{"gene":"PRDX6","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1998,"finding":"Human 1-Cys Prx (PRDX6) was shown to reduce H2O2 using Cys47 as the site of oxidation; mutation of Cys47 to serine abolished peroxidase activity. The oxidized intermediate is Cys-SOH. The enzyme is a cytosolic protein and neither thioredoxin nor glutathione could reduce the oxidized Cys47-SOH to support catalytic cycling.","method":"Recombinant protein expression in E. coli, site-directed mutagenesis (C47S), intracellular H2O2 measurement in NIH 3T3 cells, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with mutagenesis, replicated across multiple methods","pmids":["9497358"],"is_preprint":false},{"year":1998,"finding":"Crystal structure of human PRDX6 (hORF6) at 2.0 Å resolution revealed a thioredoxin fold in the N-terminal domain, a C-terminal dimerization domain, and an active-site Cys47 (present as cysteine-sulfenic acid in the crystal) located at the bottom of a narrow positively charged pocket that accounts for peroxidase activity without redox cofactors.","method":"X-ray crystallography at 2.0 Å resolution","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional active-site characterization","pmids":["9587003"],"is_preprint":false},{"year":2000,"finding":"PRDX6 (1-Cys peroxiredoxin) is a bifunctional enzyme with two distinct active sites: Cys47 in the PVCTTE motif is the catalytic residue for peroxidase (NSGPx) activity, while Ser32 in the GDSWG motif acts as the catalytic nucleophile for the acidic Ca2+-independent phospholipase A2 (aiPLA2) activity. Mutation of Ser32 to Ala abolishes PLA2 activity but not peroxidase activity; mutation of Cys47 to Ser abolishes peroxidase activity but not PLA2 activity. PLA2 activity is inhibited by MJ33 and diethyl p-nitrophenyl phosphate; peroxidase activity is inhibited by mercaptosuccinate.","method":"Recombinant protein expression in E. coli, site-directed mutagenesis (S32A, C47S), enzymatic assays (NSGPx at pH 8, aiPLA2 at pH 4), inhibitor studies, monoclonal antibody inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted bifunctional enzyme with orthogonal mutagenesis at each active site, inhibitor validation","pmids":["10893423"],"is_preprint":false},{"year":2002,"finding":"Antisense morpholino oligonucleotide-mediated suppression of PRDX6 in L2 rat lung epithelial cells led to ~44% decrease in glutathione peroxidase activity, accumulation of phosphatidylcholine hydroperoxide in plasma membranes, and apoptotic cell death (80% at 48 h), demonstrating that PRDX6 functions in intact cells to reduce phospholipid hydroperoxides and prevent apoptosis.","method":"Antisense morpholino oligonucleotide knockdown, HPLC conjugated diene assay, DPPH fluorescence for lipid peroxidation, annexin V/PI staining, TUNEL assay, adenoviral rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific lipid peroxidation readout, rescued by adenoviral PRDX6 re-expression","pmids":["12372839"],"is_preprint":false},{"year":2003,"finding":"Oxidative stress (H2O2, paraquat, hyperoxia) induces 1-Cys Prx (PRDX6) gene expression in rat lungs and lung cell lines at the transcriptional level; mRNA stability is unchanged and actinomycin D blocks induction, indicating transcriptional regulation. Induction is attenuated by antioxidants Trolox and N-acetylcysteine.","method":"Northern blot, immunoblot, actinomycin D treatment, antioxidant pre-treatment, in vivo hyperoxia mouse model","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple oxidative stimuli with transcriptional mechanistic evidence, single lab","pmids":["12851211"],"is_preprint":false},{"year":2004,"finding":"PRDX6 glutathione peroxidase activity requires heterodimerization with pi GST. Oxidized 1-cysPrx (with sulfenic acid at Cys47) heterodimerizes with GSH-saturated pi GST, which catalyzes glutathionylation of the oxidized Cys47, followed by spontaneous reduction of the mixed disulfide with GSH to restore activity. Maximum activation occurs at 1:1 molar ratio of piGST to 1-cysPrx.","method":"Partial purification co-elution, liposome-mediated delivery into NCI-H441 and MCF7 cells, in vitro reconstitution of heterodimerization and glutathionylation, enzyme activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstituted heterodimerization and glutathionylation mechanism in vitro, confirmed in two cell lines","pmids":["15004285"],"is_preprint":false},{"year":2004,"finding":"Adenovirus-mediated overexpression of 1-cysPrx (PRDX6) in mouse lungs (~2-fold increase) protected against hyperoxia-induced lung injury: reduced pleural effusion, lower lung wet/dry weight, less protein and cells in BAL fluid, lower TBARS and protein carbonyls, and improved survival during 100% O2 exposure.","method":"Adenoviral gene transfer in vivo, bronchoalveolar lavage analysis, lung injury markers (TBARS, protein carbonyls), survival analysis","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with multiple orthogonal lung injury readouts","pmids":["15136296"],"is_preprint":false},{"year":2005,"finding":"PRDX6 is a bifunctional enzyme with GSH peroxidase activity (using GSH as electron donor, rate constant ~3×10^6 M^-1 s^-1) and Ca2+-independent PLA2 activity (maximal at acidic pH). piGST-catalyzed glutathionylation of Cys47 is required to complete the enzymatic cycle. Prdx6-null mice were more sensitive to hyperoxia and paraquat. Inhibition of PLA2 activity alters lung surfactant phospholipid synthesis and turnover.","method":"In vitro enzymatic assays, Prdx6-null mice phenotyping, adenoviral overexpression, inhibitor studies (MJ33)","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical characterization combined with genetic knockout and overexpression models, multiple labs","pmids":["15890616"],"is_preprint":false},{"year":2007,"finding":"Transcriptional regulation of Prdx6 in mouse liver cells involves PKC and MEK pathways (induction by KGF, TNF-alpha is largely prevented by their inhibitors) and NF-κB normally suppresses Prdx6 expression (NF-κB inhibition markedly increases Prdx6). The first 160 bp of the proximal promoter support basal expression; 1200 bp increases expression sixfold.","method":"Reporter gene assays (promoter-CAT constructs), kinase inhibitors (PKC, MEK), NF-κB inhibitors, serum deprivation/restimulation experiments","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — promoter deletion analysis with pharmacological pathway dissection, single lab","pmids":["17382207"],"is_preprint":false},{"year":2011,"finding":"Specificity protein 1 (Sp1) directly activates PRDX6 transcription through three active Sp1 binding sites (-19/27, -61/69, -82/89) in the Prdx6 promoter. Curcumin enhances Sp1 binding and Prdx6 promoter activity; point mutagenesis of all three Sp1 sites abolishes curcumin-mediated transactivation. Sp1-driven Prdx6 upregulation protects lens epithelial cells from ROS-mediated apoptosis.","method":"DNA-protein binding assays (EMSA), ChIP assay, co-transfection with Sp1 and Prdx6 promoter-CAT constructs in LECs and Sp1-deficient SL2 cells, site-directed mutagenesis of Sp1 sites, Sp1 inhibitors","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — promoter mutagenesis, EMSA, ChIP, cell-based rescue with multiple orthogonal approaches","pmids":["22113199"],"is_preprint":false},{"year":2012,"finding":"PRDX6 physically binds to Nox activator 1 (Noxa1) via the Noxa1 SH3 domain (identified by yeast two-hybrid screening and confirmed by co-IP). Prdx6 stabilizes Noxa1 and supports Nox1-derived superoxide production. Both the peroxidase (C47S) and lipase (S32A) mutants of Prdx6 fail to bind/stabilize Nox1 components or support Nox1-mediated superoxide generation. The PLA2 inhibitor MJ-33 suppresses Nox1 activity. Wild-type but not mutant Prdx6 supports Nox1-mediated cell migration in HCT-116 cells.","method":"Yeast two-hybrid screening, co-IP in cells, Prdx6 knockdown and overexpression, site-directed mutagenesis (C47S, S32A), MJ-33 inhibitor, wound-closure assay","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1-2 — novel binding partner identified by Y2H, confirmed by Co-IP, mutagenesis at both active sites, functional migration readout","pmids":["27094494"],"is_preprint":false},{"year":2012,"finding":"The PLA2 activity of PRDX6 mediates enhancement of NADPH oxidase (phox) activity in response to fMLF (but not PMA) in differentiated PLB-985 neutrophil-like cells. Knockdown reduced oxidase activity; reintroduction of shRNA-resistant WT or peroxidase-dead (Prdx active site mutant) Prdx6-PLA2 restored the fMLF response, but PLA2 active site mutants failed to restore it.","method":"shRNA stable knockdown, stable transfection with shRNA-resistant constructs (WT, active site mutants), NADPH oxidase activity assays (fMLF vs PMA stimulation)","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean rescue experiment with active site mutant discrimination, clear functional phenotype","pmids":["22678913"],"is_preprint":false},{"year":2014,"finding":"PRDX6 promotes lung tumor growth via both its GPx (C47S mutation attenuates) and iPLA2 activities; overexpression activates p38, ERK1/2, and AP-1 signaling in lung cancer cells, and the C47S mutant (lacking peroxidase activity) attenuated these kinase activations as well as tumor growth in xenograft mice.","method":"Xenograft nude mice, site-directed mutagenesis (C47S), enzyme activity assays (GPx, iPLA2), Western blot for MAPK/AP-1, in vivo tumor growth measurement","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo xenograft with mutagenesis linking GPx active site to signaling and tumor phenotype","pmids":["24512906"],"is_preprint":false},{"year":2015,"finding":"PRDX6 physically interacts with JAK2 (co-localization in tumor tissues and co-IP in lung cancer cells) and promotes JAK2/STAT3 pathway activation and STAT3 DNA binding, contributing to urethane-induced lung tumor development in PRDX6-transgenic mice. CCL5 levels are increased in PRDX6-Tg tumors and CCL5 further activates JAK2/STAT3.","method":"PRDX6-transgenic mice, urethane carcinogen model, co-IP, co-localization (IHC/IF), STAT3 DNA binding assay, CCR5-knockout mice","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/co-localization with in vivo genetic model, single lab","pmids":["25582888"],"is_preprint":false},{"year":2017,"finding":"PRDX6 is aberrantly SUMOylated at lysines K122 and K142 by SUMO1 under oxidative stress, leading to loss of function and cell death. Sumoylation-deficient mutant Prdx6 K122/142R shows 30% increased GSH-peroxidase and 37% increased aiPLA2 activities and greater protein stability. Both peroxidase and PLA2 active sites (and phosphorylation at T177) are required for the mutant Prdx6 protective function.","method":"Site-directed mutagenesis (K122R, K142R, double mutant), enzyme activity assays, stability assays, Prdx6-/- LECs transduction with EGFP-SUMO1, TAT-fusion protein delivery, mutational analysis of functional sites","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — identification of SUMO1 conjugation sites by mutagenesis, quantified activity/stability gains, functional rescue in knockout cells","pmids":["28055018"],"is_preprint":false},{"year":2017,"finding":"Nrf2-mediated PRDX6 expression is driven through an ARE element at -357/-349 in the Prdx6 promoter. Progressive aging reduces Nrf2/ARE binding to this site, decreasing Prdx6 expression. Sulforaphane (SFN) restores Nrf2/ARE binding and Prdx6 expression; mutation of the ARE site abolishes SFN response. Knockdown of Prdx6 abrogates SFN-mediated cytoprotection, establishing Prdx6 as a prerequisite for SFN-mediated protection.","method":"Gel-shift (EMSA), ChIP assay, promoter activity assays with ARE mutation, Prdx6 siRNA knockdown, human aging lens specimens","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — EMSA and ChIP with ARE mutagenesis confirm Nrf2/ARE-Prdx6 axis; genetic requirement demonstrated by knockdown","pmids":["29074861"],"is_preprint":false},{"year":2019,"finding":"At higher doses of SFN, excessive Nrf2 activates Kruppel-like factor 9 (Klf9) through an ARE in the Klf9 promoter; Klf9 then binds repressive Klf9 binding elements (RKBE; 5'-CA/GCCC-3') in the Prdx6 promoter and suppresses Prdx6 transcription, increasing ROS and causing cell death. Klf9 depletion restores Prdx6 expression and cell survival.","method":"Klf9 promoter-ARE luciferase assay, Prdx6 promoter-reporter with RKBE mutagenesis, ChIP for Klf9 binding to Prdx6 promoter, ShKlf9 knockdown, Nrf2 gain-of-function","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic pathway defined by promoter mutagenesis, ChIP, and genetic depletion in same study","pmids":["31569690"],"is_preprint":false},{"year":2019,"finding":"PRDX6 knockdown significantly enhances lipid hydroperoxide (LOOH) accumulation and ferroptotic cell death triggered by erastin and RSL-3. This is correlated with transcriptional upregulation of heme oxygenase-1 (HO-1). The specific iPLA2 inhibitor MJ-33 synergistically enhances erastin-induced ferroptosis, indicating that PRDX6 suppresses ferroptosis through its iPLA2 activity.","method":"PRDX6 siRNA knockdown, ferroptosis inducers (erastin, RSL-3), LOOH measurement, HO-1 overexpression, MJ-33 inhibitor","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific inhibitor dissecting PLA2 vs peroxidase contributions, single lab","pmids":["31036877"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9 knockout of PRDX6 in HepG2 hepatocarcinoma cells causes mitochondrial dysfunction (reduced respiratory capacity, downregulated mitochondrial proteins, altered morphology), cell cycle arrest at G2/M, increased ROS and lipid peroxidation, autophagy, and redox changes at 254 Cys-peptides in 202 proteins. Oxidation of specific cysteines in PCNA was identified as a potential mechanism of mitosis entry block.","method":"CRISPR/Cas9 knockout, quantitative global and redox proteomics, flow cytometry, extracellular flux analysis, electron microscopy, Western blot","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multi-omics characterization and orthogonal cell biology methods","pmids":["33035814"],"is_preprint":false},{"year":2021,"finding":"PRDX6-iPLA2 activity (Asp140 site) is required for activation of astrocytes and M1 microglia polarization following ischemic stroke. PRDX6 phosphorylation at Thr177 (by ERK and p38 MAPKs) regulates its iPLA2 activity in astrocytes. Blocking iPLA2 activity (MJ33 or D140A mutation) inhibits NOX2 activation and Drp1-dependent mitochondrial fission, reducing ROS and neuroinflammation.","method":"PRDX6-D140A and T177A site-directed mutations, MJ33 inhibitor, NOX2 inhibitor (GSK2795039), ERK inhibitor (U0126), p38 inhibitor (SB202190), astrocyte-microglia co-culture, OGD/R model, in vivo ischemic stroke rat model","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic mutagenesis with specific inhibitors and co-culture functional readout, single lab","pmids":["38287382"],"is_preprint":false},{"year":2021,"finding":"Viral 3C protease (from FMDV and Senecavirus A) degrades PRDX6 via its proteolytic activity (independent of proteasome, lysosome, or caspase pathways). PRDX6 overexpression inhibits FMDV replication; knockdown promotes it. The antiviral function of PRDX6 depends on its iPLA2 activity (MJ33 promotes FMDV replication) but not peroxidase activity (mercaptosuccinate had no effect).","method":"PRDX6 overexpression and knockdown, 3Cpro expression constructs (WT and protease-dead mutant), MJ33 and mercaptosuccinate inhibitors, viral replication assays","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — active site dissection with inhibitors, protease-dead mutant control, two different picornaviruses, single lab","pmids":["33721217"],"is_preprint":false},{"year":2022,"finding":"Klf9 binds to repressive elements (RKBE) in the Prdx6 promoter and suppresses its expression under conditions of elevated oxidative stress. The Nrf2-Klf9-Prdx6 axis acts as a hormetic switch: moderate H2O2 increases Nrf2-driven Prdx6 expression, while high H2O2 (≥100 µM) causes Nrf2-mediated Klf9 upregulation that represses Prdx6, amplifying H2O2 and causing cell death. This was confirmed in Prdx6-deficient mouse LECs.","method":"Prdx6-/- mouse LECs, Klf9 overexpression and ShKlf9 knockdown, DCF oxidation (H2O2 measurement), promoter-reporter assays, dose-response H2O2 treatment","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout model with gain/loss-of-function Klf9 manipulation, single lab replicating prior finding","pmids":["35455944"],"is_preprint":false},{"year":2022,"finding":"S-palmitoylation at Cys47 of PRDX6 is predicted to competitively inhibit disulfide bond formation between Cys47 and Cys91, altering PRDX6 spatial topology. Palmitoylation status of Cys47 regulates the interaction between PRDX6 and the C-terminal domain of anion exchanger 3 (AE3), potentially affecting AE3 activity in dorsal root ganglion neurons. Immunofluorescence showed PRDX6 translocating between cytoplasm and cell membrane.","method":"Comparative proteomics (DRG of diabetic mice), palmitoylome profiling (HUVEC), bioinformatic palmitoylation site prediction, immunofluorescence for localization","journal":"Frontiers in endocrinology","confidence":"Low","confidence_rationale":"Tier 4 — palmitoylation sites computationally predicted; interaction with AE3 inferred, not biochemically validated","pmids":["36120430"],"is_preprint":false},{"year":2023,"finding":"Astragaloside IV (AST) inhibits PRDX6 PLA2 activity by binding to its PLA2 catalytic triad pocket, which alters PRDX6 conformation and disrupts the interaction between PRDX6 and RAC GTPase. This prevents RAC-GDI heterodimer activation, blocks NOX2 maturation, and reduces superoxide production.","method":"Activity-based protein profiling with AST probes, protein-protein interaction assays, molecular dynamics simulation, PLA2 activity assay, RAC activation assay, LPS-induced acute lung injury mouse model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — target engagement validated by probe capture, mechanistic interaction (PRDX6-RAC) confirmed by binding assay and functional NOX2 readout","pmids":["37030053"],"is_preprint":false},{"year":2024,"finding":"PRDX6 functions as a selenium-acceptor protein that interacts with selenophosphate synthetase 2 (SEPHS2) and facilitates intracellular selenium utilization by transferring selenium within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, enabling efficient GPX4 selenoprotein synthesis. Loss of PRDX6 reduces selenoprotein expression (including GPX4) and sensitizes cells to ferroptosis. This was confirmed in Prdx6-deficient mouse brains and tumor xenografts.","method":"PRDX6 genetic loss (CRISPR/KO), selenium metabolic tracing, biochemical selenium transfer assays, selenoprotein expression analysis, Prdx6-/- mouse brains, xenograft tumor models","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — novel selenium-transfer mechanism established by biochemical assays, confirmed in multiple in vivo models with functional ferroptosis readout","pmids":["38867112"],"is_preprint":false},{"year":2024,"finding":"PRDX6 acts as a selenium-acceptor protein that can react with selenide and interact with SEPHS2, providing an alternative pathway (independent of selenocysteine lyase SCLY) for selenium delivery to the selenocysteyl-tRNA synthesis machinery. This alternative route supports GPX4 expression and ferroptosis resistance, and is particularly relevant in MYCN-amplified neuroblastoma cells with elevated PRDX6.","method":"PRDX6 knockout in cancer cells, selenium metabolic experiments, biochemical interaction assays (PRDX6-SEPHS2), SCLY-independent pathway validation, human cancer cell line analyses","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — independent replication of selenium-transfer mechanism (concurrent with PMID 38867112), biochemical dissection of SCLY-independent pathway","pmids":["39547224"],"is_preprint":false},{"year":2024,"finding":"Cells lacking GPX4 retain substantial phospholipid hydroperoxide-reducing capacity. While PRDX6 overexpression alone does not prevent ferroptosis, genetic loss of PRDX6 sensitizes cancer cells to ferroptosis. The mechanism is that PRDX6 acts as a selenium-acceptor protein facilitating intracellular selenium utilization and GPX4 synthesis; Prdx6-deficient mouse brains show reduced GPX4 expression.","method":"GPX4 and PRDX6 double knockouts, PLOOH reduction capacity assays, PRDX6 overexpression ferroptosis assays, selenium utilization experiments, Prdx6-/- mouse brain GPX4 measurement, xenograft models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — genetic dissection of PLOOH-reducing capacity, in vivo mouse model, orthogonal selenium utilization data","pmids":["39547222"],"is_preprint":false},{"year":2017,"finding":"Nucleophosmin (NPM) forms a complex with CBX3 that promotes PRDX6 transcription; NPM knockdown reduces PRDX6 expression and increases ROS, while NPM overexpression upregulates PRDX6 and decreases ROS. Co-immunoprecipitation confirmed NPM-PRDX6 protein interaction.","method":"Co-IP, siRNA knockdown, NPM overexpression, CBX3-NPM dual luciferase reporter assay, ROS measurement","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with promoter reporter assay, functional ROS readout, single lab","pmids":["28513872"],"is_preprint":false},{"year":2021,"finding":"The TLR4/NF-κB signaling pathway mediates the radioprotective effect of exogenous Prdx6. Exogenous Prdx6 (including the peroxidase-dead C47S mutant) activates NF-κB in irradiated cells; TLR4 inhibitors (especially those targeting the extracellular domain) significantly reduce this radioprotective effect, indicating Prdx6 interacts with TLR4 receptor to trigger cellular defense independently of its peroxidase activity.","method":"Exogenous recombinant Prdx6 and Prdx6-C47S mutant protein delivery, TLR4 inhibitors, NF-κB activation assay, cell survival assay, in vitro X-ray irradiation model","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis separating peroxidase from TLR4-signaling function, pharmacological pathway validation, single lab","pmids":["33727039"],"is_preprint":false}],"current_model":"PRDX6 is a unique bifunctional 1-Cys peroxiredoxin with two distinct active sites: Cys47 (within PVCTTE) catalyzes glutathione-dependent reduction of H2O2 and phospholipid hydroperoxides (requiring piGST-mediated heterodimerization and glutathionylation to complete the catalytic cycle), while Ser32 (within GDSWG) provides the catalytic nucleophile for Ca2+-independent acidic PLA2 activity; both activities are regulated by SUMO1 conjugation at K122/K142, phosphorylation at Thr177 (by ERK/p38), and transcriptionally by Nrf2/ARE and Sp1 (counterbalanced by Klf9-mediated repression under high oxidative load); PRDX6 additionally acts as a selenium-acceptor protein that facilitates intracellular selenium transfer to the selenocysteyl-tRNA synthesis machinery (interacting with SEPHS2) to support GPX4 expression and ferroptosis resistance, and its iPLA2 activity supports NADPH oxidase (Nox1/Nox2) activation through binding to Noxa1 and RAC subunits, positioning PRDX6 as a central node linking phospholipid hydroperoxide reduction, surfactant metabolism, ROS generation, and selenoprotein synthesis."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of PRDX6 as a 1-Cys peroxiredoxin with Cys47 as the catalytic residue resolved the question of how a single-cysteine peroxiredoxin reduces H₂O₂, revealing a sulfenic acid intermediate but leaving the electron donor unknown.","evidence":"Recombinant mutagenesis (C47S) and intracellular H₂O₂ assays in NIH 3T3 cells, plus 2.0 Å crystal structure showing Cys47-SOH","pmids":["9497358","9587003"],"confidence":"High","gaps":["Physiological electron donor for Cys47-SOH regeneration not identified","Substrate specificity beyond H₂O₂ not tested","Oligomeric state in solution not characterized"]},{"year":2000,"claim":"Discovery that PRDX6 harbors a second catalytic site (Ser32/GDSWG for aiPLA2 activity) independent of the Cys47 peroxidase site established it as a unique bifunctional enzyme, raising the question of how these two activities are coordinately regulated.","evidence":"Orthogonal site-directed mutagenesis (S32A, C47S) with selective inhibitors (MJ33 vs. mercaptosuccinate) in recombinant protein assays","pmids":["10893423"],"confidence":"High","gaps":["Physiological substrates for PLA2 activity in cells not defined","Structural basis for two independent active sites in one polypeptide not resolved"]},{"year":2002,"claim":"Demonstration that PRDX6 loss in lung epithelial cells causes phosphatidylcholine hydroperoxide accumulation and apoptosis established that PRDX6 is a physiologically relevant phospholipid hydroperoxide reductase, not merely an H₂O₂ scavenger.","evidence":"Antisense morpholino knockdown in L2 cells with HPLC lipid peroxidation readout and adenoviral rescue","pmids":["12372839"],"confidence":"High","gaps":["Relative contributions of peroxidase vs. PLA2 activity to cytoprotection not dissected","In vivo lung phenotype not yet examined"]},{"year":2004,"claim":"The long-standing puzzle of how oxidized Cys47-SOH is regenerated was solved by showing that piGST heterodimerizes with PRDX6 to catalyze glutathionylation of the sulfenic acid, completing the catalytic cycle with GSH as the ultimate electron donor.","evidence":"In vitro reconstitution of piGST–PRDX6 heterodimerization and glutathionylation, confirmed by liposome-mediated delivery into NCI-H441 and MCF7 cells","pmids":["15004285"],"confidence":"High","gaps":["Structural details of the piGST–PRDX6 heterodimer interface not determined","Whether other GST isoforms can substitute is unclear"]},{"year":2004,"claim":"In vivo gain-of-function (adenoviral overexpression) and subsequent loss-of-function (Prdx6-null mice) experiments confirmed that PRDX6 is a major protective factor against oxidative lung injury, linking its biochemistry to organ-level physiology.","evidence":"Adenoviral PRDX6 overexpression in mouse lungs under hyperoxia; Prdx6-null mice showing sensitivity to hyperoxia and paraquat","pmids":["15136296","15890616"],"confidence":"High","gaps":["Relative in vivo contributions of peroxidase vs. PLA2 activity not separated","Surfactant metabolism phenotype not fully characterized"]},{"year":2011,"claim":"Mapping of the transcriptional regulatory architecture showed that Sp1 directly activates PRDX6 through three proximal promoter sites, providing the first mechanistic understanding of basal PRDX6 expression control.","evidence":"EMSA, ChIP, promoter-CAT mutagenesis in LECs and Sp1-deficient SL2 cells","pmids":["22113199"],"confidence":"High","gaps":["Interplay between Sp1 and other transcription factors (Nrf2) at the promoter not addressed","Tissue-specific regulation not explored"]},{"year":2012,"claim":"Discovery that PRDX6 binds Noxa1 and supports Nox1/Nox2-dependent superoxide production revealed a surprising pro-oxidant role for an antioxidant enzyme, showing that its iPLA2 activity directly participates in NADPH oxidase activation.","evidence":"Yeast two-hybrid, co-IP, C47S/S32A mutagenesis, MJ33 inhibition, and rescue of Nox1-mediated migration and Nox2 activity in neutrophil-like cells","pmids":["27094494","22678913"],"confidence":"High","gaps":["Whether PRDX6 provides arachidonic acid for Nox assembly or acts as a scaffolding factor not fully resolved","Structural basis of PRDX6–Noxa1 interaction unknown"]},{"year":2017,"claim":"Identification of SUMO1 conjugation at K122/K142 as an inhibitory modification and Thr177 phosphorylation as an activating modification established the post-translational regulatory code governing both PRDX6 activities, and the Nrf2/ARE element at −357 was mapped as the oxidative stress–responsive transcriptional driver.","evidence":"Site-directed mutagenesis of SUMO sites in Prdx6−/− LECs; EMSA/ChIP with ARE mutagenesis for Nrf2; promoter-reporter with RKBE mutagenesis","pmids":["28055018","29074861"],"confidence":"High","gaps":["SUMO E3 ligase responsible for PRDX6 SUMOylation not identified","Kinase specificity for Thr177 phosphorylation not fully dissected in vivo"]},{"year":2019,"claim":"The Nrf2–Klf9–PRDX6 hormetic switch was delineated: at high oxidative stress, Nrf2-induced Klf9 represses PRDX6 transcription through RKBE elements, converting a protective response into a death-promoting one, explaining dose-dependent outcomes of antioxidant signaling.","evidence":"Klf9 ChIP on PRDX6 promoter, RKBE mutagenesis, Klf9 knockdown rescue, dose-response H₂O₂ in Prdx6−/− LECs","pmids":["31569690","35455944"],"confidence":"High","gaps":["Whether Klf9 repression of PRDX6 operates in non-ocular tissues not tested","Thresholds for the hormetic switch in vivo not defined"]},{"year":2019,"claim":"PRDX6 knockdown was shown to enhance ferroptotic cell death with lipid hydroperoxide accumulation, and the iPLA2 inhibitor MJ33 synergized with erastin, implicating PRDX6's PLA2 activity specifically in ferroptosis suppression.","evidence":"siRNA knockdown with erastin/RSL-3 treatment, LOOH measurement, MJ33 inhibitor in cancer cells","pmids":["31036877"],"confidence":"Medium","gaps":["Peroxidase contribution to ferroptosis resistance not cleanly separated by mutagenesis in this study","In vivo ferroptosis relevance not established at this point"]},{"year":2021,"claim":"PRDX6-iPLA2 activity was linked to NOX2 activation and Drp1-dependent mitochondrial fission in astrocytes after ischemic stroke, extending the Nox-activating role to neuroinflammation and identifying ERK/p38-mediated Thr177 phosphorylation as the upstream activating signal.","evidence":"D140A and T177A mutagenesis, MJ33/NOX2/ERK/p38 inhibitors, astrocyte–microglia co-culture and in vivo rat stroke model","pmids":["38287382"],"confidence":"Medium","gaps":["Direct measurement of PRDX6 Thr177 phosphorylation stoichiometry in vivo not reported","Whether astrocyte PRDX6-iPLA2 generates specific lipid mediators not characterized"]},{"year":2024,"claim":"A fundamentally new function was uncovered: PRDX6 acts as a selenium-acceptor protein that interacts with SEPHS2 to channel selenium into selenocysteyl-tRNA synthesis, sustaining GPX4 expression and ferroptosis resistance independently of its own enzymatic activities.","evidence":"CRISPR knockout, selenium metabolic tracing, biochemical selenium transfer assays, Prdx6−/− mouse brains showing reduced GPX4, xenograft models; independently confirmed in two concurrent studies","pmids":["38867112","39547224","39547222"],"confidence":"High","gaps":["Structural basis of PRDX6–SEPHS2 interaction not resolved","Whether selenium-transfer function requires a specific PRDX6 oxidation state is unknown","Relative contribution of selenium-transfer vs. direct PLOOH reduction to ferroptosis resistance not quantified"]},{"year":null,"claim":"Key unresolved questions include the structural basis of how two independent active sites and the selenium-transfer function coexist in one polypeptide, the tissue-specific hierarchy of PRDX6's multiple functions, and the full spectrum of lipid mediators generated by its iPLA2 activity in different physiological contexts.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of PRDX6–piGST or PRDX6–SEPHS2 complexes","In vivo tissue-specific contributions of peroxidase vs. iPLA2 vs. selenium-transfer not genetically dissected","Identity of lipid products generated by iPLA2 activity in different cell types not systematically profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,1,2,3,5,7]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,5,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,7,10,11,17,19]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,3,7,17]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[24,25,26]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,22]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,4,6,7,14,15,16,18,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,7,24,25,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,17,24,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,23,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,12,13,19]}],"complexes":[],"partners":["GSTP1","NOXA1","SEPHS2","RAC1","JAK2","NPM1"],"other_free_text":[]},"mechanistic_narrative":"PRDX6 is a bifunctional 1-Cys peroxiredoxin that integrates phospholipid hydroperoxide reduction, phospholipid remodeling, NADPH oxidase activation, and selenium metabolism into a single polypeptide. Its peroxidase activity is mediated by Cys47 in the PVCTTE motif, which forms a sulfenic acid intermediate that is regenerated through piGST-catalyzed glutathionylation, while an independent Ca²⁺-independent acidic phospholipase A2 (aiPLA2) activity uses Ser32 in the GDSWG motif as catalytic nucleophile; both active sites are required for full cytoprotection against oxidative injury and for supporting Nox1/Nox2-dependent superoxide generation via direct binding to Noxa1 and RAC [PMID:10893423, PMID:15004285, PMID:27094494, PMID:22678913, PMID:38287382]. PRDX6 also functions as a selenium-acceptor protein that interacts with SEPHS2 to deliver selenium to the selenocysteyl-tRNA synthesis machinery, thereby sustaining GPX4 expression and conferring ferroptosis resistance independently of its own catalytic activities [PMID:38867112, PMID:39547224, PMID:39547222]. Transcription is positively regulated by Nrf2 through an ARE at −357/−349 and by Sp1 through proximal promoter sites, while excessive oxidative stress triggers Nrf2-dependent induction of Klf9, which binds repressive RKBE elements in the PRDX6 promoter to create a hormetic off-switch that amplifies ROS and promotes cell death [PMID:29074861, PMID:22113199, PMID:31569690, PMID:35455944]. Both enzymatic activities and protein stability are further modulated by SUMO1 conjugation at K122/K142 (inhibitory) and ERK/p38-mediated phosphorylation at Thr177 (activating iPLA2) [PMID:28055018, PMID:38287382]."},"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 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S32A mutation abolishes PLA2 activity without affecting peroxidase; C47S mutation abolishes peroxidase activity without affecting PLA2.\",\n      \"method\": \"Recombinant protein expression in E. coli, active-site mutagenesis (S32A, C47S), enzymatic assays for PLA2 and NSGPx activities, inhibitor studies with isoform-specific antibodies and chemical inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted enzyme with mutagenesis at both active sites plus inhibitor cross-validation\",\n      \"pmids\": [\"10893423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Activation of PRDX6 (1-cysPrx) requires heterodimerization with pi GST: pi GST saturated with GSH heterodimerizes with oxidized 1-cysPrx, catalyzes glutathionylation of the oxidized Cys47 sulfenic acid, and the resulting mixed disulfide is then spontaneously reduced by GSH to restore peroxidase activity. Maximum activation occurs at a 1:1 molar ratio of GSH-saturated pi GST to 1-cysPrx.\",\n      \"method\": \"Partial purification co-chromatography, in vitro reconstitution, liposome-mediated protein delivery into cells lacking pi GST (NCI-H441) or PRDX6 (MCF7), molar ratio titration assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mechanistic follow-up in cell-based delivery experiments\",\n      \"pmids\": [\"15004285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PRDX6 uses GSH as electron donor to reduce H2O2, organic hydroperoxides, and phospholipid hydroperoxides (kcat ~5 µmol/mg/min; k1 ~3×10^6 M^-1 s^-1). Oxidation of Cys47 to sulfenic acid during catalysis requires piGST-catalyzed glutathionylation and reduction with GSH to complete the enzymatic cycle. The PLA2 activity is Ca2+-independent and maximal at acidic pH.\",\n      \"method\": \"In vitro enzymatic assays, kinetic analysis, Prdx6-null mouse studies (hyperoxia/paraquat models), adenoviral overexpression\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinetics plus genetic (null mouse) confirmation replicated across labs\",\n      \"pmids\": [\"15890616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Knockdown of endogenous 1-cysPrx (PRDX6) in lung epithelial cells using antisense morpholino oligonucleotides causes accumulation of phosphatidylcholine hydroperoxides in plasma membranes and triggers apoptosis; this phenotype is rescued by adenoviral PRDX6 overexpression or vitamin E analogue pretreatment, establishing PRDX6 as a functional antioxidant that prevents phospholipid hydroperoxide accumulation and apoptosis.\",\n      \"method\": \"Antisense morpholino oligonucleotide knockdown, HPLC assay for phosphatidylcholine hydroperoxides, DPPP fluorescence, annexin V/PI staining, TUNEL assay, adenoviral rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with specific biochemical readout (PLOOH) and adenoviral rescue\",\n      \"pmids\": [\"12372839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRDX6 binds to and stabilizes the Nox activator 1 (Noxa1) via the Noxa1 SH3 domain (identified by yeast two-hybrid and confirmed by co-immunoprecipitation), and supports NADPH oxidase 1 (Nox1)-dependent superoxide generation and cell migration. Both the peroxidase-dead (C47S) and lipase-dead (S32A) mutants of PRDX6 fail to bind/stabilize Nox1 components or support Nox1 activity, and the PLA2 inhibitor MJ-33 suppresses Nox1 activity, indicating the PLA2 activity mediates Nox1 regulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, PRDX6 knockdown, stable transfection of wild-type and active-site mutants, superoxide production assays, wound-closure migration assay, MJ-33 inhibitor treatment\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed, mutant rescue experiments, multiple cell models\",\n      \"pmids\": [\"27094494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRDX6 promotes lung tumor progression through both its GPx and iPLA2 activities; the C47S mutant (peroxidase-dead) attenuates PRDX6-mediated activation of p38, ERK1/2, and AP-1, as well as tumor growth in nude mouse xenografts, demonstrating that peroxidase activity (Cys47) is required for MAPK/AP-1 signaling downstream of PRDX6.\",\n      \"method\": \"Xenograft nude mouse model, PRDX6 overexpression/C47S mutant transfection, Western blot for MAPK phosphorylation, AP-1 DNA binding assay, enzymatic activity assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with in vivo xenograft confirmation, single lab\",\n      \"pmids\": [\"24512906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRDX6 physically interacts with JAK2 in tumor tissues and lung cancer cells (co-localization and co-immunoprecipitation), and increasing PRDX6 levels enhances JAK2/STAT3 pathway activation and STAT3 DNA binding, linking PRDX6 to cytokine signaling via JAK2.\",\n      \"method\": \"Co-immunoprecipitation, co-localization immunofluorescence, PRDX6 transgenic mice (urethane-induced lung tumor model), STAT3 DNA binding assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with in vivo transgenic model, single lab\",\n      \"pmids\": [\"25582888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRDX6 is aberrantly sumoylated at Lys122 and Lys142 by SUMO1 under oxidative stress, which destabilizes the protein and reduces its GSH-peroxidase and aiPLA2 activities. The K122/142R mutant escapes sumoylation, gains enhanced enzymatic activities (~30% higher GPx, ~37% higher aiPLA2), and provides superior protection against oxidative stress-induced cell death. Phosphorylation at Thr177 is essential for optimal PLA2 activity.\",\n      \"method\": \"Site-directed mutagenesis (K122R, K142R, T177A), enzymatic activity assays, stability assays, EGFP-SUMO1 co-expression in Prdx6-/- lens epithelial cells, TAT-fusion protein delivery\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis at modification sites with quantitative enzymatic readouts and cell rescue experiments\",\n      \"pmids\": [\"28055018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRDX6 is a negative regulator of ferroptosis; its knockdown enhances lipid ROS (LOOH) and ferroptotic cell death triggered by erastin or RSL-3, and this enhancement is correlated with transcriptional activation of heme oxygenase-1. The PLA2-specific inhibitor MJ-33 synergistically enhances erastin-induced ferroptosis, indicating PRDX6 removes LOOH via its iPLA2 activity to suppress ferroptosis.\",\n      \"method\": \"siRNA knockdown, PRDX6 overexpression, lipid ROS measurement, ferroptosis inducers (erastin, RSL-3), MJ-33 pharmacological inhibition, heme oxygenase-1 overexpression\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with pharmacological inhibitor of specific activity, single lab\",\n      \"pmids\": [\"31036877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 acts as a selenium-acceptor/transfer protein within the selenocysteyl-tRNA[Ser]Sec synthesis machinery: loss of PRDX6 reduces efficiency of intracellular selenium utilization, decreases expression of multiple selenoproteins (including GPX4), and induces ferroptosis. PRDX6 can react with selenide and interact with SEPHS2, facilitating selenium delivery for selenophosphate production and efficient Sec-tRNA biosynthesis.\",\n      \"method\": \"Genetic loss-of-function (PRDX6 knockout), selenoprotein expression profiling, biochemical interaction with SEPHS2, selenide reactivity assays, Prdx6-deficient mouse brains (GPX4 measurement), tumor xenograft ferroptosis sensitivity\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (biochemical, genetic, in vivo), two independent papers in same issue\",\n      \"pmids\": [\"38867112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 mediates an alternative pathway of selenocysteine (Sec) metabolism independent of selenocysteine lyase (SCLY): PRDX6 reacts with selenide and interacts with SEPHS2 (selenophosphate synthetase 2), potentially acting as a selenium delivery system for selenophosphate synthesis and Sec-tRNA biosynthesis, thereby facilitating GPX4 expression and ferroptosis resistance.\",\n      \"method\": \"Biochemical reconstitution of selenide reactivity, PRDX6-SEPHS2 protein interaction, PRDX6 knockout in human cancer cells, ferroptosis sensitivity assays, SCLY-independent selenium flux studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical demonstration plus genetic KO with functional validation, independently confirmed by concurrent Nature Struct Mol Biol paper\",\n      \"pmids\": [\"39547224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cells lacking GPX4 retain substantial phospholipid hydroperoxide-reducing capacity; although PRDX6 overexpression alone does not prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis by reducing GPX4 expression (via impaired selenium utilization) rather than via direct PLOOH peroxidase activity. Prdx6-deficient mouse brains show reduced GPX4 expression.\",\n      \"method\": \"PRDX6 knockout and overexpression in cancer cells, PLOOH reduction assays, GPX4 expression analysis, Prdx6-/- mouse brain tissue, tumor xenograft ferroptosis experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic dissection across multiple models including in vivo\",\n      \"pmids\": [\"39547222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX6 knockout in HepG2 hepatocarcinoma cells (CRISPR/Cas9) causes diminished mitochondrial respiratory capacity, altered mitochondrial morphology, accumulation of autophagic vesicles, increased ROS, cell cycle arrest at G2/M transition (without apoptosis), and redox changes at critical cysteine residues in 202 proteins including PCNA oxidation. Loss of PLA2 activity affects lipid signaling; loss of peroxidase activity induces cysteine redox changes. GSH/Glutaredoxin system is downregulated.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative global and redox proteomics, flow cytometry, extracellular flux analysis, Western blot, electron microscopy\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple orthogonal readouts (proteomics, functional assays, microscopy)\",\n      \"pmids\": [\"33035814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The PLA2 activity (not the peroxidase activity) of PRDX6 mediates enhancement of phagocyte NADPH oxidase (phox) activity in response to fMLF in a neutrophil cell model: knockdown reduces fMLF-stimulated oxidase activity; reintroduction of wild-type or peroxidase-dead (C47S) PRDX6 restores activity, but PLA2-dead (S32A) mutant fails to restore it.\",\n      \"method\": \"Stable shRNA knockdown in PLB-985 cells, stable transfection of WT and active-site mutants (C47S, S32A), NADPH oxidase activity assay (fMLF vs. PMA stimulation)\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific mutant rescue experiment, single lab\",\n      \"pmids\": [\"22678913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nucleophosmin (NPM) regulates PRDX6 expression and interacts physically with PRDX6: co-immunoprecipitation confirms NPM-PRDX6 complex formation; NPM knockdown decreases PRDX6 and increases ROS, while NPM overexpression upregulates PRDX6 and decreases ROS. NPM1 inhibitor NSC348884 decreases PRDX6 and upregulates ROS.\",\n      \"method\": \"Co-immunoprecipitation, NPM knockdown/overexpression, ROS measurement, NPM inhibitor treatment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional knockdown/OE, single lab\",\n      \"pmids\": [\"28513872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRDX6 is degraded by the 3C protease (3Cpro) of porcine picornaviruses (FMDV, SVA) through direct proteolytic cleavage (protease activity required; proteasome/lysosome/caspase-independent). PRDX6 overexpression inhibits FMDV replication and enhances type I interferon signaling, while knockdown promotes viral replication; the PLA2 inhibitor MJ-33 (but not the peroxidase inhibitor mercaptosuccinate) promotes FMDV replication, indicating the antiviral function depends on PLA2 activity.\",\n      \"method\": \"Overexpression/knockdown of PRDX6, viral replication assays, 3Cpro protease mutant expression, proteasome/lysosome/caspase inhibitor treatments, MJ-33 and mercaptosuccinate pharmacological inhibition, interferon signaling assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — viral protease specificity demonstrated with mutants and pathway inhibitors, single lab\",\n      \"pmids\": [\"33721217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRDX6 protein levels are regulated post-translationally by pro-inflammatory cytokines (TNF-α + IFN-γ) via the JNK signaling pathway and calpain/proteasome proteolysis systems in pancreatic beta cells; blocking JNK or calpain/proteasome systems restores PRDX6 protein levels. PRDX6 knockdown increases beta cell susceptibility to oxidative stress.\",\n      \"method\": \"siRNA knockdown, JNK inhibitor, calpain/proteasome inhibitors, cytokine treatment, Western blot and RT-PCR, ROS measurement\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of degradation pathway with KD phenotype, single lab\",\n      \"pmids\": [\"23623867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Thr177 phosphorylation of human PRDX6 (by ERK-family kinases) increases its PLA2 activity, especially at neutral pH. This mechanism is conserved in non-mammalian Prdx6 orthologues, where phosphorylation of the conserved Thr residue by human Erk2 similarly increases PLA2 activity.\",\n      \"method\": \"In vitro phosphorylation by recombinant Erk2, mass spectrometry (phosphorylation confirmation), PLA2 enzymatic assays with unilamellar liposomes, thin-layer chromatography\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with MS confirmation and enzymatic readout\",\n      \"pmids\": [\"30832204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 iPLA2 activity in astrocytes regulates NOX2-derived ROS production and Drp1-dependent mitochondrial fission following ischemia-reperfusion; the D140A mutation (blocking iPLA2 active site) inhibits astrocyte activation and M1 microglia polarization. ERK and p38 MAPK regulate PRDX6 iPLA2 activity through phosphorylation at Thr177.\",\n      \"method\": \"PRDX6 D140A and T177A site-directed mutagenesis, co-culture system (astrocytes + microglia), NOX2 inhibitor (GSK2795039), Drp1 inhibitor (Mdivi-1), ERK inhibitor (U0126), p38 inhibitor (SB202190), OGD/R model, in vivo ischemic stroke model\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific mutagenesis with pathway inhibitors, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38287382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Astragaloside IV (AST) inhibits the PLA2 activity of PRDX6 by binding the PLA2 catalytic triad pocket, altering PRDX6 conformation and interfering with PRDX6-RAC interaction, thereby preventing RAC activation, NOX2 maturation, and superoxide production.\",\n      \"method\": \"Activity-based protein profiling with AST functional probe, small molecule-protein interaction assays, molecular dynamics simulation, PRDX6-RAC co-immunoprecipitation, NOX2 activity assay, acute lung injury mouse model\",\n      \"journal\": \"Phytomedicine : international journal of phytotherapy and phytopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical target identification with mechanistic follow-up, single lab\",\n      \"pmids\": [\"37030053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Specificity protein 1 (Sp1) directly activates PRDX6 transcription through three active Sp1 binding sites (-19/27, -61/69, -82/89) in the PRDX6 promoter; point mutagenesis of these sites abolishes curcumin-mediated transactivation, and Sp1 inhibition prevents curcumin-induced PRDX6 upregulation.\",\n      \"method\": \"Promoter-reporter (CAT) assays, Sp1 site mutagenesis, co-transfection in Sp1-deficient (SL2) cells, DNA-protein binding assays, chromatin immunoprecipitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis with co-transfection in Sp1-null cells confirms direct binding\",\n      \"pmids\": [\"22113199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kruppel-like factor 9 (Klf9) binds to repressive Klf9 binding elements (RKBE; 5-CA/GCCC-3) in the PRDX6 promoter and represses PRDX6 transcription; at high Nrf2 activity (high dose SFN), Nrf2 drives Klf9 expression via ARE in the Klf9 promoter, which then suppresses PRDX6, increases ROS, and causes cell death.\",\n      \"method\": \"Promoter-reporter assays, Klf9 knockdown (ShRNA), Klf9 overexpression, Klf9 binding element identification and mutagenesis, ROS measurement, lens epithelial cell viability assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding confirmed with functional knockdown/OE, single lab\",\n      \"pmids\": [\"31569690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Adenovirus-mediated overexpression of PRDX6 in mouse lungs (~2-fold increase) protects against hyperoxic injury, as demonstrated by reduced pleural effusion, lower lung wet/dry weight, less bronchoalveolar lavage protein/cells, and lower thiobarbituric acid-reactive substances and protein carbonyls, establishing a direct in vivo protective role for PRDX6 peroxidase function in the lung.\",\n      \"method\": \"Adenoviral gene transfer in mice, survival analysis under 100% O2, bronchoalveolar lavage analysis, oxidative damage markers (TBARS, protein carbonyls)\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo gene delivery with multiple biochemical endpoints, single lab\",\n      \"pmids\": [\"15136296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA Mir9-3hg suppresses cardiomyocyte ferroptosis by binding and downregulating Pum2 protein (demonstrated by RNA-binding protein immunoprecipitation); Pum2 binds the PRDX6 promoter (ChIP assay) and represses PRDX6 expression, thereby promoting ferroptosis. Reduced Pum2 thus de-represses PRDX6, which protects against ferroptosis.\",\n      \"method\": \"RIP (RNA binding protein immunoprecipitation), ChIP assay (Pum2 binding to PRDX6 promoter), siRNA knockdown of Mir9-3hg and Pum2, ferroptosis markers (ROS, iron, GSH, lipid peroxidation), H/R cell model and I/R mouse model\",\n      \"journal\": \"Nutrition, metabolism, and cardiovascular diseases : NMCD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and ChIP establish the Pum2-PRDX6 regulatory axis, single lab\",\n      \"pmids\": [\"34953631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S-palmitoylation of PRDX6 at Cys47 and Cys91 (bioinformatic prediction and immunofluorescence evidence for membrane translocation) may competitively inhibit disulfide bond formation between these cysteines and alter PRDX6 spatial topology. The palmitoylation status of Cys47 affects interaction between PRDX6 and the C-terminal domain of anion exchanger 3 (AE3), thereby regulating AE3 activity in neurons.\",\n      \"method\": \"Palmitoylome profiling (proteomic), immunofluorescence localization, bioinformatic palmitoylation site prediction, protein function analysis\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — primarily bioinformatic/proteomic prediction with limited direct biochemical validation of the palmitoylation-function link\",\n      \"pmids\": [\"36120430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPM1 promotes PRDX6 transcription via a complex with CBX3: co-immunoprecipitation confirms NPM1-CBX3 complex formation, and dual-luciferase reporter assays confirm that this complex promotes PRDX6 transcription. NPM1 knockdown reduces PRDX6 expression and GPx/PLA2 activities while increasing ROS.\",\n      \"method\": \"Co-immunoprecipitation (NPM1-CBX3), dual-luciferase PRDX6 promoter reporter assay, NPM1 knockdown/overexpression, enzymatic activity assays, in vivo xenograft\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus promoter reporter with functional enzymatic readouts, single lab\",\n      \"pmids\": [\"35659568\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX6 is a unique bifunctional 1-Cys peroxiredoxin that uses Cys47 for GSH-dependent reduction of H2O2, organic hydroperoxides, and phospholipid hydroperoxides (requiring heterodimerization with piGST for glutathionylation-mediated catalytic cycle completion) and Ser32 for Ca2+-independent, acidic-pH-optimal phospholipase A2 (aiPLA2) activity; its iPLA2 activity (activated by ERK/p38-mediated Thr177 phosphorylation) supports NADPH oxidase (Nox1/Nox2) activation and cell migration via binding to Noxa1/RAC, while both activities together protect cells from ferroptosis—partly by direct phospholipid hydroperoxide reduction and, critically, by facilitating intracellular selenium utilization through interaction with SEPHS2 to maintain GPX4 selenoprotein expression; aberrant SUMO1 conjugation at Lys122/142 destabilizes the protein and reduces both enzymatic activities, and transcription is activated by Sp1 and Nrf2/ARE but repressed by Klf9.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human 1-Cys Prx (PRDX6) was shown to reduce H2O2 using Cys47 as the site of oxidation; mutation of Cys47 to serine abolished peroxidase activity. The oxidized intermediate is Cys-SOH. The enzyme is a cytosolic protein and neither thioredoxin nor glutathione could reduce the oxidized Cys47-SOH to support catalytic cycling.\",\n      \"method\": \"Recombinant protein expression in E. coli, site-directed mutagenesis (C47S), intracellular H2O2 measurement in NIH 3T3 cells, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with mutagenesis, replicated across multiple methods\",\n      \"pmids\": [\"9497358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Crystal structure of human PRDX6 (hORF6) at 2.0 Å resolution revealed a thioredoxin fold in the N-terminal domain, a C-terminal dimerization domain, and an active-site Cys47 (present as cysteine-sulfenic acid in the crystal) located at the bottom of a narrow positively charged pocket that accounts for peroxidase activity without redox cofactors.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional active-site characterization\",\n      \"pmids\": [\"9587003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRDX6 (1-Cys peroxiredoxin) is a bifunctional enzyme with two distinct active sites: Cys47 in the PVCTTE motif is the catalytic residue for peroxidase (NSGPx) activity, while Ser32 in the GDSWG motif acts as the catalytic nucleophile for the acidic Ca2+-independent phospholipase A2 (aiPLA2) activity. Mutation of Ser32 to Ala abolishes PLA2 activity but not peroxidase activity; mutation of Cys47 to Ser abolishes peroxidase activity but not PLA2 activity. PLA2 activity is inhibited by MJ33 and diethyl p-nitrophenyl phosphate; peroxidase activity is inhibited by mercaptosuccinate.\",\n      \"method\": \"Recombinant protein expression in E. coli, site-directed mutagenesis (S32A, C47S), enzymatic assays (NSGPx at pH 8, aiPLA2 at pH 4), inhibitor studies, monoclonal antibody inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted bifunctional enzyme with orthogonal mutagenesis at each active site, inhibitor validation\",\n      \"pmids\": [\"10893423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Antisense morpholino oligonucleotide-mediated suppression of PRDX6 in L2 rat lung epithelial cells led to ~44% decrease in glutathione peroxidase activity, accumulation of phosphatidylcholine hydroperoxide in plasma membranes, and apoptotic cell death (80% at 48 h), demonstrating that PRDX6 functions in intact cells to reduce phospholipid hydroperoxides and prevent apoptosis.\",\n      \"method\": \"Antisense morpholino oligonucleotide knockdown, HPLC conjugated diene assay, DPPH fluorescence for lipid peroxidation, annexin V/PI staining, TUNEL assay, adenoviral rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific lipid peroxidation readout, rescued by adenoviral PRDX6 re-expression\",\n      \"pmids\": [\"12372839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Oxidative stress (H2O2, paraquat, hyperoxia) induces 1-Cys Prx (PRDX6) gene expression in rat lungs and lung cell lines at the transcriptional level; mRNA stability is unchanged and actinomycin D blocks induction, indicating transcriptional regulation. Induction is attenuated by antioxidants Trolox and N-acetylcysteine.\",\n      \"method\": \"Northern blot, immunoblot, actinomycin D treatment, antioxidant pre-treatment, in vivo hyperoxia mouse model\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple oxidative stimuli with transcriptional mechanistic evidence, single lab\",\n      \"pmids\": [\"12851211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PRDX6 glutathione peroxidase activity requires heterodimerization with pi GST. Oxidized 1-cysPrx (with sulfenic acid at Cys47) heterodimerizes with GSH-saturated pi GST, which catalyzes glutathionylation of the oxidized Cys47, followed by spontaneous reduction of the mixed disulfide with GSH to restore activity. Maximum activation occurs at 1:1 molar ratio of piGST to 1-cysPrx.\",\n      \"method\": \"Partial purification co-elution, liposome-mediated delivery into NCI-H441 and MCF7 cells, in vitro reconstitution of heterodimerization and glutathionylation, enzyme 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 — reconstituted heterodimerization and glutathionylation mechanism in vitro, confirmed in two cell lines\",\n      \"pmids\": [\"15004285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Adenovirus-mediated overexpression of 1-cysPrx (PRDX6) in mouse lungs (~2-fold increase) protected against hyperoxia-induced lung injury: reduced pleural effusion, lower lung wet/dry weight, less protein and cells in BAL fluid, lower TBARS and protein carbonyls, and improved survival during 100% O2 exposure.\",\n      \"method\": \"Adenoviral gene transfer in vivo, bronchoalveolar lavage analysis, lung injury markers (TBARS, protein carbonyls), survival analysis\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with multiple orthogonal lung injury readouts\",\n      \"pmids\": [\"15136296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PRDX6 is a bifunctional enzyme with GSH peroxidase activity (using GSH as electron donor, rate constant ~3×10^6 M^-1 s^-1) and Ca2+-independent PLA2 activity (maximal at acidic pH). piGST-catalyzed glutathionylation of Cys47 is required to complete the enzymatic cycle. Prdx6-null mice were more sensitive to hyperoxia and paraquat. Inhibition of PLA2 activity alters lung surfactant phospholipid synthesis and turnover.\",\n      \"method\": \"In vitro enzymatic assays, Prdx6-null mice phenotyping, adenoviral overexpression, inhibitor studies (MJ33)\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical characterization combined with genetic knockout and overexpression models, multiple labs\",\n      \"pmids\": [\"15890616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transcriptional regulation of Prdx6 in mouse liver cells involves PKC and MEK pathways (induction by KGF, TNF-alpha is largely prevented by their inhibitors) and NF-κB normally suppresses Prdx6 expression (NF-κB inhibition markedly increases Prdx6). The first 160 bp of the proximal promoter support basal expression; 1200 bp increases expression sixfold.\",\n      \"method\": \"Reporter gene assays (promoter-CAT constructs), kinase inhibitors (PKC, MEK), NF-κB inhibitors, serum deprivation/restimulation experiments\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter deletion analysis with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"17382207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Specificity protein 1 (Sp1) directly activates PRDX6 transcription through three active Sp1 binding sites (-19/27, -61/69, -82/89) in the Prdx6 promoter. Curcumin enhances Sp1 binding and Prdx6 promoter activity; point mutagenesis of all three Sp1 sites abolishes curcumin-mediated transactivation. Sp1-driven Prdx6 upregulation protects lens epithelial cells from ROS-mediated apoptosis.\",\n      \"method\": \"DNA-protein binding assays (EMSA), ChIP assay, co-transfection with Sp1 and Prdx6 promoter-CAT constructs in LECs and Sp1-deficient SL2 cells, site-directed mutagenesis of Sp1 sites, Sp1 inhibitors\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter mutagenesis, EMSA, ChIP, cell-based rescue with multiple orthogonal approaches\",\n      \"pmids\": [\"22113199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRDX6 physically binds to Nox activator 1 (Noxa1) via the Noxa1 SH3 domain (identified by yeast two-hybrid screening and confirmed by co-IP). Prdx6 stabilizes Noxa1 and supports Nox1-derived superoxide production. Both the peroxidase (C47S) and lipase (S32A) mutants of Prdx6 fail to bind/stabilize Nox1 components or support Nox1-mediated superoxide generation. The PLA2 inhibitor MJ-33 suppresses Nox1 activity. Wild-type but not mutant Prdx6 supports Nox1-mediated cell migration in HCT-116 cells.\",\n      \"method\": \"Yeast two-hybrid screening, co-IP in cells, Prdx6 knockdown and overexpression, site-directed mutagenesis (C47S, S32A), MJ-33 inhibitor, wound-closure assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel binding partner identified by Y2H, confirmed by Co-IP, mutagenesis at both active sites, functional migration readout\",\n      \"pmids\": [\"27094494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The PLA2 activity of PRDX6 mediates enhancement of NADPH oxidase (phox) activity in response to fMLF (but not PMA) in differentiated PLB-985 neutrophil-like cells. Knockdown reduced oxidase activity; reintroduction of shRNA-resistant WT or peroxidase-dead (Prdx active site mutant) Prdx6-PLA2 restored the fMLF response, but PLA2 active site mutants failed to restore it.\",\n      \"method\": \"shRNA stable knockdown, stable transfection with shRNA-resistant constructs (WT, active site mutants), NADPH oxidase activity assays (fMLF vs PMA stimulation)\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean rescue experiment with active site mutant discrimination, clear functional phenotype\",\n      \"pmids\": [\"22678913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRDX6 promotes lung tumor growth via both its GPx (C47S mutation attenuates) and iPLA2 activities; overexpression activates p38, ERK1/2, and AP-1 signaling in lung cancer cells, and the C47S mutant (lacking peroxidase activity) attenuated these kinase activations as well as tumor growth in xenograft mice.\",\n      \"method\": \"Xenograft nude mice, site-directed mutagenesis (C47S), enzyme activity assays (GPx, iPLA2), Western blot for MAPK/AP-1, in vivo tumor growth measurement\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft with mutagenesis linking GPx active site to signaling and tumor phenotype\",\n      \"pmids\": [\"24512906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRDX6 physically interacts with JAK2 (co-localization in tumor tissues and co-IP in lung cancer cells) and promotes JAK2/STAT3 pathway activation and STAT3 DNA binding, contributing to urethane-induced lung tumor development in PRDX6-transgenic mice. CCL5 levels are increased in PRDX6-Tg tumors and CCL5 further activates JAK2/STAT3.\",\n      \"method\": \"PRDX6-transgenic mice, urethane carcinogen model, co-IP, co-localization (IHC/IF), STAT3 DNA binding assay, CCR5-knockout mice\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/co-localization with in vivo genetic model, single lab\",\n      \"pmids\": [\"25582888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRDX6 is aberrantly SUMOylated at lysines K122 and K142 by SUMO1 under oxidative stress, leading to loss of function and cell death. Sumoylation-deficient mutant Prdx6 K122/142R shows 30% increased GSH-peroxidase and 37% increased aiPLA2 activities and greater protein stability. Both peroxidase and PLA2 active sites (and phosphorylation at T177) are required for the mutant Prdx6 protective function.\",\n      \"method\": \"Site-directed mutagenesis (K122R, K142R, double mutant), enzyme activity assays, stability assays, Prdx6-/- LECs transduction with EGFP-SUMO1, TAT-fusion protein delivery, mutational analysis of functional sites\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identification of SUMO1 conjugation sites by mutagenesis, quantified activity/stability gains, functional rescue in knockout cells\",\n      \"pmids\": [\"28055018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nrf2-mediated PRDX6 expression is driven through an ARE element at -357/-349 in the Prdx6 promoter. Progressive aging reduces Nrf2/ARE binding to this site, decreasing Prdx6 expression. Sulforaphane (SFN) restores Nrf2/ARE binding and Prdx6 expression; mutation of the ARE site abolishes SFN response. Knockdown of Prdx6 abrogates SFN-mediated cytoprotection, establishing Prdx6 as a prerequisite for SFN-mediated protection.\",\n      \"method\": \"Gel-shift (EMSA), ChIP assay, promoter activity assays with ARE mutation, Prdx6 siRNA knockdown, human aging lens specimens\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — EMSA and ChIP with ARE mutagenesis confirm Nrf2/ARE-Prdx6 axis; genetic requirement demonstrated by knockdown\",\n      \"pmids\": [\"29074861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"At higher doses of SFN, excessive Nrf2 activates Kruppel-like factor 9 (Klf9) through an ARE in the Klf9 promoter; Klf9 then binds repressive Klf9 binding elements (RKBE; 5'-CA/GCCC-3') in the Prdx6 promoter and suppresses Prdx6 transcription, increasing ROS and causing cell death. Klf9 depletion restores Prdx6 expression and cell survival.\",\n      \"method\": \"Klf9 promoter-ARE luciferase assay, Prdx6 promoter-reporter with RKBE mutagenesis, ChIP for Klf9 binding to Prdx6 promoter, ShKlf9 knockdown, Nrf2 gain-of-function\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic pathway defined by promoter mutagenesis, ChIP, and genetic depletion in same study\",\n      \"pmids\": [\"31569690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRDX6 knockdown significantly enhances lipid hydroperoxide (LOOH) accumulation and ferroptotic cell death triggered by erastin and RSL-3. This is correlated with transcriptional upregulation of heme oxygenase-1 (HO-1). The specific iPLA2 inhibitor MJ-33 synergistically enhances erastin-induced ferroptosis, indicating that PRDX6 suppresses ferroptosis through its iPLA2 activity.\",\n      \"method\": \"PRDX6 siRNA knockdown, ferroptosis inducers (erastin, RSL-3), LOOH measurement, HO-1 overexpression, MJ-33 inhibitor\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific inhibitor dissecting PLA2 vs peroxidase contributions, single lab\",\n      \"pmids\": [\"31036877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9 knockout of PRDX6 in HepG2 hepatocarcinoma cells causes mitochondrial dysfunction (reduced respiratory capacity, downregulated mitochondrial proteins, altered morphology), cell cycle arrest at G2/M, increased ROS and lipid peroxidation, autophagy, and redox changes at 254 Cys-peptides in 202 proteins. Oxidation of specific cysteines in PCNA was identified as a potential mechanism of mitosis entry block.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative global and redox proteomics, flow cytometry, extracellular flux analysis, electron microscopy, Western blot\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multi-omics characterization and orthogonal cell biology methods\",\n      \"pmids\": [\"33035814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX6-iPLA2 activity (Asp140 site) is required for activation of astrocytes and M1 microglia polarization following ischemic stroke. PRDX6 phosphorylation at Thr177 (by ERK and p38 MAPKs) regulates its iPLA2 activity in astrocytes. Blocking iPLA2 activity (MJ33 or D140A mutation) inhibits NOX2 activation and Drp1-dependent mitochondrial fission, reducing ROS and neuroinflammation.\",\n      \"method\": \"PRDX6-D140A and T177A site-directed mutations, MJ33 inhibitor, NOX2 inhibitor (GSK2795039), ERK inhibitor (U0126), p38 inhibitor (SB202190), astrocyte-microglia co-culture, OGD/R model, in vivo ischemic stroke rat model\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic mutagenesis with specific inhibitors and co-culture functional readout, single lab\",\n      \"pmids\": [\"38287382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Viral 3C protease (from FMDV and Senecavirus A) degrades PRDX6 via its proteolytic activity (independent of proteasome, lysosome, or caspase pathways). PRDX6 overexpression inhibits FMDV replication; knockdown promotes it. The antiviral function of PRDX6 depends on its iPLA2 activity (MJ33 promotes FMDV replication) but not peroxidase activity (mercaptosuccinate had no effect).\",\n      \"method\": \"PRDX6 overexpression and knockdown, 3Cpro expression constructs (WT and protease-dead mutant), MJ33 and mercaptosuccinate inhibitors, viral replication assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — active site dissection with inhibitors, protease-dead mutant control, two different picornaviruses, single lab\",\n      \"pmids\": [\"33721217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Klf9 binds to repressive elements (RKBE) in the Prdx6 promoter and suppresses its expression under conditions of elevated oxidative stress. The Nrf2-Klf9-Prdx6 axis acts as a hormetic switch: moderate H2O2 increases Nrf2-driven Prdx6 expression, while high H2O2 (≥100 µM) causes Nrf2-mediated Klf9 upregulation that represses Prdx6, amplifying H2O2 and causing cell death. This was confirmed in Prdx6-deficient mouse LECs.\",\n      \"method\": \"Prdx6-/- mouse LECs, Klf9 overexpression and ShKlf9 knockdown, DCF oxidation (H2O2 measurement), promoter-reporter assays, dose-response H2O2 treatment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout model with gain/loss-of-function Klf9 manipulation, single lab replicating prior finding\",\n      \"pmids\": [\"35455944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S-palmitoylation at Cys47 of PRDX6 is predicted to competitively inhibit disulfide bond formation between Cys47 and Cys91, altering PRDX6 spatial topology. Palmitoylation status of Cys47 regulates the interaction between PRDX6 and the C-terminal domain of anion exchanger 3 (AE3), potentially affecting AE3 activity in dorsal root ganglion neurons. Immunofluorescence showed PRDX6 translocating between cytoplasm and cell membrane.\",\n      \"method\": \"Comparative proteomics (DRG of diabetic mice), palmitoylome profiling (HUVEC), bioinformatic palmitoylation site prediction, immunofluorescence for localization\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — palmitoylation sites computationally predicted; interaction with AE3 inferred, not biochemically validated\",\n      \"pmids\": [\"36120430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Astragaloside IV (AST) inhibits PRDX6 PLA2 activity by binding to its PLA2 catalytic triad pocket, which alters PRDX6 conformation and disrupts the interaction between PRDX6 and RAC GTPase. This prevents RAC-GDI heterodimer activation, blocks NOX2 maturation, and reduces superoxide production.\",\n      \"method\": \"Activity-based protein profiling with AST probes, protein-protein interaction assays, molecular dynamics simulation, PLA2 activity assay, RAC activation assay, LPS-induced acute lung injury mouse model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — target engagement validated by probe capture, mechanistic interaction (PRDX6-RAC) confirmed by binding assay and functional NOX2 readout\",\n      \"pmids\": [\"37030053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX6 functions as a selenium-acceptor protein that interacts with selenophosphate synthetase 2 (SEPHS2) and facilitates intracellular selenium utilization by transferring selenium within the selenocysteyl-tRNA[Ser]Sec synthesis machinery, enabling efficient GPX4 selenoprotein synthesis. Loss of PRDX6 reduces selenoprotein expression (including GPX4) and sensitizes cells to ferroptosis. This was confirmed in Prdx6-deficient mouse brains and tumor xenografts.\",\n      \"method\": \"PRDX6 genetic loss (CRISPR/KO), selenium metabolic tracing, biochemical selenium transfer assays, selenoprotein expression analysis, Prdx6-/- mouse brains, xenograft tumor models\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel selenium-transfer mechanism established by biochemical assays, confirmed in multiple in vivo models with functional ferroptosis readout\",\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, providing an alternative pathway (independent of selenocysteine lyase SCLY) for selenium delivery to the selenocysteyl-tRNA synthesis machinery. This alternative route supports GPX4 expression and ferroptosis resistance, and is particularly relevant in MYCN-amplified neuroblastoma cells with elevated PRDX6.\",\n      \"method\": \"PRDX6 knockout in cancer cells, selenium metabolic experiments, biochemical interaction assays (PRDX6-SEPHS2), SCLY-independent pathway validation, human cancer cell line analyses\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — independent replication of selenium-transfer mechanism (concurrent with PMID 38867112), biochemical dissection of SCLY-independent pathway\",\n      \"pmids\": [\"39547224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cells lacking GPX4 retain substantial phospholipid hydroperoxide-reducing capacity. While PRDX6 overexpression alone does not prevent ferroptosis, genetic loss of PRDX6 sensitizes cancer cells to ferroptosis. The mechanism is that PRDX6 acts as a selenium-acceptor protein facilitating intracellular selenium utilization and GPX4 synthesis; Prdx6-deficient mouse brains show reduced GPX4 expression.\",\n      \"method\": \"GPX4 and PRDX6 double knockouts, PLOOH reduction capacity assays, PRDX6 overexpression ferroptosis assays, selenium utilization experiments, Prdx6-/- mouse brain GPX4 measurement, xenograft models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic dissection of PLOOH-reducing capacity, in vivo mouse model, orthogonal selenium utilization data\",\n      \"pmids\": [\"39547222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nucleophosmin (NPM) forms a complex with CBX3 that promotes PRDX6 transcription; NPM knockdown reduces PRDX6 expression and increases ROS, while NPM overexpression upregulates PRDX6 and decreases ROS. Co-immunoprecipitation confirmed NPM-PRDX6 protein interaction.\",\n      \"method\": \"Co-IP, siRNA knockdown, NPM overexpression, CBX3-NPM dual luciferase reporter assay, ROS measurement\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with promoter reporter assay, functional ROS readout, single lab\",\n      \"pmids\": [\"28513872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The TLR4/NF-κB signaling pathway mediates the radioprotective effect of exogenous Prdx6. Exogenous Prdx6 (including the peroxidase-dead C47S mutant) activates NF-κB in irradiated cells; TLR4 inhibitors (especially those targeting the extracellular domain) significantly reduce this radioprotective effect, indicating Prdx6 interacts with TLR4 receptor to trigger cellular defense independently of its peroxidase activity.\",\n      \"method\": \"Exogenous recombinant Prdx6 and Prdx6-C47S mutant protein delivery, TLR4 inhibitors, NF-κB activation assay, cell survival assay, in vitro X-ray irradiation model\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis separating peroxidase from TLR4-signaling function, pharmacological pathway validation, single lab\",\n      \"pmids\": [\"33727039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX6 is a unique bifunctional 1-Cys peroxiredoxin with two distinct active sites: Cys47 (within PVCTTE) catalyzes glutathione-dependent reduction of H2O2 and phospholipid hydroperoxides (requiring piGST-mediated heterodimerization and glutathionylation to complete the catalytic cycle), while Ser32 (within GDSWG) provides the catalytic nucleophile for Ca2+-independent acidic PLA2 activity; both activities are regulated by SUMO1 conjugation at K122/K142, phosphorylation at Thr177 (by ERK/p38), and transcriptionally by Nrf2/ARE and Sp1 (counterbalanced by Klf9-mediated repression under high oxidative load); PRDX6 additionally acts as a selenium-acceptor protein that facilitates intracellular selenium transfer to the selenocysteyl-tRNA synthesis machinery (interacting with SEPHS2) to support GPX4 expression and ferroptosis resistance, and its iPLA2 activity supports NADPH oxidase (Nox1/Nox2) activation through binding to Noxa1 and RAC subunits, positioning PRDX6 as a central node linking phospholipid hydroperoxide reduction, surfactant metabolism, ROS generation, and selenoprotein synthesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRDX6 is a bifunctional 1-Cys peroxiredoxin that couples antioxidant defense with phospholipid metabolism and selenium homeostasis. Its Cys47-dependent GSH peroxidase activity—requiring heterodimerization with piGST for glutathionylation-mediated catalytic recycling—reduces H₂O₂, organic hydroperoxides, and phospholipid hydroperoxides, while its Ser32-dependent, Ca²⁺-independent phospholipase A₂ (aiPLA₂) activity, activated by ERK/p38-mediated Thr177 phosphorylation, drives NADPH oxidase (Nox1/Nox2) activation through binding Noxa1 and RAC [PMID:10893423, PMID:15004285, PMID:27094494, PMID:38287382]. PRDX6 suppresses ferroptosis primarily by serving as a selenium acceptor/transfer protein that interacts with SEPHS2 to maintain selenophosphate synthesis and GPX4 selenoprotein expression, rather than solely through direct phospholipid hydroperoxide reduction [PMID:38867112, PMID:39547224, PMID:39547222]. Aberrant SUMO1 conjugation at Lys122/Lys142 destabilizes PRDX6 and diminishes both enzymatic activities, while transcription is positively regulated by Sp1 and the NPM1–CBX3 complex and repressed by Klf9 downstream of high Nrf2 activity [PMID:28055018, PMID:22113199, PMID:31569690, PMID:35659568].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that PRDX6 harbors two independent catalytic sites—Ser32 for PLA2 and Cys47 for peroxidase—resolved whether the protein was monofunctional or bifunctional and set the framework for all subsequent activity-specific dissection.\",\n      \"evidence\": \"Recombinant protein mutagenesis (S32A, C47S) with parallel PLA2 and GPx enzymatic assays in E. coli-expressed protein\",\n      \"pmids\": [\"10893423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for how the two active sites are arranged within the same fold\", \"Physiological electron donor for Cys47 recycling not yet identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that PRDX6 knockdown causes phosphatidylcholine hydroperoxide accumulation and apoptosis in lung epithelial cells established its non-redundant role as a direct phospholipid hydroperoxide reductase in vivo.\",\n      \"evidence\": \"Antisense morpholino knockdown in lung epithelial cells with PLOOH HPLC quantification, rescued by adenoviral PRDX6 overexpression or vitamin E analogue\",\n      \"pmids\": [\"12372839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PLA2 vs. peroxidase activity to PLOOH clearance not dissected\", \"Whether other peroxiredoxins compensate in other tissues unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying piGST as the obligate heterodimerization partner that glutathionylates oxidized Cys47 solved the long-standing puzzle of how a 1-Cys peroxiredoxin without a resolving cysteine completes its catalytic cycle.\",\n      \"evidence\": \"In vitro reconstitution at defined molar ratios plus liposome-mediated protein delivery into piGST-null and PRDX6-null cells\",\n      \"pmids\": [\"15004285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other GST isoforms can substitute for piGST in specific tissues\", \"Structural details of the heterodimer interface not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Adenoviral PRDX6 overexpression in mouse lungs directly protected against hyperoxic injury, providing the first in vivo evidence that PRDX6 is functionally rate-limiting for lung antioxidant defense.\",\n      \"evidence\": \"Adenoviral gene transfer in mice with survival analysis under 100% O₂ plus oxidative damage markers\",\n      \"pmids\": [\"15136296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activity-specific contributions (PLA2 vs. GPx) not separated in vivo\", \"Protective effect in non-lung tissues not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping three Sp1-binding sites in the PRDX6 promoter established the first direct transcriptional regulatory mechanism, showing how stress-responsive transcription factors control PRDX6 expression.\",\n      \"evidence\": \"Promoter-reporter mutagenesis and co-transfection in Sp1-deficient SL2 cells with ChIP confirmation\",\n      \"pmids\": [\"22113199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin context and tissue-specific regulation not addressed\", \"Nrf2/ARE-mediated activation of PRDX6 itself not directly mapped in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that the PLA2 activity (not peroxidase) mediates phagocyte NADPH oxidase activation resolved which enzymatic function links PRDX6 to innate immune superoxide production.\",\n      \"evidence\": \"Stable knockdown and rescue with WT, C47S, and S32A mutants in PLB-985 neutrophil-like cells with oxidase activity assays\",\n      \"pmids\": [\"22678913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid product mediating oxidase activation not identified\", \"Whether arachidonic acid release is the key intermediate not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of Noxa1 as a direct PRDX6 binding partner via yeast two-hybrid and co-IP showed how PRDX6 PLA2 activity couples to Nox1 complex assembly and cell migration.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, mutant rescue (C47S, S32A), MJ-33 inhibitor, wound-closure assay\",\n      \"pmids\": [\"27094494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether binding is direct or mediated by lipid products not fully resolved\", \"Structural basis of Noxa1 SH3–PRDX6 interaction unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovering that SUMO1 conjugation at Lys122/Lys142 destabilizes PRDX6 and reduces both enzymatic activities revealed a post-translational switch that modulates PRDX6 function under oxidative stress.\",\n      \"evidence\": \"K122R/K142R mutagenesis with quantitative enzymatic assays and cell rescue in Prdx6⁻/⁻ lens epithelial cells\",\n      \"pmids\": [\"28055018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase responsible for PRDX6 sumoylation not identified\", \"In vivo relevance of sumoylation-mediated destabilization not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that Thr177 phosphorylation by ERK-family kinases increases PLA2 activity at neutral pH established the signaling mechanism by which MAPK cascades acutely regulate PRDX6 lipase function.\",\n      \"evidence\": \"In vitro Erk2 phosphorylation with mass spectrometry confirmation and PLA2 activity assays on unilamellar liposomes\",\n      \"pmids\": [\"30832204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p38 contribution to Thr177 phosphorylation characterized only pharmacologically\", \"Phosphatase(s) that reverse this modification not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing PRDX6 as a negative regulator of ferroptosis—with its iPLA2 activity contributing to LOOH removal—linked the bifunctional enzyme to a regulated cell death pathway for the first time.\",\n      \"evidence\": \"siRNA knockdown and overexpression with erastin/RSL-3-induced ferroptosis and MJ-33 pharmacological inhibition\",\n      \"pmids\": [\"31036877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism was attributed solely to direct PLOOH reduction; selenium connection not yet discovered\", \"Contribution of peroxidase activity to ferroptosis resistance not separately tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR knockout in hepatocarcinoma cells revealed that PRDX6 loss causes widespread cysteine redox perturbation, mitochondrial dysfunction, and G2/M arrest, demonstrating its global impact on cellular redox homeostasis beyond simple PLOOH clearance.\",\n      \"evidence\": \"CRISPR/Cas9 knockout with quantitative global and redox proteomics, extracellular flux analysis, electron microscopy\",\n      \"pmids\": [\"33035814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which of the 202 redox-altered proteins are direct vs. indirect targets not determined\", \"Whether G2/M arrest is reversible or leads to senescence not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying that PRDX6 PLA2 activity supports NOX2/ROS-driven Drp1-dependent mitochondrial fission in astrocytes extended the Nox-regulatory function to neuroinflammatory contexts and linked it to organelle dynamics.\",\n      \"evidence\": \"D140A and T177A mutagenesis with NOX2, Drp1, ERK, and p38 inhibitors in OGD/R astrocyte model and in vivo ischemic stroke model\",\n      \"pmids\": [\"38287382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid mediator bridging PLA2 activity to NOX2 assembly not identified\", \"Whether peroxidase activity has an independent neuroprotective role not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two independent studies revealed that PRDX6's critical role in ferroptosis resistance operates primarily through selenium metabolism—reacting with selenide and delivering it to SEPHS2 for selenophosphate synthesis—rather than through direct PLOOH reduction, fundamentally reframing the mechanism of PRDX6-mediated ferroptosis suppression.\",\n      \"evidence\": \"Biochemical selenide reactivity assays, PRDX6-SEPHS2 interaction studies, PRDX6 knockout with selenoprotein expression profiling, Prdx6⁻/⁻ mouse brains showing reduced GPX4, independently confirmed in Nature Struct Mol Biol and Molecular Cell\",\n      \"pmids\": [\"38867112\", \"39547224\", \"39547222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PRDX6-SEPHS2 interaction not resolved\", \"Whether PRDX6 selenium transfer operates in all tissues or is context-dependent\", \"Relative contribution of direct PLOOH reduction vs. GPX4 maintenance varies by cell type and remains unquantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how PRDX6 accommodates dual catalytic activities within a single fold, the identity of the lipid intermediates that bridge PLA2 activity to NOX assembly, and tissue-specific quantitative partitioning between direct peroxidase/PLA2 functions and selenium delivery remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of PRDX6-piGST heterodimer or PRDX6-SEPHS2 complex\", \"Lipid product identity mediating NOX activation not established\", \"Relative importance of the three functions (GPx, PLA2, Se delivery) in different tissues not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 7, 12]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 4, 7, 13, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005740\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 7, 8, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"complexes\": [\n      \"PRDX6-piGST heterodimer\",\n      \"PRDX6-Noxa1-Nox1 complex\"\n    ],\n    \"partners\": [\n      \"GSTP1\",\n      \"NOXA1\",\n      \"RAC1\",\n      \"SEPHS2\",\n      \"NPM1\",\n      \"JAK2\",\n      \"CBX3\",\n      \"PUM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRDX6 is a bifunctional 1-Cys peroxiredoxin that integrates phospholipid hydroperoxide reduction, phospholipid remodeling, NADPH oxidase activation, and selenium metabolism into a single polypeptide. Its peroxidase activity is mediated by Cys47 in the PVCTTE motif, which forms a sulfenic acid intermediate that is regenerated through piGST-catalyzed glutathionylation, while an independent Ca²⁺-independent acidic phospholipase A2 (aiPLA2) activity uses Ser32 in the GDSWG motif as catalytic nucleophile; both active sites are required for full cytoprotection against oxidative injury and for supporting Nox1/Nox2-dependent superoxide generation via direct binding to Noxa1 and RAC [PMID:10893423, PMID:15004285, PMID:27094494, PMID:22678913, PMID:38287382]. PRDX6 also functions as a selenium-acceptor protein that interacts with SEPHS2 to deliver selenium to the selenocysteyl-tRNA synthesis machinery, thereby sustaining GPX4 expression and conferring ferroptosis resistance independently of its own catalytic activities [PMID:38867112, PMID:39547224, PMID:39547222]. Transcription is positively regulated by Nrf2 through an ARE at −357/−349 and by Sp1 through proximal promoter sites, while excessive oxidative stress triggers Nrf2-dependent induction of Klf9, which binds repressive RKBE elements in the PRDX6 promoter to create a hormetic off-switch that amplifies ROS and promotes cell death [PMID:29074861, PMID:22113199, PMID:31569690, PMID:35455944]. Both enzymatic activities and protein stability are further modulated by SUMO1 conjugation at K122/K142 (inhibitory) and ERK/p38-mediated phosphorylation at Thr177 (activating iPLA2) [PMID:28055018, PMID:38287382].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of PRDX6 as a 1-Cys peroxiredoxin with Cys47 as the catalytic residue resolved the question of how a single-cysteine peroxiredoxin reduces H₂O₂, revealing a sulfenic acid intermediate but leaving the electron donor unknown.\",\n      \"evidence\": \"Recombinant mutagenesis (C47S) and intracellular H₂O₂ assays in NIH 3T3 cells, plus 2.0 Å crystal structure showing Cys47-SOH\",\n      \"pmids\": [\"9497358\", \"9587003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological electron donor for Cys47-SOH regeneration not identified\", \"Substrate specificity beyond H₂O₂ not tested\", \"Oligomeric state in solution not characterized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that PRDX6 harbors a second catalytic site (Ser32/GDSWG for aiPLA2 activity) independent of the Cys47 peroxidase site established it as a unique bifunctional enzyme, raising the question of how these two activities are coordinately regulated.\",\n      \"evidence\": \"Orthogonal site-directed mutagenesis (S32A, C47S) with selective inhibitors (MJ33 vs. mercaptosuccinate) in recombinant protein assays\",\n      \"pmids\": [\"10893423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates for PLA2 activity in cells not defined\", \"Structural basis for two independent active sites in one polypeptide not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that PRDX6 loss in lung epithelial cells causes phosphatidylcholine hydroperoxide accumulation and apoptosis established that PRDX6 is a physiologically relevant phospholipid hydroperoxide reductase, not merely an H₂O₂ scavenger.\",\n      \"evidence\": \"Antisense morpholino knockdown in L2 cells with HPLC lipid peroxidation readout and adenoviral rescue\",\n      \"pmids\": [\"12372839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of peroxidase vs. PLA2 activity to cytoprotection not dissected\", \"In vivo lung phenotype not yet examined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The long-standing puzzle of how oxidized Cys47-SOH is regenerated was solved by showing that piGST heterodimerizes with PRDX6 to catalyze glutathionylation of the sulfenic acid, completing the catalytic cycle with GSH as the ultimate electron donor.\",\n      \"evidence\": \"In vitro reconstitution of piGST–PRDX6 heterodimerization and glutathionylation, confirmed by liposome-mediated delivery into NCI-H441 and MCF7 cells\",\n      \"pmids\": [\"15004285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the piGST–PRDX6 heterodimer interface not determined\", \"Whether other GST isoforms can substitute is unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo gain-of-function (adenoviral overexpression) and subsequent loss-of-function (Prdx6-null mice) experiments confirmed that PRDX6 is a major protective factor against oxidative lung injury, linking its biochemistry to organ-level physiology.\",\n      \"evidence\": \"Adenoviral PRDX6 overexpression in mouse lungs under hyperoxia; Prdx6-null mice showing sensitivity to hyperoxia and paraquat\",\n      \"pmids\": [\"15136296\", \"15890616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contributions of peroxidase vs. PLA2 activity not separated\", \"Surfactant metabolism phenotype not fully characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping of the transcriptional regulatory architecture showed that Sp1 directly activates PRDX6 through three proximal promoter sites, providing the first mechanistic understanding of basal PRDX6 expression control.\",\n      \"evidence\": \"EMSA, ChIP, promoter-CAT mutagenesis in LECs and Sp1-deficient SL2 cells\",\n      \"pmids\": [\"22113199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between Sp1 and other transcription factors (Nrf2) at the promoter not addressed\", \"Tissue-specific regulation not explored\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that PRDX6 binds Noxa1 and supports Nox1/Nox2-dependent superoxide production revealed a surprising pro-oxidant role for an antioxidant enzyme, showing that its iPLA2 activity directly participates in NADPH oxidase activation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, C47S/S32A mutagenesis, MJ33 inhibition, and rescue of Nox1-mediated migration and Nox2 activity in neutrophil-like cells\",\n      \"pmids\": [\"27094494\", \"22678913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX6 provides arachidonic acid for Nox assembly or acts as a scaffolding factor not fully resolved\", \"Structural basis of PRDX6–Noxa1 interaction unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of SUMO1 conjugation at K122/K142 as an inhibitory modification and Thr177 phosphorylation as an activating modification established the post-translational regulatory code governing both PRDX6 activities, and the Nrf2/ARE element at −357 was mapped as the oxidative stress–responsive transcriptional driver.\",\n      \"evidence\": \"Site-directed mutagenesis of SUMO sites in Prdx6−/− LECs; EMSA/ChIP with ARE mutagenesis for Nrf2; promoter-reporter with RKBE mutagenesis\",\n      \"pmids\": [\"28055018\", \"29074861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase responsible for PRDX6 SUMOylation not identified\", \"Kinase specificity for Thr177 phosphorylation not fully dissected in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The Nrf2–Klf9–PRDX6 hormetic switch was delineated: at high oxidative stress, Nrf2-induced Klf9 represses PRDX6 transcription through RKBE elements, converting a protective response into a death-promoting one, explaining dose-dependent outcomes of antioxidant signaling.\",\n      \"evidence\": \"Klf9 ChIP on PRDX6 promoter, RKBE mutagenesis, Klf9 knockdown rescue, dose-response H₂O₂ in Prdx6−/− LECs\",\n      \"pmids\": [\"31569690\", \"35455944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Klf9 repression of PRDX6 operates in non-ocular tissues not tested\", \"Thresholds for the hormetic switch in vivo not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PRDX6 knockdown was shown to enhance ferroptotic cell death with lipid hydroperoxide accumulation, and the iPLA2 inhibitor MJ33 synergized with erastin, implicating PRDX6's PLA2 activity specifically in ferroptosis suppression.\",\n      \"evidence\": \"siRNA knockdown with erastin/RSL-3 treatment, LOOH measurement, MJ33 inhibitor in cancer cells\",\n      \"pmids\": [\"31036877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peroxidase contribution to ferroptosis resistance not cleanly separated by mutagenesis in this study\", \"In vivo ferroptosis relevance not established at this point\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PRDX6-iPLA2 activity was linked to NOX2 activation and Drp1-dependent mitochondrial fission in astrocytes after ischemic stroke, extending the Nox-activating role to neuroinflammation and identifying ERK/p38-mediated Thr177 phosphorylation as the upstream activating signal.\",\n      \"evidence\": \"D140A and T177A mutagenesis, MJ33/NOX2/ERK/p38 inhibitors, astrocyte–microglia co-culture and in vivo rat stroke model\",\n      \"pmids\": [\"38287382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct measurement of PRDX6 Thr177 phosphorylation stoichiometry in vivo not reported\", \"Whether astrocyte PRDX6-iPLA2 generates specific lipid mediators not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A fundamentally new function was uncovered: PRDX6 acts as a selenium-acceptor protein that interacts with SEPHS2 to channel selenium into selenocysteyl-tRNA synthesis, sustaining GPX4 expression and ferroptosis resistance independently of its own enzymatic activities.\",\n      \"evidence\": \"CRISPR knockout, selenium metabolic tracing, biochemical selenium transfer assays, Prdx6−/− mouse brains showing reduced GPX4, xenograft models; independently confirmed in two concurrent studies\",\n      \"pmids\": [\"38867112\", \"39547224\", \"39547222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PRDX6–SEPHS2 interaction not resolved\", \"Whether selenium-transfer function requires a specific PRDX6 oxidation state is unknown\", \"Relative contribution of selenium-transfer vs. direct PLOOH reduction to ferroptosis resistance not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of how two independent active sites and the selenium-transfer function coexist in one polypeptide, the tissue-specific hierarchy of PRDX6's multiple functions, and the full spectrum of lipid mediators generated by its iPLA2 activity in different physiological contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of PRDX6–piGST or PRDX6–SEPHS2 complexes\", \"In vivo tissue-specific contributions of peroxidase vs. iPLA2 vs. selenium-transfer not genetically dissected\", \"Identity of lipid products generated by iPLA2 activity in different cell types not systematically profiled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 7, 10, 11, 17, 19]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 3, 7, 17]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [24, 25, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 22]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 4, 6, 7, 14, 15, 16, 18, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 7, 24, 25, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 17, 24, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 23, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 12, 13, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GSTP1\",\n      \"NOXA1\",\n      \"SEPHS2\",\n      \"RAC1\",\n      \"JAK2\",\n      \"NPM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}