GTPase), hindering RAC-GDI heterodimer activation and NOX2 maturation, thereby attenuating superoxide production.\",\n      \"method\": \"Activity-based protein profiling (ABPP), small molecule-protein interaction assays, molecular dynamics simulation, PLA2 activity assay, NOX2 activity measurement, in vivo acute lung injury model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding demonstrated by ABPP and interaction assays, functional consequence in NOX2 assay confirmed, single lab\",\n      \"pmids\": [\"37030053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Viral 3C protease (3Cpro) of foot-and-mouth disease virus (FMDV) and Senecavirus A degrades PRDX6 to overcome its antiviral function. PRDX6 overexpression inhibits FMDV replication while knockdown promotes it. The PLA2 activity (inhibited by MJ33) is required for antiviral function; peroxidase inhibition (mercaptosuccinate) does not promote viral replication. 3Cpro-mediated PRDX6 degradation is independent of proteasome, lysosome, and caspase pathways and requires protease activity.\",\n      \"method\": \"PRDX6 overexpression/knockdown, viral replication assay, MJ33 and mercaptosuccinate inhibitors, 3Cpro expression and protease-dead mutant, proteasome/lysosome/caspase inhibitors\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches distinguishing which PRDX6 activity is required, 3Cpro mechanism validated by protease-dead mutant, single lab\",\n      \"pmids\": [\"33721217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Adenovirus-mediated overexpression of 1-Cys peroxiredoxin (PRDX6) in mouse lungs protects against hyperoxic injury, as measured by decreased pleural effusion, lung wet/dry weight, protein and cells in BAL fluid, and reduced TBARS and protein carbonyls.\",\n      \"method\": \"Adenoviral gene transfer in mice, hyperoxia exposure model, BAL fluid analysis, TBARS, protein carbonyl assay, lung wet/dry weight\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple lung injury readouts, single lab\",\n      \"pmids\": [\"15136296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Downregulation of PRDX6 by TNF-α and IFN-γ in insulin-producing RINm5F cells is mediated by the calpain and proteasome proteolysis systems and JNK signaling. Blocking JNK, calpains, or the proteasome restores PRDX6 protein levels. IL-4 prevents the cytokine-induced PRDX6 decrease.\",\n      \"method\": \"Cytokine treatment, JNK inhibitor, calpain inhibitor, proteasome inhibitor, PRDX6 siRNA knockdown, Western blot, RT-PCR\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of degradation pathway with multiple inhibitors, single lab\",\n      \"pmids\": [\"23623867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Prdx6-deficient LECs show augmented NLRP3 inflammasome activation (elevated Caspase-1, IL-1β, ASC, Gasdermin-D) driven by ROS accumulation. Mechanistically, oxidative stress upregulates Klf9, which binds the NLRP3 promoter and increases NLRP3 transcription. Delivery of PRDX6 or silencing of Klf9 prevents the inflammatory response.\",\n      \"method\": \"Prdx6-/- LECs, Klf9 siRNA knockdown, PRDX6 delivery, Nlrp3 promoter assay, immunoblot for inflammasome components, ROS measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Prdx6-KO model with mechanistic Klf9-Nlrp3 pathway elucidation, rescue experiments, single lab\",\n      \"pmids\": [\"38003466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S-palmitoylation at Cys47 of PRDX6 may competitively inhibit disulfide bond formation between Cys47 and Cys91 and alters PRDX6 spatial topology. S-palmitoylation status of Cys47 affects the interaction between PRDX6 and the C-terminal domain of anion exchanger AE3 in dorsal root ganglia, potentially regulating AE3 activity and neuronal excitability.\",\n      \"method\": \"Proteomic comparison of diabetic vs normal mouse DRG, palmitoylome profiling of HUVEC, bioinformatic prediction of palmitoylation sites (Cys47, Cys91), immunofluorescence for PRDX6 subcellular localization\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily bioinformatic prediction and correlative proteomics; direct palmitoylation and AE3 interaction not biochemically validated in this study\",\n      \"pmids\": [\"36120430\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX6 is a bifunctional 25-kDa enzyme with distinct active sites for glutathione peroxidase activity (catalytic Cys47, requiring heterodimerization with piGST for glutathionylation-dependent regeneration) and Ca2+-independent acidic phospholipase A2 activity (catalytic Ser32); it reduces phospholipid hydroperoxides, supports Nox1/Nox2-mediated ROS production via its iPLA2 activity, and functions as a selenium-acceptor protein that interacts with SEPHS2 to facilitate selenocysteine-tRNA synthesis and efficient GPX4 expression, thereby suppressing ferroptosis; its activity is regulated by Cys47 hyperoxidation (which irreversibly activates iPLA2), SUMO1 conjugation at Lys122/142 (which reduces abundance and activity), phosphorylation at Thr177 (required for optimal iPLA2), and transcriptional control by Sp1, Nrf2/ARE, Bmal1 E-box, and Klf9 repressor elements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRDX6 is a bifunctional antioxidant enzyme that protects cells from oxidative and lipid-peroxidation damage through two independent catalytic activities housed in distinct active sites: a glutathione-dependent peroxidase centered on Cys47 (PVCTTE motif) and a Ca2+-independent acidic phospholipase A2 (iPLA2) centered on Ser32 (GDSWG motif), with the S32A and C47S mutants selectively abolishing one activity each [#0]. Unlike 2-Cys peroxiredoxins, regeneration of the oxidized Cys47 peroxidatic cysteine requires heterodimerization with GSH-loaded piGST (GSTπ), which glutathionylates Cys47 to permit reduction of the mixed disulfide and restore peroxidase activity at a 1:1 stoichiometry [#1, #5]. Functionally, PRDX6 reduces phospholipid hydroperoxides and H2O2 using GSH as the electron donor, preventing accumulation of phosphatidylcholine hydroperoxides, lipid peroxidation, and apoptosis, with Prdx6-null mice showing heightened sensitivity to hyperoxia and paraquat and adenoviral PRDX6 protecting lungs [#2, #3, #5]. The two activities are reciprocally and post-translationally tuned: irreversible hyperoxidation of Cys47 to sulfinic acid paradoxically activates iPLA2 and drives G2/M arrest with p53/p21 upregulation [#4], SUMO1 conjugation at Lys122/Lys142 lowers abundance and both activities [#8, #9], and MAPK-mediated phosphorylation at Thr177 supports optimal iPLA2 [#24]. Through its iPLA2 activity PRDX6 acts as a positive regulator of NADPH oxidase ROS output—binding and stabilizing Nox1/Noxa1 components and supporting RAC-dependent NOX2 maturation—thereby coupling phospholipid metabolism to redox signaling, cell migration, and inflammatory responses [#6, #14, #25]. Independently of its enzymatic redox chemistry, PRDX6 functions as a selenium-acceptor protein that reacts with selenide and interacts with SEPHS2 to feed selenocysteyl-tRNA synthesis, supporting efficient GPX4 and selenoprotein expression; loss of PRDX6 lowers GPX4 and sensitizes cells to ferroptosis, and this selenium-delivery role—rather than direct PLOOH reduction—accounts for its ferroptosis-suppressing effect [#11, #12, #13]. PRDX6 transcription is governed by Sp1, Nrf2/ARE, Bmal1 E-box, and Klf9 repressor elements, integrating its expression with stress, circadian, and survival programs [#16, #17, #18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that PRDX6 is a single protein carrying two mechanistically separable catalytic functions, defining the structural basis for its dual peroxidase and phospholipase activities.\",\n      \"evidence\": \"Site-directed mutagenesis (S32A, C47S) with recombinant enzyme assays and inhibitor mapping\",\n      \"pmids\": [\"10893423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the two activities are coordinated in vivo\", \"No structural model of the bifunctional active-site arrangement\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how the 1-Cys peroxidase regenerates its oxidized active site, showing it depends on a heterodimeric partner rather than an intramolecular resolving cysteine.\",\n      \"evidence\": \"In vitro heterodimerization with GSTπ at defined stoichiometry and liposome delivery into cells lacking the partner\",\n      \"pmids\": [\"15004285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological regulation of GSTπ availability not addressed\", \"Structural interface of the heterodimer not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Quantified the catalytic mechanism and demonstrated its physiological relevance in protecting against oxidative lung injury.\",\n      \"evidence\": \"Kinetic in vitro assays plus Prdx6-null and adenoviral-overexpression mouse hyperoxia/paraquat models\",\n      \"pmids\": [\"15890616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of peroxidase vs iPLA2 to lung protection not separated\", \"Tissue-specific substrate preferences unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed in intact cells that PRDX6 prevents phospholipid hydroperoxide accumulation and apoptosis, defining its antioxidant role at the membrane level.\",\n      \"evidence\": \"Antisense knockdown and stable overexpression in lung epithelial cells with lipid peroxidation readouts and adenoviral rescue\",\n      \"pmids\": [\"12372839\", \"12193653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine whether protection requires peroxidase, iPLA2, or both\", \"GSH-dependence mechanism not dissected at the level of membrane repair\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that irreversible hyperoxidation of the peroxidatic cysteine is not merely inactivating but switches PRDX6 toward enhanced iPLA2 activity and cell-cycle arrest, identifying a redox-driven activity switch.\",\n      \"evidence\": \"H2O2 treatment with anti-sulfinic acid immunoblot, iPLA2 assays, C47A/S32A mutants, and cell-cycle analysis\",\n      \"pmids\": [\"18826942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how Cys47 oxidation activates the distant Ser32 site unresolved\", \"Reversibility/recovery pathway in vivo unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SUMO1 conjugation at Lys122/142 and Thr177 phosphorylation as post-translational controls of PRDX6 abundance and dual activity.\",\n      \"evidence\": \"Site-directed mutagenesis with quantitative activity and stability assays in Prdx6-null complementation\",\n      \"pmids\": [\"28055018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase/protease responsible not identified here\", \"Kinase responsible for T177 not defined in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked aberrant SUMOylation to reduced PRDX6 transcription via impaired Sp1, connecting post-translational modification to gene-level decline during stress and aging.\",\n      \"evidence\": \"Sumo1-fused constructs, CAT reporter and gel-shift assays, and SENP1 rescue in lens epithelial cells\",\n      \"pmids\": [\"24910119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct evidence that SUMOylated PRDX6 modulates Sp1 not fully mechanistic\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the iPLA2 activity, not peroxidase, is specifically required for PRDX6 to support agonist-stimulated NADPH oxidase activity in phagocytes.\",\n      \"evidence\": \"shRNA knockdown and rescue with active-site mutants in PLB-985 cells under fMLF vs PMA stimulation\",\n      \"pmids\": [\"22678913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between iPLA2 product and oxidase assembly not defined\", \"Agonist-specificity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a physical-interaction mechanism for PRDX6 control of NADPH oxidase by showing it binds and stabilizes Noxa1/Nox1 components in an activity-dependent manner.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, mutant expression, MJ33 inhibition, and migration assays\",\n      \"pmids\": [\"27094494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilization is direct or requires iPLA2 lipid products unresolved\", \"Structural basis of the SH3 interaction not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended PRDX6 oxidase regulation to NOX2 by showing its PLA2 pocket mediates interaction with RAC required for oxidase maturation.\",\n      \"evidence\": \"Activity-based protein profiling, molecular dynamics, and NOX2 activity assays with the inhibitor Astragaloside IV in an acute lung injury model\",\n      \"pmids\": [\"37030053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRDX6–RAC binding interface not crystallographically resolved\", \"Single inhibitor-based mechanistic inference\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Initially attributed PRDX6 ferroptosis suppression to its iPLA2-mediated removal of lipid hydroperoxides.\",\n      \"evidence\": \"siRNA knockdown/overexpression with erastin/RSL3, LOOH measurement, and MJ33 synergy assays\",\n      \"pmids\": [\"31036877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test selenium-dependent contributions to GPX4\", \"HO-1 induction mechanism downstream of PRDX6 loss unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Redefined the dominant ferroptosis-protective mechanism, establishing PRDX6 as a selenium-acceptor protein that feeds selenocysteine-tRNA synthesis via SEPHS2 to sustain GPX4, rather than directly reducing PLOOH.\",\n      \"evidence\": \"Independent biochemical selenium-transfer assays, SEPHS2 interaction, CRISPR knockout, Prdx6-deficient mouse brains, and xenograft ferroptosis assays\",\n      \"pmids\": [\"38867112\", \"39547224\", \"39547222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selenide handoff to SEPHS2 not resolved\", \"Relationship between selenium-acceptor role and the two enzymatic activities unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the transcriptional circuitry controlling PRDX6, showing Bmal1 E-box and Nrf2 ARE cooperate for peak expression and impose circadian regulation.\",\n      \"evidence\": \"DNA-binding and reporter assays with E-box/ARE mutagenesis and in vivo rhythmic expression in mouse lenses\",\n      \"pmids\": [\"32784474\", \"29074861\", \"22113199\", \"33894270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-talk between the activators quantitatively unresolved\", \"Tissue-specificity of each element not systematically compared\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Klf9 as a direct ARE-induced repressor of PRDX6, explaining how excessive Nrf2 activation can paradoxically lower PRDX6 and promote ROS-driven death and inflammasome activation.\",\n      \"evidence\": \"Reporter/ChIP assays, Klf9 knockdown/overexpression, promoter mutagenesis, and Prdx6-null inflammasome analysis\",\n      \"pmids\": [\"31569690\", \"38003466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Threshold determinants of activator-vs-repressor balance unclear\", \"Single experimental system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the cellular consequences of complete PRDX6 loss, revealing broad redox-proteome remodeling, mitochondrial dysfunction, cell-cycle arrest, and a metabolic shift to glycolysis.\",\n      \"evidence\": \"CRISPR knockout in HepG2 with global/redox proteomics, Seahorse, flow cytometry, and electron microscopy\",\n      \"pmids\": [\"33035814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal cysteine-oxidation targets (e.g., PCNA) not functionally validated\", \"Direct vs indirect mitochondrial effects not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRDX6's three roles—peroxidase, iPLA2, and selenium-acceptor—are coordinated within a single protein and partitioned across cellular compartments and physiological contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model linking the catalytic sites to the selenium-acceptor function\", \"Compartment-specific deployment of each activity undefined\", \"Relative in vivo weight of each function across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 25]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 17, 18, 19]}\n    ],\n    \"complexes\": [\n      \"PRDX6–GSTπ heterodimer\"\n    ],\n    \"partners\": [\n      \"GSTP1\",\n      \"NOXA1\",\n      \"SEPHS2\",\n      \"JAK2\",\n      \"NPM1\",\n      \"RAC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}