Affinage

GPX8

Probable glutathione peroxidase 8 · UniProt Q8TED1

Length
209 aa
Mass
23.9 kDa
Annotated
2026-06-10
26 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPX8 is an ER-resident glutathione peroxidase that maintains redox homeostasis at the rough ER by detoxifying H2O2 generated during oxidative protein folding (PMID:24566470). It physically associates with the oxidase Ero1α, and its peroxidase activity reduces Ero1α-derived H2O2 before it can diffuse to the cytosol; loss of GPX8 causes H2O2 leakage, ER stress, and cell death, and GPX8 acts as the primary Ero1α-coupled peroxidase rather than PrxIV under normal conditions (PMID:24566470). Unlike its paralog GPX7, GPX8 has low intrinsic H2O2 reactivity and weak PDI-oxidizing activity owing to a missing catalytic tetrad, so PDI oxidation is not its central physiological role; its protective function is exerted through limiting ER H2O2 accumulation, including under lipotoxic stress (PMID:32719007, PMID:28751022). Beyond this antioxidant role, GPX8 functions as a pro-tumorigenic effector across multiple cancers, where it is transcriptionally driven by FOXC1, KLF16, and TEAD4 (PMID:33317536, PMID:41331621, PMID:41553494) and engages oncogenic signaling: it sustains IL-6/JAK/STAT3 trans-signaling to drive EMT and stemness and to control NNMT-dependent lipogenesis (PMID:32817494, PMID:36750850), activates Wnt signaling (PMID:33317536), and acts upstream of the ER-stress IRE1/JNK axis to restrain apoptosis and autophagy (PMID:35288240). GPX8 also interacts with Hsc70 to limit PI3K-AKT activation and with CTHRC1 to engage p38 MAPK/FOXO3 signaling, conferring drug and radiation resistance (PMID:38607517, PMID:41553494). GPX8 loss promotes ferroptosis via a redox-epitranscriptomic E2F4–ZC3H13–ACSL4 axis that reprograms m6A modification (PMID:37170591, PMID:42156324). It was identified as a proviral host factor cleaved by the HCV NS3-4A protease at Cys11 to favor viral particle production (PMID:23929719).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 High

    Established GPX8 as a host factor relevant to disease by mapping its cleavage by the HCV NS3-4A protease and its role in viral particle production.

    Evidence SILAC quantitative proteomics, NS3-4A cleavage assay mapping Cys11, overexpression/silencing of HCV life-cycle steps, validation in patient liver biopsies

    PMID:23929719

    Open questions at the time
    • Mechanism by which Cys11 cleavage promotes viral particle production not resolved
    • Does not address the enzyme's normal physiological function
  2. 2014 High

    Defined the core physiological function: GPX8 detoxifies Ero1α-derived H2O2 at the rough ER, establishing it as the primary Ero1α-coupled peroxidase preventing cytosolic H2O2 leakage and ER stress.

    Evidence Reciprocal co-IP of Ero1α–GPx8 complex, GPx8 knockdown with cytosolic H2O2/ER stress/cell death readouts and PrxIV comparison in 293 cells

    PMID:24566470

    Open questions at the time
    • Whether GPX8 acts catalytically or as a scavenger sink not fully separated
    • Tissue-specific requirements not assessed
  3. 2017 Medium

    Extended the antioxidant role to a disease-relevant stress context, showing GPX8 reduces ER H2O2 under lipotoxic stress but is not rate-limiting for disulfide bond formation.

    Evidence Stable GPx8 expression in GPx7/8-null rat INS-1E β-cells, FFA challenge, H2O2/ER-stress/apoptosis readouts versus ER-targeted catalase

    PMID:28751022

    Open questions at the time
    • Gain-of-function in a heterologous system, not endogenous loss-of-function
    • In vivo β-cell relevance untested
  4. 2020 High

    Clarified the biochemical basis of GPX8's activity, showing it has low H2O2 reactivity and weak PDI oxidation due to a missing catalytic tetrad, distinguishing it from GPX7.

    Evidence In vitro H2O2 reactivity and PDI oxidation assays, active-site mutagenesis comparing catalytic tetrads, complex formation in H2O2-treated cells

    PMID:32719007

    Open questions at the time
    • The physiologically dominant reductant/substrate for GPX8 not definitively established
    • How low intrinsic reactivity reconciles with protective role in cells unresolved
  5. 2020 High

    Opened the oncogenic chapter, linking GPX8 to cancer aggressiveness via IL-6/JAK/STAT3 trans-signaling driving EMT and stemness, and identifying upstream transcriptional control by FOXC1 with downstream Wnt activation.

    Evidence CRISPR KO in MDA-MB-231 with EMT/stemness/IL-6 readouts and xenografts; ChIP/luciferase showing FOXC1 binds GPX8 promoter and Wnt western blots in gastric cancer cells

    PMID:32817494 PMID:33317536

    Open questions at the time
    • How an ER peroxidase mechanistically engages cytokine and Wnt signaling not defined
    • Whether redox activity is required for the signaling effects unclear
  6. 2023 Medium

    Connected GPX8 to metabolic and epitranscriptomic reprogramming, showing it controls NNMT-dependent lipogenesis via IL6-STAT3 and that its loss reshapes the m6A landscape.

    Evidence CRISPR/shRNA KO with isotope-tracing DNL flux, metabolomics, NNMT rescue in ccRCC; MeRIP-seq m6A profiling in GPX8-KO oral cancer cells

    PMID:36750850 PMID:37170591

    Open questions at the time
    • Direct link from GPX8 redox status to m6A enzyme expression not mechanistically traced
    • Cell-type generality of the lipogenic axis untested
  7. 2024 Medium

    Identified protein-interaction routes for GPX8's signaling effects, showing it binds Hsc70 to restrain PI3K-AKT-driven tumor promotion.

    Evidence Co-IP/MS GPX8-Hsc70 interaction, phospho-kinase array, MK-2206 AKT-inhibitor rescue in vitro and in vivo in HCC

    PMID:38607517

    Open questions at the time
    • Single Co-IP/MS without reciprocal structural validation
    • How GPX8 modulates Hsc70 nuclear translocation unknown
  8. 2026 Medium

    Resolved a ferroptosis-suppressing mechanism, defining the redox-epitranscriptomic E2F4–ZC3H13–ACSL4 axis through which GPX8 loss sensitizes cells to radiation, and added CTHRC1/p38-MAPK/FOXO3 and CAF-lactylation routes to drug resistance.

    Evidence GPX8 KO orthotopic xenografts with E2F4/ZC3H13 overexpression and ACSL4 knockdown epistasis and liproxstatin-1 rescue; TEAD4 transactivation and GPX8-CTHRC1 Co-IP with pathway inhibitors; CAF GPX8 overexpression with MCT1/BRPF1 inhibitors and H3K18la ChIP

    PMID:41553494 PMID:42156324 PMID:42174112

    Open questions at the time
    • Each pathway shown in a single cancer model/lab
    • Whether GPX8 peroxidase activity per se drives these signaling/resistance phenotypes not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How an ER-localized peroxidase with low intrinsic enzymatic activity mechanistically controls cytosolic and nuclear signaling pathways (STAT3, Wnt, AKT, p38/FOXO3) and m6A epitranscriptomics remains unresolved.
  • No structural model linking catalytic state to signaling output
  • Redox-dependent versus scaffold/interaction-dependent functions not separated
  • Most oncogenic axes rest on single-lab studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016209 antioxidant activity 2
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CTHRC1ERO1AHSPA8

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 GPx8 co-resides with reduced/activated Ero1α in the rough ER subdomain and forms a complex with Ero1α. Loss of GPx8 causes leakage of Ero1α-derived H2O2 to the cytosol, ER stress, and cell death, demonstrating that GPx8 peroxidase activity detoxifies H2O2 produced by Ero1α within the rough ER, preventing its diffusion out of the ER. Co-immunoprecipitation (Ero1α-GPx8 complex), loss-of-function (GPx8 knockdown) with H2O2 cytosolic leakage measurement, ER stress and cell death readouts in 293 cells Free radical biology & medicine High 24566470
2014 Peroxiredoxin IV (PrxIV), another rough ER H2O2-detoxifying enzyme, does not protect from Ero1α-mediated toxicity under normal conditions; only when Ero1α-catalyzed H2O2 production is artificially maximized can PrxIV participate in H2O2 reduction, indicating GPx8 is the primary Ero1α-coupled peroxidase. Loss-of-function comparison between GPx8 and PrxIV knockdown with Ero1α-induced toxicity readout in 293 cells Free radical biology & medicine Medium 24566470
2013 GPx8 is cleaved by the HCV NS3-4A protease at Cys11, removing the cytosolic tip of GPx8. This cleavage was confirmed in multiple experimental systems and in liver biopsies from chronic HCV patients. GPx8 functions as a proviral host factor involved in viral particle production but not in HCV entry or RNA replication. Quantitative proteomics (SILAC/MS), NS3-4A protease cleavage assay, overexpression and RNA silencing studies for functional dissection of HCV life cycle steps Hepatology (Baltimore, Md.) High 23929719
2020 GPx8 has lower H2O2 reactivity and lower PDI oxidation activity compared to GPx7, lacking the catalytic tetrad that stabilizes the sulfenylated peroxidatic cysteine in GPx7. PDI oxidation is likely not the central physiological role of human GPx8. In vitro H2O2 reactivity assay, PDI oxidation activity assay, active-site mutagenesis analysis comparing catalytic tetrads, complex formation assay in H2O2-treated cells The Journal of biological chemistry High 32719007
2017 Exogenous expression of GPx8 in rat β-cells (which lack endogenous GPx7/8) attenuates FFA-mediated H2O2 generation, ER stress, and apoptosis, demonstrating GPx8's role in reducing ER H2O2 accumulation in response to lipotoxic stress. Neither GPx8 expression increased insulin content nor facilitated disulfide bond formation, indicating H2O2 reduction by GPx8 is not rate-limiting in oxidative protein folding in β-cells. Stable expression of GPx8 in INS-1E β-cells, H2O2 measurement, ER stress markers, apoptosis assays; comparison with ER-targeted catalase Free radical biology & medicine Medium 28751022
2020 GPX8 knockout in mesenchymal-like breast cancer cells (MDA-MB-231) causes reversion to epithelial-like morphology, loss of EMT markers and cancer stemness, and impairs the IL-6/sIL6R/JAK/STAT3 trans-signaling axis, identifying a GPX8/IL-6/STAT3 pathway regulating cancer aggressiveness. CRISPR knockout, morphological and molecular characterization of EMT markers, cytokine secretion (IL-6) measurement, JAK/STAT3 signaling assays, xenograft tumor growth in mice Proceedings of the National Academy of Sciences of the United States of America High 32817494
2020 FOXC1 is a transcription factor of GPX8 in gastric cancer cells; it directly binds the GPX8 promoter (confirmed by dual-luciferase reporter and ChIP assays) and mediates GPX8 expression. GPX8 in turn activates the Wnt signaling pathway to promote proliferation, migration, and invasion. Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), Wnt pathway western blot, functional cell assays (CCK-8, colony formation, transwell) Cancer cell international Medium 33317536
2022 GPx8 regulates apoptosis and autophagy in esophageal squamous cell carcinoma through the ER stress IRE1/JNK pathway; GPx8 knockdown induces apoptosis and autophagy that are further enhanced by IRE1 or JNK inhibitors, placing GPx8 upstream of the IRE1/JNK axis. GPx8 knockdown and overexpression in ESCC cells, IRE1/JNK pathway inhibitors, TUNEL assay, flow cytometry, TEM, xenograft models Cellular signalling Medium 35288240
2023 GPX8 regulates lipogenesis in clear cell renal cell carcinoma via IL6-STAT3 signaling to control NNMT expression; GPX8 knockout reduces lipid droplets, fatty acid de novo synthesis, and triglyceride esterification in vitro and tumor growth in vivo, and NNMT knockdown phenocopies GPX8 loss while NNMT overexpression rescues it. CRISPR-Cas9 and shRNA knockout, isotope-tracing DNL flux measurement, untargeted metabolomics, RNA-seq, NNMT rescue experiments, xenograft models Journal of experimental & clinical cancer research : CR High 36750850
2024 GPX8 directly interacts with the 71-kDa heat shock cognate protein (Hsc70) in hepatocellular carcinoma cells. GPX8 knockdown activates PI3K-AKT signaling, promoting nuclear translocation of Hsc70 and expression of the PI3K p110 subunit; AKT inhibition with MK-2206 reverses GPX8 knockdown-driven tumor promotion. Immunoprecipitation and protein mass spectrometry (GPX8-Hsc70 interaction), transcriptome sequencing, phosphorylated kinase array, AKT inhibitor (MK-2206) rescue experiment in vitro and in vivo Cellular oncology (Dordrecht, Netherlands) Medium 38607517
2023 GPX8 deficiency-induced oxidative stress reprograms m6A epitranscriptome in oral cancer cells, upregulating m6A readers IGF2BP2 and IGF2BP3 while downregulating m6A writers/erasers including FTO, RBM15, VIRMA, ZC3H13, and YTHDC2, linking GPX8-mediated redox homeostasis to m6A modification control. MeRIP-seq transcriptome-wide m6A profiling in GPX8-KO oral cancer cells, RNA-seq, H2O2 treatment experiments Epigenetics Medium 37170591
2026 GPX8 loss sensitizes oral cancer cells to ionizing radiation by promoting ferroptosis through a redox-epitranscriptomic axis: GPX8 deficiency increases ROS, which suppresses E2F4 transcription factor expression, reducing ZC3H13 (m6A writer) levels, leading to m6A hypomethylation and stabilization of ACSL4 mRNA; ACSL4 upregulation drives ferroptosis. E2F4 or ZC3H13 overexpression reverses ACSL4 upregulation. GPX8 KO in orthotopic xenograft model, E2F4/ZC3H13 overexpression epistasis, ACSL4 knockdown rescue, ferroptosis markers (lipid peroxidation, labile iron), liproxstatin-1 inhibitor rescue Antioxidants & redox signaling Medium 42156324
2025 KLF16 transcription factor directly binds the GPX8 promoter (confirmed by ChIP and dual-luciferase assay) and positively regulates GPX8 expression in osteosarcoma. GPX8 mediates the pro-tumorigenic effects of KLF16, as GPX8 knockdown reverses KLF16 overexpression effects and GPX8 overexpression reverses KLF16 knockdown effects on proliferation, invasion, and migration. Dual-luciferase reporter assay, ChIP assay, GPX8 KD/OE epistasis rescue with KLF16 KD/OE, in vivo xenograft Journal of translational medicine Medium 41331621
2026 TEAD4 transcriptionally activates GPX8 in glioblastoma. GPX8 interacts with CTHRC1 and promotes its expression. GPX8-driven CTHRC1 activates the p38 MAPK/FOXO3 pathway to suppress mitochondrial oxidative stress and confer temozolomide resistance. GPX8 knockdown induces mitochondrial ROS, apoptosis, and reverses EMT in TMZ-resistant cells. TEAD4 transactivation assay, Co-IP (GPX8-CTHRC1 interaction), CTHRC1 overexpression rescue, p38 MAPK/FOXO3 pathway inhibitor (Ade), xenograft and glioma organoid models Naunyn-Schmiedeberg's archives of pharmacology Medium 41553494
2026 GPX8 overexpression in cancer-associated fibroblasts (CAFs) activates the PI3K/AKT/mTOR signaling pathway by suppressing ER stress, driving glycolytic reprogramming and lactate production; this CAF-derived lactate is imported by HCC cells via MCT1, elevating H3K18 lactylation at the BRPF1 promoter and upregulating BRPF1 to promote lenvatinib resistance via EGFR pathway activation. GPX8 overexpression in CAFs, PI3K/AKT/mTOR pathway assays, lactate production measurement, MCT1 inhibitor (AZD3965), H3K18la ChIP at BRPF1 promoter, BRPF1 inhibitor (GSK5959), in vitro and in vivo resistance models Oncogene Medium 42174112

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 GPx8 peroxidase prevents leakage of H2O2 from the endoplasmic reticulum. Free radical biology & medicine 125 24566470
2020 The glutathione peroxidase 8 (GPX8)/IL-6/STAT3 axis is essential in maintaining an aggressive breast cancer phenotype. Proceedings of the National Academy of Sciences of the United States of America 53 32817494
2017 ER-resident antioxidative GPx7 and GPx8 enzyme isoforms protect insulin-secreting INS-1E β-cells against lipotoxicity by improving the ER antioxidative capacity. Free radical biology & medicine 53 28751022
2013 Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease. Hepatology (Baltimore, Md.) 37 23929719
2020 Characterization of the endoplasmic reticulum-resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding. The Journal of biological chemistry 33 32719007
2023 GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT. Journal of experimental & clinical cancer research : CR 29 36750850
2022 A Comprehensive Analysis of the Glutathione Peroxidase 8 (GPX8) in Human Cancer. Frontiers in oncology 29 35402257
2020 GPX8 promotes migration and invasion by regulating epithelial characteristics in non-small cell lung cancer. Thoracic cancer 26 32975378
2020 GPX8 is transcriptionally regulated by FOXC1 and promotes the growth of gastric cancer cells through activating the Wnt signaling pathway. Cancer cell international 23 33317536
2022 GPx8 regulates apoptosis and autophagy in esophageal squamous cell carcinoma through the IRE1/JNK pathway. Cellular signalling 18 35288240
2023 GPX8 deficiency-induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells. Epigenetics 8 37170591
2023 GPX8 regulates pan-apoptosis in gliomas to promote microglial migration and mediate immunotherapy responses. Frontiers in immunology 8 37795080
2023 Glutathione Peroxidase gpx1 to gpx8 Genes Expression in Experimental Brain Tumors Reveals Gender-Dependent Patterns. Genes 7 37761814
2024 GPX8+ cancer-associated fibroblast, as a cancer-promoting factor in lung adenocarcinoma, is related to the immunosuppressive microenvironment. BMC medical genomics 6 38515109
2020 GPx8 Expression in Rat Oocytes, Embryos, and Female Genital Organs During Preimplantation Period of Pregnancy. International journal of molecular sciences 6 32878231
2024 Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration. Cellular oncology (Dordrecht, Netherlands) 3 38607517
2022 Chosen Antioxidant Enzymes GPx4 and GPx8 in Human Colorectal Carcinoma: Study of the Slovak Population. Medicina (Kaunas, Lithuania) 2 35208621
2024 The presence of glutathione peroxidase 8 (GPx8) in rat male genital organs. Bratislavske lekarske listy 1 38041845
2024 Computational Mutagenesis of GPx7 and GPx8: Structural and Stability Insights into Rare Genetic and Somatic Missense Mutations and Their Implications for Cancer Development. Cancers 1 39796732
2026 GPX8 inhibits myogenic differentiation and promotes slow myofiber formation of porcine skeletal muscle satellite cells. Yi chuan = Hereditas 0 41548982
2026 TEAD4-driven GPX8 promotes temozolomide resistance in glioma by facilitating CTHRC1 expression to suppress mitochondrial oxidative stress. Naunyn-Schmiedeberg's archives of pharmacology 0 41553494
2026 Identification of a Novel Radiosensitivity-Related Signature and Validation of GPX8 in Regulating the Radiosensitivity of Glioma. CNS neuroscience & therapeutics 0 42047740
2026 Deletion of GPX8 Enhances Irradiation-Induced Ferroptosis Through m6A Hypomethylation-Mediated Upregulation of ACSL4 in Oral Cancer. Antioxidants & redox signaling 0 42156324
2026 GPX8+ cancer-associated fibroblast-derived lactate contributes to lenvatinib resistance by facilitating BRPF1 expression through histone H3 lysine 18 lactylation in hepatocellular carcinoma. Oncogene 0 42174112
2026 LINC00852 Enhances Glycolysis and Tumor Immunity in Pancreatic Cancer via the miR‑494‑3p/GPX8 Axis. Journal of biochemical and molecular toxicology 0 42204968
2025 GPX8 is transcriptionally regulated by KLF16 and promotes osteosarcoma progression. Journal of translational medicine 0 41331621

Missed literature

Know a paper Affinage missed for GPX8? Flag it for the maintainers and the community.

No submissions yet.