Affinage

TXNRD1

Thioredoxin reductase 1, cytoplasmic · UniProt Q16881

Length
649 aa
Mass
70.9 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TXNRD1 encodes cytosolic thioredoxin reductase 1 (TrxR1), a selenoprotein oxidoreductase that serves as a central node in cellular redox homeostasis by reducing thioredoxin (Trx1) and eliminating reactive oxygen species in a selenocysteine (Sec)-dependent manner (PMID:24853413, PMID:22198266). Its C-terminal Sec residue is the primary target of diverse electrophilic and gold-based inhibitors that form covalent adducts, converting the enzyme into a pro-oxidant SecTRAP (PMID:29670693, PMID:16510263, PMID:39141196); TrxR1 and glutathione reductase constitute parallel, partially redundant reductive pathways that together supply electrons to ribonucleotide reductase for DNA synthesis and maintain hepatic metabolic programming (PMID:22198266, PMID:23743293, PMID:31097586). Beyond its enzymatic role, TXNRD1 physically interacts with cGAS on cytoplasmic chromatin fragments to enhance cGAS enzymatic activity and drive the senescence-associated secretory phenotype independently of its reductase activity (PMID:38267705), and the TXNRD1_v3 splice variant localizes to membrane rafts via N-terminal myristoylation/palmitoylation to induce filopodia through its glutaredoxin domain independently of redox catalysis (PMID:23413027, PMID:19654027). A homozygous TXNRD1 missense mutation (p.Pro190Leu) that reduces enzymatic activity to 16–34% of normal causes a generalized selenoprotein deficiency disorder (PMID:28232204).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2006 Medium

    The question of how gold-based therapeutics target TrxR1 was resolved by showing that diverse gold compounds inhibit TrxR1 at nanomolar concentrations, with Au(I)-phosphine ligand configuration—not oxidation state—determining potency, establishing TrxR1 as a pharmacologically druggable selenoenzyme.

    Evidence In vitro IC50 determination with purified rat TrxR1 and structurally diverse gold compounds

    PMID:16510263

    Open questions at the time
    • Binding site on TrxR1 not mapped
    • Selectivity over TrxR2 not assessed
    • In vivo target engagement not demonstrated
  2. 2009 Medium

    The identification of the TXNRD1_v3 splice variant revealed that its N-terminal glutaredoxin domain drives filopodia formation and cytoplasmic filament assembly independently of canonical TrxR1 reductase function, establishing a non-canonical cytoskeletal role for a TrxR1 isoform.

    Evidence Live-cell imaging of overexpressed v3 with truncation and domain-deletion mutants, actin polymerization inhibitors in cell lines

    PMID:19654027

    Open questions at the time
    • Endogenous expression levels and physiological relevance of v3 unclear
    • Binding partners mediating filopodia unknown
    • Redox independence based on domain deletion, not active-site mutagenesis
  3. 2011 High

    Genetic epistasis in vivo demonstrated that TrxR1 and glutathione constitute two parallel electron-supply pathways for hepatocyte DNA replication—likely converging on ribonucleotide reductase—resolving how cells tolerate loss of either pathway alone.

    Evidence Txnrd1 conditional knockout mice with BSO-mediated GSH depletion, replicative index measurement in hepatocytes

    PMID:22198266

    Open questions at the time
    • Direct measurement of ribonucleotide reductase activity in double-depleted hepatocytes not performed
    • Contribution of other reductases not excluded
  4. 2011 High

    The strict requirement for selenocysteine in TrxR catalysis was established across species: Sec-to-Cys mutants of C. elegans TRXR-1 fail to rescue molting, and Sec-devoid TrxR1 cannot eliminate glucose-derived H₂O₂ in mouse embryonic fibroblasts, proving that Sec is not a dispensable catalytic residue.

    Evidence Sec-to-Cys mutant rescue in C. elegans molting and in Txnrd1-null MEFs under high glucose; H₂O₂ measurement

    PMID:21199936 PMID:24853413

    Open questions at the time
    • Structural basis for why Sec is required (redox potential, pKa) not resolved in these studies
    • Whether any biological context allows Sec-devoid activity remains open
  5. 2013 High

    Hepatocyte-specific Txnrd1 loss triggered a compensatory metabolic switch—upregulating GSH biosynthesis, glucuronidation, and xenobiotic export while repressing lipogenesis—revealing TrxR1 as a metabolic rheostat whose absence paradoxically confers resistance to acetaminophen hepatotoxicity.

    Evidence Hepatocyte-specific Txnrd1 conditional knockout mice with metabolomic profiling and APAP challenge; NAPQI shown to directly inactivate TrxR1 in vitro

    PMID:23743293

    Open questions at the time
    • Transcriptional mediators of the metabolic switch not fully identified
    • Whether Nrf2 drives all compensatory changes unclear
  6. 2013 High

    Membrane raft targeting of TXNRD1_v3 was shown to require N-terminal myristoylation and palmitoylation of the MGC motif, and filopodia induction depended on raft localization but not on redox-active cysteines, separating the structural/signaling role of v3 from enzymatic catalysis.

    Evidence Site-directed mutagenesis of MGC lipidation motif, lipid raft fractionation, cholera toxin B co-localization, filopodia quantification

    PMID:23413027

    Open questions at the time
    • Downstream signaling partners at membrane rafts unidentified
    • In vivo relevance of v3-driven filopodia not tested
  7. 2013 Medium

    A synthetic lethal interaction between TrxR1 inhibition and AKT inhibition was discovered in NSCLC, dependent on intact KEAP1 function, linking TrxR1 to the KEAP1/NRF2 antioxidant axis and JNK activation as a cell death mechanism.

    Evidence Genome-wide siRNA screen combined with MK2206, KEAP1-mutant cell lines, ROS quantification, xenograft validation

    PMID:23824739

    Open questions at the time
    • Whether TrxR1 directly modifies KEAP1 or acts indirectly via ROS not distinguished
    • Generalizability beyond NSCLC not tested
  8. 2015 Medium

    TrxR1 was placed upstream of the ASK1-JNK/p38-Bim apoptotic cascade in thymocytes, explaining how the Trx1/TrxR1 system supports survival of post-selected double-positive thymocytes during T-cell development.

    Evidence TrxR1 pharmacological inhibition in vitro and in vivo with phospho-ASK1/JNK/p38 and Bim readouts, flow cytometry of thymocyte subsets

    PMID:25753394

    Open questions at the time
    • Genetic TrxR1 deletion in thymocytes not performed
    • Whether Trx1 oxidation state directly controls ASK1 binding not shown in this system
  9. 2017 High

    A human homozygous TXNRD1 mutation (p.Pro190Leu) was shown to reduce enzymatic activity to 16–34% of normal in patient tissues, with recombinant mutant protein showing reduced kcat, establishing TXNRD1 as a disease gene for a selenoprotein deficiency disorder.

    Evidence Patient-derived fibroblast and muscle enzymatic assays, ⁷⁵Se labeling, recombinant mutant kinetic analysis, exome sequencing

    PMID:28232204

    Open questions at the time
    • Full clinical spectrum not defined
    • Whether residual activity is from the mutant or compensatory pathways not resolved
    • Only one family reported
  10. 2018 High

    The mechanism by which electrophilic inhibitors convert TrxR1 into a pro-oxidant was elucidated: manumycin A forms a Michael adduct specifically at the C-terminal Sec residue, generating a SecTRAP that channels NADPH electrons to O₂ to produce superoxide.

    Evidence In vitro preincubation kinetics, time-dependent irreversible inhibition, covalent modification evidence, superoxide production assay with purified TrxR1

    PMID:29670693

    Open questions at the time
    • Crystal structure of the SecTRAP not resolved
    • In vivo superoxide generation from SecTRAP not quantified
  11. 2019 High

    TrxR1 was shown to promote carcinogen-induced hepatocellular cancer initiation in vivo, as TrxR1-null livers developed threefold fewer DEN-induced tumors, while combined TrxR1/Gsr loss increased tumor malignancy independently of Nrf2, revealing opposing roles of moderate vs. excessive oxidative stress in tumorigenesis.

    Evidence Conditional TrxR1-null, Gsr-null, and double-null mouse liver models with DEN carcinogenesis, DNA damage and metabolomic profiling

    PMID:31097586

    Open questions at the time
    • Mechanism by which TrxR1 promotes initiation (DNA damage tolerance vs. proliferation support) not fully defined
    • Cell-autonomous vs. microenvironmental effects not separated
  12. 2020 Medium

    TrxR1 was identified as an upstream regulator of STAT3 redox state: its inhibition causes Prx2 and STAT3 oxidation, blocking STAT3-dependent transcription and explaining off-target mechanisms of several 'STAT3 inhibitors'.

    Evidence Luciferase reporter assays, TrxR1 inhibitor profiling, Prx2/STAT3 oxidation state analysis

    PMID:32219156

    Open questions at the time
    • Whether TrxR1→Trx1→Prx2→STAT3 is the sole pathway not excluded
    • Direct Trx1-STAT3 interaction not demonstrated
  13. 2022 Medium

    TXNRD1 was shown to modulate PTEN stability by competing with PTEN for Trx1 binding; high TXNRD1 expression accelerates PTEN degradation and activates Akt/mTOR signaling, and USF2 directly represses TXNRD1 transcription via E-box elements.

    Evidence Co-IP for Trx1-PTEN interaction ± TXNRD1, ChIP/dual-luciferase for USF2-TXNRD1 promoter binding, xenograft models

    PMID:36319631

    Open questions at the time
    • Mechanism of PTEN degradation (ubiquitin ligase identity) not identified
    • Whether this occurs in non-HCC contexts unknown
    • Reciprocal Co-IP for TXNRD1-Trx1 competition not fully shown
  14. 2023 High

    The widely used 'GPX4 inhibitors' RSL3 and ML162 were demonstrated to potently inhibit TXNRD1 without inhibiting recombinant GPX4, fundamentally reframing the ferroptosis field's tool compound specificity and indicating that many attributed GPX4-dependent effects may reflect TXNRD1 inhibition.

    Evidence In vitro enzymatic assays with recombinant GPX4 and TXNRD1, ferrostatin-1 rescue experiments

    PMID:37087975

    Open questions at the time
    • In-cell target engagement ratio (GPX4 vs. TXNRD1) not quantified
    • Whether downstream ferroptotic phenotypes are TXNRD1-dependent not fully resolved
  15. 2023 High

    TXNRD1 inhibition was linked to a novel cell death modality—disulfidptosis—in osteoclast precursors: NFATc1-driven SLC7A11 upregulation during osteoclastogenesis creates dependence on TXNRD1 for intracellular disulfide reduction, and TXNRD1 inhibition causes lethal cystine accumulation.

    Evidence Pharmacological TXNRD1 inhibition with selective death pathway inhibitors, SLC7A11 inhibitor rescue, NFATc1 transcriptional assays, OVX mouse model

    PMID:37148740

    Open questions at the time
    • Whether TXNRD1 directly reduces cystine or acts via Trx1 not resolved
    • Generalizability of disulfidptosis mechanism to other SLC7A11-high cell types not tested
  16. 2024 High

    A non-enzymatic, protein-interaction function of TXNRD1 was discovered: TXNRD1 localizes to cytoplasmic chromatin fragments in senescent cells, physically interacts with cGAS, enhances cGAS enzymatic activity, and drives the SASP and inflammaging through cGAS-STING signaling independently of TrxR1 reductase activity.

    Evidence Reciprocal Co-IP, subcellular fractionation, cGAS activity assays, enzymatic-vs-interaction-selective inhibitors, multiple mouse models

    PMID:38267705

    Open questions at the time
    • Structural basis for TXNRD1-cGAS interaction not resolved
    • Which TXNRD1 domain mediates cGAS binding unknown
    • Whether this interaction occurs in non-senescent inflammatory contexts not tested
  17. 2024 Medium

    TXNRD1 protein stability was shown to be regulated by TRIM25-mediated ubiquitination scaffolded by lncRNA CARD8-AS1, adding a post-translational degradation mechanism to the regulatory landscape of TXNRD1 abundance.

    Evidence RNA pull-down, Co-IP, ubiquitination assays, rescue with TXNRD1 overexpression in lung adenocarcinoma models

    PMID:38153696

    Open questions at the time
    • TRIM25 ubiquitination sites on TXNRD1 not mapped
    • Whether this mechanism operates outside lung adenocarcinoma not tested
    • Single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for TXNRD1's non-enzymatic interaction with cGAS; whether the SecTRAP pro-oxidant form of TrxR1 has physiological signaling roles; how TXNRD1 isoform-specific functions (v3 membrane raft signaling, cytosolic redox catalysis) are coordinated in vivo; and whether TXNRD1 loss-of-function mutations cause a broader clinical spectrum beyond the single reported family.
  • No crystal structure of TXNRD1-cGAS complex
  • SecTRAP physiological relevance untested
  • Full disease spectrum of TXNRD1 deficiency undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 8 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-1430728 Metabolism 1 R-HSA-1640170 Cell Cycle 1
Partners
CGASGSRPRDX2PTENTRIM25TXN

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 RSL3 and ML162, commonly used as GPX4 inhibitors to study ferroptosis, are in fact potent inhibitors of TXNRD1 and lack capacity to inhibit recombinant selenoprotein GPX4 enzymatic activity; other known TXNRD1 inhibitors (auranofin, TRi-1, TRi-2) also induce cell death but through ferroptosis-independent mechanisms. In vitro enzymatic activity assays with recombinant GPX4 and TXNRD1, cell death assays with ferrostatin-1 Redox biology High 37087975
2024 TXNRD1 drives the senescence-associated secretory phenotype (SASP) and inflammaging through the cGAS-STING innate immune pathway independently of its enzymatic activity; TXNRD1 localizes to cytoplasmic chromatin fragments, physically interacts with cGAS in a senescence-dependent manner, enhances cGAS enzymatic activity, and is required for SASP-mediated tumor-promoting and immune surveillance functions in vivo. Co-immunoprecipitation, subcellular fractionation, cGAS activity assays, mouse models with TXNRD1 inhibitors selective for enzymatic vs. cGAS-interaction functions, loss-of-function studies Nature aging High 38267705
2014 Selenocysteine (Sec)-containing TrxR1 is absolutely required for self-sufficient growth of mouse embryonic fibroblasts under high-glucose conditions due to its essential role in eliminating glucose-derived H2O2; Sec-devoid TrxR1 variants cannot rescue this function. Txnrd1 knockout MEFs reconstituted with wild-type vs. Sec-devoid TrxR1 variants, H2O2 measurement, cell death assays Cell death & disease High 24853413
2011 In vivo hepatocyte DNA replication requires either glutathione (GSH) or at least one functional allele of Txnrd1; complete loss of both pathways (Txnrd1-null hepatocytes + BSO-mediated GSH depletion) severely impairs hepatocyte replication, establishing that TrxR1 and GSH independently support ribonucleotide reductase electron donation in vivo. Genetic mouse models (Txnrd1 conditional knockout), BSO treatment, replicative index measurement, TrxR activity assays Free radical biology & medicine High 22198266
2013 Hepatocyte-specific disruption of Txnrd1 causes a metabolic switch repressing lipogenic genes, engorging periportal hepatocytes with glycogen, upregulating glutathione biosynthesis, UDP-glucuronate machinery, glutathione-S-transferases, UDP-glucuronyl-transferases, and xenobiotic exporters; NAPQI (from acetaminophen) directly inactivates TrxR1, yet Txnrd1-null livers are resistant to APAP hepatotoxicity due to constitutively enhanced GSH and glucuronidation systems. Hepatocyte-specific Txnrd1 conditional knockout mice, metabolomic profiling, APAP hepatotoxicity challenge, in vitro NAPQI-TrxR1 inactivation assay Free radical biology & medicine High 23743293
2009 RITA binds TrxR1 non-covalently and inhibits its activity in vitro and in cancer cells in a p53-dependent manner; RITA also induces a ~130 kDa stable covalently linked TrxR1 dimer and increases ROS specifically in cancer cells but not normal fibroblasts, in a p53-dependent fashion. In vitro TrxR1 activity assay, cell-based TrxR activity measurement, ROS detection, Western blot for TrxR1 dimer Cell cycle Medium 19838062
2013 TrxR1 inhibition (via auranofin or siRNA) combined with AKT inhibition (MK2206) induces synthetic lethality in NSCLC cells through KEAP1/NRF2-dependent ROS accumulation and JNK activation; wild-type KEAP1 function is required for this synthetic lethality. Genome-wide siRNA library screen, combinatorial drug treatment, KEAP1 mutant cell lines, ROS measurement, in vivo xenograft Cancer research Medium 23824739
2020 TrxR1 inhibition by irreversible inhibitors induces oxidation of Prx2 and STAT3, which blocks STAT3-dependent transcription; previously identified STAT3 inhibitors also inhibit TrxR1, and TrxR1 inhibitors block STAT3-dependent transcriptional activity through redox-mediated STAT3 oxidation. Luciferase reporter assays, TrxR1 inhibitor profiling, oxidation state analysis of Prx2 and STAT3, target engagement studies Science advances Medium 32219156
2011 In C. elegans, TRXR-1 (selenoprotein thioredoxin reductase) functions together with GSR-1 glutathione reductase to reduce disulfide bonds in the cuticle during molting; selenocysteine-to-cysteine TRXR-1 mutants fail to rescue molting defects, demonstrating strict selenocysteine dependence; exogenous reduced glutathione can substitute to induce apolysis. C. elegans genetic knockouts/mutants, selenocysteine-to-cysteine mutant rescue experiments, SELB-1 mutants (selenocysteine incorporation factor), exogenous GSH treatment, cuticle oxidation state analysis Proceedings of the National Academy of Sciences of the United States of America High 21199936
2009 The TXNRD1_v3 splice variant (carrying an N-terminal glutaredoxin domain) forms dynamic cytoplasmic filaments and induces filopodia formation when overexpressed; both filament formation and filopodia are dependent on the glutaredoxin domain; filopodia but not filaments require actin polymerization. Live cell imaging, truncation mutants, actin polymerization inhibitors, overexpression in cell lines Biochimica et biophysica acta Medium 19654027
2013 TXNRD1_v3 membrane targeting is mediated by myristoylation and palmitoylation of its N-terminal MGC motif, directing it specifically to membrane rafts; v3-mediated filopodia induction is independent of redox-active Cys residues but dependent on membrane raft targeting. Site-directed mutagenesis of MGC motif, lipid fractionation, cholera toxin B co-localization, truncated mutant analysis The Journal of biological chemistry High 23413027
2006 Diverse gold compounds (auranofin, gold sodium thiomalate, sodium aurothiosulfate, triphenyl phosphine gold chloride, gold acetate) all inhibit TrxR1 at nanomolar concentrations; Au(I)-phosphine compounds are most potent; ligand configuration rather than gold oxidation state determines inhibitory potency. Ex vivo TrxR1 activity assay with purified rat TrxR1, IC50 determination, comparison with cellular mitochondrial toxicity Toxicology in vitro Medium 16510263
2018 Manumycin A irreversibly inhibits TrxR1 (IC50 272 nM with preincubation) by forming a Michael adduct with the selenocysteine residue in the C-terminal redox center, converting TrxR1 into a SecTRAP that uses NADPH to reduce oxygen to superoxide. In vitro TrxR1 activity assay with/without preincubation, time-dependence analysis, covalent modification evidence, superoxide production assay ACS medicinal chemistry letters High 29670693
2017 miR-23a and miR-23b directly bind the 3' UTR of TrxR1 mRNA, repressing its expression during early C2C12 myoblast differentiation; TrxR1 depletion promotes myogenic gene expression (myogenin, Myf5 upregulation; Cyclin D1 decrease), while TrxR1 overexpression delays myogenesis. 3' UTR luciferase reporter assay, miRNA mimic/inhibitor transfection, TrxR1 KD and OE in C2C12 cells, myogenic marker expression analysis Scientific reports Medium 28775321
2015 Trx1/TrxR1 system regulates survival of post-selected CD69+ double-positive thymocytes by suppressing ASK1, JNK, and p38 MAPK phosphorylation and limiting Bim upregulation; TrxR1 inhibition specifically reduces post-selected DP thymocytes both in vitro and in vivo. TrxR1 inhibitor treatment in vitro and in vivo, Western blot for ASK1/JNK/p38 phosphorylation, flow cytometry for thymocyte subsets, Bim expression analysis Immunology and cell biology Medium 25753394
2022 TXNRD1 attenuates the interaction between Trx1 and PTEN, resulting in accelerated PTEN degradation and consequent Akt/mTOR pathway activation, promoting HCC cell mobility and metastasis; USF2 is a transcriptional suppressor that directly binds two E-box sites in the TXNRD1 promoter to repress its expression. Co-IP (Trx1-PTEN interaction), siRNA knockdown, overexpression studies, ChIP/dual-luciferase for USF2-TXNRD1 promoter interaction, in vitro and in vivo xenograft models Cell death & disease Medium 36319631
2017 A homozygous TXNRD1 mutation (p.Pro190Leu) reduces enzyme activity to 16–34% of controls in patient fibroblasts and skeletal muscle; in vitro kinetic analysis of recombinant mutant TXNRD1 shows 30–40% lower kcat/Se values; reduced enzyme abundance was confirmed by 75Se labeling; patient fibroblasts show reduced resistance to H2O2 challenge. 75Se labeling, Western blot, in vitro kinetic analysis of recombinant mutant protein, enzymatic activity assays in patient-derived cells, exome sequencing Free radical biology & medicine High 28232204
2023 During RANKL-induced osteoclastogenesis, NFATc1 transcriptionally upregulates SLC7A11 (cystine transporter); TXNRD1 inhibition reduces intracellular disulfide reduction rate, causing cystine accumulation and disulfidptosis selectively in osteoclast precursors; this cell death is blocked by SLC7A11 inhibitors but not by ferroptosis, apoptosis, necroptosis, or autophagy inhibitors. NFATc1 transcriptional reporter assays, pharmacological TXNRD1 inhibition, SLC7A11 inhibitors, selective inhibitors of multiple death pathways, OVX mouse model in vivo Redox biology High 37148740
2022 The RX1 probe selectively targets mammalian TrxR1 via a cyclic selenenylsulfide that exploits TrxR1's unique selenolthiol chemistry; probe selectivity validated by TrxR1 knockout, selenium starvation, knock-in, and chemical inhibitors; used for quantitative live-cell high-throughput screening of TrxR1 inhibitors. Genetic KO, selenium starvation, knock-in complementation, chemical inhibitors, live-cell fluorescence imaging, high-throughput screening Chem High 35936029
2019 TrxR1 and Gsr together maintain antioxidant defense in mouse liver; TrxR1-null livers develop threefold fewer DEN-induced tumors compared to wild-type, suggesting TrxR1 promotes carcinogen-induced cancer initiation; elevated oxidative stress (TrxR1/Gsr double-null) correlates with increased malignancy independently of Nrf2 expression within tumors. Conditional knockout mouse models (TrxR1-null, Gsr-null, double-null), DEN carcinogenesis model, DNA damage measurement, metabolomics, tumor burden quantification Proceedings of the National Academy of Sciences of the United States of America High 31097586
2023 Nrf2 positively regulates TXNRD1 protein expression, shown by co-immunoprecipitation and Western blotting; deferoxamine activates nuclear translocation of Nrf2 in hippocampal neurons and thereby upregulates TXNRD1 to suppress ferroptosis and inflammation after subarachnoid hemorrhage. Co-immunoprecipitation, Western blotting, Nrf2 pathway inhibitor (ML385), in vivo SAH mouse model, in vitro FIN56 ferroptosis model Molecular neurobiology Medium 37676391
2024 lncRNA CARD8-AS1 acts as a scaffold to facilitate the interaction between TXNRD1 and E3 ubiquitin ligase TRIM25, promoting TXNRD1 degradation through the ubiquitin-proteasome pathway; TXNRD1 overexpression reverses the tumor-suppressive effects of CARD8-AS1 in lung adenocarcinoma. RNA pull-down, Co-IP, ubiquitination assays, rescue experiments with TXNRD1 overexpression, in vitro and in vivo functional studies Carcinogenesis Medium 38153696
2025 Glaucocalyxin A (GLA) selectively forms covalent bonds with Cys173 of PRDX1 and Cys59, Cys64, Cys497, and Sec498 of TXNRD1 (with reactivity order Sec498 > Cys59 > Cys497 > Cys64), inhibiting their enzymatic activities, disrupting redox homeostasis, and triggering autophagy-mediated ferroptosis in NSCLC cells. Activity-based protein profiling (ABPP), covalent binding site identification by mass spectrometry, computational chemistry, in vitro enzymatic activity assays, in vivo xenograft Phytomedicine Medium 41016297
2023 Elovanoid-N34 directly modulates TXNRD1 activity by binding to TXNRD1 isoforms 2 or 3 (identified by limited proteolysis screening), inducing structural changes at the FAD interface domain; ELV-N34 decreases both membrane and cytosolic TXNRD1 activity, revealing distinct subcellular localizations of the enzyme. Limited proteolysis (LiP) mass spectrometry screening, TXNRD1 silencing to confirm isoform specificity, TXNRD1 activity assays in membrane and cytosolic fractions Cell death & disease Medium 38086796
2025 ROS-triggered prodrug 5u releases active compound 6a, which covalently binds to Cys475 and Sec498 sites on TXNRD1, inhibiting its activity, disrupting redox homeostasis, and causing apoptosis and ferroptosis in NSCLC cells. Covalent binding site identification, in vitro TrxR1 activity assay, cell death mechanism assays (apoptosis/ferroptosis markers), in vivo xenograft and organoid models Journal of medicinal chemistry Medium 39869029
2024 Butein irreversibly inhibits recombinant TXNRD1 in a time-dependent manner by modifying catalytic Cys residues, identified by TrxR1 mutant variants and LC-MS; cellular ROS accumulation results and reversal of cisplatin resistance is achieved through TXNRD1 inhibition. In vitro enzymatic assay with recombinant TXNRD1, TXNRD1 Cys mutant variants, LC-MS covalent modification identification, cellular ROS assays, cisplatin-resistant cell line studies Biological trace element research High 39141196
2023 Thimerosal competitively and reversibly inhibits TrxR1 with an IC50 of 24.08 nM, identified via a high-throughput screening assay based on enzyme kinetics. Enzyme kinetics-based high-throughput screening, IC50 determination, competitive inhibition mode analysis, cellular ROS assay Biochemical and biophysical research communications Medium 36780763
2023 TXNRD1 knockdown in oscillatory shear stress (Oss)-treated human aortic endothelial cells inhibits their proliferation, migration, and tube formation by activating the eNOS/apoptosis pathway; L-NAME (eNOS inhibitor) reverses these effects, placing eNOS downstream of TXNRD1 in this context. TXNRD1 siRNA knockdown, Oss shear stress bioreactor, L-NAME pharmacological inhibition, proliferation/migration/tube formation assays, flow cytometry for apoptosis Biochimica et biophysica acta. Molecular cell research Medium 36754152
2025 TrxR1/2 inhibition by isowalsuranolide (Hdy-7) leads to ROS accumulation that activates p53 and subsequent lysosomal biogenesis via TFEB/TFE3 nuclear translocation; knockdown of TrxR1/2 phenocopies this effect; pharmacological or genetic inhibition of autophagy prevents Hdy-7-induced cell death, indicating autophagic cell death downstream of TrxR1/2 inhibition. TrxR1/2 knockdown, ROS scavenger (NAC), p53 knockdown, SESN2 knockdown, TFEB/TFE3 nuclear translocation assays, autophagy inhibition, in vitro TrxR activity assays Science China. Life sciences Medium 40059270

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 TrxR1 as a potent regulator of the Nrf2-Keap1 response system. Antioxidants & redox signaling 201 26058897
2023 The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox biology 171 37087975
2014 Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell death & disease 150 24763048
2016 Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer. Cancer letters 109 26963494
2019 SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC. Cell death and differentiation 98 31367013
2006 Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxR1). Toxicology in vitro : an international journal published in association with BIBRA 95 16510263
2019 Dietary intakes and biomarker patterns of folate, vitamin B6, and vitamin B12 can be associated with cognitive impairment by hypermethylation of redox-related genes NUDT15 and TXNRD1. Clinical epigenetics 84 31601260
2018 Curcuminoid B63 induces ROS-mediated paraptosis-like cell death by targeting TrxR1 in gastric cells. Redox biology 82 30590310
2023 NFATc1-mediated expression of SLC7A11 drives sensitivity to TXNRD1 inhibitors in osteoclast precursors. Redox biology 79 37148740
2019 miR-125b-5p inhibits cell proliferation, migration, and invasion in hepatocellular carcinoma via targeting TXNRD1. Cancer cell international 77 31384178
2019 TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy. Proceedings of the National Academy of Sciences of the United States of America 70 31097586
2011 Selenoprotein TRXR-1 and GSR-1 are essential for removal of old cuticle during molting in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 63 21199936
2011 Hepatocyte DNA replication in growing liver requires either glutathione or a single allele of txnrd1. Free radical biology & medicine 58 22198266
2009 p53-dependent inhibition of TrxR1 contributes to the tumor-specific induction of apoptosis by RITA. Cell cycle (Georgetown, Tex.) 58 19838062
2013 A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification. Free radical biology & medicine 57 23743293
2013 KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer. Cancer research 57 23824739
2020 Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death. Science advances 55 32219156
2018 A possible role for selenoprotein glutathione peroxidase (GPx1) and thioredoxin reductases (TrxR1) in thyroid cancer: our experience in thyroid surgery. Cancer cell international 53 29371830
2021 TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro. Oxidative medicine and cellular longevity 51 34917232
2016 Selective killing of gastric cancer cells by a small molecule via targeting TrxR1 and ROS-mediated ER stress activation. Oncotarget 47 26919094
2021 Berberine accelerated wound healing by restoring TrxR1/JNK in diabetes. Clinical science (London, England : 1979) 46 33491733
2018 PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway. Frontiers in oncology 45 30619751
2016 TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition. Cell cycle (Georgetown, Tex.) 45 26743692
2017 MiR-23-TrxR1 as a novel molecular axis in skeletal muscle differentiation. Scientific reports 44 28775321
2020 DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects. Journal of cellular and molecular medicine 43 33345387
2019 Piperlongumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress. Frontiers in pharmacology 43 31680962
2014 The Au clusters induce tumor cell apoptosis via specifically targeting thioredoxin reductase 1 (TrxR1) and suppressing its activity. Chemical communications (Cambridge, England) 43 25078326
2020 LncRNA FTX inhibition restrains osteosarcoma proliferation and migration via modulating miR-320a/TXNRD1. Cancer biology & therapy 41 31920141
2020 microRNA-130b-3p Contained in MSC-Derived EVs Promotes Lung Cancer Progression by Regulating the FOXO3/NFE2L2/TXNRD1 Axis. Molecular therapy oncolytics 38 33575477
2019 Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells. Journal of experimental & clinical cancer research : CR 36 31113439
2019 Curcuminoid WZ26, a TrxR1 inhibitor, effectively inhibits colon cancer cell growth and enhances cisplatin-induced cell death through the induction of ROS. Free radical biology & medicine 35 31176737
2019 Alantolactone promotes ER stress-mediated apoptosis by inhibition of TrxR1 in triple-negative breast cancer cell lines and in a mouse model. Journal of cellular and molecular medicine 34 30609207
2017 Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy. Free radical biology & medicine 33 28232204
2022 Selective cellular probes for mammalian thioredoxin reductase TrxR1: rational design of RX1, a modular 1,2-thiaselenane redox probe. Chem 29 35936029
2017 MicroRNA-124 regulates the radiosensitivity of non-small cell lung cancer cells by targeting TXNRD1. Oncology letters 29 28454363
2012 Two thioredoxin reductases, trxr-1 and trxr-2, have differential physiological roles in Caenorhabditis elegans. Molecules and cells 29 22836943
2013 Selenite protects Caenorhabditis elegans from oxidative stress via DAF-16 and TRXR-1. Molecular nutrition & food research 28 24254253
2017 Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk. Scientific reports 27 28743999
2014 Sec-containing TrxR1 is essential for self-sufficiency of cells by control of glucose-derived H2O2. Cell death & disease 27 24853413
2022 USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling. Cell death & disease 25 36319631
2019 Potent inhibition of gastric cancer cells by a natural compound via inhibiting TrxR1 activity and activating ROS-mediated p38 MAPK pathway. Free radical research 25 30668191
2023 Deferoxamine Mitigates Ferroptosis and Inflammation in Hippocampal Neurons After Subarachnoid Hemorrhage by Activating the Nrf2/TXNRD1 Axis. Molecular neurobiology 24 37676391
2020 Circ0120816 acts as an oncogene of esophageal squamous cell carcinoma by inhibiting miR-1305 and releasing TXNRD1. Cancer cell international 24 33292234
2015 Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma. Journal of medicinal chemistry 24 26331426
2020 Licochalcone a Induces ROS-Mediated Apoptosis through TrxR1 Inactivation in Colorectal Cancer Cells. BioMed research international 23 32596335
2017 TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport. Scientific reports 23 28338004
2015 Trx1/TrxR1 system regulates post-selected DP thymocytes survival by modulating ASK1-JNK/p38 MAPK activities. Immunology and cell biology 23 25753394
2024 TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation. Nature aging 22 38267705
2020 Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a. Cancer management and research 22 32021440
2019 Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy. European journal of medicinal chemistry 22 31400708
2022 Diffractaic acid, a novel TrxR1 inhibitor, induces cytotoxicity, apoptosis, and antimigration in human breast cancer cells. Chemico-biological interactions 21 35569514
2012 TrxR1 and GPx2 are potently induced by isothiocyanates and selenium, and mutually cooperate to protect Caco-2 cells against free radical-mediated cell death. Biochimica et biophysica acta 21 22820176
2009 The human thioredoxin reductase-1 splice variant TXNRD1_v3 is an atypical inducer of cytoplasmic filaments and cell membrane filopodia. Biochimica et biophysica acta 21 19654027
2020 Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy. Frontiers in molecular biosciences 20 33134322
2018 Manumycin A Is a Potent Inhibitor of Mammalian Thioredoxin Reductase-1 (TrxR-1). ACS medicinal chemistry letters 20 29670693
2013 The rare TXNRD1_v3 ("v3") splice variant of human thioredoxin reductase 1 protein is targeted to membrane rafts by N-acylation and induces filopodia independently of its redox active site integrity. The Journal of biological chemistry 18 23413027
2023 Nitrovin (difurazone), an antibacterial growth promoter, induces ROS-mediated paraptosis-like cell death by targeting thioredoxin reductase 1 (TrxR1). Biochemical pharmacology 17 36893814
2022 Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6. Biomolecules 17 36008942
2019 Up-regulation of antioxidative proteins TRX1, TXNL1 and TXNRD1 in the cortex of PTZ kindling seizure model mice. PloS one 17 30677045
2017 PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation. Oncotarget 17 29416738
2007 Effect of selenium on thioredoxin reductase activity in Txnrd1 or Txnrd2 hemizygous mice. Biological chemistry 17 17937623
2023 Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 38537439
2022 Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors. European journal of medicinal chemistry 16 36370550
2021 N-γ-(L-glutamyl)-L-selenomethionine shows neuroprotective effects against Parkinson's disease associated with SKN-1/Nrf2 and TRXR-1 in Caenorhabditis elegans. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 34537465
2015 Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age. Oxidative medicine and cellular longevity 16 26064428
2021 miR‑875‑5p regulates IR and inflammation via targeting TXNRD1 in gestational diabetes rats. Molecular medicine reports 15 33649852
2023 Selenium-ruthenium complex blocks H1N1 influenza virus-induced cell damage by activating GPx1/TrxR1. Theranostics 14 37064873
2022 Expression of TXNRD1, HSPA4L and ATP1B1 Genes Associated with the Freezability of Boar Sperm. International journal of molecular sciences 13 36012584
2022 miR-3614-5p downregulation promotes cadmium-induced breast cancer cell proliferation and metastasis by targeting TXNRD1. Ecotoxicology and environmental safety 13 36335879
2018 miR-125a Suppresses TrxR1 Expression and Is Involved in H2O2-Induced Oxidative Stress in Endothelial Cells. Journal of immunology research 13 30225271
2021 Design, synthesis and biological evaluations of diverse Michael acceptor-based phenazine hybrid molecules as TrxR1 inhibitors. Bioorganic chemistry 11 33640630
2023 A Novel TrxR1 Inhibitor Regulates NK and CD8+ T Cell Infiltration and Cytotoxicity, Enhancing the Efficacy of Anti-PD-1 Immunotherapy against Hepatocarcinoma. Journal of immunology (Baltimore, Md. : 1950) 10 36602827
2023 Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases. Cell death & disease 10 38086796
2014 Prenatal expression of thioredoxin reductase 1 (TRXR1) and microsomal glutathione transferase 1 (MGST1) in humans. FEBS open bio 10 25379386
2022 Targeted inhibition of TXNRD1 prevents cartilage extracellular matrix degeneration by activating Nrf2 pathway in osteoarthritis. Biochemical and biophysical research communications 8 36308906
2022 Metabolism-Related Gene TXNRD1 Regulates Inflammation and Oxidative Stress Induced by Cigarette Smoke through the Nrf2/HO-1 Pathway in the Small Airway Epithelium. Oxidative medicine and cellular longevity 8 36578523
2012 Simvastatin inhibits the core promoter of the TXNRD1 gene and lowers cellular TrxR activity in HepG2 cells. Biochemical and biophysical research communications 8 23154180
2025 Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small Cell Lung Cancer. Journal of medicinal chemistry 7 39869029
2024 Combination of TrxR1 inhibitor and lenvatinib triggers ROS-dependent cell death in human lung cancer cells. International journal of biological sciences 7 38164168
2011 Genetic Variations in TXNRD1 as Potential Predictors of Drug-Induced Liver Injury. Allergy, asthma & immunology research 7 22548205
2024 Synergistic targeting of TrxR1 and ATM/AKT pathway in human colon cancer cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 6 38565059
2023 TXNRD1 knockdown inhibits the proliferation of endothelial cells subjected to oscillatory shear stress via activation of the endothelial nitric oxide synthase/apoptosis pathway. Biochimica et biophysica acta. Molecular cell research 6 36754152
2025 Cellular activity of the cytosolic selenoprotein thioredoxin reductase 1 (TXNRD1) is modulated by copper and zinc levels in the cell culture medium. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 5 39983285
2025 Isowalsuranolide targets TrxR1/2 and triggers lysosomal biogenesis and autophagy via the p53-TFEB/TFE3 axis. Science China. Life sciences 5 40059270
2025 Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1/2-Mediated ROS/MEK/ERK Pathway. Pharmaceuticals (Basel, Switzerland) 5 40143066
2024 LncRNA CARD8-AS1 suppresses lung adenocarcinoma progression by enhancing TRIM25-mediated ubiquitination of TXNRD1. Carcinogenesis 5 38153696
2024 Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production. Neoplasia (New York, N.Y.) 5 38733769
2024 Pharmacological Inhibition of TXNRD1 by a Small Molecule Flavonoid Butein Overcomes Cisplatin Resistance in Lung Cancer Cells. Biological trace element research 5 39141196
2024 Deciphering the Comprehensive Structure-Activity Relationship of Sunshinamide for Breast Cancer Therapy through Dual Modulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4 Inhibition. Journal of medicinal chemistry 5 39668144
2022 Correlation between TXNRD1/HO-1 expression and response to neoadjuvant chemoradiation therapy in patients with esophageal squamous cell carcinoma. Esophagus : official journal of the Japan Esophageal Society 5 34999996
2022 [Construction and identification of a HEK293 cell line with stable TrxR1 overexpression]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 5 35527491
2024 Investigation of the effects of thiazole compounds on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) targeted human brain glioblastoma cancer (U-87 MG). Biotechnology and applied biochemistry 4 38682343
2024 Endogenous electrophiles and peroxymonocarbonate can link tyrosine phosphorylation cascades with the cytosolic TXNRD1 selenoprotein and the KEAP1/NRF2 system. Current opinion in chemical biology 4 39243480
2023 Thimerosal, a competitive thioredoxin reductase 1 (TrxR1) inhibitor discovered via high-throughput screening. Biochemical and biophysical research communications 4 36780763
2023 RASSF1A promotes radiosensitivity in nasopharyngeal carcinoma by promoting FoxO3a and inhibiting the Nrf2/TXNRD1 signaling pathway. Neoplasma 4 38053374
2021 Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer. Journal of experimental & clinical cancer research : CR 4 34412665
2016 Association between TXNRD1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a prospective study. Genetics and molecular research : GMR 4 27706680
2025 Glaucocalyxin A induces autophagy-mediated ferroptosis by targeting PRDX1 and TXNRD1 proteins in non-small cell lung cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology 3 41016297
2024 PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway. Genes & genomics 3 38243044
2022 [Construction of a stable TrxR1 knockout HCT-116 cell line using CRISPR/Cas9 gene editing system]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 3 35355475