{"gene":"TXN","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1994,"finding":"ADF/TRX (human thioredoxin) is actively secreted from astrocytoma cells (U251) upon H2O2 exposure; recombinant ADF with intact reducing activity (but not a reducing-inactive mutant) promotes survival of embryonic cortical and striatal neurons in vitro and increases intracellular GSH levels, demonstrating that the neuroprotective function requires thiol-reductase activity.","method":"Conditioned medium transfer, recombinant protein addition, mutant ADF lacking reducing activity, intracellular GSH measurement","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutagenesis (reducing-inactive mutant) plus cell survival assay in single lab; two orthogonal readouts (neuron survival, GSH levels)","pmids":["7953744"],"is_preprint":false},{"year":1995,"finding":"ADF/TRX gene expression is induced by oxidative stress (UVB, H2O2) in human keratinocytes and HTLV-1+ T-cell lines at both mRNA and protein levels.","method":"Immunohistochemistry, Western blot, in situ hybridization","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal methods (IHC, Western, ISH) in single lab confirming oxidative-stress-induced TXN expression","pmids":["7797250"],"is_preprint":false},{"year":1996,"finding":"The ADF/TRX gene is transcriptionally upregulated by oxidative stress through a novel cis-acting element located between −976 and −890 in the 5′ promoter, distinct from known stress-response consensus sequences, and bound by a specific nuclear factor identified by gel mobility shift assay.","method":"CAT reporter deletion analysis, gel mobility shift assay (EMSA)","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion mapping plus EMSA in single lab; two orthogonal methods","pmids":["8759006"],"is_preprint":false},{"year":2001,"finding":"Truncated thioredoxin (Trx80, N-terminal 80 residues of TXN) acts as a mitogenic cytokine specifically on CD14+ monocytes (not B or T cells): it increases surface antigens (CD14, CD40, CD54, CD86), promotes monocyte proliferation, and induces IL-12 secretion synergistically with IL-2 to direct a Th1 immune response; full-length Trx does not have this effect.","method":"Flow cytometry, proliferation assay, ELISA for cytokines, PBMC culture with purified recombinant proteins","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (proliferation, surface markers, IL-12 secretion) with full-length vs. truncated protein comparison in single lab","pmids":["11342447"],"is_preprint":false},{"year":2002,"finding":"Mitochondria-specific TRX-2 (thioredoxin-2) is essential for cell viability: conditional TRX-2 knockout in chicken DT40 B-cells causes ROS accumulation, cytochrome c release, and activation of caspase-9 and caspase-3 (but not caspase-8), placing TRX-2 upstream of the intrinsic (mitochondrial) apoptosis pathway. Trx-2 and cytochrome c co-immunoprecipitate in vitro.","method":"Conditional gene knockout (tet-off system), ROS measurement, cytochrome c release assay, caspase activity assays, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype (ROS, cyt c, specific caspases), co-IP, multiple orthogonal methods; rigorous mechanistic dissection","pmids":["11927553"],"is_preprint":false},{"year":2003,"finding":"Trx80 mitogenic cytokine activity on PBMC (IL-12, IFN-γ induction and proliferation) is independent of its thiol oxidoreductase activity: active-site Cys→Ser double mutant (Trx80SGPS) and structural Cys72Ser mutant both retain full cytokine activity; Trx80 dimerization is non-covalent (no intermolecular disulfide).","method":"Site-directed mutagenesis of active-site cysteines, PBMC proliferation assay, ELISA for IL-12 and IFN-γ","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with functional cytokine assays, single lab but rigorous mechanistic separation of redox vs. cytokine function","pmids":["12650942"],"is_preprint":false},{"year":2004,"finding":"Trx80 induces differentiation of CD14+ monocytes into a novel cell type (TAMs) distinct from classical iDCs: TAMs show high CD14/CD1a/mannose receptor expression, increased pinocytic capacity, elevated TNF-α/IL-1β/IL-6/IL-10 secretion, and reduced allogeneic T-cell stimulation. This differentiation is mediated through phosphorylation of MAP kinases p38, ERK, and JNK by Trx80.","method":"Flow cytometry, cytokine ELISA, pinocytosis assay, allogeneic proliferation assay, Western blot for MAP kinase phosphorylation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts plus MAP kinase phosphorylation Western blot, single lab","pmids":["15494431"],"is_preprint":false},{"year":2004,"finding":"TRX and MIF (macrophage migration inhibitory factor) interact functionally: TRX-overexpressing Jurkat cells are resistant to H2O2-induced apoptosis and show reduced MIF/GIF expression, while CD4+ T cells from MIF-/- mice show elevated intracellular TRX, demonstrating a reciprocal regulatory relationship between TRX and MIF under oxidative stress.","method":"Stable transfection, flow cytometry/Western blot, MIF-/- mouse-derived T cells","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic (KO mice) plus overexpression, two orthogonal settings, single lab","pmids":["15081538"],"is_preprint":false},{"year":2006,"finding":"TRX-1 overexpression in transgenic mice suppresses IgE/antigen-stimulated histamine release from mast cells and reduces intracellular ROS generation in those cells, without affecting IL-6 or TNF-α cytokine production, indicating that TRX-1 specifically regulates ROS-dependent early signaling events in the FcεRI pathway.","method":"TRX-transgenic mouse model, histamine ELISA, intracellular ROS measurement, cytokine ELISA","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with specific mechanistic readouts (histamine vs. cytokine discrimination), single lab","pmids":["16474438"],"is_preprint":false},{"year":2008,"finding":"TRX-1 differentially regulates UV radiation effects on MMP-1 and collagen Iα1 in human dermal fibroblasts: Trx inhibits UVA-induced MMP-1 upregulation via NF-κB-dependent mechanism, and inhibits UVB- and IRA-induced collagen Iα1 reduction, but through distinct transcriptional pathways.","method":"UV irradiation of primary human fibroblasts, Trx overexpression, NF-κB pathway inhibition, gene expression analysis","journal":"Experimental gerontology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inferred from Trx overexpression plus NF-κB inhibitor, limited mechanistic depth","pmids":["18524517"],"is_preprint":false},{"year":2008,"finding":"TRX-ASK1-JNK signaling mediates cell density-dependent cigarette smoke extract (CSE) cytotoxicity in human bronchial epithelial cells: CSE activates ASK1, JNK, and p38 only in subconfluent (not confluent) cells; siRNA knockdown of JNK1/2 or JNK inhibitor attenuates CSE-induced death; TRX overexpression (Tet-on) attenuates CSE-induced cell death and JNK activation, placing TRX upstream of ASK1/JNK in this pathway.","method":"siRNA knockdown of JNK1/2, JNK/p38 pharmacological inhibitors, inducible TRX overexpression (Tet-on), Western blot for kinase activation, cell death assay","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi plus inducible overexpression plus pharmacological inhibitors, two orthogonal approaches, single lab","pmids":["18281606"],"is_preprint":false},{"year":2009,"finding":"TRX-1 physically interacts with MIF (macrophage migration inhibitory factor): BIAcore assay confirms specific TRX-MIF binding; TRX and MIF co-immunoprecipitate from ATL-2 cell lysates and supernatant; cell-surface TRX facilitates MIF internalization (blocked by anti-TRX antibody); anti-TRX antibody inhibits MIF-mediated TNF-α production from macrophages, demonstrating that cell-surface TRX acts as a component of the MIF receptor/internalization machinery.","method":"Co-immunoprecipitation, BIAcore binding assay, anti-TRX antibody blocking of MIF internalization and signaling, TNF-α ELISA","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — BIAcore (direct binding), reciprocal Co-IP, functional blocking antibody assays; multiple orthogonal methods, single lab","pmids":["19601712"],"is_preprint":false},{"year":2010,"finding":"The Nrf2/Trx axis counteracts ASK1 activation: Nrf2-deficient MEFs have undetectable Trx levels and are hypersensitive to paraquat-induced ASK1/JNK/p38 activation and cell death, while Keap1-deficient MEFs (constitutively high Trx) are more resistant; sulforaphane-induced Nrf2 activation increases Trx and protects SH-SY5Y cells, placing Trx as an effector downstream of Nrf2 that binds and inhibits ASK1.","method":"Nrf2-/- and Keap1-/- MEFs (genetic models), siRNA for ASK1, pharmacological JNK/p38 inhibitors, Western blot, cell death assay","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO MEFs), siRNA, and pharmacological inhibitors; orthogonal mechanistic approaches establishing pathway position","pmids":["20202476"],"is_preprint":false},{"year":2013,"finding":"SCO2 (a p53 target) promotes apoptosis by inducing dissociation of the TRX-ASK1 inhibitory complex and phosphorylation of ASK1 at Thr845, activating downstream MAP2K4/7 and MAP2K3/6 to trigger JNK/p38-dependent apoptosis in cancer cells.","method":"Tumor xenograft model, SCO2 overexpression, ROS measurement, Western blot for ASK1 phosphorylation and TRX-ASK1 complex dissociation, kinase assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined phosphorylation site on ASK1 (Thr845), complex dissociation assay, and downstream kinase activation; single lab","pmids":["23319048"],"is_preprint":false},{"year":2013,"finding":"TRX-1 nuclear translocation under nitrosative/oxidative stress is dependent on ERK1/2 MAP kinase activation and is controlled by TXNIP expression levels: ERK1/2 activation leads to TXNIP downregulation, which permits TRX-1 nuclear migration; MEK inhibitors (PD98059, UO126) or cytoplasmic ERK anchoring (PEA-15) prevent both TXNIP downregulation and TRX-1 nuclear translocation; TXNIP overexpression blocks nuclear TRX-1, while TXNIP silencing promotes nuclear TRX-1 even without stress.","method":"Immunofluorescence localization, MEK inhibitors, TXNIP overexpression and siRNA knockdown, ERK cytoplasmic anchor (PEA-15), TXNIP promoter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal perturbations (inhibitors, OE, KD, anchor protein), single lab","pmids":["24376827"],"is_preprint":false},{"year":2015,"finding":"Intranuclear TRX-1 enhances HIF-1α DNA-binding activity by interacting with and reducing Ref-1 (APE1), leading to upregulation of glycolysis-related proteins (PDHK1, HKII, LDHA) and contributing to hypoxia-induced drug resistance in HepG2 cells; GL-V9 reverses resistance by inhibiting TRX-1 nuclear translocation and the TRX-1/Ref-1 axis.","method":"Hypoxia drug-resistance cell model, Western blot, nuclear/cytoplasmic fractionation, HIF-1α DNA-binding assay, GL-V9 pharmacological inhibition, in vivo xenograft","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional TRX-1/Ref-1 interaction with HIF-1α DNA-binding readout, pharmacological rescue, in vivo validation; single lab","pmids":["25656992"],"is_preprint":false},{"year":2016,"finding":"TXN (TRX-1) overexpression in OxPhos-DLBCL cells curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, attenuating FOXO1 transcriptional activity toward apoptosis/cell cycle genes; TXN-depleted OxPhos cells showed greater sensitivity to ROS and doxorubicin, and FOXO1 knockdown in TXN-silenced cells reduced ROS-induced apoptosis, identifying FOXO1 as the major oxidative stress effector regulated by TXN.","method":"TXN siRNA knockdown, FOXO1 siRNA knockdown, FOXO1 acetylation assay, nuclear translocation assay, BCL6 ChIP for TXN promoter, cell death assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockdown epistasis, acetylation assay, and transcriptional readout; single lab, multiple orthogonal methods","pmids":["27132507"],"is_preprint":false},{"year":2016,"finding":"TRX-1 forms a multiprotein complex with MPK38, ASK1, SMADs, and ZPR9 that coordinately activates redox-dependent ASK1 and TGF-β signaling; adenoviral delivery of SMAD3 or ZPR9 restores downregulated ASK1 and TGF-β signaling in obese mice, improving glucose and lipid metabolism.","method":"Co-immunoprecipitation of multiprotein complex, adenoviral gene delivery in obese mouse models, metabolic phenotyping","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex plus in vivo rescue experiment; single lab","pmids":["26421442"],"is_preprint":false},{"year":2019,"finding":"FOXO1 is a direct transcriptional regulator of both TXNIP and TXN (TRX-1): chromatin immunoprecipitation identified TXNIP and TXN as direct FOXO1 transcriptional targets; FOXO1 knockin in HK-2 cells decreased TXNIP and increased TRX levels under high glucose, while FOXO1 KO had opposite effects; the protection was reversed by TRX inhibitor PX-12 or TXNIP siRNA.","method":"ChIP for FOXO1 at TXNIP and TXN loci, CRISPR/Cas9-mediated FOXO1 knockin/knockout, siRNA for TXNIP, pharmacological TRX inhibition (PX-12), transgenic mouse model","journal":"Oxidative medicine and cellular longevity","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP directly identifying TXN as FOXO1 target, combined with CRISPR KI/KO genetic models and pharmacological validation; multiple orthogonal methods","pmids":["30962862"],"is_preprint":false},{"year":2013,"finding":"TRX-1 down-regulation by the flavonoid LW-214 in MCF-7 cells releases ASK1, leading to sustained JNK phosphorylation, increased ROS, and activation of the mitochondrial apoptosis pathway (Bax/Bcl-2 ratio, ΔΨm loss, caspase-9 activation, cytochrome c release); TRX-1 overexpression attenuates LW-214-induced JNK activation and apoptosis, confirming TRX-1 as a functional inhibitor of ASK1 upstream of JNK.","method":"TRX-1 overexpression, Western blot for ASK1/JNK/apoptosis markers, ROS measurement, JNK inhibitor (SP600125), in vivo xenograft","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE rescue plus JNK inhibitor epistasis plus in vivo validation; single lab","pmids":["24374359"],"is_preprint":false},{"year":2022,"finding":"ALDH1L2 interacts with TXN (thioredoxin) and regulates downstream NF-κB signaling; decreased ALDH1L2 expression induces radioresistance in colorectal cancer cells by inhibiting ROS-mediated apoptosis, and TXN inhibitor PX-12 overcomes this radioresistance, demonstrating TXN as the functional mediator of ALDH1L2-regulated NF-κB signaling and radiation response.","method":"Co-immunoprecipitation (ALDH1L2–TXN interaction), immunofluorescence, flow cytometry, colony formation assay, PX-12 pharmacological inhibition, xenograft model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ALDH1L2–TXN complex, pharmacological inhibition, in vivo xenograft; single lab","pmids":["35597868"],"is_preprint":false},{"year":2023,"finding":"TXN is targeted by astragalus polysaccharides (APS) as the mechanistic basis for chondrocyte protection: co-immunoprecipitation and immunofluorescence demonstrated that TXN is required for APS-mediated inhibition of the ROS/ASK1/p38 MAPK apoptosis pathway; TXN silencing completely blocked the protective effects of APS on chondrocytes.","method":"Co-immunoprecipitation, immunofluorescence localization, TXN siRNA knockdown, ASK1/p38 western blot, in vivo OA model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus siRNA knockdown rescue plus in vivo validation; single lab","pmids":["38151083"],"is_preprint":false},{"year":2013,"finding":"miR-525-3p-mediated suppression of TXN1 (thioredoxin-1) is required for cell survival following ionizing radiation: luciferase reporter assays confirmed TXN1 as a direct miR-525-3p target; RNAi knockdown of TXN1 alone elevated radiosensitivity across multiple cell lines, establishing TXN1 as an essential pro-survival effector in the radiation response.","method":"Luciferase reporter assay (direct target validation), RNAi knockdown, miR-525-3p overexpression/inhibition, proteomic identification of targets, multi-cell-line validation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter (direct target), RNAi functional validation, replicated across multiple cell lines; single lab","pmids":["24147004"],"is_preprint":false},{"year":2018,"finding":"TRX-1 overexpression in an MPTP mouse model of Parkinson's disease ameliorates learning and memory deficits via the dopamine D1 receptor/NMDAR-ERK1/2-CREB pathway: Trx-1 transgenic mice showed restored TH and D1R expression, increased NR2B, and elevated p-ERK1/2 and p-CREB in the hippocampus compared to wild-type MPTP-treated mice.","method":"Trx-1 transgenic mouse model, Morris water maze, elevated plus-maze, Western blot for TH, D1R, NR2B, p-ERK1/2, p-CREB","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with behavioral and molecular pathway readouts; single lab","pmids":["29960099"],"is_preprint":false},{"year":2023,"finding":"TxN (thioredoxin) synthesis is linked to BCAA catabolism in glioblastoma: glutamate produced by BCAA catabolism (via BCAT1) participates in antioxidant TxN production; nuclear translocation of LDHA promotes DOT1L-mediated H3K79 hypermethylation and enhanced BCAT1/BCAA catabolism under ROS accumulation, establishing a metabolic pathway linking BCAA catabolism to TxN-mediated redox balance in GBM.","method":"Orthotopic xenograft model, BCAT1 inhibition, nuclear LDHA fractionation, H3K79 methylation ChIP, ROS measurement, glutamate/TxN quantification","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — metabolic pathway linkage inferred from multiple perturbations but TxN synthesis step not directly reconstituted; single lab","pmids":["37298317"],"is_preprint":false}],"current_model":"TXN (thioredoxin-1/TRX) is a 12-kDa redox-active dithiol protein whose canonical function is to reduce protein disulfides via its CGPC active site; it acts as an antioxidant and anti-apoptotic factor by binding and inhibiting ASK1 (releasing it upon oxidation to activate JNK/p38-dependent apoptosis), undergoes ERK1/2-dependent nuclear translocation regulated by TXNIP, promotes HIF-1α activity in the nucleus via reduction of Ref-1, and modulates immune signaling through direct interaction with MIF on the cell surface; its truncated form Trx80 functions as a redox-independent cytokine that activates monocytes via MAP kinase (p38/ERK/JNK) signaling; TXN expression is transcriptionally induced by oxidative stress through a novel promoter element, and is directly regulated by FOXO1 (ChIP-confirmed) and Nrf2."},"narrative":{"mechanistic_narrative":"TXN (thioredoxin-1) is a redox-active dithiol protein that functions as a central antioxidant and pro-survival regulator, coupling cellular thiol-reduction capacity to stress-signaling and apoptotic decisions [PMID:7953744, PMID:20202476]. Its best-defined mechanism is binding and inhibition of the apoptosis signal-regulating kinase ASK1: under basal conditions TXN holds ASK1 in an inactive inhibitory complex, and conditions that dissociate or deplete TXN release ASK1 to drive JNK/p38-dependent mitochondrial apoptosis [PMID:20202476, PMID:23319048, PMID:24374359]. This ASK1/JNK-p38 axis recurs across diverse stress settings, where TXN overexpression suppresses kinase activation and cell death and TXN loss sensitizes cells [PMID:18281606, PMID:38151083]. TXN acts as a downstream effector of the Nrf2 antioxidant program, with Nrf2-deficient cells losing TXN and becoming hypersensitive to ASK1/JNK/p38 activation [PMID:20202476], and it is a direct transcriptional target of FOXO1, which coordinately reciprocally regulates TXN and its inhibitor TXNIP [PMID:30962862]. TXN itself feeds back on FOXO1 by limiting p300-mediated FOXO1 acetylation and nuclear translocation, identifying FOXO1 as a major oxidative-stress effector controlled by TXN [PMID:27132507]. TXN expression is transcriptionally induced by oxidative stress (UVB, H2O2) through a novel cis-acting promoter element bound by a specific nuclear factor [PMID:7797250, PMID:8759006]. Beyond the cytoplasm, TXN undergoes ERK1/2-dependent, TXNIP-gated nuclear translocation [PMID:24376827], where it enhances HIF-1α DNA-binding activity by reducing Ref-1/APE1 to promote glycolytic gene expression and drug resistance [PMID:25656992]. At the cell surface TXN physically binds MIF and functions as a component of the MIF internalization/receptor machinery required for MIF-mediated TNF-α production [PMID:19601712]. A truncated form, Trx80 (N-terminal 80 residues), acts as a redox-independent cytokine on CD14+ monocytes, driving their proliferation, IL-12 secretion, and differentiation through p38/ERK/JNK MAP-kinase signaling [PMID:11342447, PMID:12650942, PMID:15494431]. Distinct mitochondrial thioredoxin-2 is essential for viability, acting upstream of cytochrome c release and the intrinsic caspase-9/-3 apoptotic cascade [PMID:11927553].","teleology":[{"year":1994,"claim":"Established that thioredoxin's neuroprotective and GSH-promoting actions require its enzymatic thiol-reductase activity, distinguishing a redox-dependent extracellular function.","evidence":"Conditioned-medium transfer and recombinant ADF/TRX addition with a reducing-inactive mutant, plus neuron survival and intracellular GSH assays","pmids":["7953744"],"confidence":"Medium","gaps":["Molecular receptor or uptake route for secreted TRX not defined","In vivo neuroprotection not tested"]},{"year":1996,"claim":"Defined how oxidative stress induces TXN at the transcriptional level by mapping a novel cis-acting promoter element distinct from known stress consensus sequences.","evidence":"CAT reporter deletion analysis and EMSA in human cells","pmids":["8759006","7797250"],"confidence":"Medium","gaps":["The specific binding transcription factor was not molecularly identified","Element's relationship to later-defined Nrf2/FOXO1 regulation unresolved"]},{"year":2002,"claim":"Showed the mitochondrial thioredoxin paralog is essential for viability and gates the intrinsic apoptotic pathway, situating thioredoxin upstream of cytochrome c release.","evidence":"Conditional TRX-2 knockout in DT40 cells with ROS, cytochrome c release, caspase assays, and co-IP","pmids":["11927553"],"confidence":"High","gaps":["This concerns the mitochondrial TRX-2 paralog, not cytoplasmic TXN/TRX-1","Direct molecular target of TRX-2 in the cascade not identified"]},{"year":2004,"claim":"Identified a redox-independent cytokine role for the truncated Trx80 fragment in monocyte activation and differentiation via MAP-kinase signaling.","evidence":"Active-site Cys→Ser mutagenesis, PBMC proliferation/cytokine ELISA, flow cytometry, and MAP-kinase phosphorylation Western blot","pmids":["11342447","12650942","15494431"],"confidence":"High","gaps":["The Trx80 cell-surface receptor is unidentified","Protease generating Trx80 in vivo unknown"]},{"year":2009,"claim":"Demonstrated a direct physical TRX-MIF interaction and that cell-surface TRX serves as part of the MIF internalization/receptor machinery driving inflammatory cytokine output.","evidence":"BIAcore binding, reciprocal co-IP, and anti-TRX antibody blocking of MIF internalization and TNF-α production","pmids":["19601712","15081538"],"confidence":"High","gaps":["Stoichiometry and structural basis of the TRX-MIF complex not defined","How surface TRX is presented and retained is unclear"]},{"year":2013,"claim":"Consolidated the TRX-ASK1 inhibitory complex as the redox switch for apoptosis, showing complex dissociation and ASK1 Thr845 phosphorylation activate JNK/p38 death signaling.","evidence":"SCO2 and pharmacological/flavonoid perturbations with ASK1 complex-dissociation and phospho-ASK1 assays, kinase assays, and xenografts","pmids":["23319048","24374359","18281606"],"confidence":"Medium","gaps":["Direct redox chemistry of the TRX-ASK1 disulfide handoff not reconstituted here","Quantitative threshold of oxidation triggering release undefined"]},{"year":2015,"claim":"Revealed a nuclear function whereby TRX-1, after ERK1/2- and TXNIP-gated translocation, reduces Ref-1/APE1 to enhance HIF-1α DNA binding and glycolytic gene expression.","evidence":"Immunofluorescence, nuclear/cytoplasmic fractionation, TXNIP overexpression/knockdown, MEK inhibitors, HIF-1α DNA-binding assay, and xenografts","pmids":["24376827","25656992"],"confidence":"Medium","gaps":["Nuclear import mechanism / NLS of TRX-1 not defined","Direct evidence that Ref-1 reduction is rate-limiting for HIF-1α not isolated"]},{"year":2016,"claim":"Positioned TXN within a feedback loop with FOXO1, showing TXN restrains p300-mediated FOXO1 acetylation/nuclear translocation while FOXO1 directly transcribes TXN and TXNIP.","evidence":"Double siRNA epistasis, FOXO1 acetylation/translocation assays, ChIP for FOXO1 at TXN/TXNIP loci, CRISPR knockin/knockout, and PX-12","pmids":["27132507","30962862"],"confidence":"High","gaps":["Whether TXN acts on FOXO1 via direct disulfide reduction not shown","Tissue specificity of the FOXO1-TXN-TXNIP loop incompletely mapped"]},{"year":2016,"claim":"Extended TRX-1 into multiprotein signaling assemblies coupling redox-dependent ASK1 and TGF-β pathways relevant to metabolic regulation.","evidence":"Co-IP of a TRX-1/MPK38/ASK1/SMAD/ZPR9 complex plus adenoviral rescue in obese mice","pmids":["26421442"],"confidence":"Medium","gaps":["Direct binary contacts within the complex not resolved","Single Co-IP-based complex without structural validation"]},{"year":2023,"claim":"Generalized TXN as the convergent effector of multiple upstream regulators (ALDH1L2, miRNA, polysaccharide, metabolic inputs) controlling ROS/ASK1-dependent survival and therapy resistance.","evidence":"Co-IP, siRNA/RNAi knockdown, luciferase reporter, PX-12 inhibition, and in vivo cancer/OA/PD models","pmids":["35597868","24147004","38151083","29960099","37298317"],"confidence":"Medium","gaps":["These are largely correlative or single-lab pathway placements","Direct enzymatic substrates for most contexts not biochemically defined"]},{"year":null,"claim":"The molecular identity of the surface receptors for full-length TRX and Trx80, the structural basis of the TRX-ASK1 redox handoff, and the import machinery for nuclear TRX-1 remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No receptor identified for secreted TRX or Trx80","No structural model of TRX-ASK1 or TRX-MIF complexes","Nuclear translocation machinery uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,12]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[8,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,13,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,13,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,14,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,11,6]}],"complexes":["TRX-ASK1 inhibitory complex","TRX-1/MPK38/ASK1/SMAD/ZPR9 complex"],"partners":["ASK1","MIF","TXNIP","APEX1","FOXO1","ALDH1L2","MPK38","ZPR9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10599","full_name":"Thioredoxin","aliases":["ATL-derived factor","ADF","Surface-associated sulphydryl protein","SASP"],"length_aa":105,"mass_kda":11.7,"function":"Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (PubMed:17182577, PubMed:19032234, PubMed:2176490). Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity (PubMed:16408020, PubMed:17606900). Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (PubMed:11118054, PubMed:9108029) ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55)","subcellular_location":"Nucleus; Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/P10599/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TXN","classification":"Common Essential","n_dependent_lines":1168,"n_total_lines":1208,"dependency_fraction":0.9668874172185431},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPC","stoichiometry":10.0},{"gene":"SNRPF","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TXN","total_profiled":1310},"omim":[{"mim_id":"621349","title":"PEROXIREDOXIN-LIKE 2B; 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thioredoxin.","date":"2013","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24316195","citation_count":19,"is_preprint":false},{"pmid":"26932791","id":"PMC_26932791","title":"Ischemic postconditioning confers cardioprotection and prevents reduction of Trx-1 in young mice, but not in middle-aged and old mice.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26932791","citation_count":19,"is_preprint":false},{"pmid":"11976948","id":"PMC_11976948","title":"A new family of cyclophilins with an RNA recognition motif that interact with members of the trx/MLL protein family in Drosophila and human cells.","date":"2002","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/11976948","citation_count":19,"is_preprint":false},{"pmid":"21304598","id":"PMC_21304598","title":"The thioredoxin TRX-1 modulates the function of the insulin-like neuropeptide DAF-28 during dauer formation in Caenorhabditis elegans.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21304598","citation_count":18,"is_preprint":false},{"pmid":"26421442","id":"PMC_26421442","title":"Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice.","date":"2016","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/26421442","citation_count":18,"is_preprint":false},{"pmid":"9170166","id":"PMC_9170166","title":"The effect of ultraviolet B induced adult T cell leukemia-derived factor/thioredoxin (ADF/TRX) on survival and growth of human melanocytes.","date":"1997","source":"Pigment cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9170166","citation_count":18,"is_preprint":false},{"pmid":"30090331","id":"PMC_30090331","title":"Sodium tanshinone IIA sulfonate suppresses pulmonary fibroblast proliferation and activation induced by silica: role of the Nrf2/Trx pathway.","date":"2015","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/30090331","citation_count":18,"is_preprint":false},{"pmid":"33275238","id":"PMC_33275238","title":"Relationships between diabetic nephropathy and insulin resistance, inflammation, Trx, Txnip, CysC and serum complement levels.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33275238","citation_count":17,"is_preprint":false},{"pmid":"26920757","id":"PMC_26920757","title":"TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans.","date":"2016","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26920757","citation_count":17,"is_preprint":false},{"pmid":"12033447","id":"PMC_12033447","title":"Redox regulation of stress signals: possible roles of dendritic stellate TRX producer cells (DST cell types).","date":"2002","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12033447","citation_count":17,"is_preprint":false},{"pmid":"17406940","id":"PMC_17406940","title":"Investigation of TXNIP (thioredoxin-interacting protein) and TRX (thioredoxin) genes for growth-related traits in pigs.","date":"2007","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/17406940","citation_count":16,"is_preprint":false},{"pmid":"24223778","id":"PMC_24223778","title":"Infusion of Trx-1-overexpressing hucMSC prolongs the survival of acutely irradiated NOD/SCID mice by decreasing excessive inflammatory injury.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24223778","citation_count":16,"is_preprint":false},{"pmid":"27177199","id":"PMC_27177199","title":"Protective function of pyridoxamine on retinal photoreceptor cells via activation of the p‑Erk1/2/Nrf2/Trx/ASK1 signalling pathway in diabetic mice.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27177199","citation_count":16,"is_preprint":false},{"pmid":"17447898","id":"PMC_17447898","title":"Expression and extracellular release of Trx80, the truncated form of thioredoxin, by TNF-alpha- and IL-1beta-stimulated human synoviocytes from patients with rheumatoid arthritis.","date":"2007","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/17447898","citation_count":15,"is_preprint":false},{"pmid":"27894668","id":"PMC_27894668","title":"Txn1, Ctsd and Cdk4 are key proteins of combination therapy with taurine, epigallocatechin gallate and genistein against liver fibrosis in rats.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27894668","citation_count":15,"is_preprint":false},{"pmid":"37298317","id":"PMC_37298317","title":"Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37298317","citation_count":15,"is_preprint":false},{"pmid":"27779244","id":"PMC_27779244","title":"Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy.","date":"2016","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/27779244","citation_count":15,"is_preprint":false},{"pmid":"37993958","id":"PMC_37993958","title":"Irisin suppresses pancreatic β cell pyroptosis in T2DM by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis.","date":"2023","source":"Diabetology & metabolic syndrome","url":"https://pubmed.ncbi.nlm.nih.gov/37993958","citation_count":15,"is_preprint":false},{"pmid":"37944440","id":"PMC_37944440","title":"TrxR/Trx inhibitor butaselen ameliorates pulmonary fibrosis by suppressing NF-κB/TGF-β1/Smads signaling.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37944440","citation_count":15,"is_preprint":false},{"pmid":"31971015","id":"PMC_31971015","title":"Neuroprotective effects of notoginsenoside R1 by upregulating Trx-1 on acrylamide-induced neurotoxicity in PC12.","date":"2020","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31971015","citation_count":15,"is_preprint":false},{"pmid":"32081809","id":"PMC_32081809","title":"Molecular and functional explication of thioredoxin mitochondrial-like protein (Trx-2) from big-belly seahorse (Hippocampus abdominalis) and expression upon immune provocation.","date":"2020","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32081809","citation_count":14,"is_preprint":false},{"pmid":"15670842","id":"PMC_15670842","title":"Synergistic action of MLL, a TRX protein with template activating factor-I, a histone chaperone.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15670842","citation_count":14,"is_preprint":false},{"pmid":"21380518","id":"PMC_21380518","title":"Functional characterization of the recombinant antimicrobial peptide Trx-Ace-AMP1 and its application on the control of tomato early blight disease.","date":"2011","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21380518","citation_count":14,"is_preprint":false},{"pmid":"24147004","id":"PMC_24147004","title":"Cell survival following radiation exposure requires miR-525-3p mediated suppression of ARRB1 and TXN1.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24147004","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53554,"output_tokens":6891,"usd":0.132014,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15843,"output_tokens":4203,"usd":0.092145,"stage2_stop_reason":"end_turn"},"total_usd":0.224159,"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\": 1994,\n      \"finding\": \"ADF/TRX (human thioredoxin) is actively secreted from astrocytoma cells (U251) upon H2O2 exposure; recombinant ADF with intact reducing activity (but not a reducing-inactive mutant) promotes survival of embryonic cortical and striatal neurons in vitro and increases intracellular GSH levels, demonstrating that the neuroprotective function requires thiol-reductase activity.\",\n      \"method\": \"Conditioned medium transfer, recombinant protein addition, mutant ADF lacking reducing activity, intracellular GSH measurement\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutagenesis (reducing-inactive mutant) plus cell survival assay in single lab; two orthogonal readouts (neuron survival, GSH levels)\",\n      \"pmids\": [\"7953744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ADF/TRX gene expression is induced by oxidative stress (UVB, H2O2) in human keratinocytes and HTLV-1+ T-cell lines at both mRNA and protein levels.\",\n      \"method\": \"Immunohistochemistry, Western blot, in situ hybridization\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal methods (IHC, Western, ISH) in single lab confirming oxidative-stress-induced TXN expression\",\n      \"pmids\": [\"7797250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The ADF/TRX gene is transcriptionally upregulated by oxidative stress through a novel cis-acting element located between −976 and −890 in the 5′ promoter, distinct from known stress-response consensus sequences, and bound by a specific nuclear factor identified by gel mobility shift assay.\",\n      \"method\": \"CAT reporter deletion analysis, gel mobility shift assay (EMSA)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion mapping plus EMSA in single lab; two orthogonal methods\",\n      \"pmids\": [\"8759006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Truncated thioredoxin (Trx80, N-terminal 80 residues of TXN) acts as a mitogenic cytokine specifically on CD14+ monocytes (not B or T cells): it increases surface antigens (CD14, CD40, CD54, CD86), promotes monocyte proliferation, and induces IL-12 secretion synergistically with IL-2 to direct a Th1 immune response; full-length Trx does not have this effect.\",\n      \"method\": \"Flow cytometry, proliferation assay, ELISA for cytokines, PBMC culture with purified recombinant proteins\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (proliferation, surface markers, IL-12 secretion) with full-length vs. truncated protein comparison in single lab\",\n      \"pmids\": [\"11342447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mitochondria-specific TRX-2 (thioredoxin-2) is essential for cell viability: conditional TRX-2 knockout in chicken DT40 B-cells causes ROS accumulation, cytochrome c release, and activation of caspase-9 and caspase-3 (but not caspase-8), placing TRX-2 upstream of the intrinsic (mitochondrial) apoptosis pathway. Trx-2 and cytochrome c co-immunoprecipitate in vitro.\",\n      \"method\": \"Conditional gene knockout (tet-off system), ROS measurement, cytochrome c release assay, caspase activity assays, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular phenotype (ROS, cyt c, specific caspases), co-IP, multiple orthogonal methods; rigorous mechanistic dissection\",\n      \"pmids\": [\"11927553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Trx80 mitogenic cytokine activity on PBMC (IL-12, IFN-γ induction and proliferation) is independent of its thiol oxidoreductase activity: active-site Cys→Ser double mutant (Trx80SGPS) and structural Cys72Ser mutant both retain full cytokine activity; Trx80 dimerization is non-covalent (no intermolecular disulfide).\",\n      \"method\": \"Site-directed mutagenesis of active-site cysteines, PBMC proliferation assay, ELISA for IL-12 and IFN-γ\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with functional cytokine assays, single lab but rigorous mechanistic separation of redox vs. cytokine function\",\n      \"pmids\": [\"12650942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Trx80 induces differentiation of CD14+ monocytes into a novel cell type (TAMs) distinct from classical iDCs: TAMs show high CD14/CD1a/mannose receptor expression, increased pinocytic capacity, elevated TNF-α/IL-1β/IL-6/IL-10 secretion, and reduced allogeneic T-cell stimulation. This differentiation is mediated through phosphorylation of MAP kinases p38, ERK, and JNK by Trx80.\",\n      \"method\": \"Flow cytometry, cytokine ELISA, pinocytosis assay, allogeneic proliferation assay, Western blot for MAP kinase phosphorylation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts plus MAP kinase phosphorylation Western blot, single lab\",\n      \"pmids\": [\"15494431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRX and MIF (macrophage migration inhibitory factor) interact functionally: TRX-overexpressing Jurkat cells are resistant to H2O2-induced apoptosis and show reduced MIF/GIF expression, while CD4+ T cells from MIF-/- mice show elevated intracellular TRX, demonstrating a reciprocal regulatory relationship between TRX and MIF under oxidative stress.\",\n      \"method\": \"Stable transfection, flow cytometry/Western blot, MIF-/- mouse-derived T cells\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic (KO mice) plus overexpression, two orthogonal settings, single lab\",\n      \"pmids\": [\"15081538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRX-1 overexpression in transgenic mice suppresses IgE/antigen-stimulated histamine release from mast cells and reduces intracellular ROS generation in those cells, without affecting IL-6 or TNF-α cytokine production, indicating that TRX-1 specifically regulates ROS-dependent early signaling events in the FcεRI pathway.\",\n      \"method\": \"TRX-transgenic mouse model, histamine ELISA, intracellular ROS measurement, cytokine ELISA\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with specific mechanistic readouts (histamine vs. cytokine discrimination), single lab\",\n      \"pmids\": [\"16474438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRX-1 differentially regulates UV radiation effects on MMP-1 and collagen Iα1 in human dermal fibroblasts: Trx inhibits UVA-induced MMP-1 upregulation via NF-κB-dependent mechanism, and inhibits UVB- and IRA-induced collagen Iα1 reduction, but through distinct transcriptional pathways.\",\n      \"method\": \"UV irradiation of primary human fibroblasts, Trx overexpression, NF-κB pathway inhibition, gene expression analysis\",\n      \"journal\": \"Experimental gerontology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inferred from Trx overexpression plus NF-κB inhibitor, limited mechanistic depth\",\n      \"pmids\": [\"18524517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRX-ASK1-JNK signaling mediates cell density-dependent cigarette smoke extract (CSE) cytotoxicity in human bronchial epithelial cells: CSE activates ASK1, JNK, and p38 only in subconfluent (not confluent) cells; siRNA knockdown of JNK1/2 or JNK inhibitor attenuates CSE-induced death; TRX overexpression (Tet-on) attenuates CSE-induced cell death and JNK activation, placing TRX upstream of ASK1/JNK in this pathway.\",\n      \"method\": \"siRNA knockdown of JNK1/2, JNK/p38 pharmacological inhibitors, inducible TRX overexpression (Tet-on), Western blot for kinase activation, cell death assay\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi plus inducible overexpression plus pharmacological inhibitors, two orthogonal approaches, single lab\",\n      \"pmids\": [\"18281606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRX-1 physically interacts with MIF (macrophage migration inhibitory factor): BIAcore assay confirms specific TRX-MIF binding; TRX and MIF co-immunoprecipitate from ATL-2 cell lysates and supernatant; cell-surface TRX facilitates MIF internalization (blocked by anti-TRX antibody); anti-TRX antibody inhibits MIF-mediated TNF-α production from macrophages, demonstrating that cell-surface TRX acts as a component of the MIF receptor/internalization machinery.\",\n      \"method\": \"Co-immunoprecipitation, BIAcore binding assay, anti-TRX antibody blocking of MIF internalization and signaling, TNF-α ELISA\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — BIAcore (direct binding), reciprocal Co-IP, functional blocking antibody assays; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19601712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Nrf2/Trx axis counteracts ASK1 activation: Nrf2-deficient MEFs have undetectable Trx levels and are hypersensitive to paraquat-induced ASK1/JNK/p38 activation and cell death, while Keap1-deficient MEFs (constitutively high Trx) are more resistant; sulforaphane-induced Nrf2 activation increases Trx and protects SH-SY5Y cells, placing Trx as an effector downstream of Nrf2 that binds and inhibits ASK1.\",\n      \"method\": \"Nrf2-/- and Keap1-/- MEFs (genetic models), siRNA for ASK1, pharmacological JNK/p38 inhibitors, Western blot, cell death assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO MEFs), siRNA, and pharmacological inhibitors; orthogonal mechanistic approaches establishing pathway position\",\n      \"pmids\": [\"20202476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCO2 (a p53 target) promotes apoptosis by inducing dissociation of the TRX-ASK1 inhibitory complex and phosphorylation of ASK1 at Thr845, activating downstream MAP2K4/7 and MAP2K3/6 to trigger JNK/p38-dependent apoptosis in cancer cells.\",\n      \"method\": \"Tumor xenograft model, SCO2 overexpression, ROS measurement, Western blot for ASK1 phosphorylation and TRX-ASK1 complex dissociation, kinase assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined phosphorylation site on ASK1 (Thr845), complex dissociation assay, and downstream kinase activation; single lab\",\n      \"pmids\": [\"23319048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRX-1 nuclear translocation under nitrosative/oxidative stress is dependent on ERK1/2 MAP kinase activation and is controlled by TXNIP expression levels: ERK1/2 activation leads to TXNIP downregulation, which permits TRX-1 nuclear migration; MEK inhibitors (PD98059, UO126) or cytoplasmic ERK anchoring (PEA-15) prevent both TXNIP downregulation and TRX-1 nuclear translocation; TXNIP overexpression blocks nuclear TRX-1, while TXNIP silencing promotes nuclear TRX-1 even without stress.\",\n      \"method\": \"Immunofluorescence localization, MEK inhibitors, TXNIP overexpression and siRNA knockdown, ERK cytoplasmic anchor (PEA-15), TXNIP promoter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal perturbations (inhibitors, OE, KD, anchor protein), single lab\",\n      \"pmids\": [\"24376827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intranuclear TRX-1 enhances HIF-1α DNA-binding activity by interacting with and reducing Ref-1 (APE1), leading to upregulation of glycolysis-related proteins (PDHK1, HKII, LDHA) and contributing to hypoxia-induced drug resistance in HepG2 cells; GL-V9 reverses resistance by inhibiting TRX-1 nuclear translocation and the TRX-1/Ref-1 axis.\",\n      \"method\": \"Hypoxia drug-resistance cell model, Western blot, nuclear/cytoplasmic fractionation, HIF-1α DNA-binding assay, GL-V9 pharmacological inhibition, in vivo xenograft\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional TRX-1/Ref-1 interaction with HIF-1α DNA-binding readout, pharmacological rescue, in vivo validation; single lab\",\n      \"pmids\": [\"25656992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TXN (TRX-1) overexpression in OxPhos-DLBCL cells curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, attenuating FOXO1 transcriptional activity toward apoptosis/cell cycle genes; TXN-depleted OxPhos cells showed greater sensitivity to ROS and doxorubicin, and FOXO1 knockdown in TXN-silenced cells reduced ROS-induced apoptosis, identifying FOXO1 as the major oxidative stress effector regulated by TXN.\",\n      \"method\": \"TXN siRNA knockdown, FOXO1 siRNA knockdown, FOXO1 acetylation assay, nuclear translocation assay, BCL6 ChIP for TXN promoter, cell death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockdown epistasis, acetylation assay, and transcriptional readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27132507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRX-1 forms a multiprotein complex with MPK38, ASK1, SMADs, and ZPR9 that coordinately activates redox-dependent ASK1 and TGF-β signaling; adenoviral delivery of SMAD3 or ZPR9 restores downregulated ASK1 and TGF-β signaling in obese mice, improving glucose and lipid metabolism.\",\n      \"method\": \"Co-immunoprecipitation of multiprotein complex, adenoviral gene delivery in obese mouse models, metabolic phenotyping\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex plus in vivo rescue experiment; single lab\",\n      \"pmids\": [\"26421442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXO1 is a direct transcriptional regulator of both TXNIP and TXN (TRX-1): chromatin immunoprecipitation identified TXNIP and TXN as direct FOXO1 transcriptional targets; FOXO1 knockin in HK-2 cells decreased TXNIP and increased TRX levels under high glucose, while FOXO1 KO had opposite effects; the protection was reversed by TRX inhibitor PX-12 or TXNIP siRNA.\",\n      \"method\": \"ChIP for FOXO1 at TXNIP and TXN loci, CRISPR/Cas9-mediated FOXO1 knockin/knockout, siRNA for TXNIP, pharmacological TRX inhibition (PX-12), transgenic mouse model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP directly identifying TXN as FOXO1 target, combined with CRISPR KI/KO genetic models and pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"30962862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRX-1 down-regulation by the flavonoid LW-214 in MCF-7 cells releases ASK1, leading to sustained JNK phosphorylation, increased ROS, and activation of the mitochondrial apoptosis pathway (Bax/Bcl-2 ratio, ΔΨm loss, caspase-9 activation, cytochrome c release); TRX-1 overexpression attenuates LW-214-induced JNK activation and apoptosis, confirming TRX-1 as a functional inhibitor of ASK1 upstream of JNK.\",\n      \"method\": \"TRX-1 overexpression, Western blot for ASK1/JNK/apoptosis markers, ROS measurement, JNK inhibitor (SP600125), in vivo xenograft\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE rescue plus JNK inhibitor epistasis plus in vivo validation; single lab\",\n      \"pmids\": [\"24374359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALDH1L2 interacts with TXN (thioredoxin) and regulates downstream NF-κB signaling; decreased ALDH1L2 expression induces radioresistance in colorectal cancer cells by inhibiting ROS-mediated apoptosis, and TXN inhibitor PX-12 overcomes this radioresistance, demonstrating TXN as the functional mediator of ALDH1L2-regulated NF-κB signaling and radiation response.\",\n      \"method\": \"Co-immunoprecipitation (ALDH1L2–TXN interaction), immunofluorescence, flow cytometry, colony formation assay, PX-12 pharmacological inhibition, xenograft model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ALDH1L2–TXN complex, pharmacological inhibition, in vivo xenograft; single lab\",\n      \"pmids\": [\"35597868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TXN is targeted by astragalus polysaccharides (APS) as the mechanistic basis for chondrocyte protection: co-immunoprecipitation and immunofluorescence demonstrated that TXN is required for APS-mediated inhibition of the ROS/ASK1/p38 MAPK apoptosis pathway; TXN silencing completely blocked the protective effects of APS on chondrocytes.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, TXN siRNA knockdown, ASK1/p38 western blot, in vivo OA model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus siRNA knockdown rescue plus in vivo validation; single lab\",\n      \"pmids\": [\"38151083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-525-3p-mediated suppression of TXN1 (thioredoxin-1) is required for cell survival following ionizing radiation: luciferase reporter assays confirmed TXN1 as a direct miR-525-3p target; RNAi knockdown of TXN1 alone elevated radiosensitivity across multiple cell lines, establishing TXN1 as an essential pro-survival effector in the radiation response.\",\n      \"method\": \"Luciferase reporter assay (direct target validation), RNAi knockdown, miR-525-3p overexpression/inhibition, proteomic identification of targets, multi-cell-line validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter (direct target), RNAi functional validation, replicated across multiple cell lines; single lab\",\n      \"pmids\": [\"24147004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRX-1 overexpression in an MPTP mouse model of Parkinson's disease ameliorates learning and memory deficits via the dopamine D1 receptor/NMDAR-ERK1/2-CREB pathway: Trx-1 transgenic mice showed restored TH and D1R expression, increased NR2B, and elevated p-ERK1/2 and p-CREB in the hippocampus compared to wild-type MPTP-treated mice.\",\n      \"method\": \"Trx-1 transgenic mouse model, Morris water maze, elevated plus-maze, Western blot for TH, D1R, NR2B, p-ERK1/2, p-CREB\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with behavioral and molecular pathway readouts; single lab\",\n      \"pmids\": [\"29960099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TxN (thioredoxin) synthesis is linked to BCAA catabolism in glioblastoma: glutamate produced by BCAA catabolism (via BCAT1) participates in antioxidant TxN production; nuclear translocation of LDHA promotes DOT1L-mediated H3K79 hypermethylation and enhanced BCAT1/BCAA catabolism under ROS accumulation, establishing a metabolic pathway linking BCAA catabolism to TxN-mediated redox balance in GBM.\",\n      \"method\": \"Orthotopic xenograft model, BCAT1 inhibition, nuclear LDHA fractionation, H3K79 methylation ChIP, ROS measurement, glutamate/TxN quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — metabolic pathway linkage inferred from multiple perturbations but TxN synthesis step not directly reconstituted; single lab\",\n      \"pmids\": [\"37298317\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TXN (thioredoxin-1/TRX) is a 12-kDa redox-active dithiol protein whose canonical function is to reduce protein disulfides via its CGPC active site; it acts as an antioxidant and anti-apoptotic factor by binding and inhibiting ASK1 (releasing it upon oxidation to activate JNK/p38-dependent apoptosis), undergoes ERK1/2-dependent nuclear translocation regulated by TXNIP, promotes HIF-1α activity in the nucleus via reduction of Ref-1, and modulates immune signaling through direct interaction with MIF on the cell surface; its truncated form Trx80 functions as a redox-independent cytokine that activates monocytes via MAP kinase (p38/ERK/JNK) signaling; TXN expression is transcriptionally induced by oxidative stress through a novel promoter element, and is directly regulated by FOXO1 (ChIP-confirmed) and Nrf2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TXN (thioredoxin-1) is a redox-active dithiol protein that functions as a central antioxidant and pro-survival regulator, coupling cellular thiol-reduction capacity to stress-signaling and apoptotic decisions [#0, #12]. Its best-defined mechanism is binding and inhibition of the apoptosis signal-regulating kinase ASK1: under basal conditions TXN holds ASK1 in an inactive inhibitory complex, and conditions that dissociate or deplete TXN release ASK1 to drive JNK/p38-dependent mitochondrial apoptosis [#12, #13, #19]. This ASK1/JNK-p38 axis recurs across diverse stress settings, where TXN overexpression suppresses kinase activation and cell death and TXN loss sensitizes cells [#10, #21]. TXN acts as a downstream effector of the Nrf2 antioxidant program, with Nrf2-deficient cells losing TXN and becoming hypersensitive to ASK1/JNK/p38 activation [#12], and it is a direct transcriptional target of FOXO1, which coordinately reciprocally regulates TXN and its inhibitor TXNIP [#18]. TXN itself feeds back on FOXO1 by limiting p300-mediated FOXO1 acetylation and nuclear translocation, identifying FOXO1 as a major oxidative-stress effector controlled by TXN [#16]. TXN expression is transcriptionally induced by oxidative stress (UVB, H2O2) through a novel cis-acting promoter element bound by a specific nuclear factor [#1, #2]. Beyond the cytoplasm, TXN undergoes ERK1/2-dependent, TXNIP-gated nuclear translocation [#14], where it enhances HIF-1\\u03b1 DNA-binding activity by reducing Ref-1/APE1 to promote glycolytic gene expression and drug resistance [#15]. At the cell surface TXN physically binds MIF and functions as a component of the MIF internalization/receptor machinery required for MIF-mediated TNF-\\u03b1 production [#11]. A truncated form, Trx80 (N-terminal 80 residues), acts as a redox-independent cytokine on CD14+ monocytes, driving their proliferation, IL-12 secretion, and differentiation through p38/ERK/JNK MAP-kinase signaling [#3, #5, #6]. Distinct mitochondrial thioredoxin-2 is essential for viability, acting upstream of cytochrome c release and the intrinsic caspase-9/-3 apoptotic cascade [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that thioredoxin's neuroprotective and GSH-promoting actions require its enzymatic thiol-reductase activity, distinguishing a redox-dependent extracellular function.\",\n      \"evidence\": \"Conditioned-medium transfer and recombinant ADF/TRX addition with a reducing-inactive mutant, plus neuron survival and intracellular GSH assays\",\n      \"pmids\": [\"7953744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular receptor or uptake route for secreted TRX not defined\", \"In vivo neuroprotection not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined how oxidative stress induces TXN at the transcriptional level by mapping a novel cis-acting promoter element distinct from known stress consensus sequences.\",\n      \"evidence\": \"CAT reporter deletion analysis and EMSA in human cells\",\n      \"pmids\": [\"8759006\", \"7797250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific binding transcription factor was not molecularly identified\", \"Element's relationship to later-defined Nrf2/FOXO1 regulation unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed the mitochondrial thioredoxin paralog is essential for viability and gates the intrinsic apoptotic pathway, situating thioredoxin upstream of cytochrome c release.\",\n      \"evidence\": \"Conditional TRX-2 knockout in DT40 cells with ROS, cytochrome c release, caspase assays, and co-IP\",\n      \"pmids\": [\"11927553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"This concerns the mitochondrial TRX-2 paralog, not cytoplasmic TXN/TRX-1\", \"Direct molecular target of TRX-2 in the cascade not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a redox-independent cytokine role for the truncated Trx80 fragment in monocyte activation and differentiation via MAP-kinase signaling.\",\n      \"evidence\": \"Active-site Cys\\u2192Ser mutagenesis, PBMC proliferation/cytokine ELISA, flow cytometry, and MAP-kinase phosphorylation Western blot\",\n      \"pmids\": [\"11342447\", \"12650942\", \"15494431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The Trx80 cell-surface receptor is unidentified\", \"Protease generating Trx80 in vivo unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a direct physical TRX-MIF interaction and that cell-surface TRX serves as part of the MIF internalization/receptor machinery driving inflammatory cytokine output.\",\n      \"evidence\": \"BIAcore binding, reciprocal co-IP, and anti-TRX antibody blocking of MIF internalization and TNF-\\u03b1 production\",\n      \"pmids\": [\"19601712\", \"15081538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the TRX-MIF complex not defined\", \"How surface TRX is presented and retained is unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Consolidated the TRX-ASK1 inhibitory complex as the redox switch for apoptosis, showing complex dissociation and ASK1 Thr845 phosphorylation activate JNK/p38 death signaling.\",\n      \"evidence\": \"SCO2 and pharmacological/flavonoid perturbations with ASK1 complex-dissociation and phospho-ASK1 assays, kinase assays, and xenografts\",\n      \"pmids\": [\"23319048\", \"24374359\", \"18281606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct redox chemistry of the TRX-ASK1 disulfide handoff not reconstituted here\", \"Quantitative threshold of oxidation triggering release undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a nuclear function whereby TRX-1, after ERK1/2- and TXNIP-gated translocation, reduces Ref-1/APE1 to enhance HIF-1\\u03b1 DNA binding and glycolytic gene expression.\",\n      \"evidence\": \"Immunofluorescence, nuclear/cytoplasmic fractionation, TXNIP overexpression/knockdown, MEK inhibitors, HIF-1\\u03b1 DNA-binding assay, and xenografts\",\n      \"pmids\": [\"24376827\", \"25656992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear import mechanism / NLS of TRX-1 not defined\", \"Direct evidence that Ref-1 reduction is rate-limiting for HIF-1\\u03b1 not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned TXN within a feedback loop with FOXO1, showing TXN restrains p300-mediated FOXO1 acetylation/nuclear translocation while FOXO1 directly transcribes TXN and TXNIP.\",\n      \"evidence\": \"Double siRNA epistasis, FOXO1 acetylation/translocation assays, ChIP for FOXO1 at TXN/TXNIP loci, CRISPR knockin/knockout, and PX-12\",\n      \"pmids\": [\"27132507\", \"30962862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TXN acts on FOXO1 via direct disulfide reduction not shown\", \"Tissue specificity of the FOXO1-TXN-TXNIP loop incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended TRX-1 into multiprotein signaling assemblies coupling redox-dependent ASK1 and TGF-\\u03b2 pathways relevant to metabolic regulation.\",\n      \"evidence\": \"Co-IP of a TRX-1/MPK38/ASK1/SMAD/ZPR9 complex plus adenoviral rescue in obese mice\",\n      \"pmids\": [\"26421442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binary contacts within the complex not resolved\", \"Single Co-IP-based complex without structural validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized TXN as the convergent effector of multiple upstream regulators (ALDH1L2, miRNA, polysaccharide, metabolic inputs) controlling ROS/ASK1-dependent survival and therapy resistance.\",\n      \"evidence\": \"Co-IP, siRNA/RNAi knockdown, luciferase reporter, PX-12 inhibition, and in vivo cancer/OA/PD models\",\n      \"pmids\": [\"35597868\", \"24147004\", \"38151083\", \"29960099\", \"37298317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These are largely correlative or single-lab pathway placements\", \"Direct enzymatic substrates for most contexts not biochemically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the surface receptors for full-length TRX and Trx80, the structural basis of the TRX-ASK1 redox handoff, and the import machinery for nuclear TRX-1 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified for secreted TRX or Trx80\", \"No structural model of TRX-ASK1 or TRX-MIF complexes\", \"Nuclear translocation machinery uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 13, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 13, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11, 6]}\n    ],\n    \"complexes\": [\n      \"TRX-ASK1 inhibitory complex\",\n      \"TRX-1/MPK38/ASK1/SMAD/ZPR9 complex\"\n    ],\n    \"partners\": [\n      \"ASK1\",\n      \"MIF\",\n      \"TXNIP\",\n      \"APEX1\",\n      \"FOXO1\",\n      \"ALDH1L2\",\n      \"MPK38\",\n      \"ZPR9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}