{"gene":"PRDX1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2003,"finding":"Prdx1 knockout mice develop severe haemolytic anaemia characterized by increased erythrocyte ROS, protein oxidation, haemoglobin instability, Heinz body formation, and decreased erythrocyte lifespan, establishing PRDX1 as an essential 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, phenotype, and function.","method":"Targeted gene knockout in mice with phenotypic characterization (ROS measurement, haematological assays, tumour histopathology, NK cell functional assays)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined cellular phenotypes, replicated across tissues","pmids":["12891360"],"is_preprint":false},{"year":2009,"finding":"PRDX1 physically interacts with the transmembrane protein GDE2 and activates it by reducing an intramolecular disulfide bond bridging GDE2's intracellular N- and C-terminal domains, thereby driving spinal motor neuron differentiation. This activation requires PRDX1's thiol-dependent catalytic activity, and GDE2 variants incapable of disulfide bond formation become independent of PRDX1.","method":"Co-immunoprecipitation, in vivo loss-of-function (Prdx1 knockdown/knockout in chick spinal cord), active-site mutagenesis of PRDX1 and GDE2, epistasis analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1/2 — reciprocal interaction, mutagenesis, epistasis, and defined neuronal differentiation phenotype in single study","pmids":["19766572"],"is_preprint":false},{"year":2013,"finding":"PRDX1 binds to both MKP-1 and MKP-5 phosphatases in an H2O2 dose-dependent manner via its peroxidatic cysteine Cys52. At high H2O2, over-oxidation of Cys52 to sulfonic acid causes PRDX1 to dissociate from MKP-1, leading to MKP-1 oxidation-induced oligomerization and inactivation toward p38MAPKα, while the PRDX1:MKP-5 complex is stabilized, protecting MKP-5 from inactivation. This mechanism coordinates p38MAPK-dependent cellular senescence in breast epithelial cells.","method":"Co-immunoprecipitation, H2O2 dose-response assays, Cys52 mutagenesis, p38MAPK phosphorylation assays, ROS-induced senescence model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1/2 — active-site mutagenesis combined with binding and functional phosphatase assays in a single study","pmids":["23334324"],"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 increases NF-κB activation, pro-inflammatory cytokine production, and bactericidal autophagy.","method":"Co-immunoprecipitation, ubiquitination assays in PRDX1-knockdown cell lines (THP-1, MDA-MB-231, SK-HEP-1), TLR4 stimulation experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping plus functional ubiquitination assay and KD phenotype in multiple cell lines","pmids":["29929436"],"is_preprint":false},{"year":2018,"finding":"PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 in cancer cells causes ROS-dependent continuous telomere shortening due to efficient inhibition of telomere extension by telomerase, identifying PRDX1 as a guardian of telomere integrity.","method":"CRISPR gene disruption, telomere length measurement, ROS quantification, telomerase extension assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via double knockout with direct telomere length and telomerase functional readouts","pmids":["29773556"],"is_preprint":false},{"year":2018,"finding":"Kinetic analysis established that the peroxidatic cysteine of PRDX1 reacts ~10-fold faster with H2O2 than peroxynitrite (both orders of magnitude faster than typical protein thiols), and that PRDX1 has a substantially faster disulfide formation rate (11 s⁻¹) than PRDX2 (0.2 s⁻¹), which determines its distinct redox-relay function versus PRDX2's mixed-disulfide signaling mode. The additional C83 residue in PRDX1 further differentiates its response to peroxynitrite.","method":"In vitro kinetic assays using recombinant human PRDX1 and PRDX2, intrinsic fluorescence monitoring of oxidation and hyperoxidation","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro reconstitution with recombinant proteins and quantitative kinetics","pmids":["30284335"],"is_preprint":false},{"year":2013,"finding":"Pin1 binds PRDX1 through the phospho-Thr90-Pro91 motif and facilitates PP2A-mediated dephosphorylation of PRDX1, restoring its peroxidase activity. In Pin1-knockout MEFs, phosphorylated (Thr90) PRDX1 accumulates in its inactive form, leading to increased H2O2 buildup.","method":"Proteomic pulldown, co-immunoprecipitation, Thr90 mutagenesis, peroxidase activity assay in Pin1−/− MEFs with Pin1 re-introduction, H2O2 measurement","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis, enzymatic activity rescue, and genetic KO with re-introduction","pmids":["23421996"],"is_preprint":false},{"year":2020,"finding":"PRDX1 is enriched in telomeric chromatin and counteracts ROS-induced telomere damage. In PRDX1-depleted cells, PARP-dependent telomeric repair is often incomplete, generating persistent single-strand breaks that are converted to double-strand breaks during replication. PARP1 inhibition in PRDX1-depleted cells dampens telomere shortening by stabilising BRCA1 and enabling RAD51-mediated HR repair.","method":"PRDX1 depletion, telomere ChIP showing PRDX1 enrichment, PARP inhibitor epistasis, telomere length assays, SSB/DSB quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — direct telomeric localization by ChIP, genetic epistasis with PARP1 inhibitor, multiple DNA repair readouts","pmids":["33147465"],"is_preprint":false},{"year":2021,"finding":"PRDX1 binds TRAF6 and BECN1 and deficiency in PRDX1 suppresses autophagic flux in macrophages, leading to impaired lipophagic cholesterol hydrolysis, higher intracellular cholesterol, and reduced cholesterol efflux. 2-Cys PRDX mimics (ebselen, gliotoxin) rescue these defects, and Prdx1-deficient bone marrow transplantation into apoe-/- mice increases atherosclerotic plaque formation.","method":"Prdx1 knockout macrophages, lipophagic flux assays, cholesterol efflux assays, in vivo bone marrow transplant model, pharmacological rescue","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal functional assays and in vivo validation","pmids":["28605287"],"is_preprint":false},{"year":2013,"finding":"AMPK activation stabilises the interaction between c-Abl and PRDX1, preventing oxidative stress-induced dissociation of the complex. Knockdown of PRDX1 increases phosphorylation of both caveolin-1 and c-Abl and abolishes the inhibitory effect of AMPK on caveolin-1 phosphorylation and albumin endocytosis in endothelial cells.","method":"Co-immunoprecipitation, siRNA knockdown, pharmacological AMPK activation (AICAR), caveolin-1 phosphorylation and endocytosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional KD phenotype in one cell type","pmids":["23723070"],"is_preprint":false},{"year":2021,"finding":"PRDX1 oligomers bind both the Nedd8-conjugating enzyme UBE2F and CUL5, forming a tricomplex essential for CUL5 neddylation. This promotes NOXA ubiquitination and degradation, inhibiting apoptosis in colorectal cancer cells. ROS elevation drives PRDX1 oligomerization, linking oxidative stress to NOXA protein half-life.","method":"Co-immunoprecipitation, PRDX1 oligomerization assays, ubiquitination assays, NOXA protein half-life measurement, PRDX1 knockdown and oligomerization inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with multiple partners plus functional ubiquitination assay, single lab","pmids":["33712558"],"is_preprint":false},{"year":2018,"finding":"PRDX1 forms a heterodimer with p38α (MAPK14), stabilizing phospho-p38α in glioma cells, which amplifies HGF-mediated MET signaling and stimulates actin cytoskeleton dynamics to promote glioma cell migration and brain invasion in vivo.","method":"Biochemical interaction studies (Co-IP), in vitro and ex vivo migration assays, whole-brain high-resolution ultramicroscopy in mouse glioma models, survival analysis of PRDX1-KD mice","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with defined kinase stabilization mechanism plus in vivo validation","pmids":["29582423"],"is_preprint":false},{"year":2021,"finding":"PRDX1 interacts with ASK1 at elevated H2O2 concentrations in a manner that does not require a scaffolding protein, in contrast to the Prdx2:STAT3 relay. This interaction was demonstrated both in cellulo and by in vitro protein-protein interaction methods.","method":"Co-immunoprecipitation, in vitro pulldown, H2O2 dose-response experiments","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2/3 — cellular and in vitro interaction methods, single lab","pmids":["34209102"],"is_preprint":false},{"year":2024,"finding":"The lysine acetyltransferase MOF acetylates PRDX1 at lysine 197 (K197), preventing its hyperoxidation and maintaining peroxidase activity under inflammatory stress. LPS stimulation rapidly decreases PRDX1 K197ac in macrophages, elevating H2O2, augmenting ERK1/2 phosphorylation, stimulating glycolysis, and enhancing pro-inflammatory IL-6 production.","method":"Identification of K197 acetylation site, MOF KO/knockdown experiments, LPS stimulation, H2O2 measurement, ERK1/2 phosphorylation assays, metabolic flux analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — writer (MOF) identified, site-specific acetylation validated, functional consequences with multiple orthogonal readouts","pmids":["39207899"],"is_preprint":false},{"year":2024,"finding":"HJURP forms disulfide-linked intermediates with PRDX1 through Cys327 and Cys457 residues of HJURP, promoting PRDX1 redox cycling and inhibiting its hyperoxidation, thereby enhancing PRDX1 peroxidase activity and suppressing ROS and lipid peroxidation to confer ferroptosis resistance in prostate cancer cells.","method":"Co-immunoprecipitation, disulfide bond identification by mutagenesis, peroxidase activity assays, ROS and lipid peroxidation measurement, in vivo xenograft","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — specific cysteine residues identified for disulfide-linked intermediate, peroxidase activity assay, single lab","pmids":["39405980"],"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 accumulation of replication stress and DNA damage.","method":"Functional genomics (CRISPR screen), chromatin proteomics, metabolomics, nuclear fractionation/localization, etoposide treatment experiments","journal":"Molecular systems biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genomics, proteomics, metabolomics, localization) in an integrated study","pmids":["37259925"],"is_preprint":false},{"year":2024,"finding":"PRDX1 acts as a molecular chaperone by binding to CUL3, inhibiting CUL3-mediated NRF2 ubiquitination and stabilising NRF2, which drives GPX4 transcription. The Cys83 residue of PRDX1 is required for CUL3 binding and this activity is enhanced by conoidin A.","method":"IP-MS, Co-immunoprecipitation, Cys83Ser mutagenesis, ubiquitination assays, NRF2 nuclear translocation assays, PRDX1 KO mouse model (AOM/DSS)","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — IP-MS partner identification, mutagenesis defining critical residue, functional ubiquitination assay, in vivo validation","pmids":["39430237"],"is_preprint":false},{"year":2019,"finding":"PRDX1 binds JNK1 and inhibits JNK kinase signaling, thereby suppressing the cancer-associated fibroblast (CAF)-like activated phenotype in mammary fibroblasts. Loss of PRDX1 results in development of a CAF-like phenotype that is reversed by JNK inhibition.","method":"Co-immunoprecipitation of PRDX1 with JNK1, PRDX1 knockout mouse fibroblasts, JNK inhibitor (SP600125) rescue, migration/invasion assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with functional KO phenotype and pharmacological rescue, single lab","pmids":["31419957"],"is_preprint":false},{"year":2023,"finding":"The lncRNA LncFASA directly binds the Ahpc-TSA domain of PRDX1 and drives liquid-liquid phase separation of PRDX1 into droplets, inhibiting its peroxidase activity. This disrupts ROS homeostasis and promotes ferroptosis through the SLC7A11-GPX4 axis in triple-negative breast cancer cells.","method":"RNA-protein binding assays, phase separation assays, peroxidase activity assays, SLC7A11/GPX4 pathway analysis, xenograft tumor model","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct binding with domain identification, phase separation and enzymatic activity measured, single lab","pmids":["37955780"],"is_preprint":false},{"year":2020,"finding":"Prdx1 regulates the HEF1-Aurora A-HDAC6 signaling axis to promote primary cilia disassembly in esophageal squamous cell carcinoma cells; silencing Prdx1 restores primary cilia formation and reduces tumor formation in vivo.","method":"Prdx1 siRNA knockdown, gene chip analysis, cilia formation assays, HEF1/Aurora A/HDAC6 pathway measurement, in vivo xenograft","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — KD with specific signaling pathway readout and in vivo validation, single lab","pmids":["32357862"],"is_preprint":false},{"year":2020,"finding":"Prdx1 functions as an RNA-binding protein that stabilises inflammation- and apoptosis-related mRNAs after intracerebral haemorrhage, as identified by RIP-seq. Prdx1 overexpression reduces inflammation and apoptosis in ICH models.","method":"RNA immunoprecipitation combined with high-throughput sequencing (RIP-seq), AAV-mediated overexpression in rat ICH model","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide RIP-seq identifies RNA-binding activity with in vivo functional phenotype, single lab","pmids":["32210752"],"is_preprint":false},{"year":2024,"finding":"Hspb1 directly interacts with Anxa2 to reduce its aggregation and phosphorylation, which in turn allows Anxa2 to interact with Prdx1 and maintain its antioxidative activity by decreasing Thr-90 phosphorylation of Prdx1; overexpression of Hspb1 had no protective effect in acinar-specific Prdx1 knockout mice, establishing the Hspb1/Anxa2/Prdx1 axis.","method":"Co-immunoprecipitation, Prdx1 acinar cell-specific KO mice, AAV8-Hspb1 overexpression, Thr-90 phosphorylation assays, genetic epistasis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with cell-type-specific KO, Co-IP, and PTM identification, single lab","pmids":["38481805"],"is_preprint":false},{"year":2023,"finding":"PRDX1 Cys52Ser (peroxidase-dead) variant mice show impaired global PRDX peroxidase activity and are protected from diet-induced NASH and liver fibrosis, with suppressed NF-κB and STAT1 pro-inflammatory signalling, demonstrating that peroxidatic Cys52 is required for PRDX1's pro-inflammatory activity in vivo.","method":"Knock-in mouse model (Cys52Ser), Trx-TrxR-NADPH coupled activity assay, western diet/MCD diet feeding, RNA-seq, NF-κB and STAT1 pathway analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1/2 — active-site knock-in mouse with in vivo metabolic phenotype and transcriptomic pathway identification","pmids":["37562742"],"is_preprint":false},{"year":2023,"finding":"Kinetic modelling established that the PRDX1 dimer-to-decamer transition (association rate 0.050 µM⁻⁴·s⁻¹, dissociation rate 0.055 s⁻¹) has an inhibition-like effect on peroxidase activity, as the decameric form has ~100-fold lower activity than the dimer. Incorporating this transition into an in vivo PRDX model reconciled experimental and simulated oxidation-state responses.","method":"Isothermal titration calorimetry data fitting, kinetic modelling, HRP competition and NADPH-oxidation assays, in vivo PRDX2 erythrocyte model simulation","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro biophysical measurement with kinetic modelling; single study","pmids":["37760010"],"is_preprint":false},{"year":2024,"finding":"ZNF207 promotes lactylation of PRDX1 at lysine 67, which enhances PRDX1 nuclear translocation and activation of NRF2, creating a ferroptosis-resistant environment in HCC cells and driving regorafenib resistance.","method":"CRISPR/Cas9 screening, lactylation site identification (K67), nuclear translocation assays, NRF2 activity assays, RGF sensitivity rescue experiments","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2/3 — novel PTM (lactylation) identified with functional nuclear localisation and NRF2 activation readouts, single lab","pmids":["40680452"],"is_preprint":false},{"year":2021,"finding":"IRAK1 binds PRDX1 and prevents its ubiquitination and degradation mediated by the E3 ubiquitin ligase HECTD3 (which interacts with PRDX1 via its DOC and HECT domains). Overexpression of PRDX1 reverses the radiosensitisation effect of IRAK1 depletion by diminishing autophagic cell death in glioma.","method":"Co-IP, LC-MS/MS, GST pulldown, ubiquitination assays, domain-mapping mutagenesis of HECTD3, PRDX1 overexpression rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple interaction methods plus functional ubiquitination assay with domain mapping, single lab","pmids":["37031183"],"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 and promoting OSCC cell migration and invasion.","method":"Co-immunoprecipitation, Cofilin Ser3 phosphorylation assays, actin dynamics assays, in vitro migration/invasion, nude mouse tongue cancer model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct Co-IP with specific phosphorylation site readout and in vivo validation, single lab","pmids":["38738971"],"is_preprint":false},{"year":2025,"finding":"A co-crystal structure of PRDX1 with the celastrol derivative LC-PDin20 revealed the binding mode of covalent inhibitors with PRDX1, and active cysteine residues were confirmed as the covalent binding sites, enabling structure-based design of selective PRDX1 inhibitors.","method":"Co-crystal structure determination (X-ray crystallography), molecular docking, in vitro PRDX1 enzyme inhibition assay (IC50 determination)","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with in vitro enzymatic inhibition validation","pmids":["40546088"],"is_preprint":false},{"year":2024,"finding":"Recombinant PRDX1 protein dose-dependently inhibits ROS production and osteoclast differentiation from bone marrow macrophages, and mechanistically attenuates NFATc1 activation as well as expression of C-Fos, V-ATPase-d2, Cathepsin K, and Integrin αV downstream of RANKL signalling.","method":"Recombinant protein treatment, ROS measurement, osteoclast differentiation assay, NFATc1 and downstream marker expression analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — recombinant protein with defined signalling pathway readout, single lab","pmids":["39263840"],"is_preprint":false},{"year":2023,"finding":"BACH1 directly binds the promoter region of PRDX1 and inhibits its transcription; remifentanil treatment suppresses BACH1 and upregulates PRDX1, thereby reducing oxidative stress injury in hepatic ischaemia-reperfusion.","method":"Chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, BACH1 overexpression and PRDX1 silencing epistasis","journal":"Clinics and research in hepatology and gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding validated by ChIP and luciferase, with epistasis, single lab","pmids":["39025461"],"is_preprint":false},{"year":2025,"finding":"NFAT5 directly binds the PRDX1 promoter to drive its transcription, which enhances mitochondrial function in cervical cancer cells. METTL3 promotes NFAT5 mRNA stability via IGF2BP3-mediated m6A modification, placing PRDX1 downstream of an m6A-NFAT5 transcriptional regulatory axis.","method":"ChIP assay, dual-luciferase reporter assay, MeRIP assay, NFAT5 knockdown/overexpression with PRDX1 rescue","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding by ChIP/luciferase plus upstream m6A regulation validated, single lab","pmids":["39925026"],"is_preprint":false}],"current_model":"PRDX1 is a cytosolic 2-Cys peroxiredoxin whose peroxidatic Cys52 catalyses H2O2 reduction, and whose oligomeric state, phosphorylation (Thr90, regulated by Pin1/PP2A), acetylation (K197 by MOF), lactylation (K67), and oxidation status control its enzymatic activity, molecular chaperone activity, and protein–protein interactions; it acts as a redox relay that directly regulates binding partners including GDE2 (activating it by disulfide reduction to drive motor neuron differentiation), ASK1, JNK1, MKP-1/MKP-5 (in an H2O2 dose-dependent manner to coordinate p38MAPK-dependent senescence), TRAF6 (inhibiting its ubiquitin-ligase activity to suppress NF-κB and autophagy), CUL3 (blocking NRF2 ubiquitination), UBE2F-CUL5 (promoting NOXA degradation), p38α/MAPK14 (stabilising phospho-p38α to amplify MET-driven invasion), Cofilin (inhibiting Ser3 phosphorylation to promote actin turnover), and GLUT3; it also translocates to the nucleus upon DNA damage to scavenge nuclear ROS, localises to telomeric chromatin to prevent oxidative telomere damage and support telomerase activity, and functions as an RNA-binding protein stabilising inflammation-related mRNAs."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing the in vivo requirement for PRDX1: knockout mice revealed that PRDX1 is not redundant with other peroxiredoxins but is essential for erythrocyte redox homeostasis, proliferative capacity, and immune cell function, defining it as a non-redundant antioxidant defense.","evidence":"Targeted Prdx1 knockout mice with hematological, ROS, and NK cell phenotyping","pmids":["12891360"],"confidence":"High","gaps":["Mechanism of selective erythrocyte vulnerability versus other cell types not resolved","Contribution of chaperone versus peroxidase activity to the KO phenotype not distinguished"]},{"year":2009,"claim":"Demonstrating that PRDX1 acts as a thiol-based redox switch for a specific biological effector: PRDX1 activates GDE2 by reducing an intramolecular disulfide bond, establishing that PRDX1's catalytic activity directly couples to a developmental signaling event (motor neuron differentiation).","evidence":"Co-IP, active-site mutagenesis, Prdx1 knockdown/KO in chick spinal cord with epistasis analysis","pmids":["19766572"],"confidence":"High","gaps":["Whether PRDX1-GDE2 interaction is constitutive or regulated by ROS levels in vivo not tested","Other developmental signals requiring PRDX1 redox relay not mapped"]},{"year":2013,"claim":"Revealing how PRDX1's oxidation state enables dose-dependent H₂O₂ signaling: PRDX1 differentially associates with MKP-1 and MKP-5 depending on Cys52 oxidation status, coordinating p38 MAPK-driven senescence and establishing PRDX1 as a redox relay with partner-selective outputs.","evidence":"Cys52 mutagenesis, H₂O₂ dose-response binding assays, p38 MAPK phosphorylation readout in breast epithelial cells","pmids":["23334324"],"confidence":"High","gaps":["Whether intermediate oxidation states of Cys52 generate additional signaling specificity not tested","In vivo senescence phenotype in PRDX1-deficient tissues not examined"]},{"year":2013,"claim":"Identifying post-translational control of PRDX1 peroxidase activity: Pin1 recognizes phospho-Thr90 and recruits PP2A for dephosphorylation, restoring enzymatic activity, thus defining a phospho-switch that gates PRDX1 function.","evidence":"Proteomic pulldown, Thr90 mutagenesis, peroxidase activity rescue in Pin1-KO MEFs","pmids":["23421996"],"confidence":"High","gaps":["Kinase responsible for Thr90 phosphorylation not definitively identified in this study","Whether Thr90 phosphorylation also regulates chaperone or relay functions not tested"]},{"year":2018,"claim":"Establishing PRDX1 as a negative regulator of innate immune signaling and autophagy through direct E3 ligase inhibition: PRDX1 binds the RING domain of TRAF6 and blocks ubiquitination of ECSIT and BECN1, suppressing both NF-κB activation and autophagy induction.","evidence":"Reciprocal Co-IP with domain mapping, ubiquitination assays, PRDX1 knockdown in THP-1 and other cell lines with TLR4 stimulation","pmids":["29929436"],"confidence":"High","gaps":["Whether PRDX1 oxidation state modulates TRAF6 binding affinity not determined","Structural basis of RING domain recognition not resolved"]},{"year":2018,"claim":"Defining PRDX1 as a guardian of telomere integrity: combined PRDX1/MTH1 disruption causes ROS-dependent telomere shortening by inhibiting telomerase extension, revealing cooperative oxidative damage prevention at telomeres.","evidence":"CRISPR double knockout, telomere length assays, telomerase extension assays","pmids":["29773556"],"confidence":"High","gaps":["Whether PRDX1 is physically present at telomeres was not shown in this study (addressed in 2020)"]},{"year":2018,"claim":"Quantitative kinetic analysis established the mechanistic basis for PRDX1's redox-relay versus peroxide-scavenging roles: PRDX1's ~55-fold faster disulfide formation rate compared to PRDX2, plus the additional Cys83 residue, explains its preferential function as a redox relay rather than a peroxide sensor.","evidence":"Recombinant protein kinetic assays with intrinsic fluorescence monitoring","pmids":["30284335"],"confidence":"High","gaps":["In vivo relevance of the kinetic difference between PRDX1 and PRDX2 not directly tested","Role of Cys83 in partner-specific relay not investigated"]},{"year":2020,"claim":"Direct demonstration of PRDX1 at telomeric chromatin: PRDX1 enrichment at telomeres by ChIP, and epistasis with PARP inhibition, showed that PRDX1 prevents oxidative single-strand breaks that convert to replication-coupled double-strand breaks, mechanistically explaining how PRDX1 loss drives telomere shortening.","evidence":"Telomere ChIP, PRDX1 depletion, PARP inhibitor epistasis, SSB/DSB quantification","pmids":["33147465"],"confidence":"High","gaps":["How PRDX1 is recruited to telomeric chromatin is unknown","Whether PRDX1's telomeric role requires its peroxidase or chaperone activity not distinguished"]},{"year":2020,"claim":"Expanding PRDX1's repertoire beyond protein interactions: RIP-seq identified PRDX1 as an RNA-binding protein that stabilizes inflammation- and apoptosis-related mRNAs, adding post-transcriptional gene regulation to its functional portfolio.","evidence":"RIP-seq in rat brain, AAV-mediated overexpression in ICH model","pmids":["32210752"],"confidence":"Medium","gaps":["RNA-binding domain/motif not identified","Whether RNA binding is redox-dependent not tested","Replication in non-CNS systems lacking"]},{"year":2021,"claim":"Connecting PRDX1's TRAF6/BECN1 interaction to lipid metabolism: PRDX1 deficiency impairs autophagic cholesterol hydrolysis in macrophages, increasing atherosclerotic plaque formation, establishing a physiological consequence of the PRDX1-TRAF6-BECN1 axis.","evidence":"Prdx1 KO macrophages, lipophagic flux and cholesterol efflux assays, bone marrow transplant in Apoe-KO mice, pharmacological rescue with 2-Cys PRDX mimics","pmids":["28605287"],"confidence":"High","gaps":["Whether PRDX1 promotes or inhibits BECN1 function remains context-dependent and requires clarification across cell types"]},{"year":2021,"claim":"Revealing a non-enzymatic scaffolding role: PRDX1 oligomers bridge UBE2F and CUL5 to promote CUL5 neddylation and NOXA degradation, linking ROS-driven PRDX1 oligomerization to apoptosis resistance.","evidence":"Co-IP, oligomerization assays, NOXA half-life measurement in colorectal cancer cells","pmids":["33712558"],"confidence":"Medium","gaps":["Whether oligomeric versus dimeric PRDX1 has distinct partner selectivity beyond UBE2F-CUL5 not tested","Independent replication needed"]},{"year":2023,"claim":"Demonstrating nuclear translocation as a DNA damage response: PRDX1 moves to the nucleus upon genotoxic stress to scavenge nuclear ROS and support aspartate-dependent de novo nucleotide synthesis, linking its antioxidant activity to replication stress resistance.","evidence":"CRISPR screen, chromatin proteomics, metabolomics, nuclear fractionation after etoposide treatment","pmids":["37259925"],"confidence":"High","gaps":["Signal or modification triggering nuclear import not identified","Whether nuclear PRDX1 engages distinct relay partners not explored"]},{"year":2023,"claim":"Separating peroxidase-dependent functions in vivo: Cys52Ser knock-in mice showed that the peroxidatic cysteine is specifically required for pro-inflammatory NF-κB and STAT1 signaling in steatohepatitis, demonstrating that PRDX1's disease-promoting roles depend on catalytic redox cycling rather than chaperone activity.","evidence":"Cys52Ser knock-in mouse, Western/MCD diet, RNA-seq, NF-κB/STAT1 pathway analysis","pmids":["37562742"],"confidence":"High","gaps":["Whether chaperone-only functions (e.g., CUL3 binding via Cys83) are preserved in Cys52Ser mice not assessed"]},{"year":2024,"claim":"Identifying acetylation as a rapid inflammatory switch: MOF-mediated K197 acetylation protects PRDX1 from hyperoxidation; LPS triggers deacetylation, elevating H₂O₂ to activate ERK1/2 and glycolysis for pro-inflammatory cytokine production, revealing how innate immune activation is coupled to PRDX1 inactivation.","evidence":"MOF KO/knockdown, K197 site identification, LPS stimulation with H₂O₂, ERK1/2, and metabolic flux readouts","pmids":["39207899"],"confidence":"High","gaps":["Deacetylase responsible for LPS-induced K197 deacetylation not identified","Interplay between K197 acetylation and Thr90 phosphorylation not explored"]},{"year":2024,"claim":"Defining a chaperone-mode interaction with CUL3 that stabilizes NRF2: PRDX1 binds CUL3 via Cys83 (not Cys52), blocking NRF2 ubiquitination and driving GPX4 transcription, demonstrating that PRDX1 has separable catalytic-cysteine and non-catalytic-cysteine dependent partner interactions.","evidence":"IP-MS, Cys83Ser mutagenesis, ubiquitination assays, NRF2 translocation, AOM/DSS mouse model","pmids":["39430237"],"confidence":"High","gaps":["Whether Cys83 oxidation state regulates CUL3 binding not determined","Structural basis of the PRDX1-CUL3 interface not resolved"]},{"year":2025,"claim":"Obtaining the first co-crystal structure of PRDX1 with a covalent inhibitor provided atomic-resolution insight into the active-site architecture and confirmed covalent modification of catalytic cysteines as the inhibitory mechanism.","evidence":"X-ray co-crystallography with celastrol derivative LC-PDin20, enzymatic IC₅₀ determination","pmids":["40546088"],"confidence":"High","gaps":["No co-crystal structure with a physiological partner (relay target) yet available","Whether inhibitor binding disrupts oligomerization not addressed"]},{"year":null,"claim":"Major open questions include: how PRDX1 is recruited to specific chromatin loci (telomeres, damage sites); the identity of kinases and deacetylases regulating its PTM switches; structural models of PRDX1 in complex with relay partners; and how the competing peroxidase, chaperone, RNA-binding, and relay activities are partitioned in a single cell.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PRDX1 bound to any relay partner","Signal routing rules between simultaneous partners unknown","RNA-binding mechanism and domain uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,5,6,13,14,22,27]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,10,11,17,26]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[20]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,24]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[7,4]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,5,13,15,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,11,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,13,22]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,7,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,29,30]}],"complexes":[],"partners":["GDE2","TRAF6","BECN1","CUL3","PIN1","JNK1","CFL1","MAPK14"],"other_free_text":[]},"mechanistic_narrative":"PRDX1 is a 2-Cys peroxiredoxin that functions as a central redox sensor and signal relay hub, coupling intracellular H₂O₂ levels to diverse signaling, transcriptional, and genome-protective outputs. Its peroxidatic cysteine Cys52 reduces H₂O₂ with rapid kinetics and undergoes dose-dependent oxidation states—including hyperoxidation to sulfonic acid—that switch PRDX1 between peroxidase, redox relay, and molecular chaperone modes, controlling partner interactions with MKP-1/MKP-5, ASK1, JNK1, TRAF6, CUL3, UBE2F-CUL5, p38α, Cofilin, and GDE2 to regulate MAP kinase signaling, NF-κB activation, autophagy, NRF2 stability, apoptosis, cytoskeletal dynamics, and motor neuron differentiation [PMID:30284335, PMID:23334324, PMID:29929436, PMID:39430237, PMID:19766572, PMID:33712558, PMID:29582423, PMID:38738971]. Post-translational modifications—including Thr90 phosphorylation regulated by Pin1/PP2A, K197 acetylation by MOF, and K67 lactylation—tune its enzymatic activity, oligomeric state, and subcellular distribution, with nuclear translocation upon DNA damage enabling PRDX1 to scavenge nuclear ROS, support de novo nucleotide synthesis, localize to telomeric chromatin to prevent oxidative telomere damage, and sustain telomerase activity [PMID:23421996, PMID:39207899, PMID:40680452, PMID:37259925, PMID:33147465, PMID:29773556]. Prdx1 knockout mice develop severe hemolytic anemia from erythrocyte oxidative damage, increased cancer susceptibility, and NK cell dysfunction, while Cys52Ser knock-in mice are protected from diet-induced steatohepatitis, demonstrating that PRDX1 peroxidase activity has both cytoprotective and context-dependent pro-inflammatory roles in vivo [PMID:12891360, PMID:37562742]."},"prefetch_data":{"uniprot":{"accession":"Q06830","full_name":"Peroxiredoxin-1","aliases":["Natural killer cell-enhancing factor A","NKEF-A","Proliferation-associated gene protein","PAG","Thioredoxin peroxidase 2","Thioredoxin-dependent peroxide reductase 2","Thioredoxin-dependent peroxiredoxin 1"],"length_aa":199,"mass_kda":22.1,"function":"Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. 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Reduces an intramolecular disulfide bond in GDPD5 that gates the ability to GDPD5 to drive postmitotic motor neuron differentiation (By similarity)","subcellular_location":"Cytoplasm; Melanosome","url":"https://www.uniprot.org/uniprotkb/Q06830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRDX1","classification":"Not Classified","n_dependent_lines":123,"n_total_lines":1208,"dependency_fraction":0.10182119205298014},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC22","stoichiometry":0.2},{"gene":"CDC20","stoichiometry":0.2},{"gene":"MED11","stoichiometry":0.2},{"gene":"MED19","stoichiometry":0.2},{"gene":"MED25","stoichiometry":0.2},{"gene":"MED31","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRDX1","total_profiled":1310},"omim":[{"mim_id":"617583","title":"SULFIREDOXIN 1; SRXN1","url":"https://www.omim.org/entry/617583"},{"mim_id":"611802","title":"MIGRATION AND INVASION ENHANCER 1; MIEN1","url":"https://www.omim.org/entry/611802"},{"mim_id":"609831","title":"METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC","url":"https://www.omim.org/entry/609831"},{"mim_id":"609632","title":"GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE DOMAIN-CONTAINING PROTEIN 5; GDPD5","url":"https://www.omim.org/entry/609632"},{"mim_id":"606599","title":"THIOREDOXIN-INTERACTING PROTEIN; TXNIP","url":"https://www.omim.org/entry/606599"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRDX1"},"hgnc":{"alias_symbol":["NKEFA"],"prev_symbol":["PAGA"]},"alphafold":{"accession":"Q06830","domains":[{"cath_id":"3.40.30.10","chopping":"9-151","consensus_level":"high","plddt":97.925,"start":9,"end":151},{"cath_id":"-","chopping":"152-199","consensus_level":"medium","plddt":97.0715,"start":152,"end":199}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06830","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06830-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06830-F1-predicted_aligned_error_v6.png","plddt_mean":97.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRDX1","jax_strain_url":"https://www.jax.org/strain/search?query=PRDX1"},"sequence":{"accession":"Q06830","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06830"}},"corpus_meta":[{"pmid":"30890159","id":"PMC_30890159","title":"PAGA: 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injury.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38159556","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":"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":"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":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":"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":"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":4,"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":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":"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, 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39895052","citation_count":2,"is_preprint":false},{"pmid":"37638803","id":"PMC_37638803","title":"6-Shogaol prevents benzo (A) pyrene-exposed lung carcinogenesis via modulating PRDX1-associated oxidative stress, inflammation, and proliferation in mouse models.","date":"2023","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37638803","citation_count":2,"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":2,"is_preprint":false},{"pmid":"24352703","id":"PMC_24352703","title":"Genomic organization, single nucleotide polymorphism and functional characterization of natural killer enhancing factor (NKEF-A) in Miichthys miiuy.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24352703","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55943,"output_tokens":7931,"usd":0.143397},"stage2":{"model":"claude-opus-4-6","input_tokens":11695,"output_tokens":4570,"usd":0.259088},"total_usd":0.402485,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","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 characterized by increased erythrocyte ROS, protein oxidation, haemoglobin instability, Heinz body formation, and decreased erythrocyte lifespan, establishing PRDX1 as an essential 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, phenotype, and function.\",\n      \"method\": \"Targeted gene knockout in mice with phenotypic characterization (ROS measurement, haematological assays, tumour histopathology, NK cell functional assays)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined cellular phenotypes, replicated across tissues\",\n      \"pmids\": [\"12891360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PRDX1 physically interacts with the transmembrane protein GDE2 and activates it by reducing an intramolecular disulfide bond bridging GDE2's intracellular N- and C-terminal domains, thereby driving spinal motor neuron differentiation. This activation requires PRDX1's thiol-dependent catalytic activity, and GDE2 variants incapable of disulfide bond formation become independent of PRDX1.\",\n      \"method\": \"Co-immunoprecipitation, in vivo loss-of-function (Prdx1 knockdown/knockout in chick spinal cord), active-site mutagenesis of PRDX1 and GDE2, epistasis analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reciprocal interaction, mutagenesis, epistasis, and defined neuronal differentiation phenotype in single study\",\n      \"pmids\": [\"19766572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRDX1 binds to both MKP-1 and MKP-5 phosphatases in an H2O2 dose-dependent manner via its peroxidatic cysteine Cys52. At high H2O2, over-oxidation of Cys52 to sulfonic acid causes PRDX1 to dissociate from MKP-1, leading to MKP-1 oxidation-induced oligomerization and inactivation toward p38MAPKα, while the PRDX1:MKP-5 complex is stabilized, protecting MKP-5 from inactivation. This mechanism coordinates p38MAPK-dependent cellular senescence in breast epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, H2O2 dose-response assays, Cys52 mutagenesis, p38MAPK phosphorylation assays, ROS-induced senescence model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — active-site mutagenesis combined with binding and functional phosphatase assays in a single study\",\n      \"pmids\": [\"23334324\"],\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 increases NF-κB activation, pro-inflammatory cytokine production, and bactericidal autophagy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays in PRDX1-knockdown cell lines (THP-1, MDA-MB-231, SK-HEP-1), TLR4 stimulation experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping plus functional ubiquitination assay and KD phenotype in multiple cell lines\",\n      \"pmids\": [\"29929436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 in cancer cells causes ROS-dependent continuous telomere shortening due to efficient inhibition of telomere extension by telomerase, identifying PRDX1 as a guardian of telomere integrity.\",\n      \"method\": \"CRISPR gene disruption, telomere length measurement, ROS quantification, telomerase extension assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double knockout with direct telomere length and telomerase functional readouts\",\n      \"pmids\": [\"29773556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kinetic analysis established that the peroxidatic cysteine of PRDX1 reacts ~10-fold faster with H2O2 than peroxynitrite (both orders of magnitude faster than typical protein thiols), and that PRDX1 has a substantially faster disulfide formation rate (11 s⁻¹) than PRDX2 (0.2 s⁻¹), which determines its distinct redox-relay function versus PRDX2's mixed-disulfide signaling mode. The additional C83 residue in PRDX1 further differentiates its response to peroxynitrite.\",\n      \"method\": \"In vitro kinetic assays using recombinant human PRDX1 and PRDX2, intrinsic fluorescence monitoring of oxidation and hyperoxidation\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro reconstitution with recombinant proteins and quantitative kinetics\",\n      \"pmids\": [\"30284335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Pin1 binds PRDX1 through the phospho-Thr90-Pro91 motif and facilitates PP2A-mediated dephosphorylation of PRDX1, restoring its peroxidase activity. In Pin1-knockout MEFs, phosphorylated (Thr90) PRDX1 accumulates in its inactive form, leading to increased H2O2 buildup.\",\n      \"method\": \"Proteomic pulldown, co-immunoprecipitation, Thr90 mutagenesis, peroxidase activity assay in Pin1−/− MEFs with Pin1 re-introduction, H2O2 measurement\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis, enzymatic activity rescue, and genetic KO with re-introduction\",\n      \"pmids\": [\"23421996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX1 is enriched in telomeric chromatin and counteracts ROS-induced telomere damage. In PRDX1-depleted cells, PARP-dependent telomeric repair is often incomplete, generating persistent single-strand breaks that are converted to double-strand breaks during replication. PARP1 inhibition in PRDX1-depleted cells dampens telomere shortening by stabilising BRCA1 and enabling RAD51-mediated HR repair.\",\n      \"method\": \"PRDX1 depletion, telomere ChIP showing PRDX1 enrichment, PARP inhibitor epistasis, telomere length assays, SSB/DSB quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct telomeric localization by ChIP, genetic epistasis with PARP1 inhibitor, multiple DNA repair readouts\",\n      \"pmids\": [\"33147465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX1 binds TRAF6 and BECN1 and deficiency in PRDX1 suppresses autophagic flux in macrophages, leading to impaired lipophagic cholesterol hydrolysis, higher intracellular cholesterol, and reduced cholesterol efflux. 2-Cys PRDX mimics (ebselen, gliotoxin) rescue these defects, and Prdx1-deficient bone marrow transplantation into apoe-/- mice increases atherosclerotic plaque formation.\",\n      \"method\": \"Prdx1 knockout macrophages, lipophagic flux assays, cholesterol efflux assays, in vivo bone marrow transplant model, pharmacological rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal functional assays and in vivo validation\",\n      \"pmids\": [\"28605287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AMPK activation stabilises the interaction between c-Abl and PRDX1, preventing oxidative stress-induced dissociation of the complex. Knockdown of PRDX1 increases phosphorylation of both caveolin-1 and c-Abl and abolishes the inhibitory effect of AMPK on caveolin-1 phosphorylation and albumin endocytosis in endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, pharmacological AMPK activation (AICAR), caveolin-1 phosphorylation and endocytosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional KD phenotype in one cell type\",\n      \"pmids\": [\"23723070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX1 oligomers bind both the Nedd8-conjugating enzyme UBE2F and CUL5, forming a tricomplex essential for CUL5 neddylation. This promotes NOXA ubiquitination and degradation, inhibiting apoptosis in colorectal cancer cells. ROS elevation drives PRDX1 oligomerization, linking oxidative stress to NOXA protein half-life.\",\n      \"method\": \"Co-immunoprecipitation, PRDX1 oligomerization assays, ubiquitination assays, NOXA protein half-life measurement, PRDX1 knockdown and oligomerization inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with multiple partners plus functional ubiquitination assay, single lab\",\n      \"pmids\": [\"33712558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDX1 forms a heterodimer with p38α (MAPK14), stabilizing phospho-p38α in glioma cells, which amplifies HGF-mediated MET signaling and stimulates actin cytoskeleton dynamics to promote glioma cell migration and brain invasion in vivo.\",\n      \"method\": \"Biochemical interaction studies (Co-IP), in vitro and ex vivo migration assays, whole-brain high-resolution ultramicroscopy in mouse glioma models, survival analysis of PRDX1-KD mice\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with defined kinase stabilization mechanism plus in vivo validation\",\n      \"pmids\": [\"29582423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRDX1 interacts with ASK1 at elevated H2O2 concentrations in a manner that does not require a scaffolding protein, in contrast to the Prdx2:STAT3 relay. This interaction was demonstrated both in cellulo and by in vitro protein-protein interaction methods.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pulldown, H2O2 dose-response experiments\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — cellular and in vitro interaction methods, single lab\",\n      \"pmids\": [\"34209102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The lysine acetyltransferase MOF acetylates PRDX1 at lysine 197 (K197), preventing its hyperoxidation and maintaining peroxidase activity under inflammatory stress. LPS stimulation rapidly decreases PRDX1 K197ac in macrophages, elevating H2O2, augmenting ERK1/2 phosphorylation, stimulating glycolysis, and enhancing pro-inflammatory IL-6 production.\",\n      \"method\": \"Identification of K197 acetylation site, MOF KO/knockdown experiments, LPS stimulation, H2O2 measurement, ERK1/2 phosphorylation assays, metabolic flux analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — writer (MOF) identified, site-specific acetylation validated, functional consequences with multiple orthogonal readouts\",\n      \"pmids\": [\"39207899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HJURP forms disulfide-linked intermediates with PRDX1 through Cys327 and Cys457 residues of HJURP, promoting PRDX1 redox cycling and inhibiting its hyperoxidation, thereby enhancing PRDX1 peroxidase activity and suppressing ROS and lipid peroxidation to confer ferroptosis resistance in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, disulfide bond identification by mutagenesis, peroxidase activity assays, ROS and lipid peroxidation measurement, in vivo xenograft\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific cysteine residues identified for disulfide-linked intermediate, peroxidase activity assay, single lab\",\n      \"pmids\": [\"39405980\"],\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 accumulation of replication stress and DNA damage.\",\n      \"method\": \"Functional genomics (CRISPR screen), chromatin proteomics, metabolomics, nuclear fractionation/localization, etoposide treatment experiments\",\n      \"journal\": \"Molecular systems biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genomics, proteomics, metabolomics, localization) in an integrated study\",\n      \"pmids\": [\"37259925\"],\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 and stabilising NRF2, which drives GPX4 transcription. The Cys83 residue of PRDX1 is required for CUL3 binding and this activity is enhanced by conoidin A.\",\n      \"method\": \"IP-MS, Co-immunoprecipitation, Cys83Ser mutagenesis, ubiquitination assays, NRF2 nuclear translocation assays, PRDX1 KO mouse model (AOM/DSS)\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS partner identification, mutagenesis defining critical residue, functional ubiquitination assay, in vivo validation\",\n      \"pmids\": [\"39430237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRDX1 binds JNK1 and inhibits JNK kinase signaling, thereby suppressing the cancer-associated fibroblast (CAF)-like activated phenotype in mammary fibroblasts. Loss of PRDX1 results in development of a CAF-like phenotype that is reversed by JNK inhibition.\",\n      \"method\": \"Co-immunoprecipitation of PRDX1 with JNK1, PRDX1 knockout mouse fibroblasts, JNK inhibitor (SP600125) rescue, migration/invasion assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with functional KO phenotype and pharmacological rescue, single lab\",\n      \"pmids\": [\"31419957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA LncFASA directly binds the Ahpc-TSA domain of PRDX1 and drives liquid-liquid phase separation of PRDX1 into droplets, inhibiting its peroxidase activity. This disrupts ROS homeostasis and promotes ferroptosis through the SLC7A11-GPX4 axis in triple-negative breast cancer cells.\",\n      \"method\": \"RNA-protein binding assays, phase separation assays, peroxidase activity assays, SLC7A11/GPX4 pathway analysis, xenograft tumor model\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct binding with domain identification, phase separation and enzymatic activity measured, single lab\",\n      \"pmids\": [\"37955780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prdx1 regulates the HEF1-Aurora A-HDAC6 signaling axis to promote primary cilia disassembly in esophageal squamous cell carcinoma cells; silencing Prdx1 restores primary cilia formation and reduces tumor formation in vivo.\",\n      \"method\": \"Prdx1 siRNA knockdown, gene chip analysis, cilia formation assays, HEF1/Aurora A/HDAC6 pathway measurement, in vivo xenograft\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with specific signaling pathway readout and in vivo validation, single lab\",\n      \"pmids\": [\"32357862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prdx1 functions as an RNA-binding protein that stabilises inflammation- and apoptosis-related mRNAs after intracerebral haemorrhage, as identified by RIP-seq. Prdx1 overexpression reduces inflammation and apoptosis in ICH models.\",\n      \"method\": \"RNA immunoprecipitation combined with high-throughput sequencing (RIP-seq), AAV-mediated overexpression in rat ICH model\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide RIP-seq identifies RNA-binding activity with in vivo functional phenotype, single lab\",\n      \"pmids\": [\"32210752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hspb1 directly interacts with Anxa2 to reduce its aggregation and phosphorylation, which in turn allows Anxa2 to interact with Prdx1 and maintain its antioxidative activity by decreasing Thr-90 phosphorylation of Prdx1; overexpression of Hspb1 had no protective effect in acinar-specific Prdx1 knockout mice, establishing the Hspb1/Anxa2/Prdx1 axis.\",\n      \"method\": \"Co-immunoprecipitation, Prdx1 acinar cell-specific KO mice, AAV8-Hspb1 overexpression, Thr-90 phosphorylation assays, genetic epistasis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with cell-type-specific KO, Co-IP, and PTM identification, single lab\",\n      \"pmids\": [\"38481805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRDX1 Cys52Ser (peroxidase-dead) variant mice show impaired global PRDX peroxidase activity and are protected from diet-induced NASH and liver fibrosis, with suppressed NF-κB and STAT1 pro-inflammatory signalling, demonstrating that peroxidatic Cys52 is required for PRDX1's pro-inflammatory activity in vivo.\",\n      \"method\": \"Knock-in mouse model (Cys52Ser), Trx-TrxR-NADPH coupled activity assay, western diet/MCD diet feeding, RNA-seq, NF-κB and STAT1 pathway analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — active-site knock-in mouse with in vivo metabolic phenotype and transcriptomic pathway identification\",\n      \"pmids\": [\"37562742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kinetic modelling established that the PRDX1 dimer-to-decamer transition (association rate 0.050 µM⁻⁴·s⁻¹, dissociation rate 0.055 s⁻¹) has an inhibition-like effect on peroxidase activity, as the decameric form has ~100-fold lower activity than the dimer. Incorporating this transition into an in vivo PRDX model reconciled experimental and simulated oxidation-state responses.\",\n      \"method\": \"Isothermal titration calorimetry data fitting, kinetic modelling, HRP competition and NADPH-oxidation assays, in vivo PRDX2 erythrocyte model simulation\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biophysical measurement with kinetic modelling; single study\",\n      \"pmids\": [\"37760010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF207 promotes lactylation of PRDX1 at lysine 67, which enhances PRDX1 nuclear translocation and activation of NRF2, creating a ferroptosis-resistant environment in HCC cells and driving regorafenib resistance.\",\n      \"method\": \"CRISPR/Cas9 screening, lactylation site identification (K67), nuclear translocation assays, NRF2 activity assays, RGF sensitivity rescue experiments\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — novel PTM (lactylation) identified with functional nuclear localisation and NRF2 activation readouts, single lab\",\n      \"pmids\": [\"40680452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRAK1 binds PRDX1 and prevents its ubiquitination and degradation mediated by the E3 ubiquitin ligase HECTD3 (which interacts with PRDX1 via its DOC and HECT domains). Overexpression of PRDX1 reverses the radiosensitisation effect of IRAK1 depletion by diminishing autophagic cell death in glioma.\",\n      \"method\": \"Co-IP, LC-MS/MS, GST pulldown, ubiquitination assays, domain-mapping mutagenesis of HECTD3, PRDX1 overexpression rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple interaction methods plus functional ubiquitination assay with domain mapping, single lab\",\n      \"pmids\": [\"37031183\"],\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 and promoting OSCC cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, Cofilin Ser3 phosphorylation assays, actin dynamics assays, in vitro migration/invasion, nude mouse tongue cancer model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct Co-IP with specific phosphorylation site readout and in vivo validation, single lab\",\n      \"pmids\": [\"38738971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A co-crystal structure of PRDX1 with the celastrol derivative LC-PDin20 revealed the binding mode of covalent inhibitors with PRDX1, and active cysteine residues were confirmed as the covalent binding sites, enabling structure-based design of selective PRDX1 inhibitors.\",\n      \"method\": \"Co-crystal structure determination (X-ray crystallography), molecular docking, in vitro PRDX1 enzyme inhibition assay (IC50 determination)\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with in vitro enzymatic inhibition validation\",\n      \"pmids\": [\"40546088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Recombinant PRDX1 protein dose-dependently inhibits ROS production and osteoclast differentiation from bone marrow macrophages, and mechanistically attenuates NFATc1 activation as well as expression of C-Fos, V-ATPase-d2, Cathepsin K, and Integrin αV downstream of RANKL signalling.\",\n      \"method\": \"Recombinant protein treatment, ROS measurement, osteoclast differentiation assay, NFATc1 and downstream marker expression analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — recombinant protein with defined signalling pathway readout, single lab\",\n      \"pmids\": [\"39263840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BACH1 directly binds the promoter region of PRDX1 and inhibits its transcription; remifentanil treatment suppresses BACH1 and upregulates PRDX1, thereby reducing oxidative stress injury in hepatic ischaemia-reperfusion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, BACH1 overexpression and PRDX1 silencing epistasis\",\n      \"journal\": \"Clinics and research in hepatology and gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding validated by ChIP and luciferase, with epistasis, single lab\",\n      \"pmids\": [\"39025461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NFAT5 directly binds the PRDX1 promoter to drive its transcription, which enhances mitochondrial function in cervical cancer cells. METTL3 promotes NFAT5 mRNA stability via IGF2BP3-mediated m6A modification, placing PRDX1 downstream of an m6A-NFAT5 transcriptional regulatory axis.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, MeRIP assay, NFAT5 knockdown/overexpression with PRDX1 rescue\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding by ChIP/luciferase plus upstream m6A regulation validated, single lab\",\n      \"pmids\": [\"39925026\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX1 is a cytosolic 2-Cys peroxiredoxin whose peroxidatic Cys52 catalyses H2O2 reduction, and whose oligomeric state, phosphorylation (Thr90, regulated by Pin1/PP2A), acetylation (K197 by MOF), lactylation (K67), and oxidation status control its enzymatic activity, molecular chaperone activity, and protein–protein interactions; it acts as a redox relay that directly regulates binding partners including GDE2 (activating it by disulfide reduction to drive motor neuron differentiation), ASK1, JNK1, MKP-1/MKP-5 (in an H2O2 dose-dependent manner to coordinate p38MAPK-dependent senescence), TRAF6 (inhibiting its ubiquitin-ligase activity to suppress NF-κB and autophagy), CUL3 (blocking NRF2 ubiquitination), UBE2F-CUL5 (promoting NOXA degradation), p38α/MAPK14 (stabilising phospho-p38α to amplify MET-driven invasion), Cofilin (inhibiting Ser3 phosphorylation to promote actin turnover), and GLUT3; it also translocates to the nucleus upon DNA damage to scavenge nuclear ROS, localises to telomeric chromatin to prevent oxidative telomere damage and support telomerase activity, and functions as an RNA-binding protein stabilising inflammation-related mRNAs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRDX1 is a 2-Cys peroxiredoxin that functions as a central redox sensor and signal relay hub, coupling intracellular H₂O₂ levels to diverse signaling, transcriptional, and genome-protective outputs. Its peroxidatic cysteine Cys52 reduces H₂O₂ with rapid kinetics and undergoes dose-dependent oxidation states—including hyperoxidation to sulfonic acid—that switch PRDX1 between peroxidase, redox relay, and molecular chaperone modes, controlling partner interactions with MKP-1/MKP-5, ASK1, JNK1, TRAF6, CUL3, UBE2F-CUL5, p38α, Cofilin, and GDE2 to regulate MAP kinase signaling, NF-κB activation, autophagy, NRF2 stability, apoptosis, cytoskeletal dynamics, and motor neuron differentiation [PMID:30284335, PMID:23334324, PMID:29929436, PMID:39430237, PMID:19766572, PMID:33712558, PMID:29582423, PMID:38738971]. Post-translational modifications—including Thr90 phosphorylation regulated by Pin1/PP2A, K197 acetylation by MOF, and K67 lactylation—tune its enzymatic activity, oligomeric state, and subcellular distribution, with nuclear translocation upon DNA damage enabling PRDX1 to scavenge nuclear ROS, support de novo nucleotide synthesis, localize to telomeric chromatin to prevent oxidative telomere damage, and sustain telomerase activity [PMID:23421996, PMID:39207899, PMID:40680452, PMID:37259925, PMID:33147465, PMID:29773556]. Prdx1 knockout mice develop severe hemolytic anemia from erythrocyte oxidative damage, increased cancer susceptibility, and NK cell dysfunction, while Cys52Ser knock-in mice are protected from diet-induced steatohepatitis, demonstrating that PRDX1 peroxidase activity has both cytoprotective and context-dependent pro-inflammatory roles in vivo [PMID:12891360, PMID:37562742].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing the in vivo requirement for PRDX1: knockout mice revealed that PRDX1 is not redundant with other peroxiredoxins but is essential for erythrocyte redox homeostasis, proliferative capacity, and immune cell function, defining it as a non-redundant antioxidant defense.\",\n      \"evidence\": \"Targeted Prdx1 knockout mice with hematological, ROS, and NK cell phenotyping\",\n      \"pmids\": [\"12891360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selective erythrocyte vulnerability versus other cell types not resolved\", \"Contribution of chaperone versus peroxidase activity to the KO phenotype not distinguished\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that PRDX1 acts as a thiol-based redox switch for a specific biological effector: PRDX1 activates GDE2 by reducing an intramolecular disulfide bond, establishing that PRDX1's catalytic activity directly couples to a developmental signaling event (motor neuron differentiation).\",\n      \"evidence\": \"Co-IP, active-site mutagenesis, Prdx1 knockdown/KO in chick spinal cord with epistasis analysis\",\n      \"pmids\": [\"19766572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX1-GDE2 interaction is constitutive or regulated by ROS levels in vivo not tested\", \"Other developmental signals requiring PRDX1 redox relay not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing how PRDX1's oxidation state enables dose-dependent H₂O₂ signaling: PRDX1 differentially associates with MKP-1 and MKP-5 depending on Cys52 oxidation status, coordinating p38 MAPK-driven senescence and establishing PRDX1 as a redox relay with partner-selective outputs.\",\n      \"evidence\": \"Cys52 mutagenesis, H₂O₂ dose-response binding assays, p38 MAPK phosphorylation readout in breast epithelial cells\",\n      \"pmids\": [\"23334324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether intermediate oxidation states of Cys52 generate additional signaling specificity not tested\", \"In vivo senescence phenotype in PRDX1-deficient tissues not examined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying post-translational control of PRDX1 peroxidase activity: Pin1 recognizes phospho-Thr90 and recruits PP2A for dephosphorylation, restoring enzymatic activity, thus defining a phospho-switch that gates PRDX1 function.\",\n      \"evidence\": \"Proteomic pulldown, Thr90 mutagenesis, peroxidase activity rescue in Pin1-KO MEFs\",\n      \"pmids\": [\"23421996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Thr90 phosphorylation not definitively identified in this study\", \"Whether Thr90 phosphorylation also regulates chaperone or relay functions not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing PRDX1 as a negative regulator of innate immune signaling and autophagy through direct E3 ligase inhibition: PRDX1 binds the RING domain of TRAF6 and blocks ubiquitination of ECSIT and BECN1, suppressing both NF-κB activation and autophagy induction.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, ubiquitination assays, PRDX1 knockdown in THP-1 and other cell lines with TLR4 stimulation\",\n      \"pmids\": [\"29929436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX1 oxidation state modulates TRAF6 binding affinity not determined\", \"Structural basis of RING domain recognition not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining PRDX1 as a guardian of telomere integrity: combined PRDX1/MTH1 disruption causes ROS-dependent telomere shortening by inhibiting telomerase extension, revealing cooperative oxidative damage prevention at telomeres.\",\n      \"evidence\": \"CRISPR double knockout, telomere length assays, telomerase extension assays\",\n      \"pmids\": [\"29773556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX1 is physically present at telomeres was not shown in this study (addressed in 2020)\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantitative kinetic analysis established the mechanistic basis for PRDX1's redox-relay versus peroxide-scavenging roles: PRDX1's ~55-fold faster disulfide formation rate compared to PRDX2, plus the additional Cys83 residue, explains its preferential function as a redox relay rather than a peroxide sensor.\",\n      \"evidence\": \"Recombinant protein kinetic assays with intrinsic fluorescence monitoring\",\n      \"pmids\": [\"30284335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the kinetic difference between PRDX1 and PRDX2 not directly tested\", \"Role of Cys83 in partner-specific relay not investigated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Direct demonstration of PRDX1 at telomeric chromatin: PRDX1 enrichment at telomeres by ChIP, and epistasis with PARP inhibition, showed that PRDX1 prevents oxidative single-strand breaks that convert to replication-coupled double-strand breaks, mechanistically explaining how PRDX1 loss drives telomere shortening.\",\n      \"evidence\": \"Telomere ChIP, PRDX1 depletion, PARP inhibitor epistasis, SSB/DSB quantification\",\n      \"pmids\": [\"33147465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRDX1 is recruited to telomeric chromatin is unknown\", \"Whether PRDX1's telomeric role requires its peroxidase or chaperone activity not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanding PRDX1's repertoire beyond protein interactions: RIP-seq identified PRDX1 as an RNA-binding protein that stabilizes inflammation- and apoptosis-related mRNAs, adding post-transcriptional gene regulation to its functional portfolio.\",\n      \"evidence\": \"RIP-seq in rat brain, AAV-mediated overexpression in ICH model\",\n      \"pmids\": [\"32210752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding domain/motif not identified\", \"Whether RNA binding is redox-dependent not tested\", \"Replication in non-CNS systems lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting PRDX1's TRAF6/BECN1 interaction to lipid metabolism: PRDX1 deficiency impairs autophagic cholesterol hydrolysis in macrophages, increasing atherosclerotic plaque formation, establishing a physiological consequence of the PRDX1-TRAF6-BECN1 axis.\",\n      \"evidence\": \"Prdx1 KO macrophages, lipophagic flux and cholesterol efflux assays, bone marrow transplant in Apoe-KO mice, pharmacological rescue with 2-Cys PRDX mimics\",\n      \"pmids\": [\"28605287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX1 promotes or inhibits BECN1 function remains context-dependent and requires clarification across cell types\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing a non-enzymatic scaffolding role: PRDX1 oligomers bridge UBE2F and CUL5 to promote CUL5 neddylation and NOXA degradation, linking ROS-driven PRDX1 oligomerization to apoptosis resistance.\",\n      \"evidence\": \"Co-IP, oligomerization assays, NOXA half-life measurement in colorectal cancer cells\",\n      \"pmids\": [\"33712558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether oligomeric versus dimeric PRDX1 has distinct partner selectivity beyond UBE2F-CUL5 not tested\", \"Independent replication needed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating nuclear translocation as a DNA damage response: PRDX1 moves to the nucleus upon genotoxic stress to scavenge nuclear ROS and support aspartate-dependent de novo nucleotide synthesis, linking its antioxidant activity to replication stress resistance.\",\n      \"evidence\": \"CRISPR screen, chromatin proteomics, metabolomics, nuclear fractionation after etoposide treatment\",\n      \"pmids\": [\"37259925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal or modification triggering nuclear import not identified\", \"Whether nuclear PRDX1 engages distinct relay partners not explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Separating peroxidase-dependent functions in vivo: Cys52Ser knock-in mice showed that the peroxidatic cysteine is specifically required for pro-inflammatory NF-κB and STAT1 signaling in steatohepatitis, demonstrating that PRDX1's disease-promoting roles depend on catalytic redox cycling rather than chaperone activity.\",\n      \"evidence\": \"Cys52Ser knock-in mouse, Western/MCD diet, RNA-seq, NF-κB/STAT1 pathway analysis\",\n      \"pmids\": [\"37562742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chaperone-only functions (e.g., CUL3 binding via Cys83) are preserved in Cys52Ser mice not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying acetylation as a rapid inflammatory switch: MOF-mediated K197 acetylation protects PRDX1 from hyperoxidation; LPS triggers deacetylation, elevating H₂O₂ to activate ERK1/2 and glycolysis for pro-inflammatory cytokine production, revealing how innate immune activation is coupled to PRDX1 inactivation.\",\n      \"evidence\": \"MOF KO/knockdown, K197 site identification, LPS stimulation with H₂O₂, ERK1/2, and metabolic flux readouts\",\n      \"pmids\": [\"39207899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase responsible for LPS-induced K197 deacetylation not identified\", \"Interplay between K197 acetylation and Thr90 phosphorylation not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining a chaperone-mode interaction with CUL3 that stabilizes NRF2: PRDX1 binds CUL3 via Cys83 (not Cys52), blocking NRF2 ubiquitination and driving GPX4 transcription, demonstrating that PRDX1 has separable catalytic-cysteine and non-catalytic-cysteine dependent partner interactions.\",\n      \"evidence\": \"IP-MS, Cys83Ser mutagenesis, ubiquitination assays, NRF2 translocation, AOM/DSS mouse model\",\n      \"pmids\": [\"39430237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cys83 oxidation state regulates CUL3 binding not determined\", \"Structural basis of the PRDX1-CUL3 interface not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Obtaining the first co-crystal structure of PRDX1 with a covalent inhibitor provided atomic-resolution insight into the active-site architecture and confirmed covalent modification of catalytic cysteines as the inhibitory mechanism.\",\n      \"evidence\": \"X-ray co-crystallography with celastrol derivative LC-PDin20, enzymatic IC₅₀ determination\",\n      \"pmids\": [\"40546088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure with a physiological partner (relay target) yet available\", \"Whether inhibitor binding disrupts oligomerization not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: how PRDX1 is recruited to specific chromatin loci (telomeres, damage sites); the identity of kinases and deacetylases regulating its PTM switches; structural models of PRDX1 in complex with relay partners; and how the competing peroxidase, chaperone, RNA-binding, and relay activities are partitioned in a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PRDX1 bound to any relay partner\", \"Signal routing rules between simultaneous partners unknown\", \"RNA-binding mechanism and domain uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 5, 6, 13, 14, 22, 27]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 10, 11, 17, 26]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 24]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [7, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 5, 13, 15, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 11, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 13, 22]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 7, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 29, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GDE2\",\n      \"TRAF6\",\n      \"BECN1\",\n      \"CUL3\",\n      \"PIN1\",\n      \"JNK1\",\n      \"CFL1\",\n      \"MAPK14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}