Affinage

TXNDC5

Thioredoxin domain-containing protein 5 · UniProt Q8NBS9

Length
432 aa
Mass
47.6 kDa
Annotated
2026-06-10
78 papers in source corpus 28 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TXNDC5 (ERp46/EndoPDI) is an endoplasmic reticulum-resident protein disulfide isomerase that catalyzes oxidative protein folding and, through stabilization of specific client proteins, drives fibrogenic and vascular disease across multiple tissues (PMID:12930873, PMID:29535165, PMID:32848143). It is distinguished from canonical PDI by three independent catalytic thioredoxin domains arranged in an extended open V-shaped architecture that engage in rapid, promiscuous disulfide bond introduction during early folding, acting cooperatively with peroxiredoxin-4 as a disulfide-bond introducer (PMID:23376096, PMID:24462249). A unifying disease mechanism centers on TXNDC5 binding and posttranslationally stabilizing the TGFβ type I receptor TGFBR1, amplifying TGFβ signaling to drive ECM accumulation in pulmonary, renal, ocular, and tumor stromal fibroblasts; its own induction is transcriptionally controlled by ER stress through ATF6 and IRE1α-XBP1 (PMID:29535165, PMID:32848143, PMID:33465051, PMID:33691254, PMID:42248857). Beyond TGFBR1, TXNDC5 promotes fibrosis through redox-dependent JNK and STAT3 activation in hepatic stellate cells and NOX4-derived ROS in cardiac fibroblasts (PMID:29535165, PMID:34933915). In endothelium, TXNDC5 promotes atherosclerosis and vascular injury by accelerating proteasomal degradation of HSF1, lowering HSP90 and destabilizing the HSP90/eNOS complex (PMID:35061532, PMID:41456650), and supports TNFα-driven angiogenesis via the Ras/Raf/MEK/ERK-AP-1 axis inducing MMP-9 and cathepsin B (PMID:24103565). In hemostasis TXNDC5 is displayed on the activated platelet surface, where it reduces the integrin αIIbβ3 Cys473-Cys503 disulfide to support αIIbβ3 activation, aggregation, and thrombosis, an activity counterbalanced by TMX1, and it oxidizes the FXII Cys540-Cys571 disulfide to enhance the intrinsic coagulation pathway (PMID:34752599, PMID:41197808, PMID:39247212). It additionally stabilizes oncogenic and viral clients including the androgen receptor and HEV ORF3 (PMID:25500540, PMID:38548704), partners with EDEM3 to trigger glycoprotein mannose trimming (PMID:29784879), and is required posttranslationally for insulin production in pancreatic β-cells (PMID:29784879, PMID:19622788).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Established that TXNDC5 is a genuine ER-resident PDI rather than a passive ER protein, defining its core enzymatic identity and a cytoprotective role under hypoxic stress.

    Evidence Yeast complementation of PDI function plus siRNA knockdown causing endothelial apoptosis and secretion defects under hypoxia

    PMID:12930873 PMID:12963716

    Open questions at the time
    • Atomic mechanism of catalysis not yet resolved
    • Physiological client proteins not identified
  2. 2014 High

    Resolved how TXNDC5's architecture differs from canonical PDI, explaining its rapid promiscuous disulfide-introducing behavior during oxidative folding.

    Evidence X-ray crystallography of the full protein and a' domain plus in vitro oxidative folding assays and domain-level activity mapping

    PMID:22505402 PMID:23376096 PMID:24462249

    Open questions at the time
    • In vivo client spectrum not defined from structure alone
    • How domain independence is regulated in cells unknown
  3. 2018 High

    Connected TXNDC5 PDI activity to disease by showing it folds ECM proteins and amplifies fibroblast activation, downstream of ER stress/ATF6 transcriptional control.

    Evidence Txndc5-/- mice in isoproterenol cardiac fibrosis, ECM folding and ROS/JNK assays, ATF6 knockdown, plus in vitro EDEM3 reconstitution

    PMID:29535165 PMID:29784879

    Open questions at the time
    • Whether ECM folding versus ROS/JNK dominates pathology unclear
    • Direct fibrogenic client receptor not yet identified at this stage
  4. 2021 High

    Identified TGFBR1 stabilization as the unifying fibrogenic mechanism across organs, establishing TXNDC5 as a posttranslational amplifier of TGFβ signaling under ATF6/IRE1α-XBP1 control.

    Evidence Co-IP of direct TXNDC5-TGFBR1 binding and fibroblast-specific inducible Txndc5 KO across pulmonary, renal, and liver fibrosis models, plus IRE1α/XBP1 pathway dissection

    PMID:32848143 PMID:33465051 PMID:33691254 PMID:34933915

    Open questions at the time
    • Whether TXNDC5 stabilizes TGFBR1 via direct disulfide chemistry not fully resolved
    • Generalizability of JNK/STAT3 versus TGFBR1 arms across tissues
  5. 2022 High

    Defined distinct vascular and hemostatic roles, showing TXNDC5 destabilizes the HSF1-HSP90-eNOS axis in endothelium and reduces specific αIIbβ3 disulfides on platelets.

    Evidence Endothelium-specific Txndc5 KO/CRISPR in ApoE-/- atherosclerosis and ERp46 KO mice with SPR binding and thiol labeling of the β3 Cys473-Cys503 bond

    PMID:34752599 PMID:35061532

    Open questions at the time
    • How TXNDC5 selects HSF1 for proteasomal degradation not defined
    • Surface localization mechanism for platelet ERp46 unclear
  6. 2025 High

    Extended the surface thiol-isomerase role to coagulation by identifying FXII as a direct oxidative substrate and TMX1 as a counter-regulator of ERp46.

    Evidence Thiol labeling/MS and cysteine mutagenesis identifying FXII Cys540-Cys571, ERp46-deficient mice in venous thrombosis, and TMX1/ERp46 KO platelet reductase assays

    PMID:39247212 PMID:41197808

    Open questions at the time
    • Balance of oxidase versus reductase activity at the cell surface not fully mapped
    • Structural basis of substrate specificity for FXII vs β3 unknown
  7. 2024 Medium

    Broadened the client-stabilization paradigm to cancer and infection, showing TXNDC5 stabilizes the androgen receptor and HEV ORF3 and is itself turned over by chaperone-mediated autophagy.

    Evidence Co-IP with domain-deletion mutants for HEV ORF3, AR Co-IP and xenografts, and CMA inhibitor experiments in trabecular meshwork cells

    PMID:25500540 PMID:38548704 PMID:42012274

    Open questions at the time
    • Whether stabilization requires catalytic Trx domains differs by client (ORF3 was Trx-independent)
    • Generalizability of CMA turnover across cell types untested
  8. 2026 High

    Demonstrated that fibroblast TXNDC5-TGFBR1 signaling shapes the tumor microenvironment, linking the fibrogenic axis to immunosuppression and immunotherapy response.

    Evidence Fibroblast-specific Txndc5 KO colorectal cancer model with tumor mechanics, T-cell infiltration, and PD-1 blockade combination

    PMID:42248857

    Open questions at the time
    • Direct molecular link from TGFBR1 stabilization to fibroblast polarization incompletely defined
    • Translational targeting strategy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TXNDC5 selects among its diverse clients (TGFBR1, AR, HEV ORF3, FXII, αIIbβ3) and whether stabilization is driven by canonical disulfide isomerase chemistry or chaperone-only activity remains unresolved.
  • No unifying structural model of TXNDC5-client recognition
  • Catalytic versus chaperone contribution to client stabilization undefined
  • Cell-surface versus ER-luminal activity partitioning unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0044183 protein folding chaperone 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-109582 Hemostasis 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
AREDEM3F12HSPA8HSPA9ITGB3PRDX6TGFBR1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TXNDC5 (EndoPDI/ERp46) is a protein disulfide isomerase with three APWCGHC thioredoxin motifs (vs. two in canonical PDI), localized to the ER, and functions as a stress survival factor in endothelial cells under hypoxia; siRNA-mediated knockdown under hypoxia caused decreased secretion of adrenomedullin, endothelin-1, and CD105, leading to increased apoptosis. siRNA knockdown, Western blot, ribonuclease protection assay, in situ hybridization The Journal of biological chemistry Medium 12963716
2003 ERp46/TXNDC5 is an ER-resident protein that can substitute for protein disulfide isomerase function in yeast complementation studies, confirming it has PDI enzymatic activity in vivo. Yeast complementation assay, proteomic analysis of ER lumen, Western blot, subcellular fractionation Molecular & cellular proteomics : MCP Medium 12930873
2010 ERp46/TXNDC5 interacts specifically with the cytoplasmic N-terminal residues (1–70) of adiponectin receptor 1 (AdipoR1) but not AdipoR2; ERp46 is present at both the ER and plasma membrane; knockdown of ERp46 increased AdipoR1 and AdipoR2 at the plasma membrane and altered adiponectin signaling (increased AMPK phosphorylation, decreased p38MAPK phosphorylation). Co-immunoprecipitation followed by mass spectrometry, GST-fusion pulldown with truncated constructs, indirect immunofluorescence, subcellular fractionation, siRNA knockdown Biochemical and biophysical research communications Medium 20074551
2013 Hyperoxidized peroxiredoxin 2 (Prx2) selectively co-precipitates with ERp46/TXNDC5 in H2O2-treated cells; the interaction requires loss of the peroxidative Cys of Prx2 and the resolving Cys of Prx2, and is disrupted by reduction of intramolecular disulfides in ERp46 or disruption of the Prx2 decameric structure, indicating a stable non-covalent interaction dependent on hyperoxidized Prx2 status. Co-immunoprecipitation, mutant analysis, biochemical dissociation experiments The Biochemical journal Medium 23713588
2013 ERp46/TXNDC5 all three catalytic domains (a0, a, a') bind peptides containing aromatic and basic residues; ERp46 shows relatively higher disulfide-reductase activity than PDI or ERp57 in vitro and possesses chaperone activity in vivo; the C-terminal a' domain alone retains chaperone activity. Crystal structure of the a' domain was determined. Peptide binding assay, in vitro disulfide reductase/oxidase/isomerase activity assay, in vivo chaperone assay, X-ray crystallography of a' domain Journal of molecular biology High 23376096
2013 Endo-PDI/ERp46/TXNDC5 mediates TNFα-induced angiogenesis in endothelial cells by supporting the Ras/Raf/MEK/ERK pathway, leading to AP-1-driven expression of MMP-9 and cathepsin B; this action is intracellular (not via extracellular thiol exchange or cell-surface PDI activity); knockdown inhibited ERK1/2 phosphorylation, Ras activation, Raf phosphorylation, MMP-9/cathepsin B induction, spheroid outgrowth, ex vivo tube formation, and in vivo Matrigel angiogenesis. siRNA knockdown, G-LISA Ras activation assay, Western blot for pathway phosphorylation, in vitro/ex vivo/in vivo angiogenesis assays, non-permeative inhibitors to exclude extracellular activity Free radical biology & medicine Medium 24103565
2014 Crystal structure of the third catalytic domain (a') of ERp46/TXNDC5 determined to 2.0 Å resolution reveals a canonical thioredoxin-like fold; Cys381 and Cys388 form a structural disulfide whose absence causes dramatic conformational changes; Trp349 inserts into a neighboring molecule's cavity, potentially mimicking substrate interactions. X-ray crystallography Acta crystallographica. Section F High 22505402
2014 Full crystal structure of ERp46/TXNDC5 reveals a radically different molecular architecture from PDI: three thioredoxin domains arranged in an extended open V-shape linked by unusually long loops, with positively charged patches near peptide-binding sites. The three Trx domains act independently and engage in rapid but promiscuous disulfide bond introduction during early oxidative protein folding, in contrast to PDI's cooperative action. ERp46 works together with Peroxiredoxin-4 (Prx4) as an efficient disulfide bond introducer. X-ray crystallography, in vitro oxidative folding assays, structural comparison with PDI Structure (London, England : 1993) High 24462249
2014 TXNDC5 directly interacts with androgen receptor (AR) protein to increase AR stability and enhance AR transcriptional activity in prostate cancer cells; TXNDC5 upregulation is induced by ADT-mediated hypoxia via HIF-1α in an miR-200b-dependent manner; TXNDC5-mediated castration-resistant prostate cancer growth is abolished by AR inhibition. Co-immunoprecipitation, in vitro and in vivo xenograft models, siRNA knockdown, AR inhibitor treatment, HIF-1α manipulation Oncogene Medium 25500540
2018 TXNDC5 promotes cardiac fibrosis by two mechanisms: (1) facilitating ECM protein folding as a PDI (depletion causes ECM protein misfolding and degradation in cardiac fibroblasts); and (2) promoting cardiac fibroblast activation and proliferation via enhanced reactive oxygen species from NOX4, leading to c-Jun N-terminal kinase (JNK) activation. TGFβ1-induced TXNDC5 upregulation is dependent on ER stress and ATF6-mediated transcriptional control. Txndc5-/- mice show ~70% reduction in isoproterenol-induced fibrosis and preserved cardiac function. siRNA knockdown and overexpression, ECM protein folding assay, ROS measurement, JNK phosphorylation assay, ATF6 knockdown, RNA-seq, Txndc5-/- mouse model with echocardiography Circulation research High 29535165
2018 ERp46/TXNDC5 stably associates with EDEM3 via a disulfide bond between ERp46 redox-active site cysteines and the EDEM3 α-mannosidase domain; this covalent interaction, dependent on ERp46 redox activity, is required to trigger EDEM3 mannose-trimming activity toward misfolded glycoprotein substrates (TCRα) in a defined in vitro reconstituted system. Co-immunoprecipitation, in vitro reconstituted mannose-trimming assay with purified recombinant proteins from HEK293 cells, redox-activity-dependent interaction analysis The Journal of biological chemistry High 29784879
2017 TXNDC5 directly interacts with HSC70 in rheumatoid arthritis synovial fibroblasts (RASFs) to sequester HSC70 in the cytoplasm; HSC70 in turn activates NF-κB signaling by destabilizing IκBβ protein (in the absence of LPS) or facilitating NF-κB nuclear translocation (in the presence of LPS); TXNDC5 regulates NF-κB activity in a HSC70-IκBβ-dependent manner. Co-immunoprecipitation, siRNA knockdown of TXNDC5 and HSC70, NF-κB signaling analysis (IκBβ stability, nuclear translocation), cytokine production assays Cellular & molecular immunology Medium 28603283
2020 TXNDC5 promotes pulmonary fibrosis by directly binding to and stabilizing TGFβ receptor 1 (TGFBR1) in lung fibroblasts, thereby enhancing TGFβ1 signaling; TGFβ1 stimulation upregulates TXNDC5 via ER stress/ATF6-dependent transcriptional control; fibroblast-specific Txndc5 deletion reduces bleomycin-induced pulmonary fibrosis and preserves lung function in mice. Co-immunoprecipitation (direct TXNDC5-TGFBR1 binding), global and fibroblast-specific Txndc5 KO mice, bleomycin fibrosis model, ATF6 pathway analysis, lung function measurements Nature communications High 32848143
2021 TXNDC5 promotes renal fibrosis by posttranslationally stabilizing and upregulating type I TGFβ receptor (TGFBR1) in kidney fibroblasts; TXNDC5 is transcriptionally controlled by the ATF6-dependent ER stress pathway; tamoxifen-inducible fibroblast-specific Txndc5 KO mice show mitigated progression of established kidney fibrosis. TXNDC5 knockdown and overexpression in human kidney fibroblasts, fibroblast-specific inducible Txndc5 KO (Col1a2-Cre/ERT2), kidney fibrosis models (unilateral ureteral obstruction, ischemia-reperfusion), TGFBR1 protein stability assay, ATF6 pathway analysis The Journal of clinical investigation High 33465051
2021 TXNDC5 promotes liver fibrosis through redox-dependent JNK and STAT3 activation in hepatic stellate cells (HSCs) via its PDI activity; TGFβ1 induces TXNDC5 expression through ER stress and ATF6-mediated transcriptional regulation; HSC-specific deletion of Txndc5 reverted established liver fibrosis in mice. HSC-specific Txndc5 KO (Col1a2-Cre/ERT2), carbon tetrachloride and bile duct ligation liver fibrosis models, JNK and STAT3 phosphorylation assays, ATF6 pathway analysis, PDI activity-dependent experiments Gut High 34933915
2022 Disturbed flow (DF) induces TXNDC5 in endothelial cells; TXNDC5 promotes atherosclerosis by increasing proteasome-mediated degradation of heat shock factor 1 (HSF1), leading to reduced HSP90 levels and accelerated eNOS protein degradation; endothelium-specific Txndc5 deletion in ApoE-/- mice markedly reduces atherosclerosis; nanoparticle-delivered endothelium-specific CRISPR-Cas9 targeting Txndc5 increases eNOS protein and reduces atherosclerosis. Endothelium-specific Txndc5 KO in ApoE-/- mice, disturbed flow cell culture model, HSF1/HSP90/eNOS protein stability assays, proteasome inhibitor experiments, nanoparticle CRISPR-Cas9 delivery Science advances High 35061532
2022 ERp46/TXNDC5 is expressed on the platelet surface (increasing upon thrombin stimulation), binds tightly to integrin αIIbβ3 and physically associates with it upon platelet activation; ERp46 more strongly reduces disulfide bonds in the β3 subunit than other PDIs and cleaves the Cys473-Cys503 disulfide bond in β3 independently of fibrinogen; ERp46 is required for αIIbβ3 activation, platelet aggregation, ATP release, P-selectin expression, clot retraction, and platelet spreading in vitro; ERp46-deficient mice have prolonged bleeding times and reduced platelet accumulation in thrombosis models. ERp46 KO mice, surface plasmon resonance (tight binding to αIIbβ3), thiol labeling of β3 disulfides, recombinant ERp46 protein with active-site mutations, platelet function assays, tail-bleeding and thrombosis models Blood High 34752599
2009 ERp46/TXNDC5 is required for insulin production at the posttranslational level in pancreatic β-cells; siRNA-mediated knockdown of ERp46 in β-TC-6 cells significantly decreases insulin content without altering insulin mRNA levels, and increases ER stress markers (CHOP, peIF2α). siRNA knockdown, proteomics (2D-gel electrophoresis/MS), insulin content measurement, RT-PCR for insulin mRNA, ER stress marker Western blot American journal of physiology. Endocrinology and metabolism Medium 19622788
2015 ERp46/TXNDC5 co-localizes with pro-insulin in pancreatic islets and physically interacts with pro-insulin as shown by co-immunoprecipitation and proximity ligation assay (<30 nm); ATF6 and XBP1 bind to the ERp46 promoter (ChIP assay), and high glucose decreases their binding, reducing ERp46 expression; GLP-1 analogue liraglutide restores ERp46 levels under high-glucose conditions. Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation (ChIP), confocal microscopy, Western blot Metabolism: clinical and experimental Medium 26683792
2021 IRE1α-XBP1 signaling (not only ATF6) regulates TXNDC5 expression in activated fibroblasts during silicosis-induced pulmonary fibrosis; pharmacological inhibition of IRE1α endoribonuclease activity or XBP1 knockdown reduces TXNDC5 expression; IRE1α inhibition in vivo ameliorates lung fibrosis. IRE1α pharmacological inhibitor, XBP1 siRNA knockdown, Western blot for TXNDC5, in vivo crystalline silica fibrosis model International immunopharmacology Medium 33691254
2022 METTL3-mediated m6A modification of TXNDC5 mRNA upregulates TXNDC5 expression in an m6A reader-dependent manner in cervical cancer; inhibition of METTL3 reduces TXNDC5 expression and suppresses ER stress; ETS1 recruits P300 and WDR5 to mediate H3K27ac and H3K4me3 histone modifications at the METTL3 promoter to activate METTL3 transcription. MeRIP-seq (m6A sequencing), siRNA knockdown, overexpression, ChIP for histone modifications, in vitro and in vivo tumor assays Oncogene Medium 35987795
2023 TXNDC5 interacts with PRDX6 and HSPA9 in hepatic AML12 cells (identified by co-immunoprecipitation and LC-MS); TXNDC5 deficiency (CRISPR KO) reduces protein levels of PRDX6 and HSPA9, decreases lipid peroxidation, glutathione levels, and iPLA2 activity, indicating TXNDC5 regulates glutathione metabolism and lipid peroxidation through these interactions. Co-immunoprecipitation, liquid chromatography-mass spectrometry, CRISPR/Cas9 KO, lipid peroxidation assay, glutathione measurement, iPLA2 activity assay, transcriptome analysis International journal of molecular sciences Medium 38138960
2024 TXNDC5 interacts with HEV ORF3 protein (non-palmitoylated form) via co-immunoprecipitation; TXNDC5 stabilizes ORF3 protein amounts through its N-terminal region (aa 1–88), independent of the Trx-like domains; TXNDC5 knockdown leads to ORF3 degradation via ER-associated protein degradation-proteasome system; TXNDC5 overexpression or knockdown positively regulates HEV release from host cells. Co-immunoprecipitation, TXNDC5 domain deletion mutants, proteasome inhibitor experiments, TXNDC5 KO stable cell lines, HEV release assay, ORF3 mutation (17FCL19) Journal of virology Medium 38548704
2024 TXNDC5 promotes TGFBR1 stabilization in trabecular meshwork (TM) cells, leading to ECM accumulation and elevated intraocular pressure in glaucoma; TXNDC5 itself is degraded through the chaperone-mediated autophagy (CMA) pathway; knockdown of TXNDC5 significantly reduces TGFβ2-induced ECM protein accumulation in TM tissues and reduces ocular hypertension in vivo. Label-free quantitative proteomics, qPCR, Western blot, autophagy/CMA inhibitors (CQ, CHX), CMA activity modulation, in vivo TM knockdown mouse model Investigative ophthalmology & visual science Medium 42012274
2025 ERp46/TXNDC5 oxidizes the Cys540-Cys571 disulfide bond in coagulation factor XII (FXII), which is partially disulfide-bonded under basal conditions, thereby enhancing FXII activity and promoting the intrinsic coagulation pathway; ERp46 deficiency in vivo reduces venous thrombus growth; FXII C540S-C571S mutant fails to restore venous thrombus growth in FXII-deficient mice. Thiol labeling and mass spectrometry to identify FXII disulfide substrates, cysteine mutagenesis of FXII, kinetic trapping to identify ERp46 substrates, chromogenic assay, activated partial thromboplastin time, thrombin generation assay, ERp46-deficient mice, inferior vena cava stenosis model Journal of thrombosis and haemostasis : JTH High 41197808
2024 TMX1 counterbalances ERp46/TXNDC5 activity in platelets by directly oxidizing ERp46 thiols and by re-oxidizing integrin αIIbβ3 disulfides that were reduced by ERp46; TMX1 inhibits ERp46 reductase activity in a concentration-dependent manner; TMX1 deficiency increases free thiols of ERp46 in platelets. ERp46- and TMX1-deficient platelets, thiol labeling, reductase activity assay, platelet aggregation and αIIbβ3 activation assays, anti-TMX1 antibody blocking Research and practice in thrombosis and haemostasis Medium 39247212
2026 Fibroblast TXNDC5 stabilizes TGFBR1 in colorectal cancer-associated fibroblasts, enhancing TGFβ signaling and driving immunosuppressive fibroblast polarization; fibroblast-specific Txndc5 deletion reduces tumor stiffness, decompresses vessels, reduces hypoxia, inhibits pro-tumorigenic inflammatory fibroblast polarization, augments cytotoxic T-cell recruitment, and sensitizes tumors to PD-1 blockade. Fibroblast-specific Txndc5 KO mouse colorectal cancer model, TGFBR1 stabilization assay, tumor mechanics measurement, immunofluorescence for T-cell infiltration, PD-1 blockade combination treatment Nature communications High 42248857
2025 ER stress promotes TXNDC5 transcription via ATF6 binding to the TXNDC5 promoter in pulmonary endothelial cells during ischemia-reperfusion injury; TXNDC5 upregulation destabilizes the HSP90/eNOS complex, impairing endothelial barrier function; TXNDC5 knockdown (AAV-shRNA) restores HSP90/eNOS stability and improves endothelial integrity in vitro and in vivo. ChIP-seq (ATF6 binding to TXNDC5 promoter), AAV-shRNA knockdown in vivo, rat LIRI model, oxygen-glucose deprivation/reperfusion in vitro, HSP90/eNOS co-IP/stability assay, ATF6 inhibitor rescue experiments Journal of advanced research Medium 41456650
2025 TXNDC5 governs extracellular matrix (ECM) homeostasis in pulmonary hypertension through biglycan (BGN); HIF-2α transcriptionally activates TXNDC5 in endothelial cells of remodeled distal pulmonary arteries; endothelial TXNDC5 overexpression exacerbates pulmonary vascular remodeling and right ventricular hypertrophy, while endothelial-specific TXNDC5 deficiency is protective; pharmacological inhibition with E64FC26 attenuates PH in rats. Single-cell RNA sequencing, immunofluorescence, Western blot, endothelial gain/loss-of-function in Sugen5416/hypoxia PH model, RNA sequencing, protein-protein interaction analysis (BGN), HIF-2α transcriptional activation assay bioRxivpreprint Low

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor. The Journal of biological chemistry 150 12963716
2003 ERp19 and ERp46, new members of the thioredoxin family of endoplasmic reticulum proteins. Molecular & cellular proteomics : MCP 111 12930873
2020 Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization. Nature communications 106 32848143
2019 CircRNA-104718 acts as competing endogenous RNA and promotes hepatocellular carcinoma progression through microRNA-218-5p/TXNDC5 signaling pathway. Clinical science (London, England : 1979) 106 31278132
2021 Endoplasmic reticulum protein TXNDC5 promotes renal fibrosis by enforcing TGF-β signaling in kidney fibroblasts. The Journal of clinical investigation 101 33465051
2018 Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation. Circulation research 92 29535165
2014 TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. International journal of molecular sciences 72 25526565
2010 ERp46 binds to AdipoR1, but not AdipoR2, and modulates adiponectin signalling. Biochemical and biophysical research communications 57 20074551
2014 Radically different thioredoxin domain arrangement of ERp46, an efficient disulfide bond introducer of the mammalian PDI family. Structure (London, England : 1993) 54 24462249
2018 A critical role of the thioredoxin domain containing protein 5 (TXNDC5) in redox homeostasis and cancer development. Genes & diseases 49 30591932
2014 The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. Oncogene 45 25500540
2013 Hyperoxidized peroxiredoxin 2 interacts with the protein disulfide- isomerase ERp46. The Biochemical journal 45 23713588
2022 METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA. Oncogene 44 35987795
2021 Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling. Gut 41 34933915
2009 ERp46 is reduced by high glucose and regulates insulin content in pancreatic beta-cells. American journal of physiology. Endocrinology and metabolism 40 19622788
2010 The influence of TXNDC5 gene on gastric cancer cell. Journal of cancer research and clinical oncology 39 20157732
2020 Circ_0000517 Contributes to Hepatocellular Carcinoma Progression by Upregulating TXNDC5 via Sponging miR-1296-5p. Cancer management and research 38 32523376
2019 HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway. Journal of experimental & clinical cancer research : CR 35 31331361
2013 Investigate pathogenic mechanism of TXNDC5 in rheumatoid arthritis. PloS one 34 23326410
2018 ER-resident protein 46 (ERp46) triggers the mannose-trimming activity of ER degradation-enhancing α-mannosidase-like protein 3 (EDEM3). The Journal of biological chemistry 33 29784879
2013 Endo-PDI is required for TNFα-induced angiogenesis. Free radical biology & medicine 33 24103565
2017 TXNDC5 synergizes with HSC70 to exacerbate the inflammatory phenotype of synovial fibroblasts in rheumatoid arthritis through NF-κB signaling. Cellular & molecular immunology 32 28603283
2013 Investigating a pathogenic role for TXNDC5 in tumors. International journal of oncology 32 24100949
2017 TXNDC5 is a cervical tumor susceptibility gene that stimulates cell migration, vasculogenic mimicry and angiogenesis by down-regulating SERPINF1 and TRAF1 expression. Oncotarget 31 29207620
2011 Overexpression of the TXNDC5 protein in non-small cell lung carcinoma. Anticancer research 28 21617212
2022 Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo. Science advances 27 35061532
2021 Inhibition of ER stress by targeting the IRE1α-TXNDC5 pathway alleviates crystalline silica-induced pulmonary fibrosis. International immunopharmacology 26 33691254
2022 A novel role for endoplasmic reticulum protein 46 (ERp46) in platelet function and arterial thrombosis in mice. Blood 25 34752599
2018 Role of TXNDC5 in tumorigenesis of colorectal cancer cells: In vivo and in vitro evidence. International journal of molecular medicine 23 29749460
2022 The role and mechanism of TXNDC5 in diseases. European journal of medical research 22 35934705
2013 Peptide binding by catalytic domains of the protein disulfide isomerase-related protein ERp46. Journal of molecular biology 22 23376096
2022 Squalene Loaded Nanoparticles Effectively Protect Hepatic AML12 Cell Lines against Oxidative and Endoplasmic Reticulum Stress in a TXNDC5-Dependent Way. Antioxidants (Basel, Switzerland) 21 35326231
2011 Investigating a pathogenic role for TXNDC5 in rheumatoid arthritis. Arthritis research & therapy 21 21801346
2022 The novel role of ER protein TXNDC5 in the pathogenesis of organ fibrosis: mechanistic insights and therapeutic implications. Journal of biomedical science 20 36050716
2020 Circ_0110805 Knockdown Enhances Cisplatin Sensitivity and Inhibits Gastric Cancer Progression by miR-299-3p/ENDOPDI Axis. OncoTargets and therapy 18 33192077
2018 Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of TXNDC5. Molecular medicine reports 18 29328423
2009 Association of TXNDC5 gene polymorphisms and susceptibility to nonsegmental vitiligo in the Korean population. The British journal of dermatology 17 19906073
2022 m6A Methyltransferase METTL3 Promotes the Progression of Primary Acral Melanoma via Mediating TXNDC5 Methylation. Frontiers in oncology 14 35117988
2012 Structure of the third catalytic domain of the protein disulfide isomerase ERp46. Acta crystallographica. Section F, Structural biology and crystallization communications 14 22505402
2021 Circ_0078710 promotes the development of liver cancer by upregulating TXNDC5 via miR-431-5p. Annals of hepatology 13 34606982
2012 Role of ERp46 in β-cell lipoapoptosis through endoplasmic reticulum stress pathway as well as the protective effect of exendin-4. Biochemical and biophysical research communications 13 22935416
2024 Parecoxib Enhances Resveratrol against Human Colorectal Cancer Cells through Akt and TXNDC5 Inhibition and MAPK Regulation. Nutrients 12 39275334
2015 Reduced expression of ERp46 under diabetic conditions in β-cells and the effect of liraglutide. Metabolism: clinical and experimental 12 26683792
2023 Endoplasmic Reticulum Protein TXNDC5 Interacts with PRDX6 and HSPA9 to Regulate Glutathione Metabolism and Lipid Peroxidation in the Hepatic AML12 Cell Line. International journal of molecular sciences 11 38138960
2020 TXNDC5 protects synovial fibroblasts of rheumatoid arthritis from the detrimental effects of endoplasmic reticulum stress. Intractable & rare diseases research 11 32201671
2017 TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression. Clinical and experimental immunology 11 29131315
2017 CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synoviocytes. The Journal of rheumatology 11 29247155
2013 TXNDC5 gene polymorphism contributes to increased risk of hepatocellular carcinoma in the Korean male population. Anticancer research 11 24023338
2024 The role and mechanism of TXNDC5 in disease progression. Frontiers in immunology 10 38629066
2024 Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe? Current issues in molecular biology 10 38666927
2021 Inhibition of TXNDC5 attenuates lipopolysaccharide-induced septic shock by altering inflammatory responses. Laboratory investigation; a journal of technical methods and pathology 10 34864825
2017 Endoplasmic reticulum protein ERp46 in prostate adenocarcinoma. Oncology letters 10 28521463
2014 Endoplasmic reticulum protein ERp46 in renal cell carcinoma. PloS one 9 24594673
2024 Deltamethrin exposure caused renal inflammation and renal fibrosis via upregulating endoplasmic reticulum stress-mediated TXNDC5 level in mice. Pesticide biochemistry and physiology 8 39672609
2024 Validation of the interaction between PRDX4 and TXNDC5 in gastric cancer and the significance of the PRDX4 gene in gastric cancer based on a data mining analysis. Translational cancer research 7 38410208
2020 A newly discovered teleost disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), from big-belly seahorse (Hippocampus abdominalis): Insights into its molecular and functional properties and immune regulatory functions. Developmental and comparative immunology 7 32805308
2024 Hepatitis E virus ORF3 protein hijacking thioredoxin domain-containing protein 5 (TXNDC5) for its stability to promote viral particle release. Journal of virology 6 38548704
2023 Knockdown of TXNDC5 alleviates CCL4-induced hepatic fibrosis in mice by enhancing endoplasmic reticulum stress. The American journal of the medical sciences 6 37716602
2018 Maternal serum TXNDC5 levels and thiol/disulfide homeostasis in preeclamptic pregnancies. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 5 30522366
2016 Enhanced photoelectrochemical aptasensing platform for TXNDC5 gene based on exciton energy transfer between NCQDs and TiO2 nanorods. Scientific reports 5 26777976
2024 TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells. International journal of molecular sciences 3 39000233
2024 Transmembrane thiol isomerase TMX1 counterbalances the effect of ERp46 to inhibit platelet activation and integrin αIIbβ3 function. Research and practice in thrombosis and haemostasis 3 39247212
2014 [TXNDC5 mediates serum starvation-induced proliferation inhibition of HeLa cell]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 3 25360642
2025 Deletion of TXNDC5 downregulates TGFβ1-αSMA-mediated testicular fibrosis in mice. Reproduction (Cambridge, England) 2 40261983
2025 Thiol isomerase ERp46 catalyzes the disulfide formation of coagulation factor XII enhancing its activity. Journal of thrombosis and haemostasis : JTH 2 41197808
2025 ALKBH5-mediated m6A demethylation of TXNDC5 drives malignant progression in gastric cancer. Epigenomics 1 41217028
2024 The role and mechanism of TXNDC5 in cardio-oncology: Killing two birds with one stone? Current problems in cardiology 1 39643150
2024 Endoplasmic reticulum protein TXNDC5 modulates thyroid eye disease TGF-β1-induced myofibroblast transdifferentiation. BMJ open ophthalmology 1 39721966
2017 [Progress of research on TXNDC5]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 28604976
2026 Intercellular Horizontal Transfer of TXNDC5 mRNA via Extracellular Vesicles Contributes to Tumor-Associated Macrophage-Mediated Prostate Cancer Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41631773
2026 TXNDC5 in POAG: Promoting Extracellular Matrix Protein Accumulation and Raising Intraocular Pressure. Investigative ophthalmology & visual science 0 42012274
2026 Combined Curcumin and Doxorubicin Induce Apoptosis via JNK-Dependent MAPK Signaling Independent of TXNDC5 in Human Osteosarcoma Cells. Nutrients 0 42075048
2026 Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits. Nature communications 0 42248857
2025 CXCL1 Promotes Fibrotic Remodeling in Atrial Fibrillation via Activation of TXNDC5 and Endoplasmic Reticulum Stress. Cardiovascular therapeutics 0 41194855
2025 ERp46 mitigates lipotoxic ER stress to preserve GLUT2 expression and insulin secretion in β-cells. Biomedical reports 0 41384131
2025 Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced pulmonary endothelial barrier dysfunction by activating TXNDC5. Journal of advanced research 0 41456650
2025 [Mechanism of Buyang Huanwu Decoction and Didang Decoction in treatment of chronic kidney disease based on ATF6/TXNDC5-regulated "macrophage-myofibroblast transformation" pathway]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 0 41508079
2024 Single-cell RNA sequencing analysis reveals the role of TXNDC5 in keloid formation. CytoJournal 0 39563670

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