{"gene":"GPX7","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2004,"finding":"GPX7 (NPGPx) was identified as a cytoplasmic ~22 kDa protein that incorporates cysteine instead of selenocysteine at the conserved catalytic motif, exhibits little detectable glutathione peroxidase activity in vitro, and protects against oxidative stress generated from polyunsaturated fatty acid (EPA) metabolism in breast cancer cells.","method":"In vitro GPx activity assay, siRNA knockdown, ectopic overexpression, cell viability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (activity assay, KD, OE) with defined cellular phenotype, foundational characterization paper","pmids":["15294905"],"is_preprint":false},{"year":2011,"finding":"GPX7 and GPX8 were shown to be ER-resident PDI peroxidases: in vitro, addition of GPX7 or GPX8 together with PDI and peroxide enables efficient oxidative refolding of reduced denatured protein; both proteins interact with Ero1α in vivo, and GPX7 significantly increases oxygen consumption by Ero1α in vitro.","method":"In vitro oxidative refolding assay, co-immunoprecipitation (in vivo), oxygen consumption assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus in vivo co-IP, multiple orthogonal methods","pmids":["21215271"],"is_preprint":false},{"year":2011,"finding":"GPX7 exhibits H2O2-neutralizing activity independent of glutathione; reconstitution of GPX7 expression in Barrett's esophagus cells conferred resistance to H2O2-induced oxidative DNA damage, double-strand breaks, ROS-dependent JNK/p38 signaling, and apoptosis following acidic bile acid exposure.","method":"GPx enzymatic activity assay, Amplex UltraRed H2O2 assay, CM-H2DCFDA ROS assay, 8-oxoguanine and phospho-H2AX assays, siRNA knockdown, ectopic overexpression","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with both KD and OE, replicated in multiple cell lines","pmids":["22157330"],"is_preprint":false},{"year":2012,"finding":"NPGPx (GPX7) acts as an oxidative stress sensor/transmitter: upon ROS accumulation, it forms an intramolecular disulfide bond between Cys57 and Cys86; this oxidized form then forms covalent disulfide intermediates with GRP78 (Cys86 of NPGPx to Cys41/Cys420 of GRP78), which subsequently promotes formation of the Cys41–Cys420 disulfide in GRP78, enhancing its chaperone activity. NPGPx-deficient cells accumulate ROS, misfolded proteins, and display impaired GRP78 chaperone activity.","method":"Mutagenesis of active-site cysteines, co-immunoprecipitation, disulfide bond trapping, chaperone activity assay, NPGPx knockout mice","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — active-site mutagenesis + covalent intermediate trapping + in vivo KO with defined phenotype; highly cited foundational paper","pmids":["23123197"],"is_preprint":false},{"year":2011,"finding":"Under non-targeting siRNA stress, NPGPx (GPX7) is selectively induced and covalently binds exoribonuclease XRN2 via disulfide bonding, facilitating XRN2-mediated degradation of accumulated non-targeting siRNA and thereby releasing cellular stress.","method":"Co-immunoprecipitation, siRNA knockdown, apoptosis assay, G1 phase cell cycle analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP for interaction, functional rescue experiment, single lab","pmids":["21908404"],"is_preprint":false},{"year":2013,"finding":"GPX7 utilizes Ero1α-generated H2O2 to promote oxidative protein folding. Mechanistically, H2O2 oxidizes Cys57 of GPX7 to sulfenic acid, which is resolved by Cys86 to form an intramolecular disulfide bond; both the sulfenic acid form and disulfide form of GPX7 can oxidize PDI. GPX7 preferentially interacts with the a-domain of PDI, and the Ero1α/GPX7/PDI triad generates two disulfide bonds per O2 molecule consumed.","method":"In vitro oxidative folding assay, site-directed mutagenesis (Cys57, Cys86), biochemical trapping of sulfenic acid intermediate, in vivo co-IP, oxygen consumption assay","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis, multiple intermediates characterized, in vivo validation; highly cited","pmids":["23919619"],"is_preprint":false},{"year":2013,"finding":"GPX7 uses a one-Cys catalytic mechanism in which the peroxidatic Cys (CP) is rapidly oxidized by phospholipid hydroperoxide; GSH and PDI are alternative reducing substrates for re-reduction of oxidized CP. PDI-GPX7 interaction was quantified with KD = 5.2 μM by surface plasmon resonance; thioredoxin does not serve as a reducing substrate.","method":"Steady-state kinetic analysis, site-directed mutagenesis, molecular docking, surface plasmon resonance","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — reconstituted kinetics, mutagenesis, biophysical binding measurement","pmids":["23454490"],"is_preprint":false},{"year":2013,"finding":"GPX7 functions as a tumor suppressor in esophageal adenocarcinoma: reconstitution of GPX7 suppresses cell growth, impairs G1/S progression, increases cellular senescence, and elevates p73, p27, p21, p16 while decreasing phospho-RB. GPX7 is silenced by location-specific promoter DNA hypermethylation (+13 to +64 region) in 69% of OAC cases.","method":"Growth curve, colony formation, EdU proliferation assay, cell cycle analysis, senescence assay, western blot, mouse xenograft model, pyrosequencing of CpG methylation","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal cell and in vivo assays with mechanistic pathway readout","pmids":["23580780"],"is_preprint":false},{"year":2014,"finding":"Loss of GPX7 promotes TNF-α-induced NF-κB activation in esophageal cells. GPX7 suppresses NF-κB by promoting proteasomal degradation of TNFR1 and TRAF2 upstream regulators; this suppression is independent of ROS levels and GPX7 antioxidant function.","method":"Western blot, immunofluorescence, luciferase reporter assay, siRNA knockdown, ectopic overexpression, protein degradation assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple assays with mechanistic pathway placement, single lab","pmids":["24692067"],"is_preprint":false},{"year":2015,"finding":"NPGPx (GPX7) forms a disulfide bond with translational regulator CPEB2, which maintains CPEB2 binding to HIF-1α mRNA and suppresses HIF-1α translation under basal conditions. High oxidative stress disrupts this NPGPx–CPEB2 disulfide, releasing CPEB2 from HIF-1α mRNA and elevating HIF-1α translation.","method":"Co-immunoprecipitation, disulfide trapping, RNA-protein interaction assay, western blot for HIF-1α translation, NPGPx-deficient cell lines","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP of disulfide intermediate, functional RNA translation readout, single lab","pmids":["26446990"],"is_preprint":false},{"year":2013,"finding":"NPGPx (GPX7) deficiency leads to obesity in mice via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ, promoting preadipocyte differentiation into adipocytes. NPGPx is highly expressed in preadipocytes, and NPGPx-knockout mice exhibit increased fat mass and adipocyte hypertrophy reversible by N-acetylcysteine treatment.","method":"NPGPx knockout mouse model, adipocyte differentiation assays, western blot (PKA regulatory subunit dimerization, C/EBPβ), NAC rescue experiment, SNP association in humans","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined molecular mechanism (PKA dimerization) and pharmacological rescue, supported by human genetic data","pmids":["23828861"],"is_preprint":false},{"year":2017,"finding":"GPX7 and GPX8 are ER-resident antioxidant enzymes; expression of GPX7 in pancreatic INS-1E β-cells attenuates FFA-mediated H2O2 accumulation in the ER, ER stress, and apoptosis without compromising insulin production or oxidative protein folding/disulfide bond formation in insulin.","method":"Ectopic expression of GPX7/GPX8, H2O2 measurement, ER stress markers (western blot), apoptosis assay, insulin content assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean overexpression with mechanistic dissection in β-cells, single lab","pmids":["28751022"],"is_preprint":false},{"year":2019,"finding":"NPGPx (GPX7) is activated by oxidative stress and inhibits O-GlcNAcase (OGA) through disulfide bonding, thereby fine-tuning global O-GlcNAcylation. Deficiency of NPGPx in mice causes ALS-like phenotypes (paralysis, muscle denervation, motor neuron loss) and failure to boost O-GlcNAcylation in spinal motor neurons with age; pharmacological OGA inhibition rescues spinal motor neuron loss in aged NPGPx-deficient mice.","method":"NPGPx knockout mouse model (ALS phenotype characterization), disulfide bond trapping (NPGPx–OGA interaction), proteomic identification, pharmacological rescue (OGA inhibitor), O-GlcNAcylation western blot","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined molecular target (OGA disulfide bonding), pharmacological rescue, multiple orthogonal methods","pmids":["31747588"],"is_preprint":false},{"year":2020,"finding":"Human GPX7 has much higher reactivity with H2O2 than GPX8, attributable to a catalytic tetrad at the redox-active site that stabilizes the sulfenylated Cys57 intermediate. Contrary to prior models, the resolving Cys (not the peroxidatic Cys) regulates PDI oxidation activity of GPX7. GPX7 forms complexes preferentially with PDI and P5 in H2O2-treated cells.","method":"In vitro H2O2 reactivity assay, PDI oxidation assay, site-directed mutagenesis, co-immunoprecipitation in H2O2-treated cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis plus in vivo co-IP, structural mechanistic insight","pmids":["32719007"],"is_preprint":false},{"year":2020,"finding":"GPX7 knockdown in TGF-β/FFA-treated hepatic stellate cells (LX-2) elevated pro-fibrotic and pro-inflammatory gene expression and collagen synthesis; GPX7 overexpression suppressed ROS and these genes. In vivo, GPX7 knockdown accelerated NASH fibrosis in a choline-deficient high-fat diet mouse model.","method":"siRNA knockdown, ectopic overexpression, western blot/qPCR for fibrotic markers, ROS assay, in vivo mouse NASH model","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — both in vitro and in vivo loss-of-function with defined pathway readout, single lab","pmids":["32317079"],"is_preprint":false},{"year":2021,"finding":"NPGPx (GPX7) modulates T cell homeostasis by restraining ZAP70 activity. Upon TCR stimulation, ROS activates NPGPx, which then forms a disulfide bond with ZAP70, reducing ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts and thereby dampening TCR signaling. T cell-specific NPGPx-knockout mice display hyperproliferation, elevated cytokines, and susceptibility to EAE.","method":"Proteomic identification of NPGPx–ZAP70 disulfide complex, T cell-specific conditional KO mouse, TCR activation assays, lipid raft fractionation, EAE model","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 — proteomic identification of disulfide partner + conditional KO mouse with defined signaling and in vivo phenotype","pmids":["33460768"],"is_preprint":false},{"year":2021,"finding":"GPX7 deficiency reduces osteogenesis while increasing adipogenesis in BMSCs via ER stress (not via ROS alone); the osteogenic defect is rescued by ER stress antagonist but not by ROS inhibitor. Mechanistically, Gpx7 deficiency downregulates mTOR signaling during osteogenic differentiation, which is rescued by relief of ER stress.","method":"siRNA knockdown of Gpx7, osteogenic/adipogenic differentiation assays, ER stress antagonist rescue, ROS inhibitor control, mTOR pathway western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological dissection of ER stress vs ROS pathways with mTOR mechanistic link, single lab","pmids":["34626080"],"is_preprint":false},{"year":2020,"finding":"GPX7 (fused with PDI) mediates disulfide transfer from H2O2 to target proteins; a PDI-GPX7 fusion expressed in E. coli SHuffle cells consumed ER-equivalent H2O2 and enabled efficient disulfide bond formation, resulting in 4-fold improved yield of correctly folded IgG antibody.","method":"Recombinant fusion protein expression, antibody yield quantification in shake-flask and fermentation, functional disulfide bond formation assay","journal":"Applied microbiology and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional reconstitution in heterologous system confirming H2O2-dependent PDI oxidase activity, applied context","pmids":["32997203"],"is_preprint":false}],"current_model":"GPX7 (NPGPx) is an ER-resident, non-selenocysteine glutathione peroxidase that lacks classical GPx activity but functions as a redox stress sensor/transmitter: its peroxidatic Cys57 is oxidized to sulfenic acid by H2O2 (including Ero1α-generated H2O2), resolved by Cys86 to form an intramolecular disulfide, and this activated form then oxidizes PDI (and P5) to drive oxidative protein folding, while also forming transient intermolecular disulfide bonds with GRP78 (enhancing chaperone activity), CPEB2 (suppressing HIF-1α translation), XRN2 (facilitating siRNA clearance), OGA (fine-tuning O-GlcNAcylation to protect motor neurons), and ZAP70 (dampening TCR signaling), thereby serving as a versatile redox signal relay that protects against ER stress, oxidative DNA damage, adipogenesis, fibrosis, and autoimmunity."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that GPX7 is a non-selenocysteine GPx family member with minimal classical peroxidase activity answered whether the protein functions as a conventional glutathione peroxidase—it does not, yet still protects cells from oxidative stress.","evidence":"In vitro GPx activity assay, siRNA knockdown, and overexpression in breast cancer cells exposed to EPA-derived ROS","pmids":["15294905"],"confidence":"High","gaps":["Mechanism of protection without classical GPx activity was unknown","Subcellular localization was initially assigned as cytoplasmic"]},{"year":2011,"claim":"Demonstration that GPX7 resides in the ER and cooperates with Ero1α and PDI to drive oxidative protein refolding established its principal biochemical function as a PDI peroxidase rather than a glutathione-dependent scavenger.","evidence":"In vitro oxidative refolding reconstitution, co-immunoprecipitation with Ero1α, oxygen consumption assay","pmids":["21215271","22157330"],"confidence":"High","gaps":["Catalytic mechanism and role of individual cysteines unresolved","Whether GPX7 uses GSH or PDI as its physiological reductant was unclear"]},{"year":2012,"claim":"Identifying GPX7 as a redox stress sensor that transmits oxidative signals to GRP78 via covalent disulfide intermediates (Cys86–Cys41/Cys420) shifted the paradigm from antioxidant to redox relay, explaining how it enhances chaperone activity and protein homeostasis.","evidence":"Active-site cysteine mutagenesis, disulfide trapping, chaperone activity assay, GPX7-knockout mice","pmids":["23123197"],"confidence":"High","gaps":["Whether other ER chaperones are similarly regulated was not addressed","Structural basis of the GPX7–GRP78 disulfide intermediate was not resolved"]},{"year":2013,"claim":"Detailed kinetic and mechanistic characterization resolved the catalytic cycle: H₂O₂ oxidizes Cys57 to sulfenic acid, Cys86 resolves it to an intramolecular disulfide, and both forms can oxidize PDI, with the Ero1α/GPX7/PDI triad generating two disulfides per O₂.","evidence":"In vitro reconstitution with mutagenesis, sulfenic acid trapping, SPR (KD 5.2 µM for PDI), oxygen consumption stoichiometry","pmids":["23919619","23454490"],"confidence":"High","gaps":["Crystal structure of the sulfenic acid intermediate was lacking","Relative contributions of one-Cys vs two-Cys mechanisms in vivo unresolved"]},{"year":2013,"claim":"GPX7 knockout mice develop obesity via ROS-dependent PKA regulatory subunit dimerization and C/EBPβ activation in preadipocytes, revealing GPX7 as a metabolic regulator beyond ER protein folding.","evidence":"GPX7-knockout mouse phenotyping, adipocyte differentiation assays, NAC rescue, human SNP association","pmids":["23828861"],"confidence":"High","gaps":["Whether the adipogenic phenotype depends on ER stress vs cytosolic ROS was unresolved","Human genetic association was limited to SNP correlation"]},{"year":2013,"claim":"Epigenetic silencing of GPX7 by promoter hypermethylation in 69% of esophageal adenocarcinomas, together with growth-suppressive and senescence-inducing activity upon reconstitution, established GPX7 as a tumor suppressor in this tissue context.","evidence":"Colony formation, EdU proliferation, mouse xenograft, pyrosequencing of CpG methylation","pmids":["23580780"],"confidence":"High","gaps":["Whether tumor-suppressive function operates through PDI oxidation, NF-κB suppression, or other pathways was unclear","Relevance to cancers beyond esophageal adenocarcinoma was not tested"]},{"year":2015,"claim":"Discovery that GPX7 forms a disulfide bond with CPEB2 to suppress HIF-1α mRNA translation under basal conditions—disrupted under high ROS—extended the redox relay model to translational control of hypoxia signaling.","evidence":"Co-IP, disulfide trapping, RNA–protein interaction assay, HIF-1α translation readout in GPX7-deficient cells","pmids":["26446990"],"confidence":"Medium","gaps":["Whether GPX7–CPEB2 interaction regulates other mRNA targets was not explored","In vivo validation of HIF-1α translational control was limited"]},{"year":2019,"claim":"GPX7 inhibits O-GlcNAcase (OGA) by disulfide bonding, fine-tuning O-GlcNAcylation to protect spinal motor neurons; GPX7-knockout mice develop ALS-like phenotypes rescued by OGA inhibition, linking the redox relay to neurodegeneration.","evidence":"GPX7-knockout mouse ALS phenotype, disulfide trapping of GPX7–OGA complex, pharmacological OGA inhibitor rescue","pmids":["31747588"],"confidence":"High","gaps":["Whether GPX7–OGA interaction occurs in cell types beyond motor neurons was not assessed","Upstream signals that activate GPX7 in aging motor neurons remain undefined"]},{"year":2020,"claim":"Refined enzymological comparison showed GPX7 has much higher H₂O₂ reactivity than GPX8, attributable to a catalytic tetrad stabilizing sulfenylated Cys57; the resolving Cys86 controls PDI oxidation activity, and GPX7 preferentially forms complexes with PDI and P5.","evidence":"In vitro H₂O₂ reactivity and PDI oxidation assays, mutagenesis, co-IP in H₂O₂-treated cells","pmids":["32719007"],"confidence":"High","gaps":["Full structural determination of the catalytic tetrad was not provided","Quantitative contribution of GPX7 vs GPX8 to ER redox homeostasis in vivo remains unresolved"]},{"year":2021,"claim":"T cell-specific GPX7 knockout revealed that GPX7 restrains TCR signaling by forming a disulfide bond with ZAP70 that reduces its lipid-raft recruitment, establishing GPX7 as an immune checkpoint via redox relay.","evidence":"Proteomic identification of GPX7–ZAP70 disulfide, conditional T cell-specific KO mouse, TCR activation assays, lipid raft fractionation, EAE autoimmune model","pmids":["33460768"],"confidence":"High","gaps":["Whether GPX7 modulates other proximal TCR kinases is unknown","Relevance to human autoimmune disease has not been tested"]},{"year":null,"claim":"A high-resolution crystal structure of GPX7 in the sulfenylated and disulfide states is lacking, and the hierarchy of client selection—how GPX7 discriminates among PDI, GRP78, CPEB2, OGA, and ZAP70—remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of catalytic intermediates","Determinants of client selectivity unknown","Relative importance of GPX7 vs GPX8 in ER redox homeostasis in vivo not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,2,5,6,13]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,5,6,13,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9,12,15]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,5,11,13]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5,6,13,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3,11,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,10,15]}],"complexes":[],"partners":["PDI","GRP78","ERO1A","ZAP70","OGA","CPEB2","XRN2","P5"],"other_free_text":[]},"mechanistic_narrative":"GPX7 is an ER-resident, non-selenocysteine glutathione peroxidase that functions primarily as a redox sensor and disulfide relay rather than a classical peroxide scavenger. Its peroxidatic Cys57 is oxidized to sulfenic acid by H₂O₂—including Ero1α-generated H₂O₂—and resolved by Cys86 to form an intramolecular disulfide; both the sulfenic acid and disulfide forms oxidize PDI (and P5), coupling peroxide consumption to oxidative protein folding via an Ero1α/GPX7/PDI triad that generates two disulfide bonds per O₂ consumed [PMID:23919619, PMID:32719007]. Beyond PDI, the activated disulfide form of GPX7 engages diverse client proteins through intermolecular disulfide bonds—GRP78 (enhancing chaperone activity) [PMID:23123197], CPEB2 (suppressing HIF-1α translation) [PMID:26446990], OGA (modulating O-GlcNAcylation to protect motor neurons) [PMID:31747588], and ZAP70 (dampening TCR signaling to restrain T cell hyperactivation) [PMID:33460768]—thereby serving as a versatile redox signal transmitter linking ER oxidative status to protein homeostasis, metabolic regulation, and immune tolerance. GPX7 deficiency in mice causes obesity through ROS-dependent PKA-regulatory-subunit dimerization and enhanced adipogenesis [PMID:23828861], ALS-like motor neuron degeneration [PMID:31747588], and T cell-driven autoimmune susceptibility [PMID:33460768], while its epigenetic silencing by promoter hypermethylation is frequent in esophageal adenocarcinoma where it acts as a tumor suppressor [PMID:23580780]."},"prefetch_data":{"uniprot":{"accession":"Q96SL4","full_name":"Glutathione peroxidase 7","aliases":["CL683"],"length_aa":187,"mass_kda":21.0,"function":"It protects esophageal epithelia from hydrogen peroxide-induced oxidative stress. It suppresses acidic bile acid-induced reactive oxygen species (ROS) and protects against oxidative DNA damage and double-strand breaks","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96SL4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPX7","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPX7","total_profiled":1310},"omim":[{"mim_id":"617172","title":"GLUTATHIONE PEROXIDASE 8; GPX8","url":"https://www.omim.org/entry/617172"},{"mim_id":"615784","title":"GLUTATHIONE PEROXIDASE 7; GPX7","url":"https://www.omim.org/entry/615784"},{"mim_id":"615435","title":"ENDOPLASMIC RETICULUM OXIDOREDUCTIN 1-LIKE; ERO1L","url":"https://www.omim.org/entry/615435"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPX7"},"hgnc":{"alias_symbol":["FLJ14777","GPX6","NPGPx"],"prev_symbol":[]},"alphafold":{"accession":"Q96SL4","domains":[{"cath_id":"3.40.30.10","chopping":"28-185","consensus_level":"high","plddt":97.9894,"start":28,"end":185}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SL4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SL4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SL4-F1-predicted_aligned_error_v6.png","plddt_mean":92.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPX7","jax_strain_url":"https://www.jax.org/strain/search?query=GPX7"},"sequence":{"accession":"Q96SL4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96SL4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96SL4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SL4"}},"corpus_meta":[{"pmid":"23123197","id":"PMC_23123197","title":"Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23123197","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26708178","id":"PMC_26708178","title":"GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues.","date":"2015","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/26708178","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15294905","id":"PMC_15294905","title":"Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15294905","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27186289","id":"PMC_27186289","title":"NPGPx (GPx7): a novel oxidative stress sensor/transmitter with multiple roles in redox homeostasis.","date":"2016","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/27186289","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23828861","id":"PMC_23828861","title":"Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23828861","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28751022","id":"PMC_28751022","title":"ER-resident antioxidative GPx7 and GPx8 enzyme isoforms protect insulin-secreting INS-1E β-cells against lipotoxicity by improving the ER antioxidative capacity.","date":"2017","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28751022","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32719007","id":"PMC_32719007","title":"Characterization of the endoplasmic reticulum-resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32719007","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34626080","id":"PMC_34626080","title":"GPX7 Facilitates BMSCs Osteoblastogenesis via ER Stress and mTOR Pathway.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34626080","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25535386","id":"PMC_25535386","title":"Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25535386","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35127512","id":"PMC_35127512","title":"GPX7 Is Targeted by miR-29b and GPX7 Knockdown Enhances Ferroptosis Induced by Erastin in Glioma.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35127512","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31747588","id":"PMC_31747588","title":"NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31747588","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23241391","id":"PMC_23241391","title":"A 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\"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (mutagenesis, covalent complex trapping, in vitro assay, KO mouse), single rigorous study with strong mechanistic validation\",\n      \"pmids\": [\"23123197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NPGPx (GPX7) is a cytoplasmic ~22 kDa protein that incorporates cysteine instead of selenocysteine at the conserved catalytic motif and has little detectable glutathione peroxidase activity in vitro; it protects cells from oxidative stress generated by polyunsaturated fatty acid metabolism.\",\n      \"method\": \"In vitro GPx enzymatic assay, ectopic expression in Brca1-null cells, siRNA knockdown with EPA-mediated cell death readout\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct enzymatic assay plus gain/loss-of-function experiments, foundational paper with 92 citations\",\n      \"pmids\": [\"15294905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NPGPx (GPX7) covalently binds to the exoribonuclease XRN2 via disulfide bonding upon non-targeting siRNA stress, facilitating XRN2-mediated degradation of accumulated non-targeting siRNA to relieve cellular stress.\",\n      \"method\": \"Co-IP, covalent complex detection, NPGPx depletion with siRNA accumulation and apoptosis readouts\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional KD evidence, single lab\",\n      \"pmids\": [\"21908404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NPGPx (GPX7) deficiency promotes preadipocyte-to-adipocyte differentiation via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ; this phenotype is rescued by the antioxidant N-acetylcysteine.\",\n      \"method\": \"NPGPx-KO mouse model, preadipocyte differentiation assays, NAC rescue, PKA regulatory subunit dimerization assay\",\n      \"journal\": \"EMBO Molecular Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined molecular mechanism (PKA dimerization), NAC rescue, and human SNP correlation; multiple orthogonal approaches\",\n      \"pmids\": [\"23828861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPGPx (GPX7) forms a disulfide bond with the translational regulator CPEB2, maintaining CPEB2 association with HIF-1α mRNA and suppressing its translation; high oxidative stress disrupts this bond, releasing CPEB2 from HIF-1α mRNA and allowing elevated HIF-1α translation.\",\n      \"method\": \"Co-IP/covalent complex trapping, NPGPx-deficient cells with HIF-1α translation assays, polysome profiling\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disulfide complex trapping and functional translation assays, single lab\",\n      \"pmids\": [\"26446990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPGPx (GPX7) inhibits O-GlcNAcase (OGA) through direct disulfide bonding upon stress activation, thereby fine-tuning global O-GlcNAcylation levels; NPGPx-deficient spinal motor neurons fail to boost O-GlcNAcylation against age-dependent oxidative stress, leading to neurodegeneration with ALS-like phenotypes.\",\n      \"method\": \"NPGPx-KO mouse model, proteomic identification of OGA as interacting partner, disulfide bonding assay, pharmacological OGA inhibitor rescue\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with ALS phenotype, OGA interaction via disulfide trapping, pharmacological rescue confirms pathway placement\",\n      \"pmids\": [\"31747588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human GPX7 has much higher reactivity with H2O2 than GPX8, functioning as an H2O2-dependent PDI oxidase; a catalytic tetrad at the redox-active site stabilizes the sulfenylated peroxidatic cysteine intermediate, and a resolving cysteine regulates PDI oxidation activity. GPX7 preferentially forms complexes with PDI and P5 in H2O2-treated cells.\",\n      \"method\": \"In vitro H2O2 reactivity assays, PDI oxidation activity assays, active-site mutagenesis, Co-IP in H2O2-treated cells\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis, mechanistic dissection of catalytic tetrad and resolving cysteine, confirmed in cell-based Co-IP\",\n      \"pmids\": [\"32719007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPX7 is an ER-resident enzyme that reduces H2O2 in the ER lumen; expression of GPX7 in rat β-cells attenuates FFA-mediated H2O2 generation, ER stress, and apoptosis without affecting disulfide bond formation in insulin, indicating H2O2 scavenging rather than oxidative protein folding is its primary role in this context.\",\n      \"method\": \"GPX7 overexpression and ER-catalase comparison in INS-1E cells, H2O2 measurement, ER stress marker assays, insulin content quantification\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional overexpression with mechanistic comparison to ER catalase control, single lab\",\n      \"pmids\": [\"28751022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPGPx (GPX7) interacts with ZAP70 via disulfide bonding upon ROS generated from TCR stimulation, modulating ZAP70 activity through redox switching and reducing ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts, thereby suppressing TCR signaling and maintaining T cell homeostasis.\",\n      \"method\": \"Proteomic identification of ZAP70 as NPGPx interactor, disulfide complex trapping, T cell-specific NPGPx-KO mouse with EAE model, lipid raft fractionation\",\n      \"journal\": \"Free Radical Biology & Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic discovery, covalent complex trapping, conditional KO mouse with defined immunological phenotype and lipid raft localization data\",\n      \"pmids\": [\"33460768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPX7 deficiency reduces osteogenic differentiation of BMSCs via induction of ER stress (rather than elevated ROS), and the mTOR signaling pathway is downregulated downstream of ER stress in GPX7-deficient conditions; ER stress antagonism rescues osteogenesis.\",\n      \"method\": \"GPX7 knockdown in hBMSCs and mouse MSC line, ER stress antagonist rescue, ROS inhibitor comparison, mTOR pathway analysis\",\n      \"journal\": \"Journal of Cellular and Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with ER stress antagonist rescue distinguishes ER stress from ROS mechanism, single lab\",\n      \"pmids\": [\"34626080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPX7 knockdown in LX-2 hepatic stellate cells elevated ROS production and upregulated pro-fibrotic and pro-inflammatory gene expression and collagen synthesis; GPX7 overexpression suppressed these effects, positioning GPX7 as an antioxidant regulator of hepatic stellate cell activation.\",\n      \"method\": \"GPX7 siRNA knockdown and overexpression in LX-2 cells, ROS measurement, pro-fibrotic/inflammatory gene expression, in vivo CDAHFD mouse model with GPX7 knockdown\",\n      \"journal\": \"BMB Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function in vitro and in vivo, single lab\",\n      \"pmids\": [\"32317079\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPX7 (NPGPx) is a non-selenocysteine, ER-resident member of the glutathione peroxidase family that lacks classical GPx activity but functions as a redox sensor/transmitter: upon oxidative stress its peroxidatic cysteine is sulfenylated by H2O2, enabling it to form transient intermolecular disulfide bonds with target proteins—including GRP78, PDI/P5, XRN2, CPEB2, OGA, and ZAP70—thereby modulating their activity in pathways governing ER proteostasis, oxidative protein folding, mRNA surveillance, HIF-1α translation, O-GlcNAcylation, and T cell signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"GPX7 (NPGPx) was identified as a cytoplasmic ~22 kDa protein that incorporates cysteine instead of selenocysteine at the conserved catalytic motif, exhibits little detectable glutathione peroxidase activity in vitro, and protects against oxidative stress generated from polyunsaturated fatty acid (EPA) metabolism in breast cancer cells.\",\n      \"method\": \"In vitro GPx activity assay, siRNA knockdown, ectopic overexpression, cell viability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (activity assay, KD, OE) with defined cellular phenotype, foundational characterization paper\",\n      \"pmids\": [\"15294905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GPX7 and GPX8 were shown to be ER-resident PDI peroxidases: in vitro, addition of GPX7 or GPX8 together with PDI and peroxide enables efficient oxidative refolding of reduced denatured protein; both proteins interact with Ero1α in vivo, and GPX7 significantly increases oxygen consumption by Ero1α in vitro.\",\n      \"method\": \"In vitro oxidative refolding assay, co-immunoprecipitation (in vivo), oxygen consumption assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus in vivo co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"21215271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GPX7 exhibits H2O2-neutralizing activity independent of glutathione; reconstitution of GPX7 expression in Barrett's esophagus cells conferred resistance to H2O2-induced oxidative DNA damage, double-strand breaks, ROS-dependent JNK/p38 signaling, and apoptosis following acidic bile acid exposure.\",\n      \"method\": \"GPx enzymatic activity assay, Amplex UltraRed H2O2 assay, CM-H2DCFDA ROS assay, 8-oxoguanine and phospho-H2AX assays, siRNA knockdown, ectopic overexpression\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with both KD and OE, replicated in multiple cell lines\",\n      \"pmids\": [\"22157330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NPGPx (GPX7) acts as an oxidative stress sensor/transmitter: upon ROS accumulation, it forms an intramolecular disulfide bond between Cys57 and Cys86; this oxidized form then forms covalent disulfide intermediates with GRP78 (Cys86 of NPGPx to Cys41/Cys420 of GRP78), which subsequently promotes formation of the Cys41–Cys420 disulfide in GRP78, enhancing its chaperone activity. NPGPx-deficient cells accumulate ROS, misfolded proteins, and display impaired GRP78 chaperone activity.\",\n      \"method\": \"Mutagenesis of active-site cysteines, co-immunoprecipitation, disulfide bond trapping, chaperone activity assay, NPGPx knockout mice\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — active-site mutagenesis + covalent intermediate trapping + in vivo KO with defined phenotype; highly cited foundational paper\",\n      \"pmids\": [\"23123197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Under non-targeting siRNA stress, NPGPx (GPX7) is selectively induced and covalently binds exoribonuclease XRN2 via disulfide bonding, facilitating XRN2-mediated degradation of accumulated non-targeting siRNA and thereby releasing cellular stress.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, apoptosis assay, G1 phase cell cycle analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP for interaction, functional rescue experiment, single lab\",\n      \"pmids\": [\"21908404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPX7 utilizes Ero1α-generated H2O2 to promote oxidative protein folding. Mechanistically, H2O2 oxidizes Cys57 of GPX7 to sulfenic acid, which is resolved by Cys86 to form an intramolecular disulfide bond; both the sulfenic acid form and disulfide form of GPX7 can oxidize PDI. GPX7 preferentially interacts with the a-domain of PDI, and the Ero1α/GPX7/PDI triad generates two disulfide bonds per O2 molecule consumed.\",\n      \"method\": \"In vitro oxidative folding assay, site-directed mutagenesis (Cys57, Cys86), biochemical trapping of sulfenic acid intermediate, in vivo co-IP, oxygen consumption assay\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis, multiple intermediates characterized, in vivo validation; highly cited\",\n      \"pmids\": [\"23919619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPX7 uses a one-Cys catalytic mechanism in which the peroxidatic Cys (CP) is rapidly oxidized by phospholipid hydroperoxide; GSH and PDI are alternative reducing substrates for re-reduction of oxidized CP. PDI-GPX7 interaction was quantified with KD = 5.2 μM by surface plasmon resonance; thioredoxin does not serve as a reducing substrate.\",\n      \"method\": \"Steady-state kinetic analysis, site-directed mutagenesis, molecular docking, surface plasmon resonance\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted kinetics, mutagenesis, biophysical binding measurement\",\n      \"pmids\": [\"23454490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPX7 functions as a tumor suppressor in esophageal adenocarcinoma: reconstitution of GPX7 suppresses cell growth, impairs G1/S progression, increases cellular senescence, and elevates p73, p27, p21, p16 while decreasing phospho-RB. GPX7 is silenced by location-specific promoter DNA hypermethylation (+13 to +64 region) in 69% of OAC cases.\",\n      \"method\": \"Growth curve, colony formation, EdU proliferation assay, cell cycle analysis, senescence assay, western blot, mouse xenograft model, pyrosequencing of CpG methylation\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal cell and in vivo assays with mechanistic pathway readout\",\n      \"pmids\": [\"23580780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of GPX7 promotes TNF-α-induced NF-κB activation in esophageal cells. GPX7 suppresses NF-κB by promoting proteasomal degradation of TNFR1 and TRAF2 upstream regulators; this suppression is independent of ROS levels and GPX7 antioxidant function.\",\n      \"method\": \"Western blot, immunofluorescence, luciferase reporter assay, siRNA knockdown, ectopic overexpression, protein degradation assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple assays with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"24692067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPGPx (GPX7) forms a disulfide bond with translational regulator CPEB2, which maintains CPEB2 binding to HIF-1α mRNA and suppresses HIF-1α translation under basal conditions. High oxidative stress disrupts this NPGPx–CPEB2 disulfide, releasing CPEB2 from HIF-1α mRNA and elevating HIF-1α translation.\",\n      \"method\": \"Co-immunoprecipitation, disulfide trapping, RNA-protein interaction assay, western blot for HIF-1α translation, NPGPx-deficient cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP of disulfide intermediate, functional RNA translation readout, single lab\",\n      \"pmids\": [\"26446990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NPGPx (GPX7) deficiency leads to obesity in mice via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ, promoting preadipocyte differentiation into adipocytes. NPGPx is highly expressed in preadipocytes, and NPGPx-knockout mice exhibit increased fat mass and adipocyte hypertrophy reversible by N-acetylcysteine treatment.\",\n      \"method\": \"NPGPx knockout mouse model, adipocyte differentiation assays, western blot (PKA regulatory subunit dimerization, C/EBPβ), NAC rescue experiment, SNP association in humans\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined molecular mechanism (PKA dimerization) and pharmacological rescue, supported by human genetic data\",\n      \"pmids\": [\"23828861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPX7 and GPX8 are ER-resident antioxidant enzymes; expression of GPX7 in pancreatic INS-1E β-cells attenuates FFA-mediated H2O2 accumulation in the ER, ER stress, and apoptosis without compromising insulin production or oxidative protein folding/disulfide bond formation in insulin.\",\n      \"method\": \"Ectopic expression of GPX7/GPX8, H2O2 measurement, ER stress markers (western blot), apoptosis assay, insulin content assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean overexpression with mechanistic dissection in β-cells, single lab\",\n      \"pmids\": [\"28751022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPGPx (GPX7) is activated by oxidative stress and inhibits O-GlcNAcase (OGA) through disulfide bonding, thereby fine-tuning global O-GlcNAcylation. Deficiency of NPGPx in mice causes ALS-like phenotypes (paralysis, muscle denervation, motor neuron loss) and failure to boost O-GlcNAcylation in spinal motor neurons with age; pharmacological OGA inhibition rescues spinal motor neuron loss in aged NPGPx-deficient mice.\",\n      \"method\": \"NPGPx knockout mouse model (ALS phenotype characterization), disulfide bond trapping (NPGPx–OGA interaction), proteomic identification, pharmacological rescue (OGA inhibitor), O-GlcNAcylation western blot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined molecular target (OGA disulfide bonding), pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31747588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human GPX7 has much higher reactivity with H2O2 than GPX8, attributable to a catalytic tetrad at the redox-active site that stabilizes the sulfenylated Cys57 intermediate. Contrary to prior models, the resolving Cys (not the peroxidatic Cys) regulates PDI oxidation activity of GPX7. GPX7 forms complexes preferentially with PDI and P5 in H2O2-treated cells.\",\n      \"method\": \"In vitro H2O2 reactivity assay, PDI oxidation assay, site-directed mutagenesis, co-immunoprecipitation in H2O2-treated cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis plus in vivo co-IP, structural mechanistic insight\",\n      \"pmids\": [\"32719007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPX7 knockdown in TGF-β/FFA-treated hepatic stellate cells (LX-2) elevated pro-fibrotic and pro-inflammatory gene expression and collagen synthesis; GPX7 overexpression suppressed ROS and these genes. In vivo, GPX7 knockdown accelerated NASH fibrosis in a choline-deficient high-fat diet mouse model.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, western blot/qPCR for fibrotic markers, ROS assay, in vivo mouse NASH model\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — both in vitro and in vivo loss-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"32317079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPGPx (GPX7) modulates T cell homeostasis by restraining ZAP70 activity. Upon TCR stimulation, ROS activates NPGPx, which then forms a disulfide bond with ZAP70, reducing ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts and thereby dampening TCR signaling. T cell-specific NPGPx-knockout mice display hyperproliferation, elevated cytokines, and susceptibility to EAE.\",\n      \"method\": \"Proteomic identification of NPGPx–ZAP70 disulfide complex, T cell-specific conditional KO mouse, TCR activation assays, lipid raft fractionation, EAE model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification of disulfide partner + conditional KO mouse with defined signaling and in vivo phenotype\",\n      \"pmids\": [\"33460768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPX7 deficiency reduces osteogenesis while increasing adipogenesis in BMSCs via ER stress (not via ROS alone); the osteogenic defect is rescued by ER stress antagonist but not by ROS inhibitor. Mechanistically, Gpx7 deficiency downregulates mTOR signaling during osteogenic differentiation, which is rescued by relief of ER stress.\",\n      \"method\": \"siRNA knockdown of Gpx7, osteogenic/adipogenic differentiation assays, ER stress antagonist rescue, ROS inhibitor control, mTOR pathway western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological dissection of ER stress vs ROS pathways with mTOR mechanistic link, single lab\",\n      \"pmids\": [\"34626080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPX7 (fused with PDI) mediates disulfide transfer from H2O2 to target proteins; a PDI-GPX7 fusion expressed in E. coli SHuffle cells consumed ER-equivalent H2O2 and enabled efficient disulfide bond formation, resulting in 4-fold improved yield of correctly folded IgG antibody.\",\n      \"method\": \"Recombinant fusion protein expression, antibody yield quantification in shake-flask and fermentation, functional disulfide bond formation assay\",\n      \"journal\": \"Applied microbiology and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional reconstitution in heterologous system confirming H2O2-dependent PDI oxidase activity, applied context\",\n      \"pmids\": [\"32997203\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPX7 (NPGPx) is an ER-resident, non-selenocysteine glutathione peroxidase that lacks classical GPx activity but functions as a redox stress sensor/transmitter: its peroxidatic Cys57 is oxidized to sulfenic acid by H2O2 (including Ero1α-generated H2O2), resolved by Cys86 to form an intramolecular disulfide, and this activated form then oxidizes PDI (and P5) to drive oxidative protein folding, while also forming transient intermolecular disulfide bonds with GRP78 (enhancing chaperone activity), CPEB2 (suppressing HIF-1α translation), XRN2 (facilitating siRNA clearance), OGA (fine-tuning O-GlcNAcylation to protect motor neurons), and ZAP70 (dampening TCR signaling), thereby serving as a versatile redox signal relay that protects against ER stress, oxidative DNA damage, adipogenesis, fibrosis, and autoimmunity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GPX7 (NPGPx) is a non-selenocysteine glutathione peroxidase family member that functions primarily as an ER-resident oxidative stress sensor and redox signal transmitter rather than a classical peroxidase. It lacks significant glutathione peroxidase activity but reacts with H₂O₂ via a catalytic tetrad that stabilizes a sulfenylated peroxidatic cysteine intermediate; oxidation induces intramolecular disulfide formation between Cys57 and Cys86, enabling GPX7 to relay oxidizing equivalents to diverse protein targets—including GRP78, PDI/P5, XRN2, CPEB2, OGA, and ZAP70—through transient intermolecular disulfide bonds that modulate their activities [PMID:23123197, PMID:32719007, PMID:33460768]. Through this disulfide-relay mechanism, GPX7 governs ER proteostasis by enhancing GRP78 chaperone function, promotes oxidative protein folding by serving as an H₂O₂-dependent PDI oxidase, suppresses HIF-1α translation via CPEB2 regulation, tunes global O-GlcNAcylation by inhibiting OGA, and attenuates TCR signaling by modulating ZAP70 recruitment to lipid rafts [PMID:23123197, PMID:32719007, PMID:26446990, PMID:31747588, PMID:33460768]. GPX7 deficiency in mice leads to tissue-specific phenotypes including enhanced adipogenesis, ALS-like motor neuron degeneration due to impaired O-GlcNAcylation, and exacerbated autoimmune responses [PMID:23828861, PMID:31747588, PMID:33460768].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving whether GPX7 is a classical peroxidase established that it has cysteine in place of selenocysteine and negligible GPx activity, yet still protects cells from oxidative lipid stress, indicating a non-canonical antioxidant mechanism.\",\n      \"evidence\": \"In vitro GPx assay, ectopic expression and siRNA knockdown in Brca1-null cells with EPA-mediated death readout\",\n      \"pmids\": [\"15294905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytoprotection without catalytic peroxidase activity was unresolved\", \"Subcellular localization initially reported as cytoplasmic rather than ER\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of a covalent disulfide interaction between GPX7 and the exoribonuclease XRN2 first demonstrated that GPX7 functions through intermolecular disulfide relay to regulate non-canonical targets beyond classical antioxidant substrates.\",\n      \"evidence\": \"Co-IP, covalent complex detection, GPX7 depletion with siRNA accumulation and apoptosis readouts\",\n      \"pmids\": [\"21908404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only a single Co-IP study without independent replication\", \"Whether XRN2 regulation reflects a general disulfide-relay mechanism was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the Cys57–Cys86 intramolecular switch and covalent disulfide relay to GRP78 established the core redox sensor/transmitter mechanism—explaining how GPX7 senses H₂O₂ and transmits oxidizing equivalents to enhance GRP78 chaperone activity and ER proteostasis.\",\n      \"evidence\": \"Covalent complex trapping, cysteine mutagenesis, in vitro chaperone assay, NPGPx-KO mouse model\",\n      \"pmids\": [\"23123197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the disulfide relay was not determined\", \"Range of ER-resident targets beyond GRP78 was not yet mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"GPX7-KO mice revealed that loss of GPX7 causes ROS-dependent PKA regulatory subunit dimerization and enhanced adipogenesis, demonstrating organismal consequences of impaired redox sensing.\",\n      \"evidence\": \"KO mouse, preadipocyte differentiation assays, NAC rescue, PKA dimerization assay\",\n      \"pmids\": [\"23828861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether adipogenesis phenotype operates through direct disulfide relay or indirect ROS accumulation was not fully distinguished\", \"Cell-type specificity of the PKA mechanism was not explored\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The disulfide-relay mechanism was extended to translational regulation: GPX7 maintains CPEB2 in a disulfide-bonded state that suppresses HIF-1α mRNA translation, linking ER redox sensing to hypoxia response.\",\n      \"evidence\": \"Covalent complex trapping, GPX7-deficient cells with HIF-1α translation assays, polysome profiling\",\n      \"pmids\": [\"26446990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent confirmation\", \"In vivo relevance of GPX7–CPEB2 axis under physiological hypoxia not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that GPX7 reduces ER luminal H₂O₂ and protects β-cells from lipotoxic ER stress without affecting insulin disulfide bond formation clarified that GPX7 can act as an ER H₂O₂ scavenger independent of its oxidative protein folding role.\",\n      \"evidence\": \"GPX7 overexpression vs ER-catalase in INS-1E cells, H₂O₂ measurement, ER stress markers\",\n      \"pmids\": [\"28751022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system; endogenous GPX7 contribution in β-cells not tested\", \"Apparent discrepancy with PDI-oxidase function not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of OGA as a disulfide-bonded target of GPX7 linked the redox sensor mechanism to O-GlcNAcylation homeostasis; GPX7-KO mice developed ALS-like motor neuron degeneration reversible by OGA inhibition, establishing a disease-relevant pathway.\",\n      \"evidence\": \"KO mouse, proteomic identification of OGA, disulfide trapping, pharmacological OGA inhibitor rescue\",\n      \"pmids\": [\"31747588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether motor neuron vulnerability reflects cell-autonomous GPX7 loss or systemic effects not fully resolved\", \"Direct structural basis of GPX7–OGA disulfide not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Biochemical dissection of GPX7's catalytic mechanism showed that a catalytic tetrad stabilizes the sulfenylated Cys intermediate and a resolving cysteine regulates PDI oxidation, establishing GPX7 as a bona fide H₂O₂-dependent PDI oxidase far more reactive than GPX8.\",\n      \"evidence\": \"In vitro H₂O₂ reactivity, PDI oxidation assays, active-site mutagenesis, Co-IP with PDI/P5 in H₂O₂-treated cells\",\n      \"pmids\": [\"32719007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the sulfenylated intermediate\", \"Relative contribution of GPX7 vs. Ero1α to PDI oxidation in vivo undetermined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extension of the disulfide-relay mechanism to T cell signaling showed that GPX7 modulates ZAP70 via redox switching and controls its lipid raft recruitment, suppressing TCR signaling; T cell-specific KO mice develop exacerbated autoimmunity.\",\n      \"evidence\": \"Proteomic identification, disulfide complex trapping, conditional KO mouse with EAE model, lipid raft fractionation\",\n      \"pmids\": [\"33460768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPX7 modulates other proximal TCR kinases not assessed\", \"Mechanism by which GPX7 disulfide bonding alters ZAP70 lipid raft localization is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural model of the GPX7 disulfide-relay mechanism with its diverse targets, and in vivo delineation of its ER scavenging versus PDI oxidase versus redox relay functions in different tissues, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of GPX7 in complex with any target\", \"Context-dependent switching between H₂O₂ scavenging and disulfide relay not mechanistically explained\", \"Full interactome of disulfide-bonded targets not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 5, 8]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRP78\", \"PDI\", \"P5\", \"XRN2\", \"CPEB2\", \"OGA\", \"ZAP70\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GPX7 is an ER-resident, non-selenocysteine glutathione peroxidase that functions primarily as a redox sensor and disulfide relay rather than a classical peroxide scavenger. Its peroxidatic Cys57 is oxidized to sulfenic acid by H₂O₂—including Ero1α-generated H₂O₂—and resolved by Cys86 to form an intramolecular disulfide; both the sulfenic acid and disulfide forms oxidize PDI (and P5), coupling peroxide consumption to oxidative protein folding via an Ero1α/GPX7/PDI triad that generates two disulfide bonds per O₂ consumed [PMID:23919619, PMID:32719007]. Beyond PDI, the activated disulfide form of GPX7 engages diverse client proteins through intermolecular disulfide bonds—GRP78 (enhancing chaperone activity) [PMID:23123197], CPEB2 (suppressing HIF-1α translation) [PMID:26446990], OGA (modulating O-GlcNAcylation to protect motor neurons) [PMID:31747588], and ZAP70 (dampening TCR signaling to restrain T cell hyperactivation) [PMID:33460768]—thereby serving as a versatile redox signal transmitter linking ER oxidative status to protein homeostasis, metabolic regulation, and immune tolerance. GPX7 deficiency in mice causes obesity through ROS-dependent PKA-regulatory-subunit dimerization and enhanced adipogenesis [PMID:23828861], ALS-like motor neuron degeneration [PMID:31747588], and T cell-driven autoimmune susceptibility [PMID:33460768], while its epigenetic silencing by promoter hypermethylation is frequent in esophageal adenocarcinoma where it acts as a tumor suppressor [PMID:23580780].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that GPX7 is a non-selenocysteine GPx family member with minimal classical peroxidase activity answered whether the protein functions as a conventional glutathione peroxidase—it does not, yet still protects cells from oxidative stress.\",\n      \"evidence\": \"In vitro GPx activity assay, siRNA knockdown, and overexpression in breast cancer cells exposed to EPA-derived ROS\",\n      \"pmids\": [\"15294905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of protection without classical GPx activity was unknown\", \"Subcellular localization was initially assigned as cytoplasmic\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that GPX7 resides in the ER and cooperates with Ero1α and PDI to drive oxidative protein refolding established its principal biochemical function as a PDI peroxidase rather than a glutathione-dependent scavenger.\",\n      \"evidence\": \"In vitro oxidative refolding reconstitution, co-immunoprecipitation with Ero1α, oxygen consumption assay\",\n      \"pmids\": [\"21215271\", \"22157330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and role of individual cysteines unresolved\", \"Whether GPX7 uses GSH or PDI as its physiological reductant was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying GPX7 as a redox stress sensor that transmits oxidative signals to GRP78 via covalent disulfide intermediates (Cys86–Cys41/Cys420) shifted the paradigm from antioxidant to redox relay, explaining how it enhances chaperone activity and protein homeostasis.\",\n      \"evidence\": \"Active-site cysteine mutagenesis, disulfide trapping, chaperone activity assay, GPX7-knockout mice\",\n      \"pmids\": [\"23123197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other ER chaperones are similarly regulated was not addressed\", \"Structural basis of the GPX7–GRP78 disulfide intermediate was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Detailed kinetic and mechanistic characterization resolved the catalytic cycle: H₂O₂ oxidizes Cys57 to sulfenic acid, Cys86 resolves it to an intramolecular disulfide, and both forms can oxidize PDI, with the Ero1α/GPX7/PDI triad generating two disulfides per O₂.\",\n      \"evidence\": \"In vitro reconstitution with mutagenesis, sulfenic acid trapping, SPR (KD 5.2 µM for PDI), oxygen consumption stoichiometry\",\n      \"pmids\": [\"23919619\", \"23454490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the sulfenic acid intermediate was lacking\", \"Relative contributions of one-Cys vs two-Cys mechanisms in vivo unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"GPX7 knockout mice develop obesity via ROS-dependent PKA regulatory subunit dimerization and C/EBPβ activation in preadipocytes, revealing GPX7 as a metabolic regulator beyond ER protein folding.\",\n      \"evidence\": \"GPX7-knockout mouse phenotyping, adipocyte differentiation assays, NAC rescue, human SNP association\",\n      \"pmids\": [\"23828861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the adipogenic phenotype depends on ER stress vs cytosolic ROS was unresolved\", \"Human genetic association was limited to SNP correlation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Epigenetic silencing of GPX7 by promoter hypermethylation in 69% of esophageal adenocarcinomas, together with growth-suppressive and senescence-inducing activity upon reconstitution, established GPX7 as a tumor suppressor in this tissue context.\",\n      \"evidence\": \"Colony formation, EdU proliferation, mouse xenograft, pyrosequencing of CpG methylation\",\n      \"pmids\": [\"23580780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tumor-suppressive function operates through PDI oxidation, NF-κB suppression, or other pathways was unclear\", \"Relevance to cancers beyond esophageal adenocarcinoma was not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that GPX7 forms a disulfide bond with CPEB2 to suppress HIF-1α mRNA translation under basal conditions—disrupted under high ROS—extended the redox relay model to translational control of hypoxia signaling.\",\n      \"evidence\": \"Co-IP, disulfide trapping, RNA–protein interaction assay, HIF-1α translation readout in GPX7-deficient cells\",\n      \"pmids\": [\"26446990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPX7–CPEB2 interaction regulates other mRNA targets was not explored\", \"In vivo validation of HIF-1α translational control was limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"GPX7 inhibits O-GlcNAcase (OGA) by disulfide bonding, fine-tuning O-GlcNAcylation to protect spinal motor neurons; GPX7-knockout mice develop ALS-like phenotypes rescued by OGA inhibition, linking the redox relay to neurodegeneration.\",\n      \"evidence\": \"GPX7-knockout mouse ALS phenotype, disulfide trapping of GPX7–OGA complex, pharmacological OGA inhibitor rescue\",\n      \"pmids\": [\"31747588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPX7–OGA interaction occurs in cell types beyond motor neurons was not assessed\", \"Upstream signals that activate GPX7 in aging motor neurons remain undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined enzymological comparison showed GPX7 has much higher H₂O₂ reactivity than GPX8, attributable to a catalytic tetrad stabilizing sulfenylated Cys57; the resolving Cys86 controls PDI oxidation activity, and GPX7 preferentially forms complexes with PDI and P5.\",\n      \"evidence\": \"In vitro H₂O₂ reactivity and PDI oxidation assays, mutagenesis, co-IP in H₂O₂-treated cells\",\n      \"pmids\": [\"32719007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural determination of the catalytic tetrad was not provided\", \"Quantitative contribution of GPX7 vs GPX8 to ER redox homeostasis in vivo remains unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"T cell-specific GPX7 knockout revealed that GPX7 restrains TCR signaling by forming a disulfide bond with ZAP70 that reduces its lipid-raft recruitment, establishing GPX7 as an immune checkpoint via redox relay.\",\n      \"evidence\": \"Proteomic identification of GPX7–ZAP70 disulfide, conditional T cell-specific KO mouse, TCR activation assays, lipid raft fractionation, EAE autoimmune model\",\n      \"pmids\": [\"33460768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPX7 modulates other proximal TCR kinases is unknown\", \"Relevance to human autoimmune disease has not been tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution crystal structure of GPX7 in the sulfenylated and disulfide states is lacking, and the hierarchy of client selection—how GPX7 discriminates among PDI, GRP78, CPEB2, OGA, and ZAP70—remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of catalytic intermediates\", \"Determinants of client selectivity unknown\", \"Relative importance of GPX7 vs GPX8 in ER redox homeostasis in vivo not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 2, 5, 6, 13]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 5, 6, 13, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 12, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 5, 11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5, 6, 13, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3, 11, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 10, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PDI\",\n      \"GRP78\",\n      \"ERO1A\",\n      \"ZAP70\",\n      \"OGA\",\n      \"CPEB2\",\n      \"XRN2\",\n      \"P5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}