{"gene":"TXNRD1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2023,"finding":"RSL3 and ML162, widely used as GPX4 inhibitors to study ferroptosis, do not inhibit recombinant selenoprotein GPX4 enzymatic activity but are instead efficient inhibitors of TXNRD1 in vitro.","method":"In vitro enzymatic assay with recombinant GPX4 and TXNRD1; biochemical inhibition profiling","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution assay with recombinant proteins, multiple inhibitors tested, orthogonal validation with known TXNRD1 inhibitors","pmids":["37087975"],"is_preprint":false},{"year":2024,"finding":"TXNRD1 drives the senescence-associated secretory phenotype (SASP) and inflammaging through the cGAS-STING innate immune pathway independently of its enzymatic reductase activity. TXNRD1 localizes to cytoplasmic chromatin fragments, physically interacts with cGAS in a senescence-dependent manner, and enhances cGAS enzymatic activity. A TXNRD1 inhibitor that disrupts TXNRD1-cGAS interaction (but not one that only inhibits enzymatic activity) suppressed inflammaging markers in aged mice.","method":"Co-immunoprecipitation (TXNRD1–cGAS interaction), subcellular fractionation/imaging, genetic KO/KD, in vivo mouse aging model with selective inhibitors, cGAS activity assay","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO phenotype, enzymatic assay, selective inhibitor dissecting enzymatic vs. protein-interaction functions, replicated in vivo","pmids":["38267705"],"is_preprint":false},{"year":2009,"finding":"The TXNRD1_v3 splice variant forms dynamic cytoplasmic filaments and induces filopodia when overexpressed. Both phenotypes depend exclusively on the N-terminal glutaredoxin domain; filopodia but not cytoplasmic filaments require actin polymerization.","method":"Overexpression of truncated/full-length TXNRD1_v3 constructs, live-cell imaging, cytochalasin D actin inhibition","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion mutagenesis combined with live imaging and pharmacological inhibition; single lab","pmids":["19654027"],"is_preprint":false},{"year":2013,"finding":"The TXNRD1_v3 splice variant is targeted to membrane rafts via N-terminal myristoylation and palmitoylation of its MGC motif. Filopodia induction by v3 is independent of the redox-active Cys residues in its active site but requires membrane raft targeting.","method":"Site-directed mutagenesis of MGC motif, lipid fractionation, cholera toxin B co-localization, fluorescence imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of acylation motif combined with lipid fractionation and imaging, single lab but multiple orthogonal methods","pmids":["23413027"],"is_preprint":false},{"year":2014,"finding":"Selenocysteine (Sec)-containing TrxR1 is essential for cell survival under high-glucose conditions: Txnrd1-null mouse embryonic fibroblasts (MEFs) undergo massive cell death linked to glucose-induced H2O2, which is rescued by reconstituted Sec-containing TrxR1 but not by Sec-devoid variants.","method":"Txnrd1 knockout MEFs, reconstitution with wild-type vs. Sec-mutant TXNRD1 constructs, H2O2 measurement, cell viability assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — genetic KO with reconstitution and Sec-mutant rescue, in vitro enzymatic context, single lab with multiple orthogonal methods","pmids":["24853413"],"is_preprint":false},{"year":2013,"finding":"Hepatocyte-specific disruption of Txnrd1 causes a metabolic switch: lipogenic gene repression, periportal glycogen accumulation, upregulation of glutathione biosynthesis, UDP-glucuronate synthesis, glutathione-S-transferases, UDP-glucuronyl-transferases, and xenobiotic exporters. NAPQI (acetaminophen metabolite) directly inactivates TrxR1, yet Txnrd1-null livers are resistant to APAP hepatotoxicity due to their constitutively enhanced GSH and glucuronidation systems.","method":"Hepatocyte-specific Txnrd1 KO mouse model, transcriptomic/metabolomic profiling, APAP challenge, TrxR1 activity assay, biochemical pathway analysis","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined metabolic phenotype plus direct NAPQI–TrxR1 inactivation; multiple orthogonal readouts in vivo","pmids":["23743293"],"is_preprint":false},{"year":2011,"finding":"In vivo hepatocyte proliferation requires either glutathione (GSH) or at least one functional allele of txnrd1: hepatocytes completely lacking txnrd1 showed severely reduced replication after GSH depletion by buthionine sulfoximine (BSO), while single-allele txnrd1 hepatocytes were unaffected, demonstrating that the GSH and TrxR1 redox pathways independently support DNA replication (via ribonucleotide reductase electron donation).","method":"Txnrd1 conditional KO mouse model, BSO-mediated GSH depletion, hepatocyte replicative index measurement (BrdU incorporation)","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with conditional KO and chemical pathway ablation; replicated across multiple genotypes","pmids":["22198266"],"is_preprint":false},{"year":2019,"finding":"TrxR1 and glutathione reductase (Gsr) together constitute the major antioxidant systems in liver. TrxR1/Gsr double-null livers show 100-fold higher DNA damage than single knockouts. TrxR1 loss reduces DEN-induced liver cancer initiation threefold (without affecting progression), and elevated oxidative stress in TrxR1/Gsr-null livers correlates with increased malignancy.","method":"Conditional single and double KO mouse models (TrxR1-null, Gsr-null, TrxR1/Gsr-null), DEN carcinogenesis model, DNA damage indices, tumor count and malignancy scoring","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO combinations in vivo, chemical carcinogenesis epistasis, quantitative phenotypic readouts","pmids":["31097586"],"is_preprint":false},{"year":2011,"finding":"In C. elegans, selenoprotein TRXR-1 (the ortholog of mammalian TrxR1) and glutathione reductase GSR-1 cooperate to reduce disulfide bonds in the old cuticle during molting; loss of either causes oxidized cuticle disulfides and molting failure. This TRXR-1 function is strictly selenocysteine-dependent: a Sec-to-Cys mutant fails to rescue.","method":"C. elegans genetic KD (RNAi), Sec→Cys knock-in mutant rescue experiments, cuticle disulfide oxidation state assay, reduced glutathione exogenous supply rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — Sec-to-Cys mutagenesis rescue in vivo, multiple genetic lines, replicated with chemical rescue","pmids":["21199936"],"is_preprint":false},{"year":2016,"finding":"TrxR1 inhibition (by auranofin or siRNA) blocks STAT3-dependent transcription indirectly: TrxR1 inhibition causes oxidation of Prx2 and then STAT3, preventing STAT3-dependent gene expression. Established STAT3 inhibitors also inhibit TrxR1.","method":"Cellular luciferase reporter for STAT3 transcription, TrxR1 inhibitor panel, STAT3/Prx2 oxidation assays (redox western blot), siRNA knockdown","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established through inhibitor + KD + redox protein oxidation assay; single lab with multiple orthogonal methods","pmids":["32219156"],"is_preprint":false},{"year":2009,"finding":"RITA (NSC 652287) inhibits TrxR1 by non-covalent binding and reduces TrxR activity in cancer cells in a p53-dependent manner, inducing a ~130 kDa TrxR1 covalent dimer and ROS generation selectively in cancer cells but not in normal fibroblasts.","method":"In vitro TrxR1 activity assay with RITA, cellular TrxR activity measurement, ROS detection, comparison across p53-status cell lines and normal fibroblasts","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding + cellular activity assay + p53-dependence shown genetically; single lab","pmids":["19838062"],"is_preprint":false},{"year":2013,"finding":"KEAP1-dependent synthetic lethality between TXNRD1 inhibition and AKT inhibition in NSCLC: simultaneous TXNRD1 (siRNA or auranofin) and AKT (MK2206) inhibition induces ROS, JNK activation, and apoptosis; this lethality is abrogated by mutant KEAP1, placing TXNRD1 within the KEAP1/NRF2 antioxidant pathway.","method":"Genome-wide siRNA library screen, pharmacological inhibitor combination, siRNA validation, ROS measurement, xenograft model, KEAP1 mutation status analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen followed by siRNA + pharmacological validation in vitro and in vivo, KEAP1 epistasis established","pmids":["23824739"],"is_preprint":false},{"year":2023,"finding":"During RANKL-induced osteoclastogenesis, NFATc1 transcriptionally upregulates SLC7A11, causing pre-osteoclasts to accumulate cystine upon TXNRD1 inhibition (since disulfide reduction rate is slowed). This cystine accumulation leads to disulfidptosis, a distinct cell death rescued by SLC7A11 inhibitors or agents preventing disulfide accumulation, but not by ferroptosis, ROS, apoptosis, or autophagy inhibitors.","method":"NFATc1 ChIP/transcriptional reporter, SLC7A11 overexpression/knockdown, TXNRD1 inhibitors, rescue with pathway-specific inhibitors, in vivo OVX mouse model, cystine measurement","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptional mechanism established by ChIP, metabolite measurements, pathway-specific rescue panel, in vivo validation","pmids":["37148740"],"is_preprint":false},{"year":2022,"finding":"TXNRD1 attenuates the interaction between Trx1 and PTEN, leading to accelerated PTEN degradation and subsequent Akt/mTOR pathway activation in hepatocellular carcinoma. Additionally, USF2 was identified as a transcriptional suppressor that directly binds two E-box sites in the TXNRD1 promoter to repress TXNRD1 expression.","method":"Co-immunoprecipitation (Trx1–PTEN interaction), TXNRD1 KD/OE, Akt/mTOR signaling readouts, USF2 ChIP on TXNRD1 promoter E-box sites","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus promoter ChIP; single lab, two orthogonal methods","pmids":["36319631"],"is_preprint":false},{"year":2018,"finding":"Manumycin A irreversibly inhibits mammalian TrxR1 with time-dependent kinetics (IC50 272 nM with pre-incubation) by forming a covalent Michael adduct with the selenocysteine residue in TrxR1's C-terminal redox center, converting TrxR1 into a SecTRAP that uses NADPH to reduce O2 to superoxide.","method":"In vitro TrxR1 activity assay (time-dependent kinetics), irreversibility testing (dialysis), mass spectrometry for Michael adduct identification at Sec residue","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinetics + covalent adduct identified by MS + mechanism-based characterization; single lab","pmids":["29670693"],"is_preprint":false},{"year":2006,"finding":"Multiple gold compounds (auranofin, gold sodium thiomalate, sodium aurothiosulfate, triphenyl phosphine gold chloride, gold acetate) inhibit TrxR1 at sublethal concentrations (IC50 5–4000 nM). Au(I)-phosphine compounds are the most potent; ligand configuration rather than gold oxidation state determines inhibitory potency.","method":"Ex vivo TrxR1 activity assay with purified rat TrxR1 and panel of gold compounds, mitochondrial activity (succinate dehydrogenase) comparison","journal":"Toxicology in vitro","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with structure-activity analysis; single lab, single method","pmids":["16510263"],"is_preprint":false},{"year":2017,"finding":"The Trx1/TrxR1 system is critically required for survival of post-selected double-positive (CD69+) thymocytes: TrxR1 inhibition (but not GSH pathway suppression) specifically reduced this subset in vitro and in vivo, associated with enhanced phosphorylation of ASK1, JNK, p38 MAPK, and upregulation of Bim.","method":"TrxR1 inhibitor (auranofin) vs. GSH pathway inhibitor treatment of thymocytes, in vitro and in vivo cell subset analysis, phospho-ASK1/JNK/p38 western blot, Bim expression","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitor selectivity comparison in vivo and in vitro with defined signaling readout; single lab","pmids":["25753394"],"is_preprint":false},{"year":2017,"finding":"TrxR1 overexpression reduces radiosensitivity of glioma cells, and TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma by inhibiting radiation-induced Trx1 nuclear transport, placing TrxR1 upstream of Trx1 nuclear localization as a radioprotective mechanism.","method":"Stable TrxR1 overexpression in glioma cells, siRNA TIGAR KD, clonogenic survival assay, Trx1 nuclear/cytoplasmic fractionation after irradiation, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic OE/KD epistasis combined with fractionation and in vivo validation; single lab","pmids":["28338004"],"is_preprint":false},{"year":2017,"finding":"TrxR1 is downregulated during skeletal muscle differentiation (myogenesis) and this decrease is functionally required: TrxR1 depletion promotes early myogenesis markers (myogenin, Myf5 upregulation; Cyclin D1 decrease), while TrxR1 overexpression delays myogenic differentiation. miR-23a and miR-23b directly bind the 3′ UTR of TrxR1 mRNA (confirmed by reporter assay) and mediate TrxR1 downregulation during early C2C12 differentiation.","method":"siRNA KD and overexpression of TrxR1 in C2C12 cells, myogenic marker expression, miR-23a/b overexpression and inhibition, 3′-UTR luciferase reporter assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function plus 3′-UTR reporter validation; single lab, two orthogonal methods","pmids":["28775321"],"is_preprint":false},{"year":2017,"finding":"Homozygous missense mutation p.Pro190Leu in TXNRD1 causes ~66–84% reduction of TrxR1 enzymatic activity in patient fibroblasts and skeletal muscle, arising from both reduced enzyme turnover (30–40% lower kcat/Se by in vitro kinetics) and reduced selenoprotein abundance (reduced 75Se labeling). Mutant cells are less resistant to hydrogen peroxide challenge.","method":"75Se metabolic labeling, western blot, TrxR1 activity assay in patient tissue fractions, in vitro kinetic analysis of recombinant mutant enzyme, H2O2 challenge","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of recombinant mutant enzyme kinetics combined with patient-derived cell biochemistry and Se labeling; single study but multiple orthogonal methods","pmids":["28232204"],"is_preprint":false},{"year":2024,"finding":"LNCRNA CARD8-AS1 acts as a scaffold that facilitates interaction between TXNRD1 and the E3 ubiquitin ligase TRIM25, promoting ubiquitin-proteasome-mediated degradation of TXNRD1, thereby suppressing lung adenocarcinoma progression.","method":"Co-immunoprecipitation (TXNRD1–TRIM25 interaction), CARD8-AS1 overexpression/KD, proteasome inhibitor rescue, in vitro and in vivo tumor models","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing scaffold function plus proteasome pathway validation; single lab","pmids":["38153696"],"is_preprint":false},{"year":2012,"finding":"Simvastatin inhibits the basal activity of the TXNRD1 core promoter (~20% reduction) and reduces cellular TrxR1 mRNA (~25%) and activity (~40%) in HepG2 cells through a mechanism independent of HMGCoA reductase inhibition (mevalonate rescue failed). This inhibition is specific to basal—not Nrf2-activated—TXNRD1 transcription.","method":"TXNRD1 promoter-luciferase reporter assay, TrxR1 mRNA qPCR, TrxR activity assay, mevalonate rescue, sulforaphane (Nrf2 activator) co-treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter + mRNA + activity assay with mechanistic dissection; single lab","pmids":["23154180"],"is_preprint":false},{"year":2022,"finding":"The selective cellular probe RX1 (a cyclic selenenylsulfide) was developed to quantify TrxR1 activity in live cells based on TrxR1's unique selenolthiol chemistry. RX1 was cross-validated as TrxR1-selective by knockout, selenium starvation, knock-in, and chemical inhibitors, enabling high-throughput live-cell screening for TrxR1 inhibitors.","method":"Fluorogenic probe design with selenylsulfide mechanism, TXNRD1 KO cells, selenium-deficient cells, TXNRD1 knock-in rescue, auranofin competition, high-throughput screening","journal":"Chem","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanism-based probe design validated by four orthogonal genetic/chemical controls in cells; single lab but rigorous multi-method validation","pmids":["35936029"],"is_preprint":false},{"year":2023,"finding":"Deferoxamine activates the Nrf2/TXNRD1 axis in hippocampal neurons: Nrf2 positively regulates TXNRD1 protein expression (shown by co-immunoprecipitation and western blotting), and this axis mediates DFO's protection against ferroptosis and inflammation following subarachnoid hemorrhage.","method":"Co-immunoprecipitation (Nrf2–TXNRD1 regulation), western blot, Nrf2 inhibitor ML385, SAH mouse model, in vitro FIN56-induced ferroptosis model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pathway inhibitor in vivo and in vitro; single lab, moderate mechanistic depth","pmids":["37676391"],"is_preprint":false},{"year":2025,"finding":"Glaucocalyxin A (GLA) covalently binds to Cys173 of PRDX1 and to Cys59, Cys64, Cys497, and Sec498 of TXNRD1, inhibiting both enzymes. Activity-based protein profiling (ABPP) identified these covalent adducts; computational modeling ranked covalent bond reactivity as Sec498 > Cys59 > Cys497 > Cys64.","method":"Activity-based protein profiling (ABPP), mass spectrometry for covalent adduct identification, computational chemistry for binding site characterization, TrxR1 activity assay","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ABPP with MS-confirmed covalent modification sites; single lab, computational analysis supporting experimental data","pmids":["41016297"],"is_preprint":false},{"year":2024,"finding":"TXNRD1 knockdown in human aortic endothelial cells (HAECs) exposed to oscillatory shear stress inhibits their proliferation by activating the eNOS/apoptosis pathway; L-NAME (eNOS inhibitor) reversed the pro-apoptotic effect of TXNRD1 knockdown, establishing eNOS as downstream of TXNRD1 in shear stress-induced endothelial proliferation.","method":"siRNA TXNRD1 KD in oscillatory shear stress model, L-NAME pharmacological inhibition of eNOS, proliferation/migration/tube formation assays, apoptosis assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD plus pharmacological epistasis (eNOS inhibitor rescue); single lab","pmids":["36754152"],"is_preprint":false},{"year":2023,"finding":"Elovanoid ELV-N34 directly binds TXNRD1 (isoforms 2 or 3) in human RPE cells identified by limited proteolysis (LiP) screening, induces conformational changes at the FAD interface domain, and decreases both membrane and cytosolic TXNRD1 activity, modulating the thioredoxin system.","method":"Limited proteolysis (LiP) screening, TXNRD1 siRNA isoform-specific silencing, TXNRD1 activity assay (membrane vs. cytosolic fractions)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LiP target identification validated by isoform-specific siRNA and activity measurement; single lab","pmids":["38086796"],"is_preprint":false},{"year":2024,"finding":"Endogenously formed electrophiles (4-HNE, methylglyoxal, lipid peroxides) and peroxymonocarbonate can inhibit TXNRD1 at its exposed catalytic selenocysteine residue, modulating RTK/PTP signaling cascades and activating KEAP1/NRF2, linking TXNRD1 to redox regulation of tyrosine phosphorylation signaling.","method":"Mechanistic review integrating prior biochemical experiments on Sec modification by electrophiles, PTP activity assays, and KEAP1/NRF2 pathway readouts (as reported in cited primary literature)","journal":"Current opinion in chemical biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review/proposal integrating prior data rather than presenting new direct experiments; mechanistic framework but insufficient primary experimental data in this paper","pmids":["39243480"],"is_preprint":false},{"year":2025,"finding":"The sesquiterpene lactone prodrug 5u (releasing active compound 6a in response to ROS) covalently binds to Cys475 and Sec498 on TrxR1, inhibiting TrxR1 activity and causing redox homeostasis disruption leading to apoptosis and ferroptosis in NSCLC cells.","method":"In vitro TrxR1 activity assay, mass spectrometry for covalent binding site identification (Cys475, Sec498), ROS measurement, xenograft and organoid models","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — MS-confirmed covalent binding at defined residues plus in vitro activity assay; single lab","pmids":["39869029"],"is_preprint":false},{"year":2025,"finding":"Micheliolide (MCL) directly interacts with both TrxR1 and TrxR2, inhibiting their enzymatic activities, as validated by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. MCL-induced TrxR1/2 inhibition elevates ROS, activates MEK/ERK, and suppresses autophagy in hepatic stellate cells.","method":"CETSA, DARTS (target engagement assays), TrxR1/2 activity assay, ROS measurement, MEK/ERK western blot, CCl4 mouse fibrosis model","journal":"Pharmaceuticals (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — two orthogonal target engagement assays (CETSA + DARTS) confirming direct binding, with functional activity assay; single lab","pmids":["40143066"],"is_preprint":false}],"current_model":"TXNRD1 encodes cytosolic selenoprotein thioredoxin reductase 1, a NADPH-dependent FAD-containing disulfide reductase that reduces thioredoxin via its C-terminal selenocysteine (Sec) residue; the Sec is essential for its canonical reductase function and for elimination of glucose-derived H2O2, but TXNRD1 also operates non-enzymatically as a scaffold that localizes to cytoplasmic chromatin fragments in senescent cells and directly stimulates cGAS to drive the cGAS-STING SASP/inflammaging pathway, and via its v3 splice variant undergoes N-myristoylation/palmitoylation to target membrane rafts where it induces actin-dependent filopodia through its glutaredoxin domain; its Sec residue is a high-reactivity target for diverse electrophiles, gold compounds, and drug-like inhibitors, and its inhibition broadly shifts cellular redox balance toward oxidation, activating KEAP1/NRF2, ASK1-JNK/p38, and Akt/mTOR signaling while TrxR1 activity in the nucleus supports Trx1 nuclear transport to confer radioresistance."},"narrative":{"mechanistic_narrative":"TXNRD1 encodes the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1), an NADPH-dependent disulfide reductase whose C-terminal selenocysteine (Sec) confers its catalytic activity and constitutes a uniquely reactive nucleophile [PMID:28232204, PMID:29670693]. Together with the glutathione system it forms one of the two principal hepatic antioxidant pathways, and the two systems are functionally redundant for survival: loss of TrxR1 is tolerated while one functional allele or intact GSH remains, but combined disruption produces massive DNA damage and supports a redox switch toward glutathione, glucuronidation, and xenobiotic export that paradoxically protects against electrophilic hepatotoxins such as the acetaminophen metabolite NAPQI [PMID:23743293, PMID:22198266, PMID:31097586]. The Sec residue is strictly required for clearing glucose-derived H2O2 and for cell survival under high-glucose stress, and across species Sec-dependent disulfide reduction by TrxR1 supports processes ranging from ribonucleotide-reductase-driven DNA replication to cuticle remodeling [PMID:24853413, PMID:21199936]. TrxR1 also sets the redox tone of multiple signaling axes: its inhibition oxidizes Prx2 and STAT3 to block STAT3-dependent transcription [PMID:32219156], engages the KEAP1/NRF2 antioxidant network where it shows KEAP1-dependent synthetic lethality with AKT inhibition [PMID:23824739], and drives ASK1-JNK/p38 signaling required for thymocyte survival [PMID:25753394]; in cancer cells TrxR1 attenuates Trx1–PTEN interaction to activate Akt/mTOR and supports Trx1 nuclear transport conferring radioresistance [PMID:36319631, PMID:28338004]. Beyond enzymatic reduction, TrxR1 acts non-enzymatically as a scaffold: in senescent cells it localizes to cytoplasmic chromatin fragments, binds cGAS, and stimulates cGAS activity to drive the cGAS-STING SASP/inflammaging program [PMID:38267705], while its v3 splice variant is acylated at an N-terminal MGC motif to target membrane rafts and induce actin-dependent filopodia through its glutaredoxin domain independently of its redox-active cysteines [PMID:19654027, PMID:23413027]. TrxR1 expression and stability are controlled by NRF2, the transcriptional repressor USF2, miR-23a/b, and TRIM25-mediated ubiquitination [PMID:36319631, PMID:28775321, PMID:38153696, PMID:37676391]. The Sec residue makes TrxR1 a high-reactivity target for gold compounds and diverse covalent and non-covalent inhibitors, several of which convert the enzyme into a superoxide-producing SecTRAP, and a homozygous p.Pro190Leu mutation that reduces TrxR1 activity and selenoprotein abundance establishes a direct human genetic link to TXNRD1 dysfunction [PMID:29670693, PMID:16510263, PMID:28232204, PMID:39869029].","teleology":[{"year":2006,"claim":"Established that diverse gold compounds inhibit TrxR1 at sublethal concentrations, defining the enzyme as a tractable, ligand-tunable pharmacological target.","evidence":"Ex vivo activity assay of purified rat TrxR1 against a panel of gold compounds with structure-activity analysis","pmids":["16510263"],"confidence":"Medium","gaps":["Single in vitro enzymatic method","Cellular selectivity over other selenoproteins not addressed","Mechanism of Sec engagement not directly mapped"]},{"year":2009,"claim":"Showed that the TXNRD1_v3 splice variant has a non-canonical cytoskeletal function, forming cytoplasmic filaments and inducing actin-dependent filopodia via its glutaredoxin domain.","evidence":"Overexpression of truncated/full-length v3 constructs, live-cell imaging, cytochalasin D actin inhibition","pmids":["19654027"],"confidence":"Medium","gaps":["Relied on overexpression","Endogenous v3 contribution unknown","Molecular link between Grx domain and actin not defined"]},{"year":2011,"claim":"Demonstrated in vivo that TrxR1 and the glutathione pathway are independent, redundant routes supporting DNA replication, resolving how cells survive loss of either system.","evidence":"Hepatocyte conditional Txnrd1 KO with BSO-mediated GSH depletion and BrdU replicative index","pmids":["22198266"],"confidence":"High","gaps":["Ribonucleotide reductase electron donation inferred not directly traced","Cell-type generality beyond hepatocytes unaddressed"]},{"year":2011,"claim":"Established that the selenocysteine of TrxR1 is strictly required for disulfide reduction in a physiological remodeling process, using cross-species genetics.","evidence":"C. elegans RNAi, Sec→Cys knock-in rescue, cuticle disulfide assays, GSH chemical rescue","pmids":["21199936"],"confidence":"High","gaps":["Mammalian equivalent of cuticle remodeling not applicable","Substrate scope beyond cuticle disulfides not defined"]},{"year":2013,"claim":"Defined a metabolic-rewiring consequence of TrxR1 loss in liver and explained why such livers resist electrophilic hepatotoxins despite NAPQI directly inactivating the enzyme.","evidence":"Hepatocyte-specific Txnrd1 KO with transcriptomics/metabolomics, APAP challenge, TrxR1 activity assay","pmids":["23743293"],"confidence":"High","gaps":["Master regulator driving the compensatory program not fully identified","Reversibility of the metabolic switch unknown"]},{"year":2013,"claim":"Anchored TXNRD1 within the KEAP1/NRF2 axis by revealing KEAP1-dependent synthetic lethality between TXNRD1 and AKT inhibition in NSCLC.","evidence":"Genome-wide siRNA screen with pharmacological combination, ROS/JNK readouts, KEAP1 mutation epistasis, xenografts","pmids":["23824739"],"confidence":"High","gaps":["Molecular link between TrxR1 and KEAP1 sensing not defined","Generality beyond KEAP1-mutant NSCLC unclear"]},{"year":2013,"claim":"Showed that v3 raft targeting via N-terminal acylation, not its redox-active cysteines, drives filopodia, separating the variant's structural role from catalysis.","evidence":"MGC-motif site-directed mutagenesis, lipid fractionation, cholera toxin B co-localization, imaging","pmids":["23413027"],"confidence":"High","gaps":["Physiological trigger of v3 localization unknown","Downstream actin effectors not identified"]},{"year":2014,"claim":"Established that Sec-containing TrxR1 is essential for clearing glucose-derived H2O2 and for survival under high-glucose stress, distinguishing the selenoprotein from Sec-devoid forms.","evidence":"Txnrd1-null MEFs with WT vs. Sec-mutant reconstitution, H2O2 and viability assays","pmids":["24853413"],"confidence":"High","gaps":["In vivo relevance of glucose-driven death not tested","Sec-devoid variant residual activity not quantified in tissue"]},{"year":2016,"claim":"Connected TrxR1 activity to transcription, showing inhibition oxidizes Prx2 and then STAT3 to block STAT3-dependent gene expression.","evidence":"STAT3 luciferase reporter, inhibitor panel, redox western blot of Prx2/STAT3 oxidation, siRNA","pmids":["32219156"],"confidence":"High","gaps":["Direct vs. relay nature of STAT3 oxidation not fully resolved","Single lab"]},{"year":2017,"claim":"Identified TrxR1 as a survival factor for post-selected thymocytes acting through suppression of ASK1-JNK/p38 stress signaling.","evidence":"Auranofin vs. GSH-pathway inhibition in vitro and in vivo, phospho-ASK1/JNK/p38 and Bim readouts","pmids":["25753394"],"confidence":"Medium","gaps":["Inhibitor specificity for TrxR1 not genetically confirmed in thymocytes","Direct redox target upstream of ASK1 unidentified"]},{"year":2017,"claim":"Placed TrxR1 upstream of Trx1 nuclear transport as a radioprotective mechanism in glioma.","evidence":"Stable TrxR1 overexpression, TIGAR knockdown, clonogenic survival, Trx1 nuclear fractionation, xenograft","pmids":["28338004"],"confidence":"Medium","gaps":["Mechanism coupling TrxR1 to Trx1 import not defined","Single lab"]},{"year":2017,"claim":"Showed that TrxR1 downregulation is required for myogenesis and identified miR-23a/b as direct repressors of TXNRD1.","evidence":"TrxR1 KD/OE in C2C12, myogenic markers, miR-23a/b modulation, 3' UTR luciferase reporter","pmids":["28775321"],"confidence":"Medium","gaps":["Redox target driving differentiation block unknown","In vivo muscle relevance not tested"]},{"year":2017,"claim":"Provided a direct human genetic link by showing a homozygous TXNRD1 p.Pro190Leu mutation reduces enzyme turnover and selenoprotein abundance with impaired H2O2 resistance.","evidence":"75Se labeling, patient-tissue activity assays, recombinant mutant kinetics, H2O2 challenge","pmids":["28232204"],"confidence":"High","gaps":["Clinical phenotype-genotype causation from single family","Mechanism of reduced selenoprotein abundance not fully resolved"]},{"year":2018,"claim":"Demonstrated mechanism-based conversion of TrxR1 into a superoxide-generating SecTRAP via covalent Sec adduct formation, defining a toxic gain-of-function inhibition mode.","evidence":"Time-dependent kinetics, dialysis irreversibility, MS adduct identification at Sec (manumycin A)","pmids":["29670693"],"confidence":"High","gaps":["Cellular contribution of SecTRAP superoxide to toxicity not quantified","Selectivity over other selenoproteins not addressed"]},{"year":2019,"claim":"Established the redundancy and tumor-suppressive context of TrxR1, with TrxR1/Gsr double loss causing severe DNA damage and TrxR1 loss reducing carcinogen-induced tumor initiation.","evidence":"Single and double conditional KO mice, DEN carcinogenesis, DNA damage indices, tumor scoring","pmids":["31097586"],"confidence":"High","gaps":["Why TrxR1 loss affects initiation but not progression unresolved","Specific oxidized lesions driving malignancy not defined"]},{"year":2022,"claim":"Showed TrxR1 promotes Akt/mTOR signaling in HCC by attenuating Trx1–PTEN interaction and accelerating PTEN degradation, and identified USF2 as a direct promoter repressor.","evidence":"Co-IP of Trx1–PTEN, TXNRD1 KD/OE with Akt/mTOR readouts, USF2 ChIP on TXNRD1 E-boxes","pmids":["36319631"],"confidence":"Medium","gaps":["Direct vs. indirect effect on PTEN stability unresolved","Single lab, two methods"]},{"year":2022,"claim":"Delivered a mechanism-based live-cell probe exploiting TrxR1's selenolthiol chemistry, enabling rigorous activity quantification and inhibitor screening.","evidence":"Selenylsulfide fluorogenic probe RX1 validated by KO, Se starvation, knock-in, and auranofin competition","pmids":["35936029"],"confidence":"High","gaps":["Isoform discrimination not addressed","Probe is a tool, not a biological finding about endogenous regulation"]},{"year":2023,"claim":"Revealed that two widely used 'GPX4 inhibitors' (RSL3, ML162) are in fact efficient TrxR1 inhibitors, correcting target attribution in ferroptosis studies.","evidence":"In vitro assays with recombinant GPX4 and TXNRD1, biochemical inhibition profiling","pmids":["37087975"],"confidence":"High","gaps":["Cellular ferroptosis contribution of TrxR1 inhibition by these compounds not fully dissected"]},{"year":2023,"claim":"Linked TrxR1's disulfide-reduction rate to a distinct death modality (disulfidptosis) in osteoclastogenesis, where SLC7A11-driven cystine accumulates when TXNRD1 is inhibited.","evidence":"NFATc1 ChIP, SLC7A11 OE/KD, TXNRD1 inhibitors, pathway-specific rescue panel, OVX mouse model","pmids":["37148740"],"confidence":"High","gaps":["Generality of disulfidptosis beyond high-SLC7A11 contexts unclear","Direct biochemical step from TrxR1 to cystine pool not isolated"]},{"year":2023,"claim":"Showed NRF2 positively regulates TXNRD1 protein expression in neurons as part of a deferoxamine-protective axis against ferroptosis.","evidence":"Co-IP of Nrf2–TXNRD1, western blot, ML385 inhibition, SAH and FIN56 ferroptosis models","pmids":["37676391"],"confidence":"Medium","gaps":["Direct transcriptional vs. indirect regulation by NRF2 not delineated","Single lab"]},{"year":2024,"claim":"Established a non-enzymatic, scaffold function of TXNRD1 in driving inflammaging via direct stimulation of cGAS in the cGAS-STING pathway, dissociable from reductase activity.","evidence":"Reciprocal Co-IP with cGAS, fractionation/imaging, KO/KD, cGAS activity assay, selective inhibitors in aged mice","pmids":["38267705"],"confidence":"High","gaps":["Structural basis of cGAS stimulation not resolved","How senescence recruits TXNRD1 to chromatin fragments unknown"]},{"year":2024,"claim":"Identified a lncRNA-scaffolded TRIM25-dependent ubiquitination route controlling TXNRD1 abundance, adding post-translational regulation as a tumor-suppressive axis.","evidence":"Co-IP of TXNRD1–TRIM25, CARD8-AS1 OE/KD, proteasome inhibitor rescue, tumor models","pmids":["38153696"],"confidence":"Medium","gaps":["Ubiquitination site on TXNRD1 not mapped","Single lab"]},{"year":2024,"claim":"Connected TXNRD1 to endothelial proliferation under shear stress through an eNOS/apoptosis axis.","evidence":"siRNA KD in oscillatory shear model, L-NAME eNOS inhibition, proliferation/apoptosis assays","pmids":["36754152"],"confidence":"Medium","gaps":["Redox intermediate linking TrxR1 to eNOS unidentified","Single lab"]},{"year":2025,"claim":"Multiple covalent natural-product and prodrug inhibitors were mapped to specific Cys/Sec residues, refining the structural basis of TrxR1 electrophile reactivity and its coupling to ROS-driven cell death.","evidence":"ABPP/MS adduct mapping, CETSA/DARTS target engagement, activity assays, xenograft/organoid models (GLA, prodrug 5u, micheliolide)","pmids":["41016297","39869029","40143066"],"confidence":"Medium","gaps":["Off-target reactivity across the selenoproteome not fully excluded","Relative contribution of each modified residue to inhibition partly computational"]},{"year":null,"claim":"How TXNRD1's enzymatic and non-enzymatic (cGAS-scaffolding, v3 cytoskeletal) functions are partitioned between isoforms, tissues, and physiological states, and the structural basis of its protein-stimulatory roles, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of TXNRD1-cGAS or TXNRD1-substrate complexes in the corpus","Endogenous regulation of v3 isoform expression undefined","Integration of redox-signaling outputs (KEAP1/NRF2, ASK1, Akt/mTOR) into a unified model not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,8,19,14]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[14,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,20]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,26,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,26]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,13,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,16,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,7]}],"complexes":[],"partners":["CGAS","TRIM25","TRX1","PTEN","CUTICLE GSR-1 (GSR)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16881","full_name":"Thioredoxin reductase 1, cytoplasmic","aliases":["Gene associated with retinoic and interferon-induced mortality 12 protein","GRIM-12","Gene associated with retinoic and IFN-induced mortality 12 protein","KM-102-derived reductase-like factor","Peroxidase TXNRD1","Thioredoxin reductase TR1"],"length_aa":649,"mass_kda":70.9,"function":"Reduces disulfide protein thioredoxin (Trx) to its dithiol-containing form (PubMed:8577704). Homodimeric flavoprotein involved in the regulation of cellular redox reactions, growth and differentiation. A selenocysteine residue at the C-terminal active site is essential for catalysis (Probable). Also has reductase activity on hydrogen peroxide (H2O2) (PubMed:10849437) Induces actin and tubulin polymerization, leading to formation of cell membrane protrusions Enhances the transcriptional activity of estrogen receptors ESR1 and ESR2 Enhances the transcriptional activity of the estrogen receptor ESR2 only (PubMed:15199063). Mediates cell death induced by a combination of interferon-beta and retinoic acid (PubMed:9774665)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q16881/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TXNRD1","classification":"Not Classified","n_dependent_lines":692,"n_total_lines":1208,"dependency_fraction":0.5728476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TXNRD1","total_profiled":1310},"omim":[{"mim_id":"616967","title":"THIOREDOXIN DOMAIN-CONTAINING PROTEIN 17; TXNDC17","url":"https://www.omim.org/entry/616967"},{"mim_id":"612986","title":"EP300-INTERACTING INHIBITOR OF DIFFERENTIATION 3; EID3","url":"https://www.omim.org/entry/612986"},{"mim_id":"609063","title":"THIOREDOXIN 2; TXN2","url":"https://www.omim.org/entry/609063"},{"mim_id":"606448","title":"THIOREDOXIN REDUCTASE 2; TXNRD2","url":"https://www.omim.org/entry/606448"},{"mim_id":"606254","title":"SELENOPROTEIN F; SELENOF","url":"https://www.omim.org/entry/606254"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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profiling\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution assay with recombinant proteins, multiple inhibitors tested, orthogonal validation with known TXNRD1 inhibitors\",\n      \"pmids\": [\"37087975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TXNRD1 drives the senescence-associated secretory phenotype (SASP) and inflammaging through the cGAS-STING innate immune pathway independently of its enzymatic reductase activity. TXNRD1 localizes to cytoplasmic chromatin fragments, physically interacts with cGAS in a senescence-dependent manner, and enhances cGAS enzymatic activity. A TXNRD1 inhibitor that disrupts TXNRD1-cGAS interaction (but not one that only inhibits enzymatic activity) suppressed inflammaging markers in aged mice.\",\n      \"method\": \"Co-immunoprecipitation (TXNRD1–cGAS interaction), subcellular fractionation/imaging, genetic KO/KD, in vivo mouse aging model with selective inhibitors, cGAS activity assay\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO phenotype, enzymatic assay, selective inhibitor dissecting enzymatic vs. protein-interaction functions, replicated in vivo\",\n      \"pmids\": [\"38267705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The TXNRD1_v3 splice variant forms dynamic cytoplasmic filaments and induces filopodia when overexpressed. Both phenotypes depend exclusively on the N-terminal glutaredoxin domain; filopodia but not cytoplasmic filaments require actin polymerization.\",\n      \"method\": \"Overexpression of truncated/full-length TXNRD1_v3 constructs, live-cell imaging, cytochalasin D actin inhibition\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion mutagenesis combined with live imaging and pharmacological inhibition; single lab\",\n      \"pmids\": [\"19654027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TXNRD1_v3 splice variant is targeted to membrane rafts via N-terminal myristoylation and palmitoylation of its MGC motif. Filopodia induction by v3 is independent of the redox-active Cys residues in its active site but requires membrane raft targeting.\",\n      \"method\": \"Site-directed mutagenesis of MGC motif, lipid fractionation, cholera toxin B co-localization, fluorescence imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of acylation motif combined with lipid fractionation and imaging, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23413027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Selenocysteine (Sec)-containing TrxR1 is essential for cell survival under high-glucose conditions: Txnrd1-null mouse embryonic fibroblasts (MEFs) undergo massive cell death linked to glucose-induced H2O2, which is rescued by reconstituted Sec-containing TrxR1 but not by Sec-devoid variants.\",\n      \"method\": \"Txnrd1 knockout MEFs, reconstitution with wild-type vs. Sec-mutant TXNRD1 constructs, H2O2 measurement, cell viability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — genetic KO with reconstitution and Sec-mutant rescue, in vitro enzymatic context, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24853413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocyte-specific disruption of Txnrd1 causes a metabolic switch: lipogenic gene repression, periportal glycogen accumulation, upregulation of glutathione biosynthesis, UDP-glucuronate synthesis, glutathione-S-transferases, UDP-glucuronyl-transferases, and xenobiotic exporters. NAPQI (acetaminophen metabolite) directly inactivates TrxR1, yet Txnrd1-null livers are resistant to APAP hepatotoxicity due to their constitutively enhanced GSH and glucuronidation systems.\",\n      \"method\": \"Hepatocyte-specific Txnrd1 KO mouse model, transcriptomic/metabolomic profiling, APAP challenge, TrxR1 activity assay, biochemical pathway analysis\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined metabolic phenotype plus direct NAPQI–TrxR1 inactivation; multiple orthogonal readouts in vivo\",\n      \"pmids\": [\"23743293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vivo hepatocyte proliferation requires either glutathione (GSH) or at least one functional allele of txnrd1: hepatocytes completely lacking txnrd1 showed severely reduced replication after GSH depletion by buthionine sulfoximine (BSO), while single-allele txnrd1 hepatocytes were unaffected, demonstrating that the GSH and TrxR1 redox pathways independently support DNA replication (via ribonucleotide reductase electron donation).\",\n      \"method\": \"Txnrd1 conditional KO mouse model, BSO-mediated GSH depletion, hepatocyte replicative index measurement (BrdU incorporation)\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with conditional KO and chemical pathway ablation; replicated across multiple genotypes\",\n      \"pmids\": [\"22198266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TrxR1 and glutathione reductase (Gsr) together constitute the major antioxidant systems in liver. TrxR1/Gsr double-null livers show 100-fold higher DNA damage than single knockouts. TrxR1 loss reduces DEN-induced liver cancer initiation threefold (without affecting progression), and elevated oxidative stress in TrxR1/Gsr-null livers correlates with increased malignancy.\",\n      \"method\": \"Conditional single and double KO mouse models (TrxR1-null, Gsr-null, TrxR1/Gsr-null), DEN carcinogenesis model, DNA damage indices, tumor count and malignancy scoring\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO combinations in vivo, chemical carcinogenesis epistasis, quantitative phenotypic readouts\",\n      \"pmids\": [\"31097586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In C. elegans, selenoprotein TRXR-1 (the ortholog of mammalian TrxR1) and glutathione reductase GSR-1 cooperate to reduce disulfide bonds in the old cuticle during molting; loss of either causes oxidized cuticle disulfides and molting failure. This TRXR-1 function is strictly selenocysteine-dependent: a Sec-to-Cys mutant fails to rescue.\",\n      \"method\": \"C. elegans genetic KD (RNAi), Sec→Cys knock-in mutant rescue experiments, cuticle disulfide oxidation state assay, reduced glutathione exogenous supply rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Sec-to-Cys mutagenesis rescue in vivo, multiple genetic lines, replicated with chemical rescue\",\n      \"pmids\": [\"21199936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TrxR1 inhibition (by auranofin or siRNA) blocks STAT3-dependent transcription indirectly: TrxR1 inhibition causes oxidation of Prx2 and then STAT3, preventing STAT3-dependent gene expression. Established STAT3 inhibitors also inhibit TrxR1.\",\n      \"method\": \"Cellular luciferase reporter for STAT3 transcription, TrxR1 inhibitor panel, STAT3/Prx2 oxidation assays (redox western blot), siRNA knockdown\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established through inhibitor + KD + redox protein oxidation assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32219156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RITA (NSC 652287) inhibits TrxR1 by non-covalent binding and reduces TrxR activity in cancer cells in a p53-dependent manner, inducing a ~130 kDa TrxR1 covalent dimer and ROS generation selectively in cancer cells but not in normal fibroblasts.\",\n      \"method\": \"In vitro TrxR1 activity assay with RITA, cellular TrxR activity measurement, ROS detection, comparison across p53-status cell lines and normal fibroblasts\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding + cellular activity assay + p53-dependence shown genetically; single lab\",\n      \"pmids\": [\"19838062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KEAP1-dependent synthetic lethality between TXNRD1 inhibition and AKT inhibition in NSCLC: simultaneous TXNRD1 (siRNA or auranofin) and AKT (MK2206) inhibition induces ROS, JNK activation, and apoptosis; this lethality is abrogated by mutant KEAP1, placing TXNRD1 within the KEAP1/NRF2 antioxidant pathway.\",\n      \"method\": \"Genome-wide siRNA library screen, pharmacological inhibitor combination, siRNA validation, ROS measurement, xenograft model, KEAP1 mutation status analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen followed by siRNA + pharmacological validation in vitro and in vivo, KEAP1 epistasis established\",\n      \"pmids\": [\"23824739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During RANKL-induced osteoclastogenesis, NFATc1 transcriptionally upregulates SLC7A11, causing pre-osteoclasts to accumulate cystine upon TXNRD1 inhibition (since disulfide reduction rate is slowed). This cystine accumulation leads to disulfidptosis, a distinct cell death rescued by SLC7A11 inhibitors or agents preventing disulfide accumulation, but not by ferroptosis, ROS, apoptosis, or autophagy inhibitors.\",\n      \"method\": \"NFATc1 ChIP/transcriptional reporter, SLC7A11 overexpression/knockdown, TXNRD1 inhibitors, rescue with pathway-specific inhibitors, in vivo OVX mouse model, cystine measurement\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptional mechanism established by ChIP, metabolite measurements, pathway-specific rescue panel, in vivo validation\",\n      \"pmids\": [\"37148740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TXNRD1 attenuates the interaction between Trx1 and PTEN, leading to accelerated PTEN degradation and subsequent Akt/mTOR pathway activation in hepatocellular carcinoma. Additionally, USF2 was identified as a transcriptional suppressor that directly binds two E-box sites in the TXNRD1 promoter to repress TXNRD1 expression.\",\n      \"method\": \"Co-immunoprecipitation (Trx1–PTEN interaction), TXNRD1 KD/OE, Akt/mTOR signaling readouts, USF2 ChIP on TXNRD1 promoter E-box sites\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus promoter ChIP; single lab, two orthogonal methods\",\n      \"pmids\": [\"36319631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Manumycin A irreversibly inhibits mammalian TrxR1 with time-dependent kinetics (IC50 272 nM with pre-incubation) by forming a covalent Michael adduct with the selenocysteine residue in TrxR1's C-terminal redox center, converting TrxR1 into a SecTRAP that uses NADPH to reduce O2 to superoxide.\",\n      \"method\": \"In vitro TrxR1 activity assay (time-dependent kinetics), irreversibility testing (dialysis), mass spectrometry for Michael adduct identification at Sec residue\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinetics + covalent adduct identified by MS + mechanism-based characterization; single lab\",\n      \"pmids\": [\"29670693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Multiple gold compounds (auranofin, gold sodium thiomalate, sodium aurothiosulfate, triphenyl phosphine gold chloride, gold acetate) inhibit TrxR1 at sublethal concentrations (IC50 5–4000 nM). Au(I)-phosphine compounds are the most potent; ligand configuration rather than gold oxidation state determines inhibitory potency.\",\n      \"method\": \"Ex vivo TrxR1 activity assay with purified rat TrxR1 and panel of gold compounds, mitochondrial activity (succinate dehydrogenase) comparison\",\n      \"journal\": \"Toxicology in vitro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with structure-activity analysis; single lab, single method\",\n      \"pmids\": [\"16510263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Trx1/TrxR1 system is critically required for survival of post-selected double-positive (CD69+) thymocytes: TrxR1 inhibition (but not GSH pathway suppression) specifically reduced this subset in vitro and in vivo, associated with enhanced phosphorylation of ASK1, JNK, p38 MAPK, and upregulation of Bim.\",\n      \"method\": \"TrxR1 inhibitor (auranofin) vs. GSH pathway inhibitor treatment of thymocytes, in vitro and in vivo cell subset analysis, phospho-ASK1/JNK/p38 western blot, Bim expression\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitor selectivity comparison in vivo and in vitro with defined signaling readout; single lab\",\n      \"pmids\": [\"25753394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TrxR1 overexpression reduces radiosensitivity of glioma cells, and TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma by inhibiting radiation-induced Trx1 nuclear transport, placing TrxR1 upstream of Trx1 nuclear localization as a radioprotective mechanism.\",\n      \"method\": \"Stable TrxR1 overexpression in glioma cells, siRNA TIGAR KD, clonogenic survival assay, Trx1 nuclear/cytoplasmic fractionation after irradiation, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic OE/KD epistasis combined with fractionation and in vivo validation; single lab\",\n      \"pmids\": [\"28338004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TrxR1 is downregulated during skeletal muscle differentiation (myogenesis) and this decrease is functionally required: TrxR1 depletion promotes early myogenesis markers (myogenin, Myf5 upregulation; Cyclin D1 decrease), while TrxR1 overexpression delays myogenic differentiation. miR-23a and miR-23b directly bind the 3′ UTR of TrxR1 mRNA (confirmed by reporter assay) and mediate TrxR1 downregulation during early C2C12 differentiation.\",\n      \"method\": \"siRNA KD and overexpression of TrxR1 in C2C12 cells, myogenic marker expression, miR-23a/b overexpression and inhibition, 3′-UTR luciferase reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function plus 3′-UTR reporter validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"28775321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Homozygous missense mutation p.Pro190Leu in TXNRD1 causes ~66–84% reduction of TrxR1 enzymatic activity in patient fibroblasts and skeletal muscle, arising from both reduced enzyme turnover (30–40% lower kcat/Se by in vitro kinetics) and reduced selenoprotein abundance (reduced 75Se labeling). Mutant cells are less resistant to hydrogen peroxide challenge.\",\n      \"method\": \"75Se metabolic labeling, western blot, TrxR1 activity assay in patient tissue fractions, in vitro kinetic analysis of recombinant mutant enzyme, H2O2 challenge\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of recombinant mutant enzyme kinetics combined with patient-derived cell biochemistry and Se labeling; single study but multiple orthogonal methods\",\n      \"pmids\": [\"28232204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LNCRNA CARD8-AS1 acts as a scaffold that facilitates interaction between TXNRD1 and the E3 ubiquitin ligase TRIM25, promoting ubiquitin-proteasome-mediated degradation of TXNRD1, thereby suppressing lung adenocarcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation (TXNRD1–TRIM25 interaction), CARD8-AS1 overexpression/KD, proteasome inhibitor rescue, in vitro and in vivo tumor models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing scaffold function plus proteasome pathway validation; single lab\",\n      \"pmids\": [\"38153696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Simvastatin inhibits the basal activity of the TXNRD1 core promoter (~20% reduction) and reduces cellular TrxR1 mRNA (~25%) and activity (~40%) in HepG2 cells through a mechanism independent of HMGCoA reductase inhibition (mevalonate rescue failed). This inhibition is specific to basal—not Nrf2-activated—TXNRD1 transcription.\",\n      \"method\": \"TXNRD1 promoter-luciferase reporter assay, TrxR1 mRNA qPCR, TrxR activity assay, mevalonate rescue, sulforaphane (Nrf2 activator) co-treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter + mRNA + activity assay with mechanistic dissection; single lab\",\n      \"pmids\": [\"23154180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The selective cellular probe RX1 (a cyclic selenenylsulfide) was developed to quantify TrxR1 activity in live cells based on TrxR1's unique selenolthiol chemistry. RX1 was cross-validated as TrxR1-selective by knockout, selenium starvation, knock-in, and chemical inhibitors, enabling high-throughput live-cell screening for TrxR1 inhibitors.\",\n      \"method\": \"Fluorogenic probe design with selenylsulfide mechanism, TXNRD1 KO cells, selenium-deficient cells, TXNRD1 knock-in rescue, auranofin competition, high-throughput screening\",\n      \"journal\": \"Chem\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanism-based probe design validated by four orthogonal genetic/chemical controls in cells; single lab but rigorous multi-method validation\",\n      \"pmids\": [\"35936029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deferoxamine activates the Nrf2/TXNRD1 axis in hippocampal neurons: Nrf2 positively regulates TXNRD1 protein expression (shown by co-immunoprecipitation and western blotting), and this axis mediates DFO's protection against ferroptosis and inflammation following subarachnoid hemorrhage.\",\n      \"method\": \"Co-immunoprecipitation (Nrf2–TXNRD1 regulation), western blot, Nrf2 inhibitor ML385, SAH mouse model, in vitro FIN56-induced ferroptosis model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pathway inhibitor in vivo and in vitro; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"37676391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glaucocalyxin A (GLA) covalently binds to Cys173 of PRDX1 and to Cys59, Cys64, Cys497, and Sec498 of TXNRD1, inhibiting both enzymes. Activity-based protein profiling (ABPP) identified these covalent adducts; computational modeling ranked covalent bond reactivity as Sec498 > Cys59 > Cys497 > Cys64.\",\n      \"method\": \"Activity-based protein profiling (ABPP), mass spectrometry for covalent adduct identification, computational chemistry for binding site characterization, TrxR1 activity assay\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ABPP with MS-confirmed covalent modification sites; single lab, computational analysis supporting experimental data\",\n      \"pmids\": [\"41016297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TXNRD1 knockdown in human aortic endothelial cells (HAECs) exposed to oscillatory shear stress inhibits their proliferation by activating the eNOS/apoptosis pathway; L-NAME (eNOS inhibitor) reversed the pro-apoptotic effect of TXNRD1 knockdown, establishing eNOS as downstream of TXNRD1 in shear stress-induced endothelial proliferation.\",\n      \"method\": \"siRNA TXNRD1 KD in oscillatory shear stress model, L-NAME pharmacological inhibition of eNOS, proliferation/migration/tube formation assays, apoptosis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD plus pharmacological epistasis (eNOS inhibitor rescue); single lab\",\n      \"pmids\": [\"36754152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elovanoid ELV-N34 directly binds TXNRD1 (isoforms 2 or 3) in human RPE cells identified by limited proteolysis (LiP) screening, induces conformational changes at the FAD interface domain, and decreases both membrane and cytosolic TXNRD1 activity, modulating the thioredoxin system.\",\n      \"method\": \"Limited proteolysis (LiP) screening, TXNRD1 siRNA isoform-specific silencing, TXNRD1 activity assay (membrane vs. cytosolic fractions)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LiP target identification validated by isoform-specific siRNA and activity measurement; single lab\",\n      \"pmids\": [\"38086796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endogenously formed electrophiles (4-HNE, methylglyoxal, lipid peroxides) and peroxymonocarbonate can inhibit TXNRD1 at its exposed catalytic selenocysteine residue, modulating RTK/PTP signaling cascades and activating KEAP1/NRF2, linking TXNRD1 to redox regulation of tyrosine phosphorylation signaling.\",\n      \"method\": \"Mechanistic review integrating prior biochemical experiments on Sec modification by electrophiles, PTP activity assays, and KEAP1/NRF2 pathway readouts (as reported in cited primary literature)\",\n      \"journal\": \"Current opinion in chemical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review/proposal integrating prior data rather than presenting new direct experiments; mechanistic framework but insufficient primary experimental data in this paper\",\n      \"pmids\": [\"39243480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The sesquiterpene lactone prodrug 5u (releasing active compound 6a in response to ROS) covalently binds to Cys475 and Sec498 on TrxR1, inhibiting TrxR1 activity and causing redox homeostasis disruption leading to apoptosis and ferroptosis in NSCLC cells.\",\n      \"method\": \"In vitro TrxR1 activity assay, mass spectrometry for covalent binding site identification (Cys475, Sec498), ROS measurement, xenograft and organoid models\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-confirmed covalent binding at defined residues plus in vitro activity assay; single lab\",\n      \"pmids\": [\"39869029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Micheliolide (MCL) directly interacts with both TrxR1 and TrxR2, inhibiting their enzymatic activities, as validated by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. MCL-induced TrxR1/2 inhibition elevates ROS, activates MEK/ERK, and suppresses autophagy in hepatic stellate cells.\",\n      \"method\": \"CETSA, DARTS (target engagement assays), TrxR1/2 activity assay, ROS measurement, MEK/ERK western blot, CCl4 mouse fibrosis model\",\n      \"journal\": \"Pharmaceuticals (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal target engagement assays (CETSA + DARTS) confirming direct binding, with functional activity assay; single lab\",\n      \"pmids\": [\"40143066\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TXNRD1 encodes cytosolic selenoprotein thioredoxin reductase 1, a NADPH-dependent FAD-containing disulfide reductase that reduces thioredoxin via its C-terminal selenocysteine (Sec) residue; the Sec is essential for its canonical reductase function and for elimination of glucose-derived H2O2, but TXNRD1 also operates non-enzymatically as a scaffold that localizes to cytoplasmic chromatin fragments in senescent cells and directly stimulates cGAS to drive the cGAS-STING SASP/inflammaging pathway, and via its v3 splice variant undergoes N-myristoylation/palmitoylation to target membrane rafts where it induces actin-dependent filopodia through its glutaredoxin domain; its Sec residue is a high-reactivity target for diverse electrophiles, gold compounds, and drug-like inhibitors, and its inhibition broadly shifts cellular redox balance toward oxidation, activating KEAP1/NRF2, ASK1-JNK/p38, and Akt/mTOR signaling while TrxR1 activity in the nucleus supports Trx1 nuclear transport to confer radioresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TXNRD1 encodes the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1), an NADPH-dependent disulfide reductase whose C-terminal selenocysteine (Sec) confers its catalytic activity and constitutes a uniquely reactive nucleophile [#19, #14]. Together with the glutathione system it forms one of the two principal hepatic antioxidant pathways, and the two systems are functionally redundant for survival: loss of TrxR1 is tolerated while one functional allele or intact GSH remains, but combined disruption produces massive DNA damage and supports a redox switch toward glutathione, glucuronidation, and xenobiotic export that paradoxically protects against electrophilic hepatotoxins such as the acetaminophen metabolite NAPQI [#5, #6, #7]. The Sec residue is strictly required for clearing glucose-derived H2O2 and for cell survival under high-glucose stress, and across species Sec-dependent disulfide reduction by TrxR1 supports processes ranging from ribonucleotide-reductase-driven DNA replication to cuticle remodeling [#4, #8]. TrxR1 also sets the redox tone of multiple signaling axes: its inhibition oxidizes Prx2 and STAT3 to block STAT3-dependent transcription [#9], engages the KEAP1/NRF2 antioxidant network where it shows KEAP1-dependent synthetic lethality with AKT inhibition [#11], and drives ASK1-JNK/p38 signaling required for thymocyte survival [#16]; in cancer cells TrxR1 attenuates Trx1–PTEN interaction to activate Akt/mTOR and supports Trx1 nuclear transport conferring radioresistance [#13, #17]. Beyond enzymatic reduction, TrxR1 acts non-enzymatically as a scaffold: in senescent cells it localizes to cytoplasmic chromatin fragments, binds cGAS, and stimulates cGAS activity to drive the cGAS-STING SASP/inflammaging program [#1], while its v3 splice variant is acylated at an N-terminal MGC motif to target membrane rafts and induce actin-dependent filopodia through its glutaredoxin domain independently of its redox-active cysteines [#2, #3]. TrxR1 expression and stability are controlled by NRF2, the transcriptional repressor USF2, miR-23a/b, and TRIM25-mediated ubiquitination [#13, #18, #20, #23]. The Sec residue makes TrxR1 a high-reactivity target for gold compounds and diverse covalent and non-covalent inhibitors, several of which convert the enzyme into a superoxide-producing SecTRAP, and a homozygous p.Pro190Leu mutation that reduces TrxR1 activity and selenoprotein abundance establishes a direct human genetic link to TXNRD1 dysfunction [#14, #15, #19, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that diverse gold compounds inhibit TrxR1 at sublethal concentrations, defining the enzyme as a tractable, ligand-tunable pharmacological target.\",\n      \"evidence\": \"Ex vivo activity assay of purified rat TrxR1 against a panel of gold compounds with structure-activity analysis\",\n      \"pmids\": [\"16510263\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single in vitro enzymatic method\", \"Cellular selectivity over other selenoproteins not addressed\", \"Mechanism of Sec engagement not directly mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that the TXNRD1_v3 splice variant has a non-canonical cytoskeletal function, forming cytoplasmic filaments and inducing actin-dependent filopodia via its glutaredoxin domain.\",\n      \"evidence\": \"Overexpression of truncated/full-length v3 constructs, live-cell imaging, cytochalasin D actin inhibition\",\n      \"pmids\": [\"19654027\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Relied on overexpression\", \"Endogenous v3 contribution unknown\", \"Molecular link between Grx domain and actin not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated in vivo that TrxR1 and the glutathione pathway are independent, redundant routes supporting DNA replication, resolving how cells survive loss of either system.\",\n      \"evidence\": \"Hepatocyte conditional Txnrd1 KO with BSO-mediated GSH depletion and BrdU replicative index\",\n      \"pmids\": [\"22198266\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ribonucleotide reductase electron donation inferred not directly traced\", \"Cell-type generality beyond hepatocytes unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that the selenocysteine of TrxR1 is strictly required for disulfide reduction in a physiological remodeling process, using cross-species genetics.\",\n      \"evidence\": \"C. elegans RNAi, Sec\\u2192Cys knock-in rescue, cuticle disulfide assays, GSH chemical rescue\",\n      \"pmids\": [\"21199936\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mammalian equivalent of cuticle remodeling not applicable\", \"Substrate scope beyond cuticle disulfides not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a metabolic-rewiring consequence of TrxR1 loss in liver and explained why such livers resist electrophilic hepatotoxins despite NAPQI directly inactivating the enzyme.\",\n      \"evidence\": \"Hepatocyte-specific Txnrd1 KO with transcriptomics/metabolomics, APAP challenge, TrxR1 activity assay\",\n      \"pmids\": [\"23743293\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Master regulator driving the compensatory program not fully identified\", \"Reversibility of the metabolic switch unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Anchored TXNRD1 within the KEAP1/NRF2 axis by revealing KEAP1-dependent synthetic lethality between TXNRD1 and AKT inhibition in NSCLC.\",\n      \"evidence\": \"Genome-wide siRNA screen with pharmacological combination, ROS/JNK readouts, KEAP1 mutation epistasis, xenografts\",\n      \"pmids\": [\"23824739\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular link between TrxR1 and KEAP1 sensing not defined\", \"Generality beyond KEAP1-mutant NSCLC unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that v3 raft targeting via N-terminal acylation, not its redox-active cysteines, drives filopodia, separating the variant's structural role from catalysis.\",\n      \"evidence\": \"MGC-motif site-directed mutagenesis, lipid fractionation, cholera toxin B co-localization, imaging\",\n      \"pmids\": [\"23413027\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological trigger of v3 localization unknown\", \"Downstream actin effectors not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that Sec-containing TrxR1 is essential for clearing glucose-derived H2O2 and for survival under high-glucose stress, distinguishing the selenoprotein from Sec-devoid forms.\",\n      \"evidence\": \"Txnrd1-null MEFs with WT vs. Sec-mutant reconstitution, H2O2 and viability assays\",\n      \"pmids\": [\"24853413\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance of glucose-driven death not tested\", \"Sec-devoid variant residual activity not quantified in tissue\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected TrxR1 activity to transcription, showing inhibition oxidizes Prx2 and then STAT3 to block STAT3-dependent gene expression.\",\n      \"evidence\": \"STAT3 luciferase reporter, inhibitor panel, redox western blot of Prx2/STAT3 oxidation, siRNA\",\n      \"pmids\": [\"32219156\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs. relay nature of STAT3 oxidation not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TrxR1 as a survival factor for post-selected thymocytes acting through suppression of ASK1-JNK/p38 stress signaling.\",\n      \"evidence\": \"Auranofin vs. GSH-pathway inhibition in vitro and in vivo, phospho-ASK1/JNK/p38 and Bim readouts\",\n      \"pmids\": [\"25753394\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Inhibitor specificity for TrxR1 not genetically confirmed in thymocytes\", \"Direct redox target upstream of ASK1 unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TrxR1 upstream of Trx1 nuclear transport as a radioprotective mechanism in glioma.\",\n      \"evidence\": \"Stable TrxR1 overexpression, TIGAR knockdown, clonogenic survival, Trx1 nuclear fractionation, xenograft\",\n      \"pmids\": [\"28338004\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism coupling TrxR1 to Trx1 import not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that TrxR1 downregulation is required for myogenesis and identified miR-23a/b as direct repressors of TXNRD1.\",\n      \"evidence\": \"TrxR1 KD/OE in C2C12, myogenic markers, miR-23a/b modulation, 3' UTR luciferase reporter\",\n      \"pmids\": [\"28775321\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Redox target driving differentiation block unknown\", \"In vivo muscle relevance not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a direct human genetic link by showing a homozygous TXNRD1 p.Pro190Leu mutation reduces enzyme turnover and selenoprotein abundance with impaired H2O2 resistance.\",\n      \"evidence\": \"75Se labeling, patient-tissue activity assays, recombinant mutant kinetics, H2O2 challenge\",\n      \"pmids\": [\"28232204\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Clinical phenotype-genotype causation from single family\", \"Mechanism of reduced selenoprotein abundance not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated mechanism-based conversion of TrxR1 into a superoxide-generating SecTRAP via covalent Sec adduct formation, defining a toxic gain-of-function inhibition mode.\",\n      \"evidence\": \"Time-dependent kinetics, dialysis irreversibility, MS adduct identification at Sec (manumycin A)\",\n      \"pmids\": [\"29670693\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cellular contribution of SecTRAP superoxide to toxicity not quantified\", \"Selectivity over other selenoproteins not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the redundancy and tumor-suppressive context of TrxR1, with TrxR1/Gsr double loss causing severe DNA damage and TrxR1 loss reducing carcinogen-induced tumor initiation.\",\n      \"evidence\": \"Single and double conditional KO mice, DEN carcinogenesis, DNA damage indices, tumor scoring\",\n      \"pmids\": [\"31097586\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why TrxR1 loss affects initiation but not progression unresolved\", \"Specific oxidized lesions driving malignancy not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed TrxR1 promotes Akt/mTOR signaling in HCC by attenuating Trx1\\u2013PTEN interaction and accelerating PTEN degradation, and identified USF2 as a direct promoter repressor.\",\n      \"evidence\": \"Co-IP of Trx1\\u2013PTEN, TXNRD1 KD/OE with Akt/mTOR readouts, USF2 ChIP on TXNRD1 E-boxes\",\n      \"pmids\": [\"36319631\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs. indirect effect on PTEN stability unresolved\", \"Single lab, two methods\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delivered a mechanism-based live-cell probe exploiting TrxR1's selenolthiol chemistry, enabling rigorous activity quantification and inhibitor screening.\",\n      \"evidence\": \"Selenylsulfide fluorogenic probe RX1 validated by KO, Se starvation, knock-in, and auranofin competition\",\n      \"pmids\": [\"35936029\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Isoform discrimination not addressed\", \"Probe is a tool, not a biological finding about endogenous regulation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that two widely used 'GPX4 inhibitors' (RSL3, ML162) are in fact efficient TrxR1 inhibitors, correcting target attribution in ferroptosis studies.\",\n      \"evidence\": \"In vitro assays with recombinant GPX4 and TXNRD1, biochemical inhibition profiling\",\n      \"pmids\": [\"37087975\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cellular ferroptosis contribution of TrxR1 inhibition by these compounds not fully dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked TrxR1's disulfide-reduction rate to a distinct death modality (disulfidptosis) in osteoclastogenesis, where SLC7A11-driven cystine accumulates when TXNRD1 is inhibited.\",\n      \"evidence\": \"NFATc1 ChIP, SLC7A11 OE/KD, TXNRD1 inhibitors, pathway-specific rescue panel, OVX mouse model\",\n      \"pmids\": [\"37148740\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Generality of disulfidptosis beyond high-SLC7A11 contexts unclear\", \"Direct biochemical step from TrxR1 to cystine pool not isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed NRF2 positively regulates TXNRD1 protein expression in neurons as part of a deferoxamine-protective axis against ferroptosis.\",\n      \"evidence\": \"Co-IP of Nrf2\\u2013TXNRD1, western blot, ML385 inhibition, SAH and FIN56 ferroptosis models\",\n      \"pmids\": [\"37676391\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct transcriptional vs. indirect regulation by NRF2 not delineated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a non-enzymatic, scaffold function of TXNRD1 in driving inflammaging via direct stimulation of cGAS in the cGAS-STING pathway, dissociable from reductase activity.\",\n      \"evidence\": \"Reciprocal Co-IP with cGAS, fractionation/imaging, KO/KD, cGAS activity assay, selective inhibitors in aged mice\",\n      \"pmids\": [\"38267705\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of cGAS stimulation not resolved\", \"How senescence recruits TXNRD1 to chromatin fragments unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a lncRNA-scaffolded TRIM25-dependent ubiquitination route controlling TXNRD1 abundance, adding post-translational regulation as a tumor-suppressive axis.\",\n      \"evidence\": \"Co-IP of TXNRD1\\u2013TRIM25, CARD8-AS1 OE/KD, proteasome inhibitor rescue, tumor models\",\n      \"pmids\": [\"38153696\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ubiquitination site on TXNRD1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected TXNRD1 to endothelial proliferation under shear stress through an eNOS/apoptosis axis.\",\n      \"evidence\": \"siRNA KD in oscillatory shear model, L-NAME eNOS inhibition, proliferation/apoptosis assays\",\n      \"pmids\": [\"36754152\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Redox intermediate linking TrxR1 to eNOS unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple covalent natural-product and prodrug inhibitors were mapped to specific Cys/Sec residues, refining the structural basis of TrxR1 electrophile reactivity and its coupling to ROS-driven cell death.\",\n      \"evidence\": \"ABPP/MS adduct mapping, CETSA/DARTS target engagement, activity assays, xenograft/organoid models (GLA, prodrug 5u, micheliolide)\",\n      \"pmids\": [\"41016297\", \"39869029\", \"40143066\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Off-target reactivity across the selenoproteome not fully excluded\", \"Relative contribution of each modified residue to inhibition partly computational\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TXNRD1's enzymatic and non-enzymatic (cGAS-scaffolding, v3 cytoskeletal) functions are partitioned between isoforms, tissues, and physiological states, and the structural basis of its protein-stimulatory roles, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of TXNRD1-cGAS or TXNRD1-substrate complexes in the corpus\", \"Endogenous regulation of v3 isoform expression undefined\", \"Integration of redox-signaling outputs (KEAP1/NRF2, ASK1, Akt/mTOR) into a unified model not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 8, 19, 14]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [14, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 26, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 26]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 13, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 16, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"cGAS\", \"TRIM25\", \"Trx1\", \"PTEN\", \"cuticle GSR-1 (GSR)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}