{"gene":"TXNDC5","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"siRNA knockdown, Western blot, ribonuclease protection assay, in situ hybridization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with defined cellular phenotype (apoptosis, secretion defects), single lab, multiple readouts","pmids":["12963716"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Yeast complementation assay, proteomic analysis of ER lumen, Western blot, subcellular fractionation","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vivo complementation assay, single lab, corroborated by localization data","pmids":["12930873"],"is_preprint":false},{"year":2010,"finding":"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).","method":"Co-immunoprecipitation followed by mass spectrometry, GST-fusion pulldown with truncated constructs, indirect immunofluorescence, subcellular fractionation, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP/MS plus functional signaling readout, single lab, multiple orthogonal methods","pmids":["20074551"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, mutant analysis, biochemical dissociation experiments","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutant characterization defining interaction requirements, single lab, mechanistic follow-up with controls","pmids":["23713588"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Peptide binding assay, in vitro disulfide reductase/oxidase/isomerase activity assay, in vivo chaperone assay, X-ray crystallography of a' domain","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, crystal structure, domain-level functional mapping, multiple orthogonal methods in single study","pmids":["23376096"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple pathway and functional readouts including in vivo, single lab, non-permeative controls exclude extracellular mechanism","pmids":["24103565"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography","journal":"Acta crystallographica. Section F","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with atomic resolution revealing mechanistically relevant disulfide and substrate-mimicking interaction","pmids":["22505402"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography, in vitro oxidative folding assays, structural comparison with PDI","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro functional reconstitution establishing catalytic mechanism and domain independence","pmids":["24462249"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, in vitro and in vivo xenograft models, siRNA knockdown, AR inhibitor treatment, HIF-1α manipulation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating direct AR interaction, epistasis via AR inhibitor rescue, in vivo validation, single lab","pmids":["25500540"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown and overexpression, ECM protein folding assay, ROS measurement, JNK phosphorylation assay, ATF6 knockdown, RNA-seq, Txndc5-/- mouse model with echocardiography","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal mechanisms demonstrated (PDI folding assay, ROS/JNK pathway, ATF6 transcriptional control) with in vivo KO validation","pmids":["29535165"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, in vitro reconstituted mannose-trimming assay with purified recombinant proteins from HEK293 cells, redox-activity-dependent interaction analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins demonstrating covalent interaction and functional requirement, single lab with rigorous controls","pmids":["29784879"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown of TXNDC5 and HSC70, NF-κB signaling analysis (IκBβ stability, nuclear translocation), cytokine production assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus siRNA epistasis identifying TXNDC5→HSC70→IκBβ→NF-κB pathway, single lab, multiple readouts","pmids":["28603283"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation (direct TXNDC5-TGFBR1 binding), global and fibroblast-specific Txndc5 KO mice, bleomycin fibrosis model, ATF6 pathway analysis, lung function measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing direct protein interaction, genetic epistasis via fibroblast-specific KO, in vivo functional validation with lung function, replicated mechanistic finding across fibrosis contexts","pmids":["32848143"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible fibroblast-specific KO with established disease model, TGFBR1 stabilization mechanism, consistent with findings from cardiac and pulmonary fibrosis studies","pmids":["33465051"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell type-specific inducible KO with established fibrosis models, redox-dependent mechanistic pathway defined, consistent with multi-organ TXNDC5-fibrosis mechanism","pmids":["34933915"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo endothelium-specific KO and CRISPR therapy both demonstrate atherosclerosis reduction, HSF1→HSP90→eNOS degradation pathway established mechanistically","pmids":["35061532"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR quantifying direct binding, thiol labeling identifying specific disulfide substrate (Cys473-Cys503), KO mouse phenotype, in vitro reconstitution with mutant proteins","pmids":["34752599"],"is_preprint":false},{"year":2009,"finding":"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).","method":"siRNA knockdown, proteomics (2D-gel electrophoresis/MS), insulin content measurement, RT-PCR for insulin mRNA, ER stress marker Western blot","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with posttranslational mechanism established (mRNA unchanged, protein decreased), single lab","pmids":["19622788"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation (ChIP), confocal microscopy, Western blot","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus PLA establish direct protein interaction with pro-insulin; ChIP identifies transcriptional regulators; single lab, multiple orthogonal methods","pmids":["26683792"],"is_preprint":false},{"year":2021,"finding":"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.","method":"IRE1α pharmacological inhibitor, XBP1 siRNA knockdown, Western blot for TXNDC5, in vivo crystalline silica fibrosis model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic approaches establish IRE1α→XBP1→TXNDC5 pathway, single lab, in vivo confirmation","pmids":["33691254"],"is_preprint":false},{"year":2022,"finding":"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.","method":"MeRIP-seq (m6A sequencing), siRNA knockdown, overexpression, ChIP for histone modifications, in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq identifies m6A site on TXNDC5 mRNA, ChIP establishes upstream transcriptional control, single lab","pmids":["35987795"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, liquid chromatography-mass spectrometry, CRISPR/Cas9 KO, lipid peroxidation assay, glutathione measurement, iPLA2 activity assay, transcriptome analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies interaction partners, KO cell line establishes functional consequences, single lab, multiple orthogonal readouts","pmids":["38138960"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, TXNDC5 domain deletion mutants, proteasome inhibitor experiments, TXNDC5 KO stable cell lines, HEV release assay, ORF3 mutation (17FCL19)","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mutants identifies interaction domain, proteasome inhibitor experiments establish degradation pathway, single lab with multiple mechanistic approaches","pmids":["38548704"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Label-free quantitative proteomics, qPCR, Western blot, autophagy/CMA inhibitors (CQ, CHX), CMA activity modulation, in vivo TM knockdown mouse model","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CMA degradation pathway established with pharmacological tools, TGFBR1 stabilization mechanism and in vivo IOP reduction demonstrated, single lab","pmids":["42012274"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis identifying specific FXII disulfide substrate, mass spectrometry substrate identification, in vivo genetic epistasis confirming pathway","pmids":["41197808"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ERp46- and TMX1-deficient platelets, thiol labeling, reductase activity assay, platelet aggregation and αIIbβ3 activation assays, anti-TMX1 antibody blocking","journal":"Research and practice in thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — thiol labeling and reductase activity assays establish direct inhibition mechanism, KO platelets confirm in vivo relevance, single lab","pmids":["39247212"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Fibroblast-specific Txndc5 KO mouse colorectal cancer model, TGFBR1 stabilization assay, tumor mechanics measurement, immunofluorescence for T-cell infiltration, PD-1 blockade combination treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — fibroblast-specific genetic KO with multiple mechanistic readouts (TGFBR1 stabilization, tumor mechanics, immune infiltration), consistent with TXNDC5-TGFBR1 axis across multiple fibrosis studies","pmids":["42248857"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq identifies direct ATF6 promoter binding, in vivo KD and rescue experiments, HSP90/eNOS complex stability mechanistically linked, single lab","pmids":["41456650"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, protein-protein interaction with BGN inferred from RNA-seq/PPI analysis rather than direct binding assay","pmids":[],"is_preprint":true}],"current_model":"TXNDC5 (ERp46/EndoPDI) is an ER-resident protein disulfide isomerase with three independent catalytic thioredoxin domains arranged in an extended V-shaped architecture that catalyze rapid, promiscuous disulfide bond formation during early oxidative protein folding; it acts as a multifunctional redox chaperone whose PDI activity enables it to stabilize client proteins (including TGFBR1, AR, and HEV ORF3), facilitate ECM protein folding, and activate redox-sensitive JNK and STAT3 signaling—thereby driving fibrogenesis in cardiac, pulmonary, renal, liver, and other tissues downstream of TGFβ1/ATF6-mediated ER stress transcriptional control; in endothelial cells it promotes atherosclerosis by degrading HSF1→HSP90→eNOS and mediates TNFα-driven angiogenesis via the Ras/ERK/AP-1 axis; in platelets it reduces specific αIIbβ3 disulfide bonds (Cys473-Cys503) to support integrin activation and thrombosis, and in coagulation it oxidizes FXII Cys540-Cys571 to enhance the intrinsic coagulation pathway."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12930873","12963716"],"confidence":"Medium","gaps":["Atomic mechanism of catalysis not yet resolved","Physiological client proteins not identified"]},{"year":2014,"claim":"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","pmids":["24462249","23376096","22505402"],"confidence":"High","gaps":["In vivo client spectrum not defined from structure alone","How domain independence is regulated in cells unknown"]},{"year":2018,"claim":"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","pmids":["29535165","29784879"],"confidence":"High","gaps":["Whether ECM folding versus ROS/JNK dominates pathology unclear","Direct fibrogenic client receptor not yet identified at this stage"]},{"year":2021,"claim":"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","pmids":["32848143","33465051","34933915","33691254"],"confidence":"High","gaps":["Whether TXNDC5 stabilizes TGFBR1 via direct disulfide chemistry not fully resolved","Generalizability of JNK/STAT3 versus TGFBR1 arms across tissues"]},{"year":2022,"claim":"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","pmids":["35061532","34752599"],"confidence":"High","gaps":["How TXNDC5 selects HSF1 for proteasomal degradation not defined","Surface localization mechanism for platelet ERp46 unclear"]},{"year":2025,"claim":"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","pmids":["41197808","39247212"],"confidence":"High","gaps":["Balance of oxidase versus reductase activity at the cell surface not fully mapped","Structural basis of substrate specificity for FXII vs β3 unknown"]},{"year":2024,"claim":"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","pmids":["38548704","25500540","42012274"],"confidence":"Medium","gaps":["Whether stabilization requires catalytic Trx domains differs by client (ORF3 was Trx-independent)","Generalizability of CMA turnover across cell types untested"]},{"year":2026,"claim":"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","pmids":["42248857"],"confidence":"High","gaps":["Direct molecular link from TGFBR1 stabilization to fibroblast polarization incompletely defined","Translational targeting strategy not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,7,16,24]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,7,16,24]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[4,9,10]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,12,22]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2,9]},{"term_id":"GO:0005886","term_label":"plasma 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cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/39643150","citation_count":1,"is_preprint":false},{"pmid":"41217028","id":"PMC_41217028","title":"ALKBH5-mediated m6A demethylation of TXNDC5 drives malignant progression in gastric cancer.","date":"2025","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/41217028","citation_count":1,"is_preprint":false},{"pmid":"39563670","id":"PMC_39563670","title":"Single-cell RNA sequencing analysis reveals the role of TXNDC5 in keloid formation.","date":"2024","source":"CytoJournal","url":"https://pubmed.ncbi.nlm.nih.gov/39563670","citation_count":0,"is_preprint":false},{"pmid":"41456650","id":"PMC_41456650","title":"Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced pulmonary endothelial barrier dysfunction by activating TXNDC5.","date":"2025","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/41456650","citation_count":0,"is_preprint":false},{"pmid":"41384131","id":"PMC_41384131","title":"ERp46 mitigates lipotoxic ER stress to preserve GLUT2 expression and insulin secretion in β-cells.","date":"2025","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/41384131","citation_count":0,"is_preprint":false},{"pmid":"42012274","id":"PMC_42012274","title":"TXNDC5 in POAG: Promoting Extracellular Matrix Protein Accumulation and Raising Intraocular Pressure.","date":"2026","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/42012274","citation_count":0,"is_preprint":false},{"pmid":"41194855","id":"PMC_41194855","title":"CXCL1 Promotes Fibrotic Remodeling in Atrial Fibrillation via Activation of TXNDC5 and Endoplasmic Reticulum Stress.","date":"2025","source":"Cardiovascular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41194855","citation_count":0,"is_preprint":false},{"pmid":"41631773","id":"PMC_41631773","title":"Intercellular Horizontal Transfer of TXNDC5 mRNA via Extracellular Vesicles Contributes to Tumor-Associated Macrophage-Mediated Prostate Cancer Metastasis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41631773","citation_count":0,"is_preprint":false},{"pmid":"41508079","id":"PMC_41508079","title":"[Mechanism of Buyang Huanwu Decoction and Didang Decoction in treatment of chronic kidney disease based on ATF6/TXNDC5-regulated \"macrophage-myofibroblast transformation\" pathway].","date":"2025","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/41508079","citation_count":0,"is_preprint":false},{"pmid":"42075048","id":"PMC_42075048","title":"Combined Curcumin and Doxorubicin Induce Apoptosis via JNK-Dependent MAPK Signaling Independent of TXNDC5 in Human Osteosarcoma Cells.","date":"2026","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/42075048","citation_count":0,"is_preprint":false},{"pmid":"42248857","id":"PMC_42248857","title":"Targeting fibroblast TXNDC5 resolves tumor desmoplasia and PD-1 resistance in colorectal cancer with mesenchymal traits.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42248857","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.21.689856","title":"TXNDC5 Governs Extracellular Matrix Homeostasis in Pulmonary Hypertension","date":"2025-11-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.21.689856","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45950,"output_tokens":8642,"usd":0.13374,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18530,"output_tokens":3750,"usd":0.0932,"stage2_stop_reason":"end_turn"},"total_usd":0.22694,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Western blot, ribonuclease protection assay, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD with defined cellular phenotype (apoptosis, secretion defects), single lab, multiple readouts\",\n      \"pmids\": [\"12963716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast complementation assay, proteomic analysis of ER lumen, Western blot, subcellular fractionation\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vivo complementation assay, single lab, corroborated by localization data\",\n      \"pmids\": [\"12930873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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).\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, GST-fusion pulldown with truncated constructs, indirect immunofluorescence, subcellular fractionation, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP/MS plus functional signaling readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20074551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mutant analysis, biochemical dissociation experiments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutant characterization defining interaction requirements, single lab, mechanistic follow-up with controls\",\n      \"pmids\": [\"23713588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Peptide binding assay, in vitro disulfide reductase/oxidase/isomerase activity assay, in vivo chaperone assay, X-ray crystallography of a' domain\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, crystal structure, domain-level functional mapping, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23376096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple pathway and functional readouts including in vivo, single lab, non-permeative controls exclude extracellular mechanism\",\n      \"pmids\": [\"24103565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with atomic resolution revealing mechanistically relevant disulfide and substrate-mimicking interaction\",\n      \"pmids\": [\"22505402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, in vitro oxidative folding assays, structural comparison with PDI\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro functional reconstitution establishing catalytic mechanism and domain independence\",\n      \"pmids\": [\"24462249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo xenograft models, siRNA knockdown, AR inhibitor treatment, HIF-1α manipulation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating direct AR interaction, epistasis via AR inhibitor rescue, in vivo validation, single lab\",\n      \"pmids\": [\"25500540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown and overexpression, ECM protein folding assay, ROS measurement, JNK phosphorylation assay, ATF6 knockdown, RNA-seq, Txndc5-/- mouse model with echocardiography\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal mechanisms demonstrated (PDI folding assay, ROS/JNK pathway, ATF6 transcriptional control) with in vivo KO validation\",\n      \"pmids\": [\"29535165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro reconstituted mannose-trimming assay with purified recombinant proteins from HEK293 cells, redox-activity-dependent interaction analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins demonstrating covalent interaction and functional requirement, single lab with rigorous controls\",\n      \"pmids\": [\"29784879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of TXNDC5 and HSC70, NF-κB signaling analysis (IκBβ stability, nuclear translocation), cytokine production assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus siRNA epistasis identifying TXNDC5→HSC70→IκBβ→NF-κB pathway, single lab, multiple readouts\",\n      \"pmids\": [\"28603283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (direct TXNDC5-TGFBR1 binding), global and fibroblast-specific Txndc5 KO mice, bleomycin fibrosis model, ATF6 pathway analysis, lung function measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing direct protein interaction, genetic epistasis via fibroblast-specific KO, in vivo functional validation with lung function, replicated mechanistic finding across fibrosis contexts\",\n      \"pmids\": [\"32848143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible fibroblast-specific KO with established disease model, TGFBR1 stabilization mechanism, consistent with findings from cardiac and pulmonary fibrosis studies\",\n      \"pmids\": [\"33465051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell type-specific inducible KO with established fibrosis models, redox-dependent mechanistic pathway defined, consistent with multi-organ TXNDC5-fibrosis mechanism\",\n      \"pmids\": [\"34933915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo endothelium-specific KO and CRISPR therapy both demonstrate atherosclerosis reduction, HSF1→HSP90→eNOS degradation pathway established mechanistically\",\n      \"pmids\": [\"35061532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR quantifying direct binding, thiol labeling identifying specific disulfide substrate (Cys473-Cys503), KO mouse phenotype, in vitro reconstitution with mutant proteins\",\n      \"pmids\": [\"34752599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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).\",\n      \"method\": \"siRNA knockdown, proteomics (2D-gel electrophoresis/MS), insulin content measurement, RT-PCR for insulin mRNA, ER stress marker Western blot\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with posttranslational mechanism established (mRNA unchanged, protein decreased), single lab\",\n      \"pmids\": [\"19622788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation (ChIP), confocal microscopy, Western blot\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus PLA establish direct protein interaction with pro-insulin; ChIP identifies transcriptional regulators; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26683792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"IRE1α pharmacological inhibitor, XBP1 siRNA knockdown, Western blot for TXNDC5, in vivo crystalline silica fibrosis model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic approaches establish IRE1α→XBP1→TXNDC5 pathway, single lab, in vivo confirmation\",\n      \"pmids\": [\"33691254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"MeRIP-seq (m6A sequencing), siRNA knockdown, overexpression, ChIP for histone modifications, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq identifies m6A site on TXNDC5 mRNA, ChIP establishes upstream transcriptional control, single lab\",\n      \"pmids\": [\"35987795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, liquid chromatography-mass spectrometry, CRISPR/Cas9 KO, lipid peroxidation assay, glutathione measurement, iPLA2 activity assay, transcriptome analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies interaction partners, KO cell line establishes functional consequences, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"38138960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, TXNDC5 domain deletion mutants, proteasome inhibitor experiments, TXNDC5 KO stable cell lines, HEV release assay, ORF3 mutation (17FCL19)\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mutants identifies interaction domain, proteasome inhibitor experiments establish degradation pathway, single lab with multiple mechanistic approaches\",\n      \"pmids\": [\"38548704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Label-free quantitative proteomics, qPCR, Western blot, autophagy/CMA inhibitors (CQ, CHX), CMA activity modulation, in vivo TM knockdown mouse model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CMA degradation pathway established with pharmacological tools, TGFBR1 stabilization mechanism and in vivo IOP reduction demonstrated, single lab\",\n      \"pmids\": [\"42012274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis identifying specific FXII disulfide substrate, mass spectrometry substrate identification, in vivo genetic epistasis confirming pathway\",\n      \"pmids\": [\"41197808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ERp46- and TMX1-deficient platelets, thiol labeling, reductase activity assay, platelet aggregation and αIIbβ3 activation assays, anti-TMX1 antibody blocking\",\n      \"journal\": \"Research and practice in thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — thiol labeling and reductase activity assays establish direct inhibition mechanism, KO platelets confirm in vivo relevance, single lab\",\n      \"pmids\": [\"39247212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Fibroblast-specific Txndc5 KO mouse colorectal cancer model, TGFBR1 stabilization assay, tumor mechanics measurement, immunofluorescence for T-cell infiltration, PD-1 blockade combination treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fibroblast-specific genetic KO with multiple mechanistic readouts (TGFBR1 stabilization, tumor mechanics, immune infiltration), consistent with TXNDC5-TGFBR1 axis across multiple fibrosis studies\",\n      \"pmids\": [\"42248857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq identifies direct ATF6 promoter binding, in vivo KD and rescue experiments, HSP90/eNOS complex stability mechanistically linked, single lab\",\n      \"pmids\": [\"41456650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, protein-protein interaction with BGN inferred from RNA-seq/PPI analysis rather than direct binding assay\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TXNDC5 (ERp46/EndoPDI) is an ER-resident protein disulfide isomerase with three independent catalytic thioredoxin domains arranged in an extended V-shaped architecture that catalyze rapid, promiscuous disulfide bond formation during early oxidative protein folding; it acts as a multifunctional redox chaperone whose PDI activity enables it to stabilize client proteins (including TGFBR1, AR, and HEV ORF3), facilitate ECM protein folding, and activate redox-sensitive JNK and STAT3 signaling—thereby driving fibrogenesis in cardiac, pulmonary, renal, liver, and other tissues downstream of TGFβ1/ATF6-mediated ER stress transcriptional control; in endothelial cells it promotes atherosclerosis by degrading HSF1→HSP90→eNOS and mediates TNFα-driven angiogenesis via the Ras/ERK/AP-1 axis; in platelets it reduces specific αIIbβ3 disulfide bonds (Cys473-Cys503) to support integrin activation and thrombosis, and in coagulation it oxidizes FXII Cys540-Cys571 to enhance the intrinsic coagulation pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #9, #12]. 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 [#4, #7]. 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 [#9, #12, #13, #19, #26]. Beyond TGFBR1, TXNDC5 promotes fibrosis through redox-dependent JNK and STAT3 activation in hepatic stellate cells and NOX4-derived ROS in cardiac fibroblasts [#9, #14]. In endothelium, TXNDC5 promotes atherosclerosis and vascular injury by accelerating proteasomal degradation of HSF1, lowering HSP90 and destabilizing the HSP90/eNOS complex [#15, #27], and supports TNFα-driven angiogenesis via the Ras/Raf/MEK/ERK-AP-1 axis inducing MMP-9 and cathepsin B [#5]. 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 [#16, #24, #25]. It additionally stabilizes oncogenic and viral clients including the androgen receptor and HEV ORF3 [#8, #22], partners with EDEM3 to trigger glycoprotein mannose trimming [#10], and is required posttranslationally for insulin production in pancreatic β-cells [#10, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast complementation of PDI function plus siRNA knockdown causing endothelial apoptosis and secretion defects under hypoxia\",\n      \"pmids\": [\"12930873\", \"12963716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic mechanism of catalysis not yet resolved\", \"Physiological client proteins not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how TXNDC5's architecture differs from canonical PDI, explaining its rapid promiscuous disulfide-introducing behavior during oxidative folding.\",\n      \"evidence\": \"X-ray crystallography of the full protein and a' domain plus in vitro oxidative folding assays and domain-level activity mapping\",\n      \"pmids\": [\"24462249\", \"23376096\", \"22505402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo client spectrum not defined from structure alone\", \"How domain independence is regulated in cells unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected TXNDC5 PDI activity to disease by showing it folds ECM proteins and amplifies fibroblast activation, downstream of ER stress/ATF6 transcriptional control.\",\n      \"evidence\": \"Txndc5-/- mice in isoproterenol cardiac fibrosis, ECM folding and ROS/JNK assays, ATF6 knockdown, plus in vitro EDEM3 reconstitution\",\n      \"pmids\": [\"29535165\", \"29784879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ECM folding versus ROS/JNK dominates pathology unclear\", \"Direct fibrogenic client receptor not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TGFBR1 stabilization as the unifying fibrogenic mechanism across organs, establishing TXNDC5 as a posttranslational amplifier of TGFβ signaling under ATF6/IRE1α-XBP1 control.\",\n      \"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\",\n      \"pmids\": [\"32848143\", \"33465051\", \"34933915\", \"33691254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TXNDC5 stabilizes TGFBR1 via direct disulfide chemistry not fully resolved\", \"Generalizability of JNK/STAT3 versus TGFBR1 arms across tissues\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined distinct vascular and hemostatic roles, showing TXNDC5 destabilizes the HSF1-HSP90-eNOS axis in endothelium and reduces specific αIIbβ3 disulfides on platelets.\",\n      \"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\",\n      \"pmids\": [\"35061532\", \"34752599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TXNDC5 selects HSF1 for proteasomal degradation not defined\", \"Surface localization mechanism for platelet ERp46 unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the surface thiol-isomerase role to coagulation by identifying FXII as a direct oxidative substrate and TMX1 as a counter-regulator of ERp46.\",\n      \"evidence\": \"Thiol labeling/MS and cysteine mutagenesis identifying FXII Cys540-Cys571, ERp46-deficient mice in venous thrombosis, and TMX1/ERp46 KO platelet reductase assays\",\n      \"pmids\": [\"41197808\", \"39247212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance of oxidase versus reductase activity at the cell surface not fully mapped\", \"Structural basis of substrate specificity for FXII vs β3 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP with domain-deletion mutants for HEV ORF3, AR Co-IP and xenografts, and CMA inhibitor experiments in trabecular meshwork cells\",\n      \"pmids\": [\"38548704\", \"25500540\", \"42012274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization requires catalytic Trx domains differs by client (ORF3 was Trx-independent)\", \"Generalizability of CMA turnover across cell types untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that fibroblast TXNDC5-TGFBR1 signaling shapes the tumor microenvironment, linking the fibrogenic axis to immunosuppression and immunotherapy response.\",\n      \"evidence\": \"Fibroblast-specific Txndc5 KO colorectal cancer model with tumor mechanics, T-cell infiltration, and PD-1 blockade combination\",\n      \"pmids\": [\"42248857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from TGFBR1 stabilization to fibroblast polarization incompletely defined\", \"Translational targeting strategy not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural model of TXNDC5-client recognition\", \"Catalytic versus chaperone contribution to client stabilization undefined\", \"Cell-surface versus ER-luminal activity partitioning unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 7, 16, 24]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 7, 16, 24]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [4, 9, 10]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 12, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [9, 12, 13, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 12, 14]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [16, 24, 25]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [9, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TGFBR1\", \"AR\", \"EDEM3\", \"HSPA8\", \"PRDX6\", \"HSPA9\", \"ITGB3\", \"F12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}