{"gene":"PRDX1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"Prdx1 knockout mice develop severe haemolytic anaemia with increased erythrocyte ROS, protein oxidation, haemoglobin instability, and Heinz body formation, demonstrating Prdx1's essential role as an antioxidant defence in erythrocytes. Prdx1-deficient fibroblasts show decreased proliferation and increased sensitivity to oxidative DNA damage, and Prdx1-null mice have abnormalities in NK cell numbers and function.","method":"Targeted gene inactivation (knockout mouse), phenotypic analysis including erythrocyte ROS measurement, haemoglobin stability assay, Heinz body staining, NK cell functional assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes, multiple orthogonal methods, published in Nature","pmids":["12891360"],"is_preprint":false},{"year":2009,"finding":"Prdx1 interacts with the transmembrane protein GDE2 and activates it through reduction of an intramolecular disulfide bond bridging GDE2's intracellular N- and C-terminal domains; this thiol-redox-dependent activation is required for spinal motor neuron differentiation. GDE2 variants incapable of disulfide bond formation are constitutively active and independent of Prdx1, establishing catalytic mechanism.","method":"Co-immunoprecipitation, genetic loss-of-function (Prdx1 and GDE2 ablation), active-site mutagenesis of Prdx1 (thiol-dead variants), GDE2 disulfide bond-null mutants, motor neuron differentiation assays in chick spinal cord","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo epistasis, mutagenesis of both proteins, reconstitution of mechanism with multiple orthogonal methods in a single rigorous study","pmids":["19766572"],"is_preprint":false},{"year":2013,"finding":"Prdx1 binds to both MKP-1 and MKP-5 (MAPK phosphatases). When its peroxidatic cysteine Cys52 is over-oxidised to sulfonic acid, Prdx1 dissociates from MKP-1, leading to MKP-1 oxidation-induced oligomerisation and inactivation toward p38MAPKα. Conversely, over-oxidised Prdx1 enhances the Prdx1:MKP-5 complex, protecting MKP-5 from inactivation, thereby maintaining MKP-5 activity toward p38MAPK and controlling ROS-induced senescence in breast epithelial cells.","method":"Co-immunoprecipitation, active-site mutant analysis (Cys52), H2O2 dose-response experiments, p38MAPKα activity assays in human breast epithelial cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, dose-response with two orthogonal methods, single lab","pmids":["23334324"],"is_preprint":false},{"year":2013,"finding":"Pin1 binds to the phospho-Thr90-Pro91 motif of PRDX1 and facilitates PP2A-mediated dephosphorylation of PRDX1, thereby restoring its peroxidase activity. In Pin1-/- MEFs, PRDX1 accumulates in an inactive phosphorylated form, leading to increased H2O2 and decreased peroxidase activity, which is rescued by re-introduction of Pin1.","method":"Proteomic identification of Pin1 binding partners, co-immunoprecipitation, Thr90 mutagenesis, Pin1 knockout MEFs, Pin1 rescue experiments, peroxidase activity assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, KO cells with rescue, peroxidase activity assay; single lab","pmids":["23421996"],"is_preprint":false},{"year":2013,"finding":"PRDX1 associated with c-Abl kinase under basal conditions; oxidative stress promotes dissociation of the Prdx1:c-Abl complex, leading to c-Abl activation and subsequent caveolin-1 phosphorylation and albumin endocytosis. AMPK activation suppresses this pathway by stabilising the Prdx1:c-Abl interaction. Prdx1 knockdown increased phosphorylation of both c-Abl and caveolin-1 and abolished AMPK's inhibitory effect.","method":"Co-immunoprecipitation, siRNA knockdown of Prdx1 and c-Abl, pharmacological AMPK activation/inhibition, caveolin-1 phosphorylation assay, albumin endocytosis assay in HUVEC cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD with defined phenotype, single lab, two orthogonal methods","pmids":["23723070"],"is_preprint":false},{"year":2018,"finding":"PRDX1 interacts with the RING finger domain of TRAF6 and inhibits its ubiquitin-ligase activity, thereby suppressing ubiquitination of ECSIT (required for NF-κB activation) and BECN1 (required for autophagy). PRDX1 knockdown in THP-1, MDA-MB-231, and SK-HEP-1 cells increased NF-κB activation, pro-inflammatory cytokines, and enhanced cancer cell migration/invasion.","method":"Co-immunoprecipitation (PRDX1 with TRAF6 RING domain), ubiquitination assay for ECSIT and BECN1, PRDX1 knockdown (siRNA), NF-κB reporter assay, cytokine ELISA, migration/invasion assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying domain, ubiquitination assay, KD phenotype in three cell lines; single lab","pmids":["29929436"],"is_preprint":false},{"year":2018,"finding":"PRDX1 and MTH1 cooperate to prevent accumulation of oxidised guanine in the genome. Concomitant disruption of PRDX1 and MTH1 genes in cancer cells leads to ROS-dependent continuous telomere shortening due to inhibition of telomerase-mediated telomere extension by oxidised guanine.","method":"CRISPR gene disruption of PRDX1 and MTH1, telomere length measurement, telomerase activity assay, ROS quantification","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts, telomerase activity measured directly, multiple orthogonal methods, rigorous controls","pmids":["29773556"],"is_preprint":false},{"year":2018,"finding":"PRDX1 forms a heterodimer with p38α (MAPK14), stabilising phospho-p38α in glioma cells. This complex amplifies HGF/MET-driven signalling and promotes actin cytoskeleton dynamics and glioma cell migration in vitro and invasion in vivo.","method":"Biochemical interaction studies (co-immunoprecipitation), in vitro and ex vivo migration assays, whole-brain ultramicroscopy, mouse glioma survival models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo validation; single lab, multiple methods","pmids":["29582423"],"is_preprint":false},{"year":2018,"finding":"Differential kinetics between PRDX1 and PRDX2: the rate of disulfide formation (resolution step) is 11 s⁻¹ for PRDX1 vs 0.2 s⁻¹ for PRDX2, making PRDX1 less susceptible to hyperoxidation and directing it toward a classical disulfide relay rather than a sulfenic-acid-mediated redox relay used by PRDX2.","method":"In vitro kinetic assays with recombinant human PRDX1 and PRDX2, intrinsic fluorescence monitoring of oxidation and hyperoxidation by H2O2 and peroxynitrite","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro enzyme kinetics with recombinant proteins, rate constants directly measured; single lab","pmids":["30284335"],"is_preprint":false},{"year":2020,"finding":"PRDX1 is enriched in telomeric chromatin. In PRDX1-depleted cells, PARP-dependent telomeric repair is often incomplete, generating persistent single-strand breaks that are converted into double-strand breaks during replication, causing rapid telomere shortening. PARP1 inhibition dampens this telomere shortening by promoting BRCA1/RAD51-mediated homologous recombination repair.","method":"PRDX1 depletion (siRNA/CRISPR), telomeric chromatin ChIP, PARP inhibition, telomere length assays, DNA damage marker assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with multiple repair pathway interventions; single lab","pmids":["33147465"],"is_preprint":false},{"year":2021,"finding":"PRDX1 oligomers bind with both the Nedd8-conjugating enzyme UBE2F and CUL5, forming a tricomplex critical for CUL5 neddylation. This promotes ubiquitination and degradation of the pro-apoptotic protein NOXA. Silencing PRDX1 or inhibiting PRDX1 oligomerisation greatly dampened CUL5 neddylation and extended the NOXA protein half-life.","method":"Co-immunoprecipitation, PRDX1 knockdown, PRDX1 oligomerisation inhibition, NOXA ubiquitination and protein stability assays, CUL5 neddylation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying tricomplex, functional ubiquitination assay; single lab","pmids":["33712558"],"is_preprint":false},{"year":2021,"finding":"Prdx1 interacts with ASK1 at elevated H2O2 concentrations independently of a scaffolding protein, constituting a redox-relay. This differs from the Prdx2:STAT3 relay and the Prdx2:ASK1 interaction (which requires a facilitator that is not annexin A2).","method":"Co-immunoprecipitation in cells, in vitro protein-protein interaction assays, H2O2 dose-response, comparison with Prdx2","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined cellular and in vitro interaction methods, multiple controls; single lab","pmids":["34209102"],"is_preprint":false},{"year":2022,"finding":"18β-glycyrrhetinic acid covalently binds to active cysteine residues of PRDX1 (and PRDX2), inhibiting their peroxidase activities, leading to ROS elevation and apoptosis in activated hepatic stellate cells. PRDX1 knockdown alone also produced ROS-mediated apoptosis.","method":"Activity-based protein profiling (chemoproteomic), cellular thermal shift assay, surface plasmon resonance, PRDX1 knockdown, enzymatic activity assay","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — covalent target identification by ABPP plus biophysical binding confirmation; single lab","pmids":["36105163"],"is_preprint":false},{"year":2023,"finding":"During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear ROS. Loss of PRDX1 lowers aspartate availability, impairing DNA damage-induced upregulation of de novo nucleotide synthesis, and causes replication stress accumulation.","method":"Functional genomics screen integrated with chromatin proteomics and metabolomics, PRDX1 KO, nuclear fractionation/localisation experiments, aspartate and nucleotide metabolite measurements","journal":"Molecular systems biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation with functional consequence, metabolomics; single lab, multi-method","pmids":["37259925"],"is_preprint":false},{"year":2023,"finding":"LncFASA directly binds to the Ahpc-TSA domain of PRDX1 and drives liquid-liquid phase separation of PRDX1, forming droplets that inhibit its peroxidase activity and disrupt ROS homeostasis, thereby promoting ferroptosis via the SLC7A11-GPX4 axis.","method":"RNA-protein binding assay (Ahpc-TSA domain mapping), phase separation droplet assay, PRDX1 peroxidase activity assay, SLC7A11-GPX4 pathway analysis, xenograft tumor model","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding mapped to domain, phase separation assay, enzymatic activity measurement; single lab","pmids":["37955780"],"is_preprint":false},{"year":2024,"finding":"MOF acetyltransferase acetylates PRDX1 at lysine 197 (K197), preventing its hyperoxidation and maintaining peroxidase activity under stress. LPS-induced inflammatory signalling rapidly decreases PRDX1 K197 acetylation in macrophages, elevating H2O2 accumulation, augmenting ERK1/2 phosphorylation, stimulating glycolysis, and enhancing pro-inflammatory mediator production (IL-6).","method":"Identification of MOF as PRDX1 acetyltransferase, K197 acetylation mass spectrometry, MOF KO macrophages, LPS stimulation, hyperoxidation assays, ERK1/2 phosphorylation, metabolic (glycolysis) assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — writer enzyme identified, specific acetylation site mapped by MS, KO with multiple orthogonal functional readouts","pmids":["39207899"],"is_preprint":false},{"year":2024,"finding":"HJURP forms disulfide-linked intermediates with PRDX1 through its Cys327 and Cys457 residues, promoting PRDX1 redox cycling and inhibiting its hyperoxidation, thereby enhancing PRDX1 peroxidase activity and reducing ROS/lipid peroxidation to suppress ferroptosis in prostate cancer cells.","method":"Co-immunoprecipitation, disulfide bond formation assay, mutagenesis of HJURP cysteines, PRDX1 peroxidase activity assay, ROS and lipid peroxidation measurements, in vitro and in vivo ferroptosis assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cysteine mutagenesis plus enzymatic activity assay; single lab","pmids":["39405980"],"is_preprint":false},{"year":2024,"finding":"PRDX1 acts as a molecular chaperone by binding to CUL3, inhibiting CUL3-mediated NRF2 ubiquitination, thereby promoting NRF2 nuclear translocation and transcription of GPX4. This chaperone binding requires PRDX1 Cys83; the Cys83Ser mutant abolishes CUL3 binding. Conoidin A enhances CUL3 binding.","method":"IP-mass spectrometry, Co-immunoprecipitation (PRDX1 with CUL3), Cys83Ser mutagenesis, NRF2 ubiquitination assay, PRDX1 KO mice (AOM/DSS CRC model), RNA sequencing, GPX4 transcription assay","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — IP-MS plus Co-IP, active-site mutagenesis, in vivo KO model with mechanistic rescue; multiple orthogonal methods","pmids":["39430237"],"is_preprint":false},{"year":2024,"finding":"Hspb1 directly interacts with Anxa2 to decrease its aggregation and phosphorylation, enabling Anxa2 to interact with Prdx1 and maintain its antioxidative activity by decreasing Prdx1 Thr90 phosphorylation. Overexpression of Hspb1 did not protect against pancreatitis in acinar-specific Prdx1 knockout mice, establishing Prdx1 as the downstream effector.","method":"Co-immunoprecipitation (Hspb1 with Anxa2 and Prdx1), Anxa2 KO mice, acinar-specific Prdx1 KO mice, Thr90 phosphorylation assay, AAV8-Hspb1 rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, tissue-specific KO epistasis, multiple orthogonal genetic tools; single lab","pmids":["38481805"],"is_preprint":false},{"year":2024,"finding":"PRDX1 directly interacts with the actin-binding protein Cofilin, inhibiting phosphorylation of Cofilin at Ser3, thereby accelerating actin depolymerisation and turnover, promoting oral squamous cell carcinoma cell movement, invasion, and metastasis.","method":"Co-immunoprecipitation (PRDX1 with Cofilin), Cofilin Ser3 phosphorylation assay, actin dynamics assay, in vitro migration/invasion assays, nude mouse tongue cancer model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation readout, in vivo validation; single lab","pmids":["38738971"],"is_preprint":false},{"year":2024,"finding":"IRAK1 binds to PRDX1 and prevents ubiquitination and proteasomal degradation of PRDX1 mediated by the E3 ubiquitin ligase HECTD3. Both the DOC and HECT domains of HECTD3 directly interact with PRDX1.","method":"IP/Co-IP, LC-MS/MS, GST pull-down, ubiquitination assay, HECTD3 domain mapping","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, ubiquitination assay, domain mapping; single lab","pmids":["37031183"],"is_preprint":false},{"year":2025,"finding":"ZNF207 promotes lactylation of PRDX1 at lysine 67, which enhances PRDX1 nuclear translocation and activation of NRF2, creating a ferroptosis-resistant environment and conferring regorafenib resistance in HCC cells. Disrupting PRDX1 K67 lactylation or NRF2 activity reverses resistance.","method":"CRISPR/Cas9 screening, lactylation modification assay (K67 site), nuclear fractionation/localisation, NRF2 activity assay, ferroptosis functional assays, drug resistance assays","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus PTM mapping plus functional pathway validation; single lab","pmids":["40680452"],"is_preprint":false},{"year":2025,"finding":"Artesunate directly binds to PRDX1 (interacting at Gly4) and PRDX2, inhibiting their peroxidase activities and inducing ferroptosis in diffuse large B-cell lymphoma cells. PRDX1 knockdown reproduced ferroptosis and reduced sensitivity to artesunate; PRDX2 overexpression attenuated artesunate-induced ROS and cytotoxicity.","method":"Small-molecule pull-down/LC-MS/MS, CETSA, fluorescence titration, circular dichroism, molecular docking, PRDX1/2 knockdown and overexpression, peroxidase activity assay, xenograft model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical binding methods plus enzymatic activity assay plus genetic validation in vitro and in vivo; single lab but multiple orthogonal methods","pmids":["40645965"],"is_preprint":false},{"year":2025,"finding":"A co-crystal structure of PRDX1 with the celastrol derivative LC-PDin20, combined with molecular docking, revealed the binding mode of covalent inhibitors to PRDX1 active site, enabling structure-based design of selective PRDX1 inhibitors.","method":"Co-crystal structure determination, molecular docking, in vitro PRDX1 enzymatic inhibition assay (IC50 determination), cell antiproliferation assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation (IC50), structure-guided SAR; single lab","pmids":["40546088"],"is_preprint":false},{"year":2017,"finding":"Prdx1 deficiency impairs lipophagic flux in macrophages by causing excessive oxidative stress, leading to reduced free cholesterol formation, decreased NR1H3 (LXRα) activity, and lower cholesterol efflux. 2-Cys PRDX mimics ebselen and gliotoxin restored both lipophagic flux and cholesterol efflux in Prdx1-deficient macrophages.","method":"Prdx1 KO macrophages, autophagic flux assay, cholesterol efflux assay, NR1H3 activity assay, ebselen/gliotoxin rescue, bone marrow transplant into apoe-/- mice with plaque measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype, pharmacological rescue, in vivo BM transplant; single lab","pmids":["28605287"],"is_preprint":false},{"year":2019,"finding":"PRDX1 inhibits the activated (cancer-associated) fibroblast phenotype by binding to JNK1 and regulating JNK kinase signalling; loss of PRDX1 results in development of a CAF-like phenotype in mammary fibroblasts. JNK inhibition with SP600125 reduced CAF-like behaviors in Prdx1 KO fibroblasts.","method":"Co-immunoprecipitation (PRDX1 with JNK1), PRDX1 KO mouse fibroblasts, JNK inhibitor (SP600125), transwell migration/invasion assay, immunofluorescence","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO phenotype, pharmacological inhibitor rescue; single lab","pmids":["31419957"],"is_preprint":false},{"year":2021,"finding":"PRDX1 activates autophagy in spiral ganglion neurons at least partially through activation of the PTEN-AKT signalling pathway; PRDX1 deficiency suppresses autophagy and increases neuronal loss after cisplatin exposure, while PRDX1 upregulation (pharmacologically or by AAV) activates autophagy and reduces ROS accumulation.","method":"PRDX1 KO and AAV-mediated overexpression, autophagy flux assay (LC3B, p62), PTEN/AKT pathway western blot, ROS measurement, SGN survival and hearing function assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain- and loss-of-function with pathway readout; single lab","pmids":["33749526"],"is_preprint":false},{"year":2023,"finding":"PRDX1 Cys52Ser (peroxidase-dead) variant mice show impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, the Cys52Ser variant suppresses NF-κB and STAT1 signalling, indicating that PRDX1 peroxidatic Cys52 is required for its pro-inflammatory activity in vivo.","method":"Knock-in mouse (PRDX1 Cys52Ser), Trx-TrxR-NADPH coupled peroxidase activity assay, western diet/MCD diet NASH model, RNA sequencing, NF-κB and STAT1 pathway analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site knock-in mutation with mechanistic pathway readout, in vivo model; single lab, multiple orthogonal methods","pmids":["37562742"],"is_preprint":false},{"year":2024,"finding":"PRDX1 interacts with DOK3 and modulates DOK3 degradation via the autophagy-lysosome pathway, thereby inhibiting plasma cell differentiation. The small molecule Salvianolic acid B acts as a molecular glue enhancing the PRDX1-DOK3 interaction, further impairing plasma cell differentiation and collagen-induced arthritis progression.","method":"Co-immunoprecipitation (PRDX1-DOK3), autophagy-lysosome pathway inhibition assay, plasma cell differentiation assay, collagen-induced arthritis mouse model, small molecule (SAB) functional validation","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pathway inhibition assay, in vivo model; single lab","pmids":["40893682"],"is_preprint":false},{"year":2023,"finding":"Modelling shows that the PRDX1 dimer-to-decamer transition has an inhibition-like effect on peroxidase activity; association and dissociation rate constants of 0.050 µM⁻⁴·s⁻¹ and 0.055 s⁻¹ respectively were obtained from isothermal titration calorimetry data and incorporated into kinetic models.","method":"Kinetic modelling using isothermal titration calorimetry data, HRP competition assay simulation, NADPH-oxidation linked assay simulation","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/kinetic modelling based on published data, no direct new experiment on PRDX1","pmids":["37760010"],"is_preprint":false},{"year":2025,"finding":"BACH1 directly binds to the PRDX1 promoter region and inhibits PRDX1 transcription. Remifentanil treatment inactivates BACH1, relieving PRDX1 repression and thereby reducing oxidative stress in hepatic ischemia-reperfusion injury.","method":"Chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, PRDX1 silencing rescue, HIRI mouse model, mRNA microarray","journal":"Clinics and research in hepatology and gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter establishing direct promoter binding; single lab","pmids":["39025461"],"is_preprint":false}],"current_model":"PRDX1 is a cytosolic 2-Cys peroxiredoxin whose peroxidatic Cys52 catalyses H2O2 reduction via a disulfide-relay cycle; its activity is regulated by multiple post-translational modifications (MOF-mediated K197 acetylation prevents hyperoxidation; Pin1/PP2A-mediated dephosphorylation of Thr90 restores activity; ZNF207-driven K67 lactylation promotes nuclear translocation; IRAK1 protects it from HECTD3-mediated ubiquitin degradation; Hspb1/Anxa2 complex suppresses Thr90 phosphorylation) and by oligomeric state (decamer has reduced peroxidase activity). Beyond ROS scavenging, PRDX1 functions as a redox relay/signal transducer: it activates GDE2 (motor neuron differentiation) by reducing an intramolecular disulfide bond, modulates MAPK signalling by differentially protecting MKP-1 vs MKP-5 in an H2O2 dose-dependent manner, forms a heterodimer with p38α to amplify MET/HGF invasion signals, binds ASK1 at elevated H2O2, inhibits TRAF6 ubiquitin-ligase activity to suppress NF-κB/autophagy, acts as a molecular chaperone binding CUL3 to prevent NRF2 ubiquitination and promote GPX4 transcription, and interacts with Cofilin to promote actin turnover. PRDX1 also translocates to the nucleus during DNA damage to scavenge nuclear ROS and preserve aspartate for nucleotide synthesis, cooperates with MTH1 to protect telomeres from oxidative damage, and promotes CUL5 neddylation via a PRDX1 oligomer/UBE2F/CUL5 tricomplex to degrade the pro-apoptotic protein NOXA."},"narrative":{"mechanistic_narrative":"PRDX1 is a 2-Cys peroxiredoxin that provides essential antioxidant defence, with its catalytic peroxidatic Cys52 reducing H2O2 through a fast disulfide-relay cycle that makes it relatively resistant to hyperoxidation [PMID:12891360, PMID:30284335, PMID:37562742]. Genetic loss causes erythrocyte oxidative damage and haemolytic anaemia, impaired fibroblast proliferation, and increased sensitivity to oxidative DNA damage, while the Cys52Ser peroxidase-dead knock-in reduces NASH and fibrosis by suppressing NF-κB and STAT1 signalling, demonstrating that catalytic activity drives both protective and pro-inflammatory phenotypes [PMID:12891360, PMID:37562742]. Beyond bulk ROS scavenging, PRDX1 acts as a redox relay and signalling adaptor: it reductively activates GDE2 to permit motor neuron differentiation [PMID:19766572], engages MAPK pathway components by differentially protecting MKP-1 versus MKP-5 in an H2O2-dose-dependent manner [PMID:23334324], binds ASK1 at elevated H2O2 [PMID:34209102], and inhibits TRAF6 ubiquitin-ligase activity to restrain NF-κB activation and autophagy [PMID:29929436]. PRDX1 also functions as a molecular chaperone for the NRF2 axis, binding CUL3 via Cys83 to block NRF2 ubiquitination and induce GPX4 transcription, thereby suppressing ferroptosis [PMID:39430237]. It translocates to the nucleus during the DNA damage response to scavenge nuclear ROS and sustain aspartate-dependent nucleotide synthesis [PMID:37259925], is enriched in telomeric chromatin where it cooperates with MTH1 to limit oxidative guanine damage and telomere shortening [PMID:29773556, PMID:33147465], and promotes CUL5 neddylation through a PRDX1-oligomer/UBE2F/CUL5 tricomplex to degrade pro-apoptotic NOXA [PMID:33712558]. PRDX1 activity is tuned by multiple post-translational modifications, including MOF-mediated K197 acetylation that prevents hyperoxidation, Pin1/PP2A-mediated dephosphorylation of Thr90 that restores peroxidase activity, and ZNF207-driven K67 lactylation that promotes nuclear translocation and NRF2 activation [PMID:39207899, PMID:23421996, PMID:40680452]. Its active-site cysteine is targeted by several covalent small-molecule inhibitors whose binding mode has been resolved by co-crystallography, providing a structural basis for selective inhibition [PMID:40645965, PMID:40546088].","teleology":[{"year":2003,"claim":"Established that PRDX1 is physiologically essential for antioxidant defence rather than redundant, by showing knockout animals suffer systemic oxidative pathology.","evidence":"Targeted knockout mouse with erythrocyte ROS, haemoglobin stability, Heinz body, and NK/fibroblast assays","pmids":["12891360"],"confidence":"High","gaps":["Did not resolve which catalytic residue or relay mechanism underlies protection","Did not distinguish cell-autonomous from systemic effects"]},{"year":2009,"claim":"Moved PRDX1 beyond bulk scavenging by demonstrating it acts as a specific redox enzyme that reductively activates a defined substrate to control a developmental program.","evidence":"Co-IP, thiol-dead PRDX1 and disulfide-null GDE2 mutants, motor neuron differentiation in chick spinal cord","pmids":["19766572"],"confidence":"High","gaps":["Whether other transmembrane substrates are activated this way unknown","Cytosolic-to-membrane targeting mechanism not defined"]},{"year":2013,"claim":"Showed PRDX1's oxidation state itself encodes signalling information, partitioning MAPK phosphatase protection in an H2O2-dose-dependent manner.","evidence":"Reciprocal Co-IP, Cys52 mutants, H2O2 dose-response, p38 activity in breast epithelial cells","pmids":["23334324"],"confidence":"Medium","gaps":["Direct redox transfer between PRDX1 and MKPs not reconstituted","Single cell-type context"]},{"year":2013,"claim":"Identified phosphorylation as a reversible off-switch for PRDX1, with Pin1/PP2A restoring peroxidase activity, linking proline isomerisation to redox capacity.","evidence":"Proteomics, Co-IP, Thr90 mutagenesis, Pin1 KO/rescue MEFs, peroxidase assay","pmids":["23421996"],"confidence":"Medium","gaps":["Kinase phosphorylating Thr90 not identified here","In vivo relevance not tested"]},{"year":2018,"claim":"Defined PRDX1 as a non-catalytic inhibitor of TRAF6 ubiquitin-ligase activity, coupling it to NF-κB inflammation and autophagy control.","evidence":"Co-IP to TRAF6 RING domain, ECSIT/BECN1 ubiquitination, knockdown across three cancer lines","pmids":["29929436"],"confidence":"Medium","gaps":["Whether this requires PRDX1 redox cycling unclear","Stoichiometry of inhibition not quantified"]},{"year":2018,"claim":"Provided the kinetic basis for PRDX1's distinct biological behaviour, measuring fast resolution that disfavours hyperoxidation relative to PRDX2.","evidence":"In vitro kinetics with recombinant PRDX1/PRDX2, intrinsic fluorescence","pmids":["30284335"],"confidence":"High","gaps":["In-cell relevance of measured rates not directly validated"]},{"year":2018,"claim":"Placed PRDX1 at telomeric chromatin protecting genome integrity by cooperating with MTH1 against oxidised guanine.","evidence":"CRISPR double knockout, telomere length, telomerase activity, ROS quantification","pmids":["29773556"],"confidence":"High","gaps":["How PRDX1 is recruited to telomeres not established"]},{"year":2018,"claim":"Showed PRDX1 can act as a positive signalling cofactor, heterodimerising with p38α to amplify MET/HGF-driven invasion.","evidence":"Co-IP, migration assays, glioma mouse survival and brain imaging","pmids":["29582423"],"confidence":"Medium","gaps":["Redox dependence of the heterodimer not dissected","Direct vs indirect p38 stabilisation unresolved"]},{"year":2020,"claim":"Refined the telomere role by showing PRDX1 supports PARP-dependent telomeric repair, preventing single- to double-strand break conversion.","evidence":"PRDX1 depletion, telomeric ChIP, PARP inhibition, DNA damage markers","pmids":["33147465"],"confidence":"Medium","gaps":["Direct enzymatic role at break sites versus general ROS control not separated"]},{"year":2021,"claim":"Demonstrated a scaffold-independent PRDX1:ASK1 redox relay at high H2O2, distinguishing PRDX1 relay logic from PRDX2.","evidence":"Cellular and in vitro interaction assays, H2O2 dose-response, PRDX2 comparison","pmids":["34209102"],"confidence":"Medium","gaps":["Downstream ASK1 signalling output not quantified","Disulfide intermediate not mapped"]},{"year":2021,"claim":"Revealed an oligomer-specific scaffolding function whereby PRDX1 enables CUL5 neddylation to degrade pro-apoptotic NOXA.","evidence":"Co-IP tricomplex, knockdown, oligomerisation inhibition, NOXA stability and neddylation assays","pmids":["33712558"],"confidence":"Medium","gaps":["Structural basis of UBE2F/CUL5 docking on PRDX1 oligomer unknown"]},{"year":2023,"claim":"Established a nuclear DNA-damage-response role for PRDX1 linking nuclear ROS scavenging to aspartate availability and nucleotide synthesis.","evidence":"Functional genomics, chromatin proteomics, metabolomics, PRDX1 KO, fractionation","pmids":["37259925"],"confidence":"Medium","gaps":["Mechanism of nuclear import signal not defined","Direct vs indirect aspartate link unresolved"]},{"year":2023,"claim":"Genetically proved Cys52 peroxidase activity is required for PRDX1's pro-inflammatory function in vivo via NF-κB/STAT1.","evidence":"Cys52Ser knock-in mice, coupled peroxidase assay, NASH diet models, RNA-seq","pmids":["37562742"],"confidence":"High","gaps":["Catalytic-independent signalling functions not addressed by this allele"]},{"year":2024,"claim":"Identified MOF-mediated K197 acetylation as a writer-controlled switch protecting PRDX1 from hyperoxidation, coupling acetylation loss to inflammatory glycolytic reprogramming.","evidence":"MOF as acetyltransferase, K197 MS, MOF KO macrophages, LPS, ERK/glycolysis readouts","pmids":["39207899"],"confidence":"High","gaps":["Deacetylase removing K197 not identified","Structural effect of K197 acetylation on active site unresolved"]},{"year":2024,"claim":"Showed PRDX1 functions as a chaperone for the NRF2-GPX4 anti-ferroptosis axis through Cys83-dependent CUL3 binding.","evidence":"IP-MS, Co-IP, Cys83Ser mutant, NRF2 ubiquitination, PRDX1 KO CRC mice, RNA-seq","pmids":["39430237"],"confidence":"High","gaps":["Whether chaperone activity is redox-state dependent unclear"]},{"year":2024,"claim":"Defined PRDX1 protein stability and activity as controlled by interacting partners that tune disulfide cycling and degradation (HJURP redox cycling, IRAK1/HECTD3 turnover, Hspb1/Anxa2 Thr90 phosphorylation, Cofilin actin turnover, DOK3 degradation).","evidence":"Co-IP, cysteine and Thr90 mutagenesis, ubiquitination and autophagy-lysosome assays, in vivo disease models","pmids":["39405980","37031183","38481805","38738971","40893682"],"confidence":"Medium","gaps":["Most interactions rest on single-lab Co-IP without reciprocal structural validation","Interplay among these regulators not integrated"]},{"year":2025,"claim":"Showed lactylation at K67 by ZNF207 and transcriptional repression by BACH1 add further layers controlling PRDX1 nuclear localisation and abundance in disease contexts.","evidence":"CRISPR screen, K67 lactylation mapping, nuclear fractionation, ChIP/luciferase, drug-resistance and ischemia models","pmids":["40680452","39025461"],"confidence":"Medium","gaps":["Eraser of K67 lactylation unknown","Crosstalk between transcriptional and PTM control not addressed"]},{"year":2025,"claim":"Validated PRDX1's active-site cysteine as a druggable covalent target and provided a co-crystal structure enabling structure-based inhibitor design.","evidence":"ABPP/pull-down, CETSA, SPR/fluorescence titration, co-crystal structure with celastrol derivative, IC50, ferroptosis xenografts (18β-GA, artesunate, LC-PDin20)","pmids":["36105163","40645965","40546088"],"confidence":"High","gaps":["Selectivity over PRDX2 for several compounds incomplete","In vivo therapeutic 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enzyme PRDX1 activity promotes MPP+-induced death in differentiated SH-SY5Y cells and may impair its colocalization with eEF1A2.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32781074","citation_count":14,"is_preprint":false},{"pmid":"37714033","id":"PMC_37714033","title":"Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/37714033","citation_count":14,"is_preprint":false},{"pmid":"28965027","id":"PMC_28965027","title":"l-carnitine supplementation during vitrification or warming of in vivo-produced ovine embryos does not affect embryonic survival rates, but alters CrAT and PRDX1 expression.","date":"2017","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/28965027","citation_count":14,"is_preprint":false},{"pmid":"37562742","id":"PMC_37562742","title":"PRDX1 Cys52Ser variant alleviates nonalcoholic steatohepatitis by reducing inflammation in mice.","date":"2023","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37562742","citation_count":13,"is_preprint":false},{"pmid":"36388649","id":"PMC_36388649","title":"miR-375 suppresses the growth and metastasis of esophageal squamous cell carcinoma by targeting PRDX1.","date":"2022","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36388649","citation_count":13,"is_preprint":false},{"pmid":"39079582","id":"PMC_39079582","title":"Furanodienone induces apoptosis via regulating the PRDX1/MAPKs/p53/caspases signaling axis through NOX4-derived mitochondrial ROS in colorectal cancer cells.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39079582","citation_count":13,"is_preprint":false},{"pmid":"34209102","id":"PMC_34209102","title":"Prdx1 Interacts with ASK1 upon Exposure to H2O2 and Independently of a Scaffolding Protein.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34209102","citation_count":12,"is_preprint":false},{"pmid":"29582423","id":"PMC_29582423","title":"A PRDX1-p38α heterodimer amplifies MET-driven invasion of IDH-wildtype and IDH-mutant gliomas.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29582423","citation_count":12,"is_preprint":false},{"pmid":"29908016","id":"PMC_29908016","title":"Peroxiredoxin 1 (PRDX1) Suppresses Progressions and Metastasis of Osteosarcoma and Fibrosarcoma of Bone.","date":"2018","source":"Medical science monitor : international medical journal of experimental and clinical 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/40645965","citation_count":9,"is_preprint":false},{"pmid":"38104368","id":"PMC_38104368","title":"TDP43/HDAC6/Prdx1 signaling pathway participated in the cognitive impairment of obstructive sleep apnea via regulating inflammation and oxidative stress.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38104368","citation_count":9,"is_preprint":false},{"pmid":"21434354","id":"PMC_21434354","title":"[Effects of yiqi chutan recipe on tumor growth, survival time and expressions of PRDX-1 and PRDX-6 in Lewis lung carcinoma model mice with pi-deficiency syndrome].","date":"2011","source":"Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21434354","citation_count":8,"is_preprint":false},{"pmid":"38738971","id":"PMC_38738971","title":"The interaction of PRDX1 with Cofilin promotes oral squamous cell carcinoma metastasis.","date":"2024","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38738971","citation_count":7,"is_preprint":false},{"pmid":"38159556","id":"PMC_38159556","title":"Hepatocytes-derived Prdx1 regulates macrophage phenotypes via TLR4 activation in acute liver injury.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38159556","citation_count":7,"is_preprint":false},{"pmid":"38780721","id":"PMC_38780721","title":"PRDX1 Interfering Peptide Disrupts Amino Acids 70-90 of PRDX1 to Inhibit the TLR4/NF-κB Signaling Pathway and Attenuate Neuroinflammation and Ischemic Brain Injury.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38780721","citation_count":7,"is_preprint":false},{"pmid":"40546088","id":"PMC_40546088","title":"Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40546088","citation_count":6,"is_preprint":false},{"pmid":"40693141","id":"PMC_40693141","title":"Tumor-associated bacteria activate PRDX1-driven glycolysis to promote immune evasion and PD-1 antibody resistance in hepatocellular carcinoma.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40693141","citation_count":6,"is_preprint":false},{"pmid":"16254121","id":"PMC_16254121","title":"Rare allelic imbalances, but no mutations of the PRDX1 gene in human hepatocellular carcinomas.","date":"2005","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16254121","citation_count":6,"is_preprint":false},{"pmid":"39263840","id":"PMC_39263840","title":"Antioxidant enzyme Prdx1 inhibits osteoclastogenesis via suppressing ROS and NFATc1 signaling pathways.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39263840","citation_count":5,"is_preprint":false},{"pmid":"40307771","id":"PMC_40307771","title":"PRDX1 knockdown promotes erastin-induced ferroptosis and impedes diffuse large B-cell lymphoma development by inhibiting the MAPK/ERK pathway.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40307771","citation_count":5,"is_preprint":false},{"pmid":"38844903","id":"PMC_38844903","title":"PRDX1 exerts a photoprotection effect by inhibiting oxidative stress and regulating MAPK signaling on retinal pigment epithelium.","date":"2024","source":"BMC ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/38844903","citation_count":5,"is_preprint":false},{"pmid":"38067110","id":"PMC_38067110","title":"Altered Regulation of the Glucose Transporter GLUT3 in PRDX1 Null Cells Caused Hypersensitivity to Arsenite.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38067110","citation_count":5,"is_preprint":false},{"pmid":"39025461","id":"PMC_39025461","title":"Remifentanil represses oxidative stress to relieve hepatic ischemia/reperfusion injury via regulating BACH1/PRDX1 axis.","date":"2024","source":"Clinics and research in hepatology and gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/39025461","citation_count":5,"is_preprint":false},{"pmid":"33744653","id":"PMC_33744653","title":"Fish natural killer enhancing factor-A (NKEF-A) enhance cytotoxicity of nonspecific cytotoxic cells against bacterial infection.","date":"2021","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33744653","citation_count":5,"is_preprint":false},{"pmid":"41016297","id":"PMC_41016297","title":"Glaucocalyxin A induces autophagy-mediated ferroptosis by targeting PRDX1 and TXNRD1 proteins in non-small cell lung cancer.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41016297","citation_count":4,"is_preprint":false},{"pmid":"38574831","id":"PMC_38574831","title":"Molecular characterization, cytoprotective, DNA protective, and immunological assessment of peroxiredoxin-1 (Prdx1) from yellowtail clownfish (Amphiprion clarkii).","date":"2024","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38574831","citation_count":4,"is_preprint":false},{"pmid":"37760010","id":"PMC_37760010","title":"Modelling the Decamerisation Cycle of PRDX1 and the Inhibition-like Effect on Its Peroxidase Activity.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37760010","citation_count":4,"is_preprint":false},{"pmid":"37063344","id":"PMC_37063344","title":"MicroRNA-146a Improved Acute Lung Injury Induced by hepatic Ischemia-reperfusion Injury by Inhibiting PRDX1.","date":"2023","source":"Dose-response : a publication of International Hormesis Society","url":"https://pubmed.ncbi.nlm.nih.gov/37063344","citation_count":4,"is_preprint":false},{"pmid":"37183847","id":"PMC_37183847","title":"Effects of Date Palm Pollen Supplementations on The Expression of PRDX1 and PRDX6 Genes in Infertile Men: A Controlled Clinical Trial.","date":"2023","source":"International journal of fertility & sterility","url":"https://pubmed.ncbi.nlm.nih.gov/37183847","citation_count":4,"is_preprint":false},{"pmid":"40893682","id":"PMC_40893682","title":"Augmentation of PRDX1-DOK3 interaction alleviates rheumatoid arthritis progression by suppressing plasma cell differentiation.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/40893682","citation_count":3,"is_preprint":false},{"pmid":"41108004","id":"PMC_41108004","title":"Investigating the potential causal link between BPA and ovarian carcinogenesis: a network toxicology and mendelian randomization study on the CTRC/PRDX1/SKP1 pathway.","date":"2025","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/41108004","citation_count":3,"is_preprint":false},{"pmid":"40114419","id":"PMC_40114419","title":"Panoptosis Targets the Mechanism of PRDX1 Involvement in Acute Myocardial Infarction via ZBP1.","date":"2025","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40114419","citation_count":3,"is_preprint":false},{"pmid":"35284843","id":"PMC_35284843","title":"A simple protocol to isolate a single human cell PRDX1 knockout generated by CRISPR-Cas9 system.","date":"2022","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/35284843","citation_count":3,"is_preprint":false},{"pmid":"33256302","id":"PMC_33256302","title":"[Effect and mechanism of PRDX1 in epithelial mesenchymal transformationin of gastric cancer cells].","date":"2020","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/33256302","citation_count":3,"is_preprint":false},{"pmid":"39925026","id":"PMC_39925026","title":"METTL3-mediated NFAT5 Upregulation Promotes Cervical Cancer Progression Through Enhancing the Mitochondrial Function by Transcriptional Regulation of PRDX1.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39925026","citation_count":3,"is_preprint":false},{"pmid":"40825764","id":"PMC_40825764","title":"Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40825764","citation_count":2,"is_preprint":false},{"pmid":"40189060","id":"PMC_40189060","title":"PRDX1 affects acrylamide-induced neural damage through the PTEN/AKT signaling pathway.","date":"2025","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40189060","citation_count":2,"is_preprint":false},{"pmid":"39895052","id":"PMC_39895052","title":"l-Glutamic Acid Alleviates Mastitis in Dairy Cows by Targeting the Sirt5/Nrf2/Prdx1 Signaling Axis and Mitochondrial Function.","date":"2025","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39895052","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56364,"output_tokens":8523,"usd":0.148469,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18080,"output_tokens":5500,"usd":0.11395,"stage2_stop_reason":"end_turn"},"total_usd":0.262419,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Prdx1 knockout mice develop severe haemolytic anaemia with increased erythrocyte ROS, protein oxidation, haemoglobin instability, and Heinz body formation, demonstrating Prdx1's essential role as an antioxidant defence in erythrocytes. Prdx1-deficient fibroblasts show decreased proliferation and increased sensitivity to oxidative DNA damage, and Prdx1-null mice have abnormalities in NK cell numbers and function.\",\n      \"method\": \"Targeted gene inactivation (knockout mouse), phenotypic analysis including erythrocyte ROS measurement, haemoglobin stability assay, Heinz body staining, NK cell functional assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes, multiple orthogonal methods, published in Nature\",\n      \"pmids\": [\"12891360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Prdx1 interacts with the transmembrane protein GDE2 and activates it through reduction of an intramolecular disulfide bond bridging GDE2's intracellular N- and C-terminal domains; this thiol-redox-dependent activation is required for spinal motor neuron differentiation. GDE2 variants incapable of disulfide bond formation are constitutively active and independent of Prdx1, establishing catalytic mechanism.\",\n      \"method\": \"Co-immunoprecipitation, genetic loss-of-function (Prdx1 and GDE2 ablation), active-site mutagenesis of Prdx1 (thiol-dead variants), GDE2 disulfide bond-null mutants, motor neuron differentiation assays in chick spinal cord\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo epistasis, mutagenesis of both proteins, reconstitution of mechanism with multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"19766572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prdx1 binds to both MKP-1 and MKP-5 (MAPK phosphatases). When its peroxidatic cysteine Cys52 is over-oxidised to sulfonic acid, Prdx1 dissociates from MKP-1, leading to MKP-1 oxidation-induced oligomerisation and inactivation toward p38MAPKα. Conversely, over-oxidised Prdx1 enhances the Prdx1:MKP-5 complex, protecting MKP-5 from inactivation, thereby maintaining MKP-5 activity toward p38MAPK and controlling ROS-induced senescence in breast epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, active-site mutant analysis (Cys52), H2O2 dose-response experiments, p38MAPKα activity assays in human breast epithelial cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, dose-response with two orthogonal methods, single lab\",\n      \"pmids\": [\"23334324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pin1 binds to the phospho-Thr90-Pro91 motif of PRDX1 and facilitates PP2A-mediated dephosphorylation of PRDX1, thereby restoring its peroxidase activity. In Pin1-/- MEFs, PRDX1 accumulates in an inactive phosphorylated form, leading to increased H2O2 and decreased peroxidase activity, which is rescued by re-introduction of Pin1.\",\n      \"method\": \"Proteomic identification of Pin1 binding partners, co-immunoprecipitation, Thr90 mutagenesis, Pin1 knockout MEFs, Pin1 rescue experiments, peroxidase activity assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, KO cells with rescue, peroxidase activity assay; single lab\",\n      \"pmids\": [\"23421996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRDX1 associated with c-Abl kinase under basal conditions; oxidative stress promotes dissociation of the Prdx1:c-Abl complex, leading to c-Abl activation and subsequent caveolin-1 phosphorylation and albumin endocytosis. AMPK activation suppresses this pathway by stabilising the Prdx1:c-Abl interaction. Prdx1 knockdown increased phosphorylation of both c-Abl and caveolin-1 and abolished AMPK's inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Prdx1 and c-Abl, pharmacological AMPK activation/inhibition, caveolin-1 phosphorylation assay, albumin endocytosis assay in HUVEC cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD with defined phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"23723070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX1 interacts with the RING finger domain of TRAF6 and inhibits its ubiquitin-ligase activity, thereby suppressing ubiquitination of ECSIT (required for NF-κB activation) and BECN1 (required for autophagy). PRDX1 knockdown in THP-1, MDA-MB-231, and SK-HEP-1 cells increased NF-κB activation, pro-inflammatory cytokines, and enhanced cancer cell migration/invasion.\",\n      \"method\": \"Co-immunoprecipitation (PRDX1 with TRAF6 RING domain), ubiquitination assay for ECSIT and BECN1, PRDX1 knockdown (siRNA), NF-κB reporter assay, cytokine ELISA, migration/invasion assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying domain, ubiquitination assay, KD phenotype in three cell lines; single lab\",\n      \"pmids\": [\"29929436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX1 and MTH1 cooperate to prevent accumulation of oxidised guanine in the genome. Concomitant disruption of PRDX1 and MTH1 genes in cancer cells leads to ROS-dependent continuous telomere shortening due to inhibition of telomerase-mediated telomere extension by oxidised guanine.\",\n      \"method\": \"CRISPR gene disruption of PRDX1 and MTH1, telomere length measurement, telomerase activity assay, ROS quantification\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts, telomerase activity measured directly, multiple orthogonal methods, rigorous controls\",\n      \"pmids\": [\"29773556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX1 forms a heterodimer with p38α (MAPK14), stabilising phospho-p38α in glioma cells. This complex amplifies HGF/MET-driven signalling and promotes actin cytoskeleton dynamics and glioma cell migration in vitro and invasion in vivo.\",\n      \"method\": \"Biochemical interaction studies (co-immunoprecipitation), in vitro and ex vivo migration assays, whole-brain ultramicroscopy, mouse glioma survival models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo validation; single lab, multiple methods\",\n      \"pmids\": [\"29582423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Differential kinetics between PRDX1 and PRDX2: the rate of disulfide formation (resolution step) is 11 s⁻¹ for PRDX1 vs 0.2 s⁻¹ for PRDX2, making PRDX1 less susceptible to hyperoxidation and directing it toward a classical disulfide relay rather than a sulfenic-acid-mediated redox relay used by PRDX2.\",\n      \"method\": \"In vitro kinetic assays with recombinant human PRDX1 and PRDX2, intrinsic fluorescence monitoring of oxidation and hyperoxidation by H2O2 and peroxynitrite\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro enzyme kinetics with recombinant proteins, rate constants directly measured; single lab\",\n      \"pmids\": [\"30284335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX1 is enriched in telomeric chromatin. In PRDX1-depleted cells, PARP-dependent telomeric repair is often incomplete, generating persistent single-strand breaks that are converted into double-strand breaks during replication, causing rapid telomere shortening. PARP1 inhibition dampens this telomere shortening by promoting BRCA1/RAD51-mediated homologous recombination repair.\",\n      \"method\": \"PRDX1 depletion (siRNA/CRISPR), telomeric chromatin ChIP, PARP inhibition, telomere length assays, DNA damage marker assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with multiple repair pathway interventions; single lab\",\n      \"pmids\": [\"33147465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX1 oligomers bind with both the Nedd8-conjugating enzyme UBE2F and CUL5, forming a tricomplex critical for CUL5 neddylation. This promotes ubiquitination and degradation of the pro-apoptotic protein NOXA. Silencing PRDX1 or inhibiting PRDX1 oligomerisation greatly dampened CUL5 neddylation and extended the NOXA protein half-life.\",\n      \"method\": \"Co-immunoprecipitation, PRDX1 knockdown, PRDX1 oligomerisation inhibition, NOXA ubiquitination and protein stability assays, CUL5 neddylation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying tricomplex, functional ubiquitination assay; single lab\",\n      \"pmids\": [\"33712558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Prdx1 interacts with ASK1 at elevated H2O2 concentrations independently of a scaffolding protein, constituting a redox-relay. This differs from the Prdx2:STAT3 relay and the Prdx2:ASK1 interaction (which requires a facilitator that is not annexin A2).\",\n      \"method\": \"Co-immunoprecipitation in cells, in vitro protein-protein interaction assays, H2O2 dose-response, comparison with Prdx2\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined cellular and in vitro interaction methods, multiple controls; single lab\",\n      \"pmids\": [\"34209102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"18β-glycyrrhetinic acid covalently binds to active cysteine residues of PRDX1 (and PRDX2), inhibiting their peroxidase activities, leading to ROS elevation and apoptosis in activated hepatic stellate cells. PRDX1 knockdown alone also produced ROS-mediated apoptosis.\",\n      \"method\": \"Activity-based protein profiling (chemoproteomic), cellular thermal shift assay, surface plasmon resonance, PRDX1 knockdown, enzymatic activity assay\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — covalent target identification by ABPP plus biophysical binding confirmation; single lab\",\n      \"pmids\": [\"36105163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear ROS. Loss of PRDX1 lowers aspartate availability, impairing DNA damage-induced upregulation of de novo nucleotide synthesis, and causes replication stress accumulation.\",\n      \"method\": \"Functional genomics screen integrated with chromatin proteomics and metabolomics, PRDX1 KO, nuclear fractionation/localisation experiments, aspartate and nucleotide metabolite measurements\",\n      \"journal\": \"Molecular systems biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation with functional consequence, metabolomics; single lab, multi-method\",\n      \"pmids\": [\"37259925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LncFASA directly binds to the Ahpc-TSA domain of PRDX1 and drives liquid-liquid phase separation of PRDX1, forming droplets that inhibit its peroxidase activity and disrupt ROS homeostasis, thereby promoting ferroptosis via the SLC7A11-GPX4 axis.\",\n      \"method\": \"RNA-protein binding assay (Ahpc-TSA domain mapping), phase separation droplet assay, PRDX1 peroxidase activity assay, SLC7A11-GPX4 pathway analysis, xenograft tumor model\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapped to domain, phase separation assay, enzymatic activity measurement; single lab\",\n      \"pmids\": [\"37955780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MOF acetyltransferase acetylates PRDX1 at lysine 197 (K197), preventing its hyperoxidation and maintaining peroxidase activity under stress. LPS-induced inflammatory signalling rapidly decreases PRDX1 K197 acetylation in macrophages, elevating H2O2 accumulation, augmenting ERK1/2 phosphorylation, stimulating glycolysis, and enhancing pro-inflammatory mediator production (IL-6).\",\n      \"method\": \"Identification of MOF as PRDX1 acetyltransferase, K197 acetylation mass spectrometry, MOF KO macrophages, LPS stimulation, hyperoxidation assays, ERK1/2 phosphorylation, metabolic (glycolysis) assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — writer enzyme identified, specific acetylation site mapped by MS, KO with multiple orthogonal functional readouts\",\n      \"pmids\": [\"39207899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HJURP forms disulfide-linked intermediates with PRDX1 through its Cys327 and Cys457 residues, promoting PRDX1 redox cycling and inhibiting its hyperoxidation, thereby enhancing PRDX1 peroxidase activity and reducing ROS/lipid peroxidation to suppress ferroptosis in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, disulfide bond formation assay, mutagenesis of HJURP cysteines, PRDX1 peroxidase activity assay, ROS and lipid peroxidation measurements, in vitro and in vivo ferroptosis assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cysteine mutagenesis plus enzymatic activity assay; single lab\",\n      \"pmids\": [\"39405980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX1 acts as a molecular chaperone by binding to CUL3, inhibiting CUL3-mediated NRF2 ubiquitination, thereby promoting NRF2 nuclear translocation and transcription of GPX4. This chaperone binding requires PRDX1 Cys83; the Cys83Ser mutant abolishes CUL3 binding. Conoidin A enhances CUL3 binding.\",\n      \"method\": \"IP-mass spectrometry, Co-immunoprecipitation (PRDX1 with CUL3), Cys83Ser mutagenesis, NRF2 ubiquitination assay, PRDX1 KO mice (AOM/DSS CRC model), RNA sequencing, GPX4 transcription assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — IP-MS plus Co-IP, active-site mutagenesis, in vivo KO model with mechanistic rescue; multiple orthogonal methods\",\n      \"pmids\": [\"39430237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hspb1 directly interacts with Anxa2 to decrease its aggregation and phosphorylation, enabling Anxa2 to interact with Prdx1 and maintain its antioxidative activity by decreasing Prdx1 Thr90 phosphorylation. Overexpression of Hspb1 did not protect against pancreatitis in acinar-specific Prdx1 knockout mice, establishing Prdx1 as the downstream effector.\",\n      \"method\": \"Co-immunoprecipitation (Hspb1 with Anxa2 and Prdx1), Anxa2 KO mice, acinar-specific Prdx1 KO mice, Thr90 phosphorylation assay, AAV8-Hspb1 rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, tissue-specific KO epistasis, multiple orthogonal genetic tools; single lab\",\n      \"pmids\": [\"38481805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX1 directly interacts with the actin-binding protein Cofilin, inhibiting phosphorylation of Cofilin at Ser3, thereby accelerating actin depolymerisation and turnover, promoting oral squamous cell carcinoma cell movement, invasion, and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (PRDX1 with Cofilin), Cofilin Ser3 phosphorylation assay, actin dynamics assay, in vitro migration/invasion assays, nude mouse tongue cancer model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation readout, in vivo validation; single lab\",\n      \"pmids\": [\"38738971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRAK1 binds to PRDX1 and prevents ubiquitination and proteasomal degradation of PRDX1 mediated by the E3 ubiquitin ligase HECTD3. Both the DOC and HECT domains of HECTD3 directly interact with PRDX1.\",\n      \"method\": \"IP/Co-IP, LC-MS/MS, GST pull-down, ubiquitination assay, HECTD3 domain mapping\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pull-down, ubiquitination assay, domain mapping; single lab\",\n      \"pmids\": [\"37031183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF207 promotes lactylation of PRDX1 at lysine 67, which enhances PRDX1 nuclear translocation and activation of NRF2, creating a ferroptosis-resistant environment and conferring regorafenib resistance in HCC cells. Disrupting PRDX1 K67 lactylation or NRF2 activity reverses resistance.\",\n      \"method\": \"CRISPR/Cas9 screening, lactylation modification assay (K67 site), nuclear fractionation/localisation, NRF2 activity assay, ferroptosis functional assays, drug resistance assays\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus PTM mapping plus functional pathway validation; single lab\",\n      \"pmids\": [\"40680452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Artesunate directly binds to PRDX1 (interacting at Gly4) and PRDX2, inhibiting their peroxidase activities and inducing ferroptosis in diffuse large B-cell lymphoma cells. PRDX1 knockdown reproduced ferroptosis and reduced sensitivity to artesunate; PRDX2 overexpression attenuated artesunate-induced ROS and cytotoxicity.\",\n      \"method\": \"Small-molecule pull-down/LC-MS/MS, CETSA, fluorescence titration, circular dichroism, molecular docking, PRDX1/2 knockdown and overexpression, peroxidase activity assay, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical binding methods plus enzymatic activity assay plus genetic validation in vitro and in vivo; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40645965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A co-crystal structure of PRDX1 with the celastrol derivative LC-PDin20, combined with molecular docking, revealed the binding mode of covalent inhibitors to PRDX1 active site, enabling structure-based design of selective PRDX1 inhibitors.\",\n      \"method\": \"Co-crystal structure determination, molecular docking, in vitro PRDX1 enzymatic inhibition assay (IC50 determination), cell antiproliferation assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation (IC50), structure-guided SAR; single lab\",\n      \"pmids\": [\"40546088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prdx1 deficiency impairs lipophagic flux in macrophages by causing excessive oxidative stress, leading to reduced free cholesterol formation, decreased NR1H3 (LXRα) activity, and lower cholesterol efflux. 2-Cys PRDX mimics ebselen and gliotoxin restored both lipophagic flux and cholesterol efflux in Prdx1-deficient macrophages.\",\n      \"method\": \"Prdx1 KO macrophages, autophagic flux assay, cholesterol efflux assay, NR1H3 activity assay, ebselen/gliotoxin rescue, bone marrow transplant into apoe-/- mice with plaque measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype, pharmacological rescue, in vivo BM transplant; single lab\",\n      \"pmids\": [\"28605287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRDX1 inhibits the activated (cancer-associated) fibroblast phenotype by binding to JNK1 and regulating JNK kinase signalling; loss of PRDX1 results in development of a CAF-like phenotype in mammary fibroblasts. JNK inhibition with SP600125 reduced CAF-like behaviors in Prdx1 KO fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation (PRDX1 with JNK1), PRDX1 KO mouse fibroblasts, JNK inhibitor (SP600125), transwell migration/invasion assay, immunofluorescence\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO phenotype, pharmacological inhibitor rescue; single lab\",\n      \"pmids\": [\"31419957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX1 activates autophagy in spiral ganglion neurons at least partially through activation of the PTEN-AKT signalling pathway; PRDX1 deficiency suppresses autophagy and increases neuronal loss after cisplatin exposure, while PRDX1 upregulation (pharmacologically or by AAV) activates autophagy and reduces ROS accumulation.\",\n      \"method\": \"PRDX1 KO and AAV-mediated overexpression, autophagy flux assay (LC3B, p62), PTEN/AKT pathway western blot, ROS measurement, SGN survival and hearing function assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain- and loss-of-function with pathway readout; single lab\",\n      \"pmids\": [\"33749526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRDX1 Cys52Ser (peroxidase-dead) variant mice show impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, the Cys52Ser variant suppresses NF-κB and STAT1 signalling, indicating that PRDX1 peroxidatic Cys52 is required for its pro-inflammatory activity in vivo.\",\n      \"method\": \"Knock-in mouse (PRDX1 Cys52Ser), Trx-TrxR-NADPH coupled peroxidase activity assay, western diet/MCD diet NASH model, RNA sequencing, NF-κB and STAT1 pathway analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site knock-in mutation with mechanistic pathway readout, in vivo model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37562742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRDX1 interacts with DOK3 and modulates DOK3 degradation via the autophagy-lysosome pathway, thereby inhibiting plasma cell differentiation. The small molecule Salvianolic acid B acts as a molecular glue enhancing the PRDX1-DOK3 interaction, further impairing plasma cell differentiation and collagen-induced arthritis progression.\",\n      \"method\": \"Co-immunoprecipitation (PRDX1-DOK3), autophagy-lysosome pathway inhibition assay, plasma cell differentiation assay, collagen-induced arthritis mouse model, small molecule (SAB) functional validation\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pathway inhibition assay, in vivo model; single lab\",\n      \"pmids\": [\"40893682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Modelling shows that the PRDX1 dimer-to-decamer transition has an inhibition-like effect on peroxidase activity; association and dissociation rate constants of 0.050 µM⁻⁴·s⁻¹ and 0.055 s⁻¹ respectively were obtained from isothermal titration calorimetry data and incorporated into kinetic models.\",\n      \"method\": \"Kinetic modelling using isothermal titration calorimetry data, HRP competition assay simulation, NADPH-oxidation linked assay simulation\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/kinetic modelling based on published data, no direct new experiment on PRDX1\",\n      \"pmids\": [\"37760010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BACH1 directly binds to the PRDX1 promoter region and inhibits PRDX1 transcription. Remifentanil treatment inactivates BACH1, relieving PRDX1 repression and thereby reducing oxidative stress in hepatic ischemia-reperfusion injury.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, PRDX1 silencing rescue, HIRI mouse model, mRNA microarray\",\n      \"journal\": \"Clinics and research in hepatology and gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter establishing direct promoter binding; single lab\",\n      \"pmids\": [\"39025461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX1 is a cytosolic 2-Cys peroxiredoxin whose peroxidatic Cys52 catalyses H2O2 reduction via a disulfide-relay cycle; its activity is regulated by multiple post-translational modifications (MOF-mediated K197 acetylation prevents hyperoxidation; Pin1/PP2A-mediated dephosphorylation of Thr90 restores activity; ZNF207-driven K67 lactylation promotes nuclear translocation; IRAK1 protects it from HECTD3-mediated ubiquitin degradation; Hspb1/Anxa2 complex suppresses Thr90 phosphorylation) and by oligomeric state (decamer has reduced peroxidase activity). Beyond ROS scavenging, PRDX1 functions as a redox relay/signal transducer: it activates GDE2 (motor neuron differentiation) by reducing an intramolecular disulfide bond, modulates MAPK signalling by differentially protecting MKP-1 vs MKP-5 in an H2O2 dose-dependent manner, forms a heterodimer with p38α to amplify MET/HGF invasion signals, binds ASK1 at elevated H2O2, inhibits TRAF6 ubiquitin-ligase activity to suppress NF-κB/autophagy, acts as a molecular chaperone binding CUL3 to prevent NRF2 ubiquitination and promote GPX4 transcription, and interacts with Cofilin to promote actin turnover. PRDX1 also translocates to the nucleus during DNA damage to scavenge nuclear ROS and preserve aspartate for nucleotide synthesis, cooperates with MTH1 to protect telomeres from oxidative damage, and promotes CUL5 neddylation via a PRDX1 oligomer/UBE2F/CUL5 tricomplex to degrade the pro-apoptotic protein NOXA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRDX1 is a 2-Cys peroxiredoxin that provides essential antioxidant defence, with its catalytic peroxidatic Cys52 reducing H2O2 through a fast disulfide-relay cycle that makes it relatively resistant to hyperoxidation [#0, #8, #27]. Genetic loss causes erythrocyte oxidative damage and haemolytic anaemia, impaired fibroblast proliferation, and increased sensitivity to oxidative DNA damage, while the Cys52Ser peroxidase-dead knock-in reduces NASH and fibrosis by suppressing NF-\\u03baB and STAT1 signalling, demonstrating that catalytic activity drives both protective and pro-inflammatory phenotypes [#0, #27]. Beyond bulk ROS scavenging, PRDX1 acts as a redox relay and signalling adaptor: it reductively activates GDE2 to permit motor neuron differentiation [#1], engages MAPK pathway components by differentially protecting MKP-1 versus MKP-5 in an H2O2-dose-dependent manner [#2], binds ASK1 at elevated H2O2 [#11], and inhibits TRAF6 ubiquitin-ligase activity to restrain NF-\\u03baB activation and autophagy [#5]. PRDX1 also functions as a molecular chaperone for the NRF2 axis, binding CUL3 via Cys83 to block NRF2 ubiquitination and induce GPX4 transcription, thereby suppressing ferroptosis [#17]. It translocates to the nucleus during the DNA damage response to scavenge nuclear ROS and sustain aspartate-dependent nucleotide synthesis [#13], is enriched in telomeric chromatin where it cooperates with MTH1 to limit oxidative guanine damage and telomere shortening [#6, #9], and promotes CUL5 neddylation through a PRDX1-oligomer/UBE2F/CUL5 tricomplex to degrade pro-apoptotic NOXA [#10]. PRDX1 activity is tuned by multiple post-translational modifications, including MOF-mediated K197 acetylation that prevents hyperoxidation, Pin1/PP2A-mediated dephosphorylation of Thr90 that restores peroxidase activity, and ZNF207-driven K67 lactylation that promotes nuclear translocation and NRF2 activation [#15, #3, #21]. Its active-site cysteine is targeted by several covalent small-molecule inhibitors whose binding mode has been resolved by co-crystallography, providing a structural basis for selective inhibition [#22, #23].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that PRDX1 is physiologically essential for antioxidant defence rather than redundant, by showing knockout animals suffer systemic oxidative pathology.\",\n      \"evidence\": \"Targeted knockout mouse with erythrocyte ROS, haemoglobin stability, Heinz body, and NK/fibroblast assays\",\n      \"pmids\": [\"12891360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which catalytic residue or relay mechanism underlies protection\", \"Did not distinguish cell-autonomous from systemic effects\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Moved PRDX1 beyond bulk scavenging by demonstrating it acts as a specific redox enzyme that reductively activates a defined substrate to control a developmental program.\",\n      \"evidence\": \"Co-IP, thiol-dead PRDX1 and disulfide-null GDE2 mutants, motor neuron differentiation in chick spinal cord\",\n      \"pmids\": [\"19766572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other transmembrane substrates are activated this way unknown\", \"Cytosolic-to-membrane targeting mechanism not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PRDX1's oxidation state itself encodes signalling information, partitioning MAPK phosphatase protection in an H2O2-dose-dependent manner.\",\n      \"evidence\": \"Reciprocal Co-IP, Cys52 mutants, H2O2 dose-response, p38 activity in breast epithelial cells\",\n      \"pmids\": [\"23334324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct redox transfer between PRDX1 and MKPs not reconstituted\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified phosphorylation as a reversible off-switch for PRDX1, with Pin1/PP2A restoring peroxidase activity, linking proline isomerisation to redox capacity.\",\n      \"evidence\": \"Proteomics, Co-IP, Thr90 mutagenesis, Pin1 KO/rescue MEFs, peroxidase assay\",\n      \"pmids\": [\"23421996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase phosphorylating Thr90 not identified here\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined PRDX1 as a non-catalytic inhibitor of TRAF6 ubiquitin-ligase activity, coupling it to NF-\\u03baB inflammation and autophagy control.\",\n      \"evidence\": \"Co-IP to TRAF6 RING domain, ECSIT/BECN1 ubiquitination, knockdown across three cancer lines\",\n      \"pmids\": [\"29929436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this requires PRDX1 redox cycling unclear\", \"Stoichiometry of inhibition not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the kinetic basis for PRDX1's distinct biological behaviour, measuring fast resolution that disfavours hyperoxidation relative to PRDX2.\",\n      \"evidence\": \"In vitro kinetics with recombinant PRDX1/PRDX2, intrinsic fluorescence\",\n      \"pmids\": [\"30284335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of measured rates not directly validated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PRDX1 at telomeric chromatin protecting genome integrity by cooperating with MTH1 against oxidised guanine.\",\n      \"evidence\": \"CRISPR double knockout, telomere length, telomerase activity, ROS quantification\",\n      \"pmids\": [\"29773556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRDX1 is recruited to telomeres not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PRDX1 can act as a positive signalling cofactor, heterodimerising with p38\\u03b1 to amplify MET/HGF-driven invasion.\",\n      \"evidence\": \"Co-IP, migration assays, glioma mouse survival and brain imaging\",\n      \"pmids\": [\"29582423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redox dependence of the heterodimer not dissected\", \"Direct vs indirect p38 stabilisation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined the telomere role by showing PRDX1 supports PARP-dependent telomeric repair, preventing single- to double-strand break conversion.\",\n      \"evidence\": \"PRDX1 depletion, telomeric ChIP, PARP inhibition, DNA damage markers\",\n      \"pmids\": [\"33147465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic role at break sites versus general ROS control not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a scaffold-independent PRDX1:ASK1 redox relay at high H2O2, distinguishing PRDX1 relay logic from PRDX2.\",\n      \"evidence\": \"Cellular and in vitro interaction assays, H2O2 dose-response, PRDX2 comparison\",\n      \"pmids\": [\"34209102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream ASK1 signalling output not quantified\", \"Disulfide intermediate not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an oligomer-specific scaffolding function whereby PRDX1 enables CUL5 neddylation to degrade pro-apoptotic NOXA.\",\n      \"evidence\": \"Co-IP tricomplex, knockdown, oligomerisation inhibition, NOXA stability and neddylation assays\",\n      \"pmids\": [\"33712558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of UBE2F/CUL5 docking on PRDX1 oligomer unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a nuclear DNA-damage-response role for PRDX1 linking nuclear ROS scavenging to aspartate availability and nucleotide synthesis.\",\n      \"evidence\": \"Functional genomics, chromatin proteomics, metabolomics, PRDX1 KO, fractionation\",\n      \"pmids\": [\"37259925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear import signal not defined\", \"Direct vs indirect aspartate link unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetically proved Cys52 peroxidase activity is required for PRDX1's pro-inflammatory function in vivo via NF-\\u03baB/STAT1.\",\n      \"evidence\": \"Cys52Ser knock-in mice, coupled peroxidase assay, NASH diet models, RNA-seq\",\n      \"pmids\": [\"37562742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic-independent signalling functions not addressed by this allele\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified MOF-mediated K197 acetylation as a writer-controlled switch protecting PRDX1 from hyperoxidation, coupling acetylation loss to inflammatory glycolytic reprogramming.\",\n      \"evidence\": \"MOF as acetyltransferase, K197 MS, MOF KO macrophages, LPS, ERK/glycolysis readouts\",\n      \"pmids\": [\"39207899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase removing K197 not identified\", \"Structural effect of K197 acetylation on active site unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PRDX1 functions as a chaperone for the NRF2-GPX4 anti-ferroptosis axis through Cys83-dependent CUL3 binding.\",\n      \"evidence\": \"IP-MS, Co-IP, Cys83Ser mutant, NRF2 ubiquitination, PRDX1 KO CRC mice, RNA-seq\",\n      \"pmids\": [\"39430237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chaperone activity is redox-state dependent unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined PRDX1 protein stability and activity as controlled by interacting partners that tune disulfide cycling and degradation (HJURP redox cycling, IRAK1/HECTD3 turnover, Hspb1/Anxa2 Thr90 phosphorylation, Cofilin actin turnover, DOK3 degradation).\",\n      \"evidence\": \"Co-IP, cysteine and Thr90 mutagenesis, ubiquitination and autophagy-lysosome assays, in vivo disease models\",\n      \"pmids\": [\"39405980\", \"37031183\", \"38481805\", \"38738971\", \"40893682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most interactions rest on single-lab Co-IP without reciprocal structural validation\", \"Interplay among these regulators not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed lactylation at K67 by ZNF207 and transcriptional repression by BACH1 add further layers controlling PRDX1 nuclear localisation and abundance in disease contexts.\",\n      \"evidence\": \"CRISPR screen, K67 lactylation mapping, nuclear fractionation, ChIP/luciferase, drug-resistance and ischemia models\",\n      \"pmids\": [\"40680452\", \"39025461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Eraser of K67 lactylation unknown\", \"Crosstalk between transcriptional and PTM control not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validated PRDX1's active-site cysteine as a druggable covalent target and provided a co-crystal structure enabling structure-based inhibitor design.\",\n      \"evidence\": \"ABPP/pull-down, CETSA, SPR/fluorescence titration, co-crystal structure with celastrol derivative, IC50, ferroptosis xenografts (18\\u03b2-GA, artesunate, LC-PDin20)\",\n      \"pmids\": [\"36105163\", \"40645965\", \"40546088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over PRDX2 for several compounds incomplete\", \"In vivo therapeutic window not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRDX1's many context-specific roles (cytosolic scavenging, nuclear DNA-damage response, signalling relays, scaffolding/chaperone functions) are coordinated by oligomeric state and the PTM code remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking redox state, oligomerisation, and partner selection\", \"Quantitative contribution of each function in normal physiology unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 8, 27]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [8, 27, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 10, 2]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 27, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 11, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 17, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 24, 26]}\n    ],\n    \"complexes\": [\n      \"PRDX1-oligomer/UBE2F/CUL5 neddylation tricomplex\"\n    ],\n    \"partners\": [\n      \"GDE2\",\n      \"TRAF6\",\n      \"CUL3\",\n      \"ASK1\",\n      \"MAPK14\",\n      \"CUL5\",\n      \"CFL1\",\n      \"MTH1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}