{"gene":"TXNRD2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"EGFP-TrxR2 fusion protein is enzymatically active as a thioredoxin reductase and localizes to mitochondria when overexpressed in Neuro2A cells; overexpression of TrxR2 up to 6-fold did not protect cells against apoptotic stimuli (prooxidant or non-oxidant) nor prevent mitochondrial membrane potential dissipation, ROS induction, or caspase activation, indicating that excess TrxR2 does not regulate mitochondria-dependent apoptosis.","method":"Stable transfection of EGFP-TrxR2 fusion, enzymatic activity assay, mitochondrial fractionation, flow cytometry for apoptosis markers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional assay, enzymatic activity measurement, multiple apoptotic stimuli tested; single lab","pmids":["15082714"],"is_preprint":false},{"year":2003,"finding":"A dominant-negative form of TrxR2 (TrxR2DN) in HeLa cells caused increased hydrogen peroxide production upon EGF stimulation, elevated protein tyrosine phosphorylation of ERK and other proteins, and accelerated G1-to-S phase cell cycle progression and cell proliferation, establishing TrxR2 as a component of the mitochondrial H2O2-eliminating system (together with Prxm III and Trx2) that regulates protein tyrosine phosphorylation and cell growth.","method":"Tetracycline-off dominant-negative stable cell line, ROS measurement (H2O2), immunoblot for phosphotyrosine/ERK, flow cytometry for cell cycle","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative loss-of-function with multiple orthogonal readouts (ROS, phosphorylation, cell cycle); single lab","pmids":["12705894"],"is_preprint":false},{"year":2011,"finding":"Two DCM-associated TXNRD2 missense mutations (Ala59Thr and Gly375Arg) affect conserved residues in helices of the FAD-binding domain; neither mutant restored TrxR2 function in Txnrd2-/- mouse fibroblasts, and both exerted dominant-negative effects impairing survival of wild-type cells under oxidative stress, defining the FAD-binding domain as essential for enzymatic activity.","method":"Sequencing, reconstitution in Txnrd2-/- mouse fibroblasts, functional enzymatic assay, oxidative stress survival assay","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — loss-of-function reconstitution in null cells, active-site mutagenesis linked to defined enzymatic activity, dominant-negative mechanism confirmed","pmids":["21247928"],"is_preprint":false},{"year":2015,"finding":"Heart-specific, tamoxifen-inducible knockout of Txnrd2 in adult mice leads to dilated cardiomyopathy with decreased fractional shortening and ejection fraction, mitochondrial degeneration, accumulation of autophagic bodies, elevated LAMP1/LC3-I/p62, reduced mitochondrial oxygen consumption, increased mitochondrial ROS, and HIF-1α stabilization, establishing Txnrd2 as required for mitochondrial integrity, autophagic flux, and energy metabolism in the aging heart.","method":"Conditional cardiac-specific Cre/loxP knockout, echocardiography, electron microscopy, mitochondrial oxygen consumption assay, metabolomics, Western blot","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean tissue-specific KO with multiple orthogonal phenotypic and biochemical readouts, functional mitochondrial assays","pmids":["26199228"],"is_preprint":false},{"year":2014,"finding":"A homozygous stop-gain mutation (p.Y447X) in TXNRD2 causes complete absence of TXNRD2 protein (confirmed by Western blot) and impairs redox homeostasis in a human adrenocortical cell line (H295R TXNRD2-knockdown), establishing TXNRD2 as required for adrenocortical redox homeostasis and glucocorticoid production in humans.","method":"Whole-exome sequencing, Sanger sequencing, RT-PCR, Western blot, shRNA knockdown in H295R cells, redox assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function mutation with functional validation in human adrenocortical cell line, multiple molecular methods","pmids":["24601690"],"is_preprint":false},{"year":2016,"finding":"p53R2 directly binds TrxR2 (shown by co-immunoprecipitation and pulldown), stimulates TrxR2 enzymatic activity in vitro, and is required for full TrxR2 activity in cells: TrxR2 activity is lower in p53R2-knockdown cells and higher upon p53R2 overexpression, in a p53-independent manner; p53R2 knockdown also suppresses UV-induced TrxR activity.","method":"Co-immunoprecipitation, direct interaction assay, in vitro TrxR enzymatic activity assay, siRNA knockdown, overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus reciprocal binding assay and cellular KD/OE; single lab","pmids":["27866984"],"is_preprint":false},{"year":2021,"finding":"Endothelial-specific deletion of Txnrd2 in mice increases steady-state peroxynitrite levels (measured by fluorescein-boronate probe) in vascular endothelial cells and vessels, elevates protein tyrosine nitration, oxidizes Prx3, and causes increased vascular stiffness, vascular wall hypertrophy, and renal pathology (glomerulosclerosis, Bowman's capsule thickening); peroxynitrite is generated in mitochondria (MitoPY1 probe) and peroxynitrite-decomposition catalyst Mn(III)TMPyP blunted the intravascular peroxynitrite. This establishes TrxR2 as regulator of the nitric oxide/peroxynitrite balance in endothelium.","method":"Endothelial-specific conditional knockout, redox-sensitive fluorescent probes (fluorescein-boronate, MitoPY1), protein nitration assay, redox state of Prx3, pharmacological rescue with Mn(III)TMPyP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple orthogonal mechanistic readouts including direct peroxynitrite measurement and pharmacological rescue in vivo","pmids":["33579817"],"is_preprint":false},{"year":2002,"finding":"The mouse TrxR2 gene spans 53 kb with 18 exons; an alternative splice variant lacking intron 14 produces a protein with a shorter interface domain, predicted to enable a heterodimeric or small-subunit homodimeric conformation, expanding the known homodimeric structure of TrxR2.","method":"Genomic sequencing, intron–exon mapping, RT-PCR identification of splice variant, structural prediction","journal":"Molecules and cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene structure and splice variant identified by sequencing/RT-PCR; functional consequence of splice variant not experimentally confirmed","pmids":["12132591"],"is_preprint":false},{"year":2012,"finding":"TrxR2 (and GPx2 and TrxR3) expression is dependent on Wnt/β-catenin pathway activity in intestinal epithelium: expression is higher in proliferative crypt compartments where Wnt is active, is consistent with activated versus inhibited Wnt pathway in cell culture models, and is reduced by inducible knockout of β-catenin in colonic crypt base cells ex vivo, identifying TrxR2 as a novel Wnt target selenoprotein.","method":"Cell culture models with Wnt3a overexpression and APC-mediated inhibition, intestinal crypt/villus fractionation, inducible β-catenin knockout, RT-PCR and Western blot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (in vitro and ex vivo), inducible β-catenin KO confirming pathway dependence; single lab","pmids":["22683372"],"is_preprint":false},{"year":2016,"finding":"TrxR2 deficiency in chondrogenic ATDC5 cells (via shRNA) increases mitochondrial ROS without altering mitochondrial membrane potential or ATP, enhances chondrogenic differentiation (elevated collagen II, aggrecan, GAG accumulation, mineralization), activates Akt signaling required for chondrogenesis, promotes cell cycle progression (increased S and G2/M phase), and induces apoptosis. NAC (antioxidant) reversed all these effects, placing mitochondrial ROS downstream of TrxR2 loss as the mechanistic driver.","method":"shRNA knockdown, ROS measurement, mitochondrial membrane potential assay, ATP assay, chondrogenic differentiation markers (qPCR, staining), flow cytometry (cell cycle, apoptosis), NAC rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with pharmacological rescue (NAC) and multiple orthogonal readouts; single lab","pmids":["27107686"],"is_preprint":false},{"year":2022,"finding":"Transgenic mice overexpressing TrxR2 show enhanced glucose tolerance, decreased fat deposition on high-fat diet, and increased mitochondrial function driven by enhanced tricarboxylic acid cycle and electron transport chain function, establishing TrxR2 as a rate-limiting enzyme in the mitochondrial thioredoxin system that regulates mitochondrial metabolic function.","method":"Transgenic mouse overexpression, metabolic phenotyping (glucose tolerance test), mitochondrial function assays, TCA/ETC activity measurements","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic overexpression in vivo with multiple metabolic and mitochondrial functional readouts; single lab","pmids":["35577894"],"is_preprint":false},{"year":2024,"finding":"Txnrd2 knockdown (siRNA) in a rat intracerebral hemorrhage model increases lipid peroxidation and ER stress (Trx2 and Prx3 pathway disrupted), worsens brain edema and neurological deficits. Pharmacological selenium (sodium selenite) restores Txnrd2 expression, inhibits ER stress markers, and reduces ROS via the Trx2/Prx3 pathway, positioning Txnrd2 upstream of Trx2/Prx3 in the mitochondrial antioxidant cascade controlling neuronal ER stress.","method":"siRNA knockdown in vivo (rat ICH model), selenium supplementation rescue, lipid peroxidation assay, ER stress protein expression, neurological deficit scoring","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD in vivo with pharmacological rescue and multiple molecular readouts; single lab","pmids":["38513765"],"is_preprint":false},{"year":2024,"finding":"A homozygous TXNRD2 splice variant (c.1348-1G>T) produces a shorter protein lacking the C-terminus, affecting homodimerization and FAD-binding. Patient-derived induced pluripotent stem cell-derived adrenal-like cells (iALC) with this variant show loss of cortisol production, diminished overall adrenal steroidogenesis, and significantly increased ROS production, directly linking TXNRD2 enzymatic activity (FAD-binding and dimerization) to adrenal ROS detoxification and steroidogenesis.","method":"Whole exome sequencing, RNA analysis, protein structure modeling, iPS-cell-derived adrenal-like cells, cortisol and steroidogenesis assays, ROS measurement","journal":"European journal of endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional characterization of splice variant in patient-derived iPSC-differentiated cell model with structural analysis, enzymatic domain assignment, and multiple biochemical readouts","pmids":["39097530"],"is_preprint":false},{"year":2026,"finding":"Endothelial-specific TrxR2 knockout exacerbates cardiac microvascular dysfunction and diabetic cardiomyopathy; TrxR2 inhibits mitochondria-associated ferroptosis by facilitating SCP2 degradation and blocking mitochondrial translocation of ACSL4 via mitophagy; TrxR2 maintains TUFM expression by scavenging oxygen radicals, enabling mitochondrial AMPK translocation for mitophagy activation. TrxR2 undergoes lactylation at lysine 340, mediated by mitochondrial AARS2; this modification enhances mitoTrxR activity and promotes mitophagy, conferring ferroptosis resistance.","method":"Endothelial-specific knockout mice, transgenic overexpression, mass spectrometry (lactylation site identification), custom lactylation antibody, bulk RNA-sequencing, fluorescence staining for mitoTrxR activity and lipid peroxyl radicals, mitophagy assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transgenic/KO models and MS-based PTM identification with functional assays; single lab, newly published","pmids":["41704008"],"is_preprint":false},{"year":2007,"finding":"Txnrd2 hemizygosity (+/-) in mice reduces TrxR2 enzymatic activity in a gene-dose-dependent manner across all tissues examined; selenium depletion further reduces activity but not below levels seen with Se depletion alone, except in kidney, heart, and muscle where hemizygosity and Se depletion have an additive effect on TrxR2 activity.","method":"Hemizygous mouse model, selenium dietary manipulation, tissue Se content measurement, enzymatic activity assay across multiple tissues","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic and dietary manipulation with enzymatic activity measurements across multiple tissues; single lab","pmids":["17937623"],"is_preprint":false},{"year":2025,"finding":"Non-covalent TXNRD inhibitors inhibit both TXNRD1 and TXNRD2 enzymatic activity; dual inhibition of TXNRD1 and TXNRD2 is more effective in suppressing TNBC cell growth than inhibiting either alone; the primary anti-cancer mechanism is depletion of endogenous deoxynucleotide pools and impairment of ribonucleotide reductase activity leading to G1 arrest, not the pro-oxidant effect, as exogenous deoxynucleotide supplementation restores cell viability and cycle progression.","method":"TXNRD1/2 dual inhibition with non-covalent inhibitors, transcriptomics, cell viability assay, cell cycle analysis, deoxynucleotide rescue experiment, TNBC xenograft in vivo","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint; multiple orthogonal methods including rescue experiment and in vivo xenograft; single lab, not peer-reviewed","pmids":["bio_10.1101_2025.09.04.674327"],"is_preprint":true}],"current_model":"TXNRD2 encodes a mitochondrial selenoprotein thioredoxin reductase that reduces oxidized thioredoxin-2 (Trx2) using NADPH, operating through an FAD-binding homodimeric catalytic mechanism; it controls mitochondrial ROS and peroxynitrite levels (regulating the NO/peroxynitrite balance in endothelium), supports adrenal steroidogenesis by detoxifying mitochondrial ROS, is required for normal cardiac structure and energy metabolism, regulates cell proliferation via the mitochondrial H2O2/Trx2/Prx3 axis, acts upstream of Trx2/Prx3 to suppress ER stress, undergoes activating lactylation at K340 (mediated by AARS2) to promote mitophagy and ferroptosis resistance, and is positively regulated in activity by direct interaction with p53R2 and in expression by the Wnt/β-catenin pathway."},"narrative":{"mechanistic_narrative":"TXNRD2 encodes a mitochondrial thioredoxin reductase that constitutes the upstream node of the mitochondrial thioredoxin antioxidant system, scavenging mitochondrial ROS and reactive nitrogen species to protect organelle integrity and metabolic function [PMID:26199228, PMID:33579817]. Its catalytic activity depends on a conserved FAD-binding domain and C-terminal homodimerization; disease-associated missense and splice mutations that disrupt these features abolish enzymatic activity and act dominant-negatively [PMID:21247928, PMID:39097530]. TXNRD2 operates upstream of thioredoxin-2 and peroxiredoxin-3 (Prx3) to eliminate mitochondrial H2O2, and loss of function oxidizes Prx3 and raises mitochondrial ROS and peroxynitrite, dysregulating protein tyrosine phosphorylation, nitration, and cell-cycle progression [PMID:12705894, PMID:33579817, PMID:38513765]. Through this redox control TXNRD2 is required for cardiac mitochondrial integrity, autophagic flux, and energy metabolism—its cardiac-specific loss causes dilated cardiomyopathy with mitochondrial degeneration and HIF-1α stabilization [PMID:26199228]—and for adrenocortical redox homeostasis and glucocorticoid/cortisol production, with human loss-of-function alleles causing adrenal failure [PMID:24601690, PMID:39097530]. Its activity is positively regulated by direct binding of p53R2 and its expression is a target of Wnt/β-catenin signaling [PMID:27866984, PMID:22683372], and activating lysine-340 lactylation by AARS2 enhances mitochondrial TrxR activity to promote mitophagy and ferroptosis resistance [PMID:41704008].","teleology":[{"year":2002,"claim":"Defining the gene architecture established TrxR2 as a homodimeric enzyme and revealed a splice variant predicted to alter the dimerization interface, framing later structure-function work.","evidence":"Genomic sequencing, intron-exon mapping, and RT-PCR of mouse TrxR2","pmids":["12132591"],"confidence":"Low","gaps":["Functional consequence of the intron-14-lacking splice variant was not experimentally tested","No biochemical demonstration of altered dimer conformation"]},{"year":2003,"claim":"Dominant-negative disruption showed TrxR2 is an active component of the mitochondrial H2O2-eliminating system that constrains redox-dependent signaling and proliferation.","evidence":"Tetracycline-regulated dominant-negative TrxR2 in HeLa cells with ROS, phosphotyrosine/ERK, and cell-cycle readouts","pmids":["12705894"],"confidence":"Medium","gaps":["Dominant-negative effects not confirmed against clean genetic loss","Direct substrate relationship with Trx2/Prx3 inferred, not biochemically reconstituted here"]},{"year":2004,"claim":"Testing whether excess enzyme is protective showed overexpression does not regulate mitochondria-dependent apoptosis, indicating TrxR2 is not rate-limiting for cell-death decisions under these conditions.","evidence":"Stable EGFP-TrxR2 overexpression with enzymatic activity, mitochondrial fractionation, and apoptosis flow cytometry in Neuro2A cells","pmids":["15082714"],"confidence":"Medium","gaps":["Negative result limited to overexpression in one cell type","Does not address loss-of-function consequences for apoptosis"]},{"year":2007,"claim":"Gene-dosage analysis established that TrxR2 enzymatic activity scales with gene copy and interacts with selenium availability tissue-specifically.","evidence":"Hemizygous mouse model with dietary selenium manipulation and tissue enzymatic activity assays","pmids":["17937623"],"confidence":"Medium","gaps":["Phenotypic consequences of dose reduction not assessed","Mechanism of tissue-specific Se additivity unexplained"]},{"year":2011,"claim":"Disease-mutation reconstitution localized catalytic essentiality to the FAD-binding domain and demonstrated a dominant-negative mechanism linking TXNRD2 to dilated cardiomyopathy.","evidence":"Reconstitution of DCM-associated mutants in Txnrd2-/- fibroblasts with enzymatic and oxidative-stress survival assays","pmids":["21247928"],"confidence":"High","gaps":["Causality in human DCM rests on association plus cellular dominant-negative effect","Structural basis of FAD-domain disruption not crystallographically defined"]},{"year":2012,"claim":"Identifying TXNRD2 as a Wnt/β-catenin target connected its expression to proliferative epithelial compartments.","evidence":"Wnt3a/APC cell models, crypt-villus fractionation, and inducible β-catenin knockout with RT-PCR and Western blot","pmids":["22683372"],"confidence":"Medium","gaps":["Direct β-catenin/TCF occupancy at the TXNRD2 locus not demonstrated","Functional importance of Wnt-driven expression for crypt biology untested"]},{"year":2014,"claim":"A human stop-gain null allele established TXNRD2 as required for adrenocortical redox homeostasis and glucocorticoid production.","evidence":"Whole-exome sequencing plus shRNA knockdown in H295R adrenocortical cells with redox assays","pmids":["24601690"],"confidence":"High","gaps":["Mechanistic link between redox imbalance and steroidogenic failure not detailed here","Single family genetic evidence"]},{"year":2015,"claim":"Adult cardiac-specific knockout demonstrated TrxR2 is required in vivo for mitochondrial integrity, autophagic flux, and energy metabolism, recapitulating dilated cardiomyopathy.","evidence":"Tamoxifen-inducible cardiac Cre/loxP knockout with echocardiography, electron microscopy, respirometry, and metabolomics","pmids":["26199228"],"confidence":"High","gaps":["Whether autophagic accumulation is protective or pathological not resolved","Upstream trigger linking ROS to HIF-1α stabilization not defined"]},{"year":2016,"claim":"Two studies extended the activity axis: p53R2 was shown to directly bind and stimulate TrxR2 activity, and TrxR2 loss was shown to drive ROS-dependent chondrogenic differentiation and proliferation.","evidence":"Co-IP/pulldown and in vitro enzymatic assays with p53R2 KD/OE; shRNA knockdown in ATDC5 cells with NAC rescue","pmids":["27866984","27107686"],"confidence":"Medium","gaps":["p53R2 interaction from a single lab without reciprocal in vivo validation","Structural basis of p53R2-mediated activation unknown"]},{"year":2021,"claim":"Endothelial-specific deletion established TrxR2 as a regulator of the NO/peroxynitrite balance, with mitochondrial peroxynitrite driving vascular and renal pathology.","evidence":"Endothelial conditional knockout with fluorescein-boronate/MitoPY1 probes, Prx3 redox state, nitration assays, and Mn(III)TMPyP rescue","pmids":["33579817"],"confidence":"High","gaps":["Direct enzymatic handling of peroxynitrite versus indirect via Trx2/Prx3 not separated","Tissue specificity of vascular versus renal effects unresolved"]},{"year":2022,"claim":"Transgenic overexpression positioned TrxR2 as a rate-limiting enzyme of the mitochondrial thioredoxin system that enhances TCA/ETC function and systemic metabolism.","evidence":"Transgenic overexpression mice with glucose tolerance testing and mitochondrial/TCA/ETC activity assays","pmids":["35577894"],"confidence":"Medium","gaps":["Molecular link between thioredoxin reduction and ETC enhancement not defined","Single overexpression model"]},{"year":2024,"claim":"Two studies localized TXNRD2 upstream of Trx2/Prx3 in suppressing ER stress and lipid peroxidation, and confirmed FAD-binding/dimerization as the enzymatically critical features in a patient adrenal cell model.","evidence":"siRNA knockdown in rat ICH model with selenium rescue; patient iPSC-derived adrenal-like cells carrying a C-terminal splice variant with steroidogenesis and ROS assays","pmids":["38513765","39097530"],"confidence":"High","gaps":["ER stress link from single in vivo KD model (Medium)","Direct biochemical demonstration of impaired dimerization for the splice variant not shown"]},{"year":2026,"claim":"Identification of AARS2-mediated K340 lactylation revealed a post-translational activating modification that couples TrxR2 to mitophagy and ferroptosis resistance in cardiac microvasculature.","evidence":"Endothelial KO and transgenic mice, mass-spectrometry lactylation site mapping, custom lactylation antibody, and mitophagy/ferroptosis assays","pmids":["41704008"],"confidence":"Medium","gaps":["SCP2/ACSL4/TUFM mechanistic chain from single lab","Stoichiometry and regulation of K340 lactylation in vivo not quantified"]},{"year":null,"claim":"How TrxR2's distinct functional outputs—peroxynitrite handling, ER-stress suppression, metabolic regulation, and lactylation-driven mitophagy—are coordinated, and the structural basis of its activation by p53R2, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the p53R2-TrxR2 complex","Tissue-specific selection among redox outputs not mechanistically explained","Direct substrate spectrum beyond Trx2 not enumerated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,5,14]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,6,11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,6]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,6,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,10]}],"complexes":[],"partners":["RRM2B","TXN2","PRDX3","AARS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NNW7","full_name":"Thioredoxin reductase 2, mitochondrial","aliases":["Selenoprotein Z","SelZ","TR-beta","Thioredoxin reductase TR3"],"length_aa":524,"mass_kda":56.5,"function":"Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis (PubMed:24601690). Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9NNW7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TXNRD2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TXNRD2","total_profiled":1310},"omim":[{"mim_id":"617825","title":"GLUCOCORTICOID DEFICIENCY 5; GCCD5","url":"https://www.omim.org/entry/617825"},{"mim_id":"616967","title":"THIOREDOXIN DOMAIN-CONTAINING PROTEIN 17; TXNDC17","url":"https://www.omim.org/entry/616967"},{"mim_id":"608363","title":"CHROMOSOME 22q11.2 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/608363"},{"mim_id":"606448","title":"THIOREDOXIN REDUCTASE 2; TXNRD2","url":"https://www.omim.org/entry/606448"},{"mim_id":"606235","title":"THIOREDOXIN REDUCTASE 3; TXNRD3","url":"https://www.omim.org/entry/606235"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TXNRD2"},"hgnc":{"alias_symbol":["TR","TRXR2","TR3","SELZ","TXNR2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NNW7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNW7","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TXNRD2","jax_strain_url":"https://www.jax.org/strain/search?query=TXNRD2"},"sequence":{"accession":"Q9NNW7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NNW7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NNW7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NNW7"}},"corpus_meta":[{"pmid":"26752265","id":"PMC_26752265","title":"Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26752265","citation_count":207,"is_preprint":false},{"pmid":"15082714","id":"PMC_15082714","title":"Mitochondrial thioredoxin system: effects of TrxR2 overexpression on redox balance, cell growth, and apoptosis.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15082714","citation_count":90,"is_preprint":false},{"pmid":"24601690","id":"PMC_24601690","title":"Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD).","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24601690","citation_count":90,"is_preprint":false},{"pmid":"21247928","id":"PMC_21247928","title":"Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy.","date":"2011","source":"European heart 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Rats.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38513765","citation_count":9,"is_preprint":false},{"pmid":"31588341","id":"PMC_31588341","title":"TrxR2 overexpression alleviates inflammation-mediated neuronal death via reducing the oxidative stress and activating the Akt-Parkin pathway.","date":"2019","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/31588341","citation_count":7,"is_preprint":false},{"pmid":"34431894","id":"PMC_34431894","title":"TXNRD2 (rs35934224) CT genotype as possible protective marker for primary open-angle glaucoma in a Brazilian population.","date":"2021","source":"Arquivos brasileiros de oftalmologia","url":"https://pubmed.ncbi.nlm.nih.gov/34431894","citation_count":6,"is_preprint":false},{"pmid":"34408771","id":"PMC_34408771","title":"Lack of Association Between Polymorphisms in TXNRD2 and LMX1B and Primary Open-Angle Glaucoma in a Saudi Cohort.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34408771","citation_count":5,"is_preprint":false},{"pmid":"39900986","id":"PMC_39900986","title":"Elevated serum levels of GPX4, NDUFS4, PRDX5, and TXNRD2 as predictive biomarkers for castration resistance in prostate cancer patients: an exploratory study.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39900986","citation_count":4,"is_preprint":false},{"pmid":"39097530","id":"PMC_39097530","title":"Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant.","date":"2024","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/39097530","citation_count":3,"is_preprint":false},{"pmid":"34461764","id":"PMC_34461764","title":"Association analysis of variants rs35934224 in TXNRD2 and rs6478746 in LMX1B in primary angle-closure and pseudoexfoliation glaucoma.","date":"2021","source":"European journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/34461764","citation_count":2,"is_preprint":false},{"pmid":"35085721","id":"PMC_35085721","title":"Synthesis of mitochondria-targeted menadione cation derivatives: Inhibiting mitochondrial thioredoxin reductase (TrxR2) and inducing apoptosis in MGC-803 cells.","date":"2022","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/35085721","citation_count":2,"is_preprint":false},{"pmid":"20965815","id":"PMC_20965815","title":"[TrxR2 gene polymorphisms may not be associated with the susceptibility to Kashin-Beck disease].","date":"2010","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/20965815","citation_count":2,"is_preprint":false},{"pmid":"40726908","id":"PMC_40726908","title":"Case report and literature review: novel TXNRD2 compound heterozygous variants in familial glucocorticoid deficiency type 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up-regulates their expression including SOD-1.","date":"2025","source":"Xenobiotica; the fate of foreign compounds in biological systems","url":"https://pubmed.ncbi.nlm.nih.gov/40238463","citation_count":0,"is_preprint":false},{"pmid":"34136125","id":"PMC_34136125","title":"Erratum: Expression of concern: TrxR2 overexpression alleviates inflammation-mediated neuronal death via reducing the oxidative stress and activating the Akt-Parkin pathway.","date":"2021","source":"Toxicology research","url":"https://pubmed.ncbi.nlm.nih.gov/34136125","citation_count":0,"is_preprint":false},{"pmid":"40841993","id":"PMC_40841993","title":"The methylation of TXNRD2 with chronic heart failure: the interaction effect between methylation regulation and clinical parameters-- a single center pilot study.","date":"2025","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/40841993","citation_count":0,"is_preprint":false},{"pmid":"40468356","id":"PMC_40468356","title":"The bidirectional regulatory effect of TXNRD2 methylation in patients with chronic heart failure and its nonlinear dose-response relationship with key clinical parameters.","date":"2025","source":"Journal of cardiothoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/40468356","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.04.674327","title":"Unravelling the anti-cancer mechanisms elicited by non-covalent thioredoxin reductase inhibitors for triple negative breast cancer 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or caspase activation, indicating that excess TrxR2 does not regulate mitochondria-dependent apoptosis.\",\n      \"method\": \"Stable transfection of EGFP-TrxR2 fusion, enzymatic activity assay, mitochondrial fractionation, flow cytometry for apoptosis markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional assay, enzymatic activity measurement, multiple apoptotic stimuli tested; single lab\",\n      \"pmids\": [\"15082714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A dominant-negative form of TrxR2 (TrxR2DN) in HeLa cells caused increased hydrogen peroxide production upon EGF stimulation, elevated protein tyrosine phosphorylation of ERK and other proteins, and accelerated G1-to-S phase cell cycle progression and cell proliferation, establishing TrxR2 as a component of the mitochondrial H2O2-eliminating system (together with Prxm III and Trx2) that regulates protein tyrosine phosphorylation and cell growth.\",\n      \"method\": \"Tetracycline-off dominant-negative stable cell line, ROS measurement (H2O2), immunoblot for phosphotyrosine/ERK, flow cytometry for cell cycle\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative loss-of-function with multiple orthogonal readouts (ROS, phosphorylation, cell cycle); single lab\",\n      \"pmids\": [\"12705894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two DCM-associated TXNRD2 missense mutations (Ala59Thr and Gly375Arg) affect conserved residues in helices of the FAD-binding domain; neither mutant restored TrxR2 function in Txnrd2-/- mouse fibroblasts, and both exerted dominant-negative effects impairing survival of wild-type cells under oxidative stress, defining the FAD-binding domain as essential for enzymatic activity.\",\n      \"method\": \"Sequencing, reconstitution in Txnrd2-/- mouse fibroblasts, functional enzymatic assay, oxidative stress survival assay\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — loss-of-function reconstitution in null cells, active-site mutagenesis linked to defined enzymatic activity, dominant-negative mechanism confirmed\",\n      \"pmids\": [\"21247928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Heart-specific, tamoxifen-inducible knockout of Txnrd2 in adult mice leads to dilated cardiomyopathy with decreased fractional shortening and ejection fraction, mitochondrial degeneration, accumulation of autophagic bodies, elevated LAMP1/LC3-I/p62, reduced mitochondrial oxygen consumption, increased mitochondrial ROS, and HIF-1α stabilization, establishing Txnrd2 as required for mitochondrial integrity, autophagic flux, and energy metabolism in the aging heart.\",\n      \"method\": \"Conditional cardiac-specific Cre/loxP knockout, echocardiography, electron microscopy, mitochondrial oxygen consumption assay, metabolomics, Western blot\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean tissue-specific KO with multiple orthogonal phenotypic and biochemical readouts, functional mitochondrial assays\",\n      \"pmids\": [\"26199228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous stop-gain mutation (p.Y447X) in TXNRD2 causes complete absence of TXNRD2 protein (confirmed by Western blot) and impairs redox homeostasis in a human adrenocortical cell line (H295R TXNRD2-knockdown), establishing TXNRD2 as required for adrenocortical redox homeostasis and glucocorticoid production in humans.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, RT-PCR, Western blot, shRNA knockdown in H295R cells, redox assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function mutation with functional validation in human adrenocortical cell line, multiple molecular methods\",\n      \"pmids\": [\"24601690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p53R2 directly binds TrxR2 (shown by co-immunoprecipitation and pulldown), stimulates TrxR2 enzymatic activity in vitro, and is required for full TrxR2 activity in cells: TrxR2 activity is lower in p53R2-knockdown cells and higher upon p53R2 overexpression, in a p53-independent manner; p53R2 knockdown also suppresses UV-induced TrxR activity.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assay, in vitro TrxR enzymatic activity assay, siRNA knockdown, overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus reciprocal binding assay and cellular KD/OE; single lab\",\n      \"pmids\": [\"27866984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial-specific deletion of Txnrd2 in mice increases steady-state peroxynitrite levels (measured by fluorescein-boronate probe) in vascular endothelial cells and vessels, elevates protein tyrosine nitration, oxidizes Prx3, and causes increased vascular stiffness, vascular wall hypertrophy, and renal pathology (glomerulosclerosis, Bowman's capsule thickening); peroxynitrite is generated in mitochondria (MitoPY1 probe) and peroxynitrite-decomposition catalyst Mn(III)TMPyP blunted the intravascular peroxynitrite. This establishes TrxR2 as regulator of the nitric oxide/peroxynitrite balance in endothelium.\",\n      \"method\": \"Endothelial-specific conditional knockout, redox-sensitive fluorescent probes (fluorescein-boronate, MitoPY1), protein nitration assay, redox state of Prx3, pharmacological rescue with Mn(III)TMPyP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple orthogonal mechanistic readouts including direct peroxynitrite measurement and pharmacological rescue in vivo\",\n      \"pmids\": [\"33579817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The mouse TrxR2 gene spans 53 kb with 18 exons; an alternative splice variant lacking intron 14 produces a protein with a shorter interface domain, predicted to enable a heterodimeric or small-subunit homodimeric conformation, expanding the known homodimeric structure of TrxR2.\",\n      \"method\": \"Genomic sequencing, intron–exon mapping, RT-PCR identification of splice variant, structural prediction\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene structure and splice variant identified by sequencing/RT-PCR; functional consequence of splice variant not experimentally confirmed\",\n      \"pmids\": [\"12132591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TrxR2 (and GPx2 and TrxR3) expression is dependent on Wnt/β-catenin pathway activity in intestinal epithelium: expression is higher in proliferative crypt compartments where Wnt is active, is consistent with activated versus inhibited Wnt pathway in cell culture models, and is reduced by inducible knockout of β-catenin in colonic crypt base cells ex vivo, identifying TrxR2 as a novel Wnt target selenoprotein.\",\n      \"method\": \"Cell culture models with Wnt3a overexpression and APC-mediated inhibition, intestinal crypt/villus fractionation, inducible β-catenin knockout, RT-PCR and Western blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (in vitro and ex vivo), inducible β-catenin KO confirming pathway dependence; single lab\",\n      \"pmids\": [\"22683372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TrxR2 deficiency in chondrogenic ATDC5 cells (via shRNA) increases mitochondrial ROS without altering mitochondrial membrane potential or ATP, enhances chondrogenic differentiation (elevated collagen II, aggrecan, GAG accumulation, mineralization), activates Akt signaling required for chondrogenesis, promotes cell cycle progression (increased S and G2/M phase), and induces apoptosis. NAC (antioxidant) reversed all these effects, placing mitochondrial ROS downstream of TrxR2 loss as the mechanistic driver.\",\n      \"method\": \"shRNA knockdown, ROS measurement, mitochondrial membrane potential assay, ATP assay, chondrogenic differentiation markers (qPCR, staining), flow cytometry (cell cycle, apoptosis), NAC rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with pharmacological rescue (NAC) and multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"27107686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Transgenic mice overexpressing TrxR2 show enhanced glucose tolerance, decreased fat deposition on high-fat diet, and increased mitochondrial function driven by enhanced tricarboxylic acid cycle and electron transport chain function, establishing TrxR2 as a rate-limiting enzyme in the mitochondrial thioredoxin system that regulates mitochondrial metabolic function.\",\n      \"method\": \"Transgenic mouse overexpression, metabolic phenotyping (glucose tolerance test), mitochondrial function assays, TCA/ETC activity measurements\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic overexpression in vivo with multiple metabolic and mitochondrial functional readouts; single lab\",\n      \"pmids\": [\"35577894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Txnrd2 knockdown (siRNA) in a rat intracerebral hemorrhage model increases lipid peroxidation and ER stress (Trx2 and Prx3 pathway disrupted), worsens brain edema and neurological deficits. Pharmacological selenium (sodium selenite) restores Txnrd2 expression, inhibits ER stress markers, and reduces ROS via the Trx2/Prx3 pathway, positioning Txnrd2 upstream of Trx2/Prx3 in the mitochondrial antioxidant cascade controlling neuronal ER stress.\",\n      \"method\": \"siRNA knockdown in vivo (rat ICH model), selenium supplementation rescue, lipid peroxidation assay, ER stress protein expression, neurological deficit scoring\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD in vivo with pharmacological rescue and multiple molecular readouts; single lab\",\n      \"pmids\": [\"38513765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous TXNRD2 splice variant (c.1348-1G>T) produces a shorter protein lacking the C-terminus, affecting homodimerization and FAD-binding. Patient-derived induced pluripotent stem cell-derived adrenal-like cells (iALC) with this variant show loss of cortisol production, diminished overall adrenal steroidogenesis, and significantly increased ROS production, directly linking TXNRD2 enzymatic activity (FAD-binding and dimerization) to adrenal ROS detoxification and steroidogenesis.\",\n      \"method\": \"Whole exome sequencing, RNA analysis, protein structure modeling, iPS-cell-derived adrenal-like cells, cortisol and steroidogenesis assays, ROS measurement\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional characterization of splice variant in patient-derived iPSC-differentiated cell model with structural analysis, enzymatic domain assignment, and multiple biochemical readouts\",\n      \"pmids\": [\"39097530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endothelial-specific TrxR2 knockout exacerbates cardiac microvascular dysfunction and diabetic cardiomyopathy; TrxR2 inhibits mitochondria-associated ferroptosis by facilitating SCP2 degradation and blocking mitochondrial translocation of ACSL4 via mitophagy; TrxR2 maintains TUFM expression by scavenging oxygen radicals, enabling mitochondrial AMPK translocation for mitophagy activation. TrxR2 undergoes lactylation at lysine 340, mediated by mitochondrial AARS2; this modification enhances mitoTrxR activity and promotes mitophagy, conferring ferroptosis resistance.\",\n      \"method\": \"Endothelial-specific knockout mice, transgenic overexpression, mass spectrometry (lactylation site identification), custom lactylation antibody, bulk RNA-sequencing, fluorescence staining for mitoTrxR activity and lipid peroxyl radicals, mitophagy assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transgenic/KO models and MS-based PTM identification with functional assays; single lab, newly published\",\n      \"pmids\": [\"41704008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Txnrd2 hemizygosity (+/-) in mice reduces TrxR2 enzymatic activity in a gene-dose-dependent manner across all tissues examined; selenium depletion further reduces activity but not below levels seen with Se depletion alone, except in kidney, heart, and muscle where hemizygosity and Se depletion have an additive effect on TrxR2 activity.\",\n      \"method\": \"Hemizygous mouse model, selenium dietary manipulation, tissue Se content measurement, enzymatic activity assay across multiple tissues\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic and dietary manipulation with enzymatic activity measurements across multiple tissues; single lab\",\n      \"pmids\": [\"17937623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Non-covalent TXNRD inhibitors inhibit both TXNRD1 and TXNRD2 enzymatic activity; dual inhibition of TXNRD1 and TXNRD2 is more effective in suppressing TNBC cell growth than inhibiting either alone; the primary anti-cancer mechanism is depletion of endogenous deoxynucleotide pools and impairment of ribonucleotide reductase activity leading to G1 arrest, not the pro-oxidant effect, as exogenous deoxynucleotide supplementation restores cell viability and cycle progression.\",\n      \"method\": \"TXNRD1/2 dual inhibition with non-covalent inhibitors, transcriptomics, cell viability assay, cell cycle analysis, deoxynucleotide rescue experiment, TNBC xenograft in vivo\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint; multiple orthogonal methods including rescue experiment and in vivo xenograft; single lab, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674327\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TXNRD2 encodes a mitochondrial selenoprotein thioredoxin reductase that reduces oxidized thioredoxin-2 (Trx2) using NADPH, operating through an FAD-binding homodimeric catalytic mechanism; it controls mitochondrial ROS and peroxynitrite levels (regulating the NO/peroxynitrite balance in endothelium), supports adrenal steroidogenesis by detoxifying mitochondrial ROS, is required for normal cardiac structure and energy metabolism, regulates cell proliferation via the mitochondrial H2O2/Trx2/Prx3 axis, acts upstream of Trx2/Prx3 to suppress ER stress, undergoes activating lactylation at K340 (mediated by AARS2) to promote mitophagy and ferroptosis resistance, and is positively regulated in activity by direct interaction with p53R2 and in expression by the Wnt/β-catenin pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TXNRD2 encodes a mitochondrial thioredoxin reductase that constitutes the upstream node of the mitochondrial thioredoxin antioxidant system, scavenging mitochondrial ROS and reactive nitrogen species to protect organelle integrity and metabolic function [#3, #6]. Its catalytic activity depends on a conserved FAD-binding domain and C-terminal homodimerization; disease-associated missense and splice mutations that disrupt these features abolish enzymatic activity and act dominant-negatively [#2, #12]. TXNRD2 operates upstream of thioredoxin-2 and peroxiredoxin-3 (Prx3) to eliminate mitochondrial H2O2, and loss of function oxidizes Prx3 and raises mitochondrial ROS and peroxynitrite, dysregulating protein tyrosine phosphorylation, nitration, and cell-cycle progression [#1, #6, #11]. Through this redox control TXNRD2 is required for cardiac mitochondrial integrity, autophagic flux, and energy metabolism—its cardiac-specific loss causes dilated cardiomyopathy with mitochondrial degeneration and HIF-1α stabilization [#3]—and for adrenocortical redox homeostasis and glucocorticoid/cortisol production, with human loss-of-function alleles causing adrenal failure [#4, #12]. Its activity is positively regulated by direct binding of p53R2 and its expression is a target of Wnt/β-catenin signaling [#5, #8], and activating lysine-340 lactylation by AARS2 enhances mitochondrial TrxR activity to promote mitophagy and ferroptosis resistance [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining the gene architecture established TrxR2 as a homodimeric enzyme and revealed a splice variant predicted to alter the dimerization interface, framing later structure-function work.\",\n      \"evidence\": \"Genomic sequencing, intron-exon mapping, and RT-PCR of mouse TrxR2\",\n      \"pmids\": [\"12132591\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence of the intron-14-lacking splice variant was not experimentally tested\", \"No biochemical demonstration of altered dimer conformation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Dominant-negative disruption showed TrxR2 is an active component of the mitochondrial H2O2-eliminating system that constrains redox-dependent signaling and proliferation.\",\n      \"evidence\": \"Tetracycline-regulated dominant-negative TrxR2 in HeLa cells with ROS, phosphotyrosine/ERK, and cell-cycle readouts\",\n      \"pmids\": [\"12705894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative effects not confirmed against clean genetic loss\", \"Direct substrate relationship with Trx2/Prx3 inferred, not biochemically reconstituted here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Testing whether excess enzyme is protective showed overexpression does not regulate mitochondria-dependent apoptosis, indicating TrxR2 is not rate-limiting for cell-death decisions under these conditions.\",\n      \"evidence\": \"Stable EGFP-TrxR2 overexpression with enzymatic activity, mitochondrial fractionation, and apoptosis flow cytometry in Neuro2A cells\",\n      \"pmids\": [\"15082714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result limited to overexpression in one cell type\", \"Does not address loss-of-function consequences for apoptosis\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Gene-dosage analysis established that TrxR2 enzymatic activity scales with gene copy and interacts with selenium availability tissue-specifically.\",\n      \"evidence\": \"Hemizygous mouse model with dietary selenium manipulation and tissue enzymatic activity assays\",\n      \"pmids\": [\"17937623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotypic consequences of dose reduction not assessed\", \"Mechanism of tissue-specific Se additivity unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Disease-mutation reconstitution localized catalytic essentiality to the FAD-binding domain and demonstrated a dominant-negative mechanism linking TXNRD2 to dilated cardiomyopathy.\",\n      \"evidence\": \"Reconstitution of DCM-associated mutants in Txnrd2-/- fibroblasts with enzymatic and oxidative-stress survival assays\",\n      \"pmids\": [\"21247928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causality in human DCM rests on association plus cellular dominant-negative effect\", \"Structural basis of FAD-domain disruption not crystallographically defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying TXNRD2 as a Wnt/β-catenin target connected its expression to proliferative epithelial compartments.\",\n      \"evidence\": \"Wnt3a/APC cell models, crypt-villus fractionation, and inducible β-catenin knockout with RT-PCR and Western blot\",\n      \"pmids\": [\"22683372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct β-catenin/TCF occupancy at the TXNRD2 locus not demonstrated\", \"Functional importance of Wnt-driven expression for crypt biology untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A human stop-gain null allele established TXNRD2 as required for adrenocortical redox homeostasis and glucocorticoid production.\",\n      \"evidence\": \"Whole-exome sequencing plus shRNA knockdown in H295R adrenocortical cells with redox assays\",\n      \"pmids\": [\"24601690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between redox imbalance and steroidogenic failure not detailed here\", \"Single family genetic evidence\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Adult cardiac-specific knockout demonstrated TrxR2 is required in vivo for mitochondrial integrity, autophagic flux, and energy metabolism, recapitulating dilated cardiomyopathy.\",\n      \"evidence\": \"Tamoxifen-inducible cardiac Cre/loxP knockout with echocardiography, electron microscopy, respirometry, and metabolomics\",\n      \"pmids\": [\"26199228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagic accumulation is protective or pathological not resolved\", \"Upstream trigger linking ROS to HIF-1α stabilization not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two studies extended the activity axis: p53R2 was shown to directly bind and stimulate TrxR2 activity, and TrxR2 loss was shown to drive ROS-dependent chondrogenic differentiation and proliferation.\",\n      \"evidence\": \"Co-IP/pulldown and in vitro enzymatic assays with p53R2 KD/OE; shRNA knockdown in ATDC5 cells with NAC rescue\",\n      \"pmids\": [\"27866984\", \"27107686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53R2 interaction from a single lab without reciprocal in vivo validation\", \"Structural basis of p53R2-mediated activation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Endothelial-specific deletion established TrxR2 as a regulator of the NO/peroxynitrite balance, with mitochondrial peroxynitrite driving vascular and renal pathology.\",\n      \"evidence\": \"Endothelial conditional knockout with fluorescein-boronate/MitoPY1 probes, Prx3 redox state, nitration assays, and Mn(III)TMPyP rescue\",\n      \"pmids\": [\"33579817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic handling of peroxynitrite versus indirect via Trx2/Prx3 not separated\", \"Tissue specificity of vascular versus renal effects unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transgenic overexpression positioned TrxR2 as a rate-limiting enzyme of the mitochondrial thioredoxin system that enhances TCA/ETC function and systemic metabolism.\",\n      \"evidence\": \"Transgenic overexpression mice with glucose tolerance testing and mitochondrial/TCA/ETC activity assays\",\n      \"pmids\": [\"35577894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between thioredoxin reduction and ETC enhancement not defined\", \"Single overexpression model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two studies localized TXNRD2 upstream of Trx2/Prx3 in suppressing ER stress and lipid peroxidation, and confirmed FAD-binding/dimerization as the enzymatically critical features in a patient adrenal cell model.\",\n      \"evidence\": \"siRNA knockdown in rat ICH model with selenium rescue; patient iPSC-derived adrenal-like cells carrying a C-terminal splice variant with steroidogenesis and ROS assays\",\n      \"pmids\": [\"38513765\", \"39097530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER stress link from single in vivo KD model (Medium)\", \"Direct biochemical demonstration of impaired dimerization for the splice variant not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of AARS2-mediated K340 lactylation revealed a post-translational activating modification that couples TrxR2 to mitophagy and ferroptosis resistance in cardiac microvasculature.\",\n      \"evidence\": \"Endothelial KO and transgenic mice, mass-spectrometry lactylation site mapping, custom lactylation antibody, and mitophagy/ferroptosis assays\",\n      \"pmids\": [\"41704008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SCP2/ACSL4/TUFM mechanistic chain from single lab\", \"Stoichiometry and regulation of K340 lactylation in vivo not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TrxR2's distinct functional outputs—peroxynitrite handling, ER-stress suppression, metabolic regulation, and lactylation-driven mitophagy—are coordinated, and the structural basis of its activation by p53R2, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the p53R2-TrxR2 complex\", \"Tissue-specific selection among redox outputs not mechanistically explained\", \"Direct substrate spectrum beyond Trx2 not enumerated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 5, 14]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RRM2B\",\n      \"TXN2\",\n      \"PRDX3\",\n      \"AARS2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}