{"gene":"GPX7","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2004,"finding":"NPGPx (GPX7) is a cytoplasmic protein (~22 kDa) that incorporates cysteine instead of selenocysteine at the conserved catalytic motif and has little detectable glutathione peroxidase activity in vitro. Re-expression of NPGPx in breast cancer cells conferred resistance to eicosapentaenoic acid-mediated oxidative cell death, while siRNA-mediated knockdown increased sensitivity, establishing a functional role in alleviating oxidative stress from polyunsaturated fatty acid metabolism.","method":"In vitro GPx activity assay, ectopic expression rescue, siRNA knockdown with cell viability readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro activity assay plus loss- and gain-of-function in cells with defined phenotypic readout, single lab","pmids":["15294905"],"is_preprint":false},{"year":2011,"finding":"Under non-targeting siRNA (NT-siRNA) stress, NPGPx (GPX7) is selectively induced and covalently binds (via disulfide bond) to exoribonuclease XRN2, facilitating XRN2-mediated removal of accumulated NT-siRNA. NPGPx-depleted cells accumulated mature NT-siRNA and underwent apoptosis, demonstrating that NPGPx–XRN2 interaction is required to resolve NT-siRNA stress.","method":"Co-immunoprecipitation, covalent complex detection, siRNA knockdown with apoptosis and NT-siRNA accumulation readouts","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed, loss-of-function phenotype, single lab, two orthogonal methods","pmids":["21908404"],"is_preprint":false},{"year":2012,"finding":"NPGPx (GPX7) acts as an oxidative stress sensor by forming an intramolecular disulfide bond between Cys57 and Cys86 in response to ROS. The oxidized form binds GRP78 and forms covalent intermediates between Cys86 of NPGPx and Cys41/Cys420 of GRP78, subsequently promoting the Cys41–Cys420 disulfide bond in GRP78 to enhance its chaperone activity. NPGPx-deficient cells show increased ROS, accumulated misfolded proteins, and impaired GRP78 chaperone activity.","method":"Mass spectrometry identification of disulfide bond sites, cysteine mutagenesis, Co-IP/covalent complex detection, in vitro chaperone activity assay, NPGPx-knockout cells/mice","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis, in vitro functional assay, covalent complex mapped by MS, KO phenotype in cells and animals; multiple orthogonal methods","pmids":["23123197"],"is_preprint":false},{"year":2012,"finding":"The proximal promoter of NPGPx (GPX7) contains a mixed G-quadruplex (G4) structure essential for NT-siRNA-induced transcriptional activation. Nucleolin (NCL) specifically binds the G4-containing sequences, replacing Sp1, to transactivate NPGPx expression under NT-siRNA stress; disrupting the G4 structure or depleting NCL abolished this induction.","method":"Promoter reporter assays with G4-disrupting mutations, ChIP, nucleolin overexpression/knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of cis-element, ChIP, gain- and loss-of-function for NCL, single lab","pmids":["23241391"],"is_preprint":false},{"year":2013,"finding":"NPGPx (GPX7) deficiency promotes preadipocyte-to-adipocyte differentiation via ROS-dependent dimerization of protein kinase A (PKA) regulatory subunits and consequent activation of C/EBPβ. Antioxidant N-acetylcysteine treatment rescued the enhanced adipogenesis, placing GPX7 upstream of PKA regulatory subunit dimerization in the ROS–C/EBPβ axis.","method":"NPGPx-knockout mice and cells, PKA regulatory subunit dimerization assay, C/EBPβ activation assay, NAC rescue experiment, adipogenic differentiation assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model, defined biochemical mechanism (PKA dimerization), pharmacological rescue, replicated in multiple cell and mouse contexts","pmids":["23828861"],"is_preprint":false},{"year":2015,"finding":"NPGPx (GPX7) forms a disulfide bond with the translational regulator CPEB2, keeping CPEB2 associated with HIF-1α mRNA and suppressing its translation. Under high oxidative stress, this disulfide bond is disrupted, releasing CPEB2 from HIF-1α mRNA and allowing elevated HIF-1α translation. NPGPx-deficient cells show constitutively elevated HIF-1α translation under normoxia.","method":"Co-IP of disulfide-bonded NPGPx–CPEB2 complex, cysteine mutagenesis, polysome profiling/RNA-IP for HIF-1α mRNA association, NPGPx-KD cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — covalent complex identification, mutagenesis, translational readout, single lab","pmids":["26446990"],"is_preprint":false},{"year":2017,"finding":"GPX7 (and GPX8) are ER-resident peroxidases whose expression in rat β-cells attenuates FFA-mediated H2O2 generation, ER stress, and apoptosis. An ER-targeted catalase produced the same protective effect, establishing that accumulation of H2O2 in the ER lumen is the critical mediator of FFA-induced ER stress. GPX7/GPX8 expression did not increase disulfide bond formation in insulin, indicating H2O2 scavenging rather than oxidative protein folding is the primary protective function in β-cells.","method":"Stable expression of GPX7/GPX8 in INS-1E cells, ER-targeted catalase as comparator, H2O2 measurement, ER stress markers, apoptosis assays, insulin content/disulfide bond assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in defined cell model, comparator (ER catalase) mechanistically informative, negative result for disulfide role, single lab","pmids":["28751022"],"is_preprint":false},{"year":2019,"finding":"Stress-activated NPGPx (GPX7) inhibits O-GlcNAcase (OGA) through direct disulfide bond formation, thereby elevating global O-GlcNAcylation. In NPGPx-deficient motor neurons, OGA inhibition fails, O-GlcNAcylation cannot be boosted against age-dependent oxidative stress, and ROS accumulation leads to cell death. Pharmacological OGA inhibition rescued motor neuron loss in aged NPGPx-deficient mice, placing NPGPx upstream of OGA in this neuroprotective axis.","method":"NPGPx-KO mice (ALS-like phenotype), disulfide bond Co-IP between NPGPx and OGA, pharmacological OGA inhibitor rescue in vivo, O-GlcNAcylation western blot","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, biochemical disulfide interaction, pharmacological rescue in vivo, multiple orthogonal methods","pmids":["31747588"],"is_preprint":false},{"year":2020,"finding":"Human GPX7 has much higher reactivity with H2O2 than GPX8, owing to a catalytic tetrad at its redox-active site that stabilizes the sulfenylated peroxidatic cysteine intermediate. A resolving cysteine (not the peroxidatic cysteine) regulates GPX7's PDI oxidation activity. In H2O2-treated cells, GPX7 preferentially forms complexes with PDI and P5, functioning as an H2O2-dependent PDI oxidase for oxidative protein folding.","method":"In vitro H2O2 reactivity assays, PDI oxidation activity assays, active-site mutagenesis, Co-IP of GPX7 with PDI/P5 in H2O2-treated cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity, mutagenesis identifying resolving cysteine role, cellular Co-IP, single lab but multiple orthogonal methods","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, while GPX7 overexpression suppressed ROS and reduced these responses. In vivo, GPX7 knockdown accelerated NASH fibrosis in CDAHFD-fed mice, establishing GPX7 as a negative regulator of hepatic stellate cell activation and fibrosis via ROS suppression.","method":"siRNA knockdown and overexpression in LX-2 cells, ROS measurement, fibrosis/inflammation gene expression, in vivo CDAHFD mouse model with hepatic GPX7 knockdown","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paired gain- and loss-of-function in cells and in vivo model, defined molecular readouts, single lab","pmids":["32317079"],"is_preprint":false},{"year":2021,"finding":"NPGPx (GPX7) deficiency in BMSCs reduces osteogenic differentiation and increases adipogenic differentiation. Unlike adipogenesis (which is ROS-dependent), inhibition of osteogenesis by GPX7 deficiency is mediated through elevated ER stress (rescued by ER stress antagonist, not ROS inhibitor), and involves downregulation of mTOR signaling that can be rescued by relief of ER stress.","method":"GPX7-deficient human BMSCs and mouse MSC line, osteogenic/adipogenic differentiation assays, ER stress antagonist and ROS inhibitor rescue experiments, mTOR pathway western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two cell models, pharmacological epistasis distinguishing ROS vs. ER stress pathway, single lab","pmids":["34626080"],"is_preprint":false},{"year":2021,"finding":"NPGPx (GPX7) restrains ZAP70 kinase activity in T cells through direct disulfide bond formation with ZAP70 (identified by proteomic approaches). ROS generated upon TCR stimulation activate NPGPx, which reduces ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts, thereby subduing TCR responses. T cell-specific NPGPx-knockout mice show hyperproliferation, elevated cytokines, enhanced humoral responses, and susceptibility to EAE.","method":"Proteomic identification of NPGPx–ZAP70 disulfide complex, T cell-specific KO mice, TCR signaling assays, lipid raft fractionation, EAE model","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification of covalent complex, T cell-specific KO with defined immune phenotypes, signaling mechanism (lipid raft recruitment), in vivo disease model","pmids":["33460768"],"is_preprint":false},{"year":2016,"finding":"GPX7 (NPGPx) functions as a redox stress sensor/transmitter that lacks GPx activity but shuttles disulfide bonds to interacting proteins (GRP78, PDI, CPEB2, XRN2) in response to oxidative and other cellular stresses, thereby modulating unfolded protein response, oxidative stress signaling, and non-targeting siRNA stress response.","method":"Review/synthesis of prior experimental findings from the same group (no new primary experiments described)","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review article summarizing prior findings; no new primary experimental data","pmids":["27186289"],"is_preprint":false}],"current_model":"GPX7 (NPGPx) is an ER-resident, non-selenocysteine glutathione peroxidase family member that lacks classical GPx activity but functions as an H2O2 sensor/transmitter: upon oxidative activation it forms transient intermolecular disulfide bonds with specific partners — including GRP78 (enhancing chaperone activity), PDI/P5 (acting as an H2O2-dependent PDI oxidase for oxidative protein folding), CPEB2 (repressing HIF-1α translation), XRN2 (clearing non-targeting siRNA), OGA (boosting O-GlcNAcylation to protect motor neurons), and ZAP70 (restraining TCR signaling) — thereby transmitting redox stress signals to regulate ER homeostasis, protein folding, translation, RNA quality control, neuronal survival, adipogenesis, and T cell activation."},"narrative":{"mechanistic_narrative":"GPX7 (NPGPx) is a glutathione peroxidase family member that incorporates cysteine rather than selenocysteine at its catalytic motif and possesses little classical glutathione peroxidase activity, instead acting as an H2O2 sensor and transmitter that relays redox stress to specific protein partners via transient disulfide-bond exchange [PMID:15294905, PMID:23123197]. Upon oxidation it forms an intramolecular Cys57–Cys86 disulfide and then transfers oxidizing equivalents to GRP78, driving formation of GRP78's Cys41–Cys420 bond to enhance chaperone activity and limit accumulation of misfolded ER proteins [PMID:23123197]; its catalytic tetrad stabilizes a sulfenylated peroxidatic cysteine, enabling it to act as an H2O2-dependent PDI/P5 oxidase that supports oxidative protein folding [PMID:32719007]. Through analogous disulfide coupling GPX7 engages a diverse set of effectors to transmit redox state: it binds XRN2 to clear non-targeting siRNA and prevent apoptosis [PMID:21908404], holds CPEB2 on HIF-1α mRNA to repress its translation [PMID:26446990], inhibits OGA to elevate O-GlcNAcylation and protect motor neurons from age-dependent oxidative death [PMID:31747588], and restrains ZAP70 to dampen TCR signaling in T cells [PMID:33460768]. By scavenging or transmitting H2O2 it also acts as a general ROS suppressor in adipogenic, osteogenic, β-cell, and hepatic stellate cell contexts, where loss of GPX7 promotes adipocyte differentiation via ROS-dependent PKA/C-EBPβ activation [PMID:23828861], impairs osteogenesis through ER stress and mTOR downregulation [PMID:34626080], and accelerates ER-stress-driven β-cell death and NASH fibrosis [PMID:28751022, PMID:32317079]. Its transcription is itself stress-responsive, induced under non-targeting siRNA stress through a promoter G-quadruplex bound by nucleolin [PMID:23241391].","teleology":[{"year":2004,"claim":"Established that GPX7 is a cysteine-containing peroxidase family member with negligible classical GPx activity yet a real cellular role in mitigating oxidative stress, reframing it away from a canonical glutathione peroxidase.","evidence":"In vitro GPx activity assay plus ectopic expression and siRNA knockdown with oxidative cell-death readouts in breast cancer cells","pmids":["15294905"],"confidence":"Medium","gaps":["Did not identify the molecular mechanism of protection","No interacting partners or substrates defined","Localization not resolved"]},{"year":2011,"claim":"Showed GPX7 acts through covalent disulfide partnering rather than catalysis, here binding XRN2 to resolve non-targeting siRNA stress and prevent apoptosis.","evidence":"Co-IP and covalent complex detection with XRN2, siRNA knockdown with NT-siRNA accumulation and apoptosis readouts","pmids":["21908404"],"confidence":"Medium","gaps":["Disulfide-bond residues on GPX7 and XRN2 not mapped","Single lab, not reconstituted in vitro","Generality beyond NT-siRNA stress unclear"]},{"year":2012,"claim":"Defined the core sensor mechanism: ROS induces an intramolecular Cys57–Cys86 disulfide that is relayed to GRP78 to enhance chaperone activity, establishing GPX7 as an ER redox-relay enzyme rather than a peroxide-detoxifying GPx.","evidence":"MS mapping of disulfide sites, cysteine mutagenesis, covalent complex detection, in vitro chaperone assays, and KO cells/mice","pmids":["23123197"],"confidence":"High","gaps":["Upstream activation kinetics not fully resolved","Selectivity for GRP78 over other clients not addressed"]},{"year":2012,"claim":"Explained how GPX7 expression is switched on under stress, identifying a promoter G-quadruplex bound by nucleolin that displaces Sp1 to transactivate the gene during NT-siRNA stress.","evidence":"Promoter reporter assays with G4-disrupting mutations, ChIP, and nucleolin gain/loss-of-function","pmids":["23241391"],"confidence":"Medium","gaps":["Signal linking NT-siRNA stress to nucleolin recruitment unknown","Applicability to other stress inducers untested","Single lab"]},{"year":2013,"claim":"Placed GPX7 in metabolic differentiation by showing its loss drives adipogenesis through ROS-dependent PKA regulatory-subunit dimerization and C/EBPβ activation.","evidence":"KO mice and cells, PKA dimerization and C/EBPβ activation assays, NAC pharmacological rescue, adipogenic differentiation assays","pmids":["23828861"],"confidence":"High","gaps":["Whether effect is direct disulfide transmission or bulk ROS scavenging not distinguished","Direct GPX7–PKA interaction not shown"]},{"year":2015,"claim":"Demonstrated translational control: GPX7 disulfide-bonds CPEB2 to keep it on HIF-1α mRNA, so oxidative stress releases CPEB2 and de-represses HIF-1α translation.","evidence":"Co-IP of disulfide-bonded complex, cysteine mutagenesis, polysome/RNA-IP for HIF-1α mRNA, knockdown cells","pmids":["26446990"],"confidence":"Medium","gaps":["Disulfide residues not exhaustively mapped","Single lab","Breadth of CPEB2-regulated transcripts affected unclear"]},{"year":2017,"claim":"Clarified that in β-cells GPX7 acts primarily by scavenging luminal ER H2O2 to limit FFA-induced ER stress and apoptosis, not by enhancing disulfide bond formation in secreted protein.","evidence":"Stable GPX7/GPX8 expression in INS-1E cells with ER-targeted catalase comparator, H2O2 and ER stress measurements, insulin disulfide assays","pmids":["28751022"],"confidence":"Medium","gaps":["Context-dependence of scavenging vs oxidase roles not reconciled","No loss-of-function in primary β-cells","Single lab"]},{"year":2019,"claim":"Extended the disulfide-relay paradigm to neuroprotection, showing stress-activated GPX7 inhibits OGA to boost O-GlcNAcylation, with pharmacological OGA inhibition rescuing motor neuron loss in aged KO mice.","evidence":"KO mice with ALS-like phenotype, disulfide Co-IP with OGA, in vivo OGA-inhibitor rescue, O-GlcNAcylation western blots","pmids":["31747588"],"confidence":"High","gaps":["Disulfide residues on OGA not mapped","Generalizability beyond motor neurons unaddressed"]},{"year":2020,"claim":"Provided the enzymatic basis for GPX7's oxidase function, showing a catalytic tetrad confers high H2O2 reactivity and a distinct resolving cysteine governs its activity as an H2O2-dependent PDI/P5 oxidase for oxidative folding.","evidence":"In vitro H2O2 reactivity and PDI oxidation assays, active-site mutagenesis, Co-IP with PDI/P5 in H2O2-treated cells","pmids":["32719007"],"confidence":"High","gaps":["In-cell flux through PDI vs other partners not quantified","Single lab"]},{"year":2020,"claim":"Showed GPX7 is a negative regulator of hepatic stellate cell activation and fibrosis, suppressing ROS and pro-fibrotic gene expression in vitro and in a NASH mouse model.","evidence":"siRNA knockdown and overexpression in LX-2 cells, ROS and fibrosis gene readouts, in vivo CDAHFD model with hepatic knockdown","pmids":["32317079"],"confidence":"Medium","gaps":["No direct partner identified in this context","Mechanism beyond bulk ROS suppression unresolved","Single lab"]},{"year":2021,"claim":"Distinguished GPX7's ER-stress-dependent role in lineage choice, showing its loss impairs osteogenesis via elevated ER stress and mTOR downregulation while promoting adipogenesis via ROS.","evidence":"GPX7-deficient human BMSCs and mouse MSC line, differentiation assays, ER-stress vs ROS-inhibitor epistasis, mTOR western blots","pmids":["34626080"],"confidence":"Medium","gaps":["Molecular link between GPX7 loss and ER-stress/mTOR not defined","Direct partners in BMSCs unknown","Single lab"]},{"year":2021,"claim":"Established a role in adaptive immunity: TCR-induced ROS activate GPX7 to disulfide-bond ZAP70, reducing its raft recruitment and restraining T cell activation.","evidence":"Proteomic identification of GPX7–ZAP70 complex, T cell-specific KO mice, TCR signaling and lipid raft assays, EAE model","pmids":["33460768"],"confidence":"High","gaps":["Disulfide residues on ZAP70 not mapped","Reversibility/resolution of the GPX7–ZAP70 bond not characterized"]},{"year":null,"claim":"How GPX7 selects among its many disulfide partners in a given cell type, and what determines the switch between H2O2 scavenging, PDI-oxidase folding, and targeted disulfide relay, remain unresolved.","evidence":"No single study reconciles partner selectivity across contexts","pmids":[],"confidence":"Low","gaps":["No unified model of partner selection","Quantitative redox flux partitioning unmeasured","Structural basis of partner discrimination unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,8]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11]}],"complexes":[],"partners":["HSPA5","PDIA1","PDIA6","CPEB2","XRN2","OGA","ZAP70"],"other_free_text":[]}},"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},{"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},{"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},{"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":76,"is_preprint":false},{"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},{"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":53,"is_preprint":false},{"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},{"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":30,"is_preprint":false},{"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":26,"is_preprint":false},{"pmid":"31747588","id":"PMC_31747588","title":"NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating 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biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32997203","citation_count":10,"is_preprint":false},{"pmid":"38757339","id":"PMC_38757339","title":"GPX7 reduces chondrocyte inflammation and extracellular matrix degradation triggered by IL‑1β, via a mechanism mediated by ferroptosis.","date":"2024","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/38757339","citation_count":8,"is_preprint":false},{"pmid":"40306480","id":"PMC_40306480","title":"Metformin's mechanism in reducing oxidative stress and promoting bone regeneration in T2DM rat BMMSCs: A focus on NRF2-GPX7 signaling pathway.","date":"2025","source":"Journal of dentistry","url":"https://pubmed.ncbi.nlm.nih.gov/40306480","citation_count":7,"is_preprint":false},{"pmid":"35117014","id":"PMC_35117014","title":"GPX7 promotes the growth of human papillary thyroid carcinoma via enhancement of cell proliferation and inhibition of cell apoptosis.","date":"2019","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35117014","citation_count":7,"is_preprint":false},{"pmid":"40563300","id":"PMC_40563300","title":"Multi-Omics and Experimental Validation Identify GPX7 and Glutathione-Associated Oxidative Stress as Potential Biomarkers in Ischemic Stroke.","date":"2025","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40563300","citation_count":5,"is_preprint":false},{"pmid":"40238493","id":"PMC_40238493","title":"Co-Exposure to Different Zinc Concentrations and High-Fat Diet Modules Endoplasmic Reticulum Stress and Lipotoxicity through the MTF-1/GPx7 Axis in Yellow Catfish (Pelteobagrus fulvidraco).","date":"2025","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40238493","citation_count":3,"is_preprint":false},{"pmid":"33460768","id":"PMC_33460768","title":"Redox sensor NPGPx restrains ZAP70 activity and modulates T cell homeostasis.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33460768","citation_count":2,"is_preprint":false},{"pmid":"39796732","id":"PMC_39796732","title":"Computational Mutagenesis of GPx7 and GPx8: Structural and Stability Insights into Rare Genetic and Somatic Missense Mutations and Their Implications for Cancer Development.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39796732","citation_count":1,"is_preprint":false},{"pmid":"39589110","id":"PMC_39589110","title":"Papain expression in the Escherichia coli cytoplasm by T7-promoter engineering and co-expression with human protein disulfide isomerase (PDI) and thiol peroxidase (GPx7) genes.","date":"2024","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39589110","citation_count":1,"is_preprint":false},{"pmid":"42253985","id":"PMC_42253985","title":"GPX7 marks fibroblast-associated stromal-innate immune crosstalk in ulcerative colitis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42253985","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14300,"output_tokens":3807,"usd":0.050002,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11664,"output_tokens":4317,"usd":0.083123,"stage2_stop_reason":"end_turn"},"total_usd":0.133125,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"NPGPx (GPX7) is a cytoplasmic protein (~22 kDa) that incorporates cysteine instead of selenocysteine at the conserved catalytic motif and has little detectable glutathione peroxidase activity in vitro. Re-expression of NPGPx in breast cancer cells conferred resistance to eicosapentaenoic acid-mediated oxidative cell death, while siRNA-mediated knockdown increased sensitivity, establishing a functional role in alleviating oxidative stress from polyunsaturated fatty acid metabolism.\",\n      \"method\": \"In vitro GPx activity assay, ectopic expression rescue, siRNA knockdown with cell viability readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro activity assay plus loss- and gain-of-function in cells with defined phenotypic readout, single lab\",\n      \"pmids\": [\"15294905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Under non-targeting siRNA (NT-siRNA) stress, NPGPx (GPX7) is selectively induced and covalently binds (via disulfide bond) to exoribonuclease XRN2, facilitating XRN2-mediated removal of accumulated NT-siRNA. NPGPx-depleted cells accumulated mature NT-siRNA and underwent apoptosis, demonstrating that NPGPx–XRN2 interaction is required to resolve NT-siRNA stress.\",\n      \"method\": \"Co-immunoprecipitation, covalent complex detection, siRNA knockdown with apoptosis and NT-siRNA accumulation readouts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed, loss-of-function phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"21908404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NPGPx (GPX7) acts as an oxidative stress sensor by forming an intramolecular disulfide bond between Cys57 and Cys86 in response to ROS. The oxidized form binds GRP78 and forms covalent intermediates between Cys86 of NPGPx and Cys41/Cys420 of GRP78, subsequently promoting the Cys41–Cys420 disulfide bond in GRP78 to enhance its chaperone activity. NPGPx-deficient cells show increased ROS, accumulated misfolded proteins, and impaired GRP78 chaperone activity.\",\n      \"method\": \"Mass spectrometry identification of disulfide bond sites, cysteine mutagenesis, Co-IP/covalent complex detection, in vitro chaperone activity assay, NPGPx-knockout cells/mice\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis, in vitro functional assay, covalent complex mapped by MS, KO phenotype in cells and animals; multiple orthogonal methods\",\n      \"pmids\": [\"23123197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The proximal promoter of NPGPx (GPX7) contains a mixed G-quadruplex (G4) structure essential for NT-siRNA-induced transcriptional activation. Nucleolin (NCL) specifically binds the G4-containing sequences, replacing Sp1, to transactivate NPGPx expression under NT-siRNA stress; disrupting the G4 structure or depleting NCL abolished this induction.\",\n      \"method\": \"Promoter reporter assays with G4-disrupting mutations, ChIP, nucleolin overexpression/knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of cis-element, ChIP, gain- and loss-of-function for NCL, single lab\",\n      \"pmids\": [\"23241391\"],\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 (PKA) regulatory subunits and consequent activation of C/EBPβ. Antioxidant N-acetylcysteine treatment rescued the enhanced adipogenesis, placing GPX7 upstream of PKA regulatory subunit dimerization in the ROS–C/EBPβ axis.\",\n      \"method\": \"NPGPx-knockout mice and cells, PKA regulatory subunit dimerization assay, C/EBPβ activation assay, NAC rescue experiment, adipogenic differentiation assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model, defined biochemical mechanism (PKA dimerization), pharmacological rescue, replicated in multiple cell and mouse contexts\",\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, keeping CPEB2 associated with HIF-1α mRNA and suppressing its translation. Under high oxidative stress, this disulfide bond is disrupted, releasing CPEB2 from HIF-1α mRNA and allowing elevated HIF-1α translation. NPGPx-deficient cells show constitutively elevated HIF-1α translation under normoxia.\",\n      \"method\": \"Co-IP of disulfide-bonded NPGPx–CPEB2 complex, cysteine mutagenesis, polysome profiling/RNA-IP for HIF-1α mRNA association, NPGPx-KD cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — covalent complex identification, mutagenesis, translational readout, single lab\",\n      \"pmids\": [\"26446990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPX7 (and GPX8) are ER-resident peroxidases whose expression in rat β-cells attenuates FFA-mediated H2O2 generation, ER stress, and apoptosis. An ER-targeted catalase produced the same protective effect, establishing that accumulation of H2O2 in the ER lumen is the critical mediator of FFA-induced ER stress. GPX7/GPX8 expression did not increase disulfide bond formation in insulin, indicating H2O2 scavenging rather than oxidative protein folding is the primary protective function in β-cells.\",\n      \"method\": \"Stable expression of GPX7/GPX8 in INS-1E cells, ER-targeted catalase as comparator, H2O2 measurement, ER stress markers, apoptosis assays, insulin content/disulfide bond assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in defined cell model, comparator (ER catalase) mechanistically informative, negative result for disulfide role, single lab\",\n      \"pmids\": [\"28751022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Stress-activated NPGPx (GPX7) inhibits O-GlcNAcase (OGA) through direct disulfide bond formation, thereby elevating global O-GlcNAcylation. In NPGPx-deficient motor neurons, OGA inhibition fails, O-GlcNAcylation cannot be boosted against age-dependent oxidative stress, and ROS accumulation leads to cell death. Pharmacological OGA inhibition rescued motor neuron loss in aged NPGPx-deficient mice, placing NPGPx upstream of OGA in this neuroprotective axis.\",\n      \"method\": \"NPGPx-KO mice (ALS-like phenotype), disulfide bond Co-IP between NPGPx and OGA, pharmacological OGA inhibitor rescue in vivo, O-GlcNAcylation western blot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, biochemical disulfide interaction, pharmacological rescue in vivo, 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, owing to a catalytic tetrad at its redox-active site that stabilizes the sulfenylated peroxidatic cysteine intermediate. A resolving cysteine (not the peroxidatic cysteine) regulates GPX7's PDI oxidation activity. In H2O2-treated cells, GPX7 preferentially forms complexes with PDI and P5, functioning as an H2O2-dependent PDI oxidase for oxidative protein folding.\",\n      \"method\": \"In vitro H2O2 reactivity assays, PDI oxidation activity assays, active-site mutagenesis, Co-IP of GPX7 with PDI/P5 in H2O2-treated cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity, mutagenesis identifying resolving cysteine role, cellular Co-IP, single lab but multiple orthogonal methods\",\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, while GPX7 overexpression suppressed ROS and reduced these responses. In vivo, GPX7 knockdown accelerated NASH fibrosis in CDAHFD-fed mice, establishing GPX7 as a negative regulator of hepatic stellate cell activation and fibrosis via ROS suppression.\",\n      \"method\": \"siRNA knockdown and overexpression in LX-2 cells, ROS measurement, fibrosis/inflammation gene expression, in vivo CDAHFD mouse model with hepatic GPX7 knockdown\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paired gain- and loss-of-function in cells and in vivo model, defined molecular readouts, single lab\",\n      \"pmids\": [\"32317079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPGPx (GPX7) deficiency in BMSCs reduces osteogenic differentiation and increases adipogenic differentiation. Unlike adipogenesis (which is ROS-dependent), inhibition of osteogenesis by GPX7 deficiency is mediated through elevated ER stress (rescued by ER stress antagonist, not ROS inhibitor), and involves downregulation of mTOR signaling that can be rescued by relief of ER stress.\",\n      \"method\": \"GPX7-deficient human BMSCs and mouse MSC line, osteogenic/adipogenic differentiation assays, ER stress antagonist and ROS inhibitor rescue experiments, mTOR pathway western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two cell models, pharmacological epistasis distinguishing ROS vs. ER stress pathway, single lab\",\n      \"pmids\": [\"34626080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPGPx (GPX7) restrains ZAP70 kinase activity in T cells through direct disulfide bond formation with ZAP70 (identified by proteomic approaches). ROS generated upon TCR stimulation activate NPGPx, which reduces ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts, thereby subduing TCR responses. T cell-specific NPGPx-knockout mice show hyperproliferation, elevated cytokines, enhanced humoral responses, and susceptibility to EAE.\",\n      \"method\": \"Proteomic identification of NPGPx–ZAP70 disulfide complex, T cell-specific KO mice, TCR signaling assays, lipid raft fractionation, EAE model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification of covalent complex, T cell-specific KO with defined immune phenotypes, signaling mechanism (lipid raft recruitment), in vivo disease model\",\n      \"pmids\": [\"33460768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GPX7 (NPGPx) functions as a redox stress sensor/transmitter that lacks GPx activity but shuttles disulfide bonds to interacting proteins (GRP78, PDI, CPEB2, XRN2) in response to oxidative and other cellular stresses, thereby modulating unfolded protein response, oxidative stress signaling, and non-targeting siRNA stress response.\",\n      \"method\": \"Review/synthesis of prior experimental findings from the same group (no new primary experiments described)\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review article summarizing prior findings; no new primary experimental data\",\n      \"pmids\": [\"27186289\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPX7 (NPGPx) is an ER-resident, non-selenocysteine glutathione peroxidase family member that lacks classical GPx activity but functions as an H2O2 sensor/transmitter: upon oxidative activation it forms transient intermolecular disulfide bonds with specific partners — including GRP78 (enhancing chaperone activity), PDI/P5 (acting as an H2O2-dependent PDI oxidase for oxidative protein folding), CPEB2 (repressing HIF-1α translation), XRN2 (clearing non-targeting siRNA), OGA (boosting O-GlcNAcylation to protect motor neurons), and ZAP70 (restraining TCR signaling) — thereby transmitting redox stress signals to regulate ER homeostasis, protein folding, translation, RNA quality control, neuronal survival, adipogenesis, and T cell activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPX7 (NPGPx) is a glutathione peroxidase family member that incorporates cysteine rather than selenocysteine at its catalytic motif and possesses little classical glutathione peroxidase activity, instead acting as an H2O2 sensor and transmitter that relays redox stress to specific protein partners via transient disulfide-bond exchange [#0, #2]. Upon oxidation it forms an intramolecular Cys57–Cys86 disulfide and then transfers oxidizing equivalents to GRP78, driving formation of GRP78's Cys41–Cys420 bond to enhance chaperone activity and limit accumulation of misfolded ER proteins [#2]; its catalytic tetrad stabilizes a sulfenylated peroxidatic cysteine, enabling it to act as an H2O2-dependent PDI/P5 oxidase that supports oxidative protein folding [#8]. Through analogous disulfide coupling GPX7 engages a diverse set of effectors to transmit redox state: it binds XRN2 to clear non-targeting siRNA and prevent apoptosis [#1], holds CPEB2 on HIF-1\\u03b1 mRNA to repress its translation [#5], inhibits OGA to elevate O-GlcNAcylation and protect motor neurons from age-dependent oxidative death [#7], and restrains ZAP70 to dampen TCR signaling in T cells [#11]. By scavenging or transmitting H2O2 it also acts as a general ROS suppressor in adipogenic, osteogenic, \\u03b2-cell, and hepatic stellate cell contexts, where loss of GPX7 promotes adipocyte differentiation via ROS-dependent PKA/C-EBP\\u03b2 activation [#4], impairs osteogenesis through ER stress and mTOR downregulation [#10], and accelerates ER-stress-driven \\u03b2-cell death and NASH fibrosis [#6, #9]. Its transcription is itself stress-responsive, induced under non-targeting siRNA stress through a promoter G-quadruplex bound by nucleolin [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that GPX7 is a cysteine-containing peroxidase family member with negligible classical GPx activity yet a real cellular role in mitigating oxidative stress, reframing it away from a canonical glutathione peroxidase.\",\n      \"evidence\": \"In vitro GPx activity assay plus ectopic expression and siRNA knockdown with oxidative cell-death readouts in breast cancer cells\",\n      \"pmids\": [\"15294905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular mechanism of protection\", \"No interacting partners or substrates defined\", \"Localization not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed GPX7 acts through covalent disulfide partnering rather than catalysis, here binding XRN2 to resolve non-targeting siRNA stress and prevent apoptosis.\",\n      \"evidence\": \"Co-IP and covalent complex detection with XRN2, siRNA knockdown with NT-siRNA accumulation and apoptosis readouts\",\n      \"pmids\": [\"21908404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disulfide-bond residues on GPX7 and XRN2 not mapped\", \"Single lab, not reconstituted in vitro\", \"Generality beyond NT-siRNA stress unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the core sensor mechanism: ROS induces an intramolecular Cys57\\u2013Cys86 disulfide that is relayed to GRP78 to enhance chaperone activity, establishing GPX7 as an ER redox-relay enzyme rather than a peroxide-detoxifying GPx.\",\n      \"evidence\": \"MS mapping of disulfide sites, cysteine mutagenesis, covalent complex detection, in vitro chaperone assays, and KO cells/mice\",\n      \"pmids\": [\"23123197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activation kinetics not fully resolved\", \"Selectivity for GRP78 over other clients not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Explained how GPX7 expression is switched on under stress, identifying a promoter G-quadruplex bound by nucleolin that displaces Sp1 to transactivate the gene during NT-siRNA stress.\",\n      \"evidence\": \"Promoter reporter assays with G4-disrupting mutations, ChIP, and nucleolin gain/loss-of-function\",\n      \"pmids\": [\"23241391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal linking NT-siRNA stress to nucleolin recruitment unknown\", \"Applicability to other stress inducers untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed GPX7 in metabolic differentiation by showing its loss drives adipogenesis through ROS-dependent PKA regulatory-subunit dimerization and C/EBP\\u03b2 activation.\",\n      \"evidence\": \"KO mice and cells, PKA dimerization and C/EBP\\u03b2 activation assays, NAC pharmacological rescue, adipogenic differentiation assays\",\n      \"pmids\": [\"23828861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether effect is direct disulfide transmission or bulk ROS scavenging not distinguished\", \"Direct GPX7\\u2013PKA interaction not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated translational control: GPX7 disulfide-bonds CPEB2 to keep it on HIF-1\\u03b1 mRNA, so oxidative stress releases CPEB2 and de-represses HIF-1\\u03b1 translation.\",\n      \"evidence\": \"Co-IP of disulfide-bonded complex, cysteine mutagenesis, polysome/RNA-IP for HIF-1\\u03b1 mRNA, knockdown cells\",\n      \"pmids\": [\"26446990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disulfide residues not exhaustively mapped\", \"Single lab\", \"Breadth of CPEB2-regulated transcripts affected unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified that in \\u03b2-cells GPX7 acts primarily by scavenging luminal ER H2O2 to limit FFA-induced ER stress and apoptosis, not by enhancing disulfide bond formation in secreted protein.\",\n      \"evidence\": \"Stable GPX7/GPX8 expression in INS-1E cells with ER-targeted catalase comparator, H2O2 and ER stress measurements, insulin disulfide assays\",\n      \"pmids\": [\"28751022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of scavenging vs oxidase roles not reconciled\", \"No loss-of-function in primary \\u03b2-cells\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the disulfide-relay paradigm to neuroprotection, showing stress-activated GPX7 inhibits OGA to boost O-GlcNAcylation, with pharmacological OGA inhibition rescuing motor neuron loss in aged KO mice.\",\n      \"evidence\": \"KO mice with ALS-like phenotype, disulfide Co-IP with OGA, in vivo OGA-inhibitor rescue, O-GlcNAcylation western blots\",\n      \"pmids\": [\"31747588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disulfide residues on OGA not mapped\", \"Generalizability beyond motor neurons unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the enzymatic basis for GPX7's oxidase function, showing a catalytic tetrad confers high H2O2 reactivity and a distinct resolving cysteine governs its activity as an H2O2-dependent PDI/P5 oxidase for oxidative folding.\",\n      \"evidence\": \"In vitro H2O2 reactivity and PDI oxidation assays, active-site mutagenesis, Co-IP with PDI/P5 in H2O2-treated cells\",\n      \"pmids\": [\"32719007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell flux through PDI vs other partners not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed GPX7 is a negative regulator of hepatic stellate cell activation and fibrosis, suppressing ROS and pro-fibrotic gene expression in vitro and in a NASH mouse model.\",\n      \"evidence\": \"siRNA knockdown and overexpression in LX-2 cells, ROS and fibrosis gene readouts, in vivo CDAHFD model with hepatic knockdown\",\n      \"pmids\": [\"32317079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct partner identified in this context\", \"Mechanism beyond bulk ROS suppression unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished GPX7's ER-stress-dependent role in lineage choice, showing its loss impairs osteogenesis via elevated ER stress and mTOR downregulation while promoting adipogenesis via ROS.\",\n      \"evidence\": \"GPX7-deficient human BMSCs and mouse MSC line, differentiation assays, ER-stress vs ROS-inhibitor epistasis, mTOR western blots\",\n      \"pmids\": [\"34626080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between GPX7 loss and ER-stress/mTOR not defined\", \"Direct partners in BMSCs unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a role in adaptive immunity: TCR-induced ROS activate GPX7 to disulfide-bond ZAP70, reducing its raft recruitment and restraining T cell activation.\",\n      \"evidence\": \"Proteomic identification of GPX7\\u2013ZAP70 complex, T cell-specific KO mice, TCR signaling and lipid raft assays, EAE model\",\n      \"pmids\": [\"33460768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disulfide residues on ZAP70 not mapped\", \"Reversibility/resolution of the GPX7\\u2013ZAP70 bond not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GPX7 selects among its many disulfide partners in a given cell type, and what determines the switch between H2O2 scavenging, PDI-oxidase folding, and targeted disulfide relay, remain unresolved.\",\n      \"evidence\": \"No single study reconciles partner selectivity across contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of partner selection\", \"Quantitative redox flux partitioning unmeasured\", \"Structural basis of partner discrimination unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA5\", \"PDIA1\", \"PDIA6\", \"CPEB2\", \"XRN2\", \"OGA\", \"ZAP70\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}