{"gene":"PRDX5","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1999,"finding":"AOEB166 (PRDX5) is a peroxiredoxin-family antioxidant enzyme with demonstrated peroxidase activity in vitro; recombinant protein expressed in E. coli exhibits peroxidase activity and antioxidant activity comparable to catalase in a glutamine synthetase protection assay against DTT/Fe3+/O2 oxidation.","method":"Recombinant protein expression in E. coli, in vitro peroxidase assay, glutamine synthetase protection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution with two orthogonal activity assays, replicated in initial characterization paper","pmids":["10521424"],"is_preprint":false},{"year":1999,"finding":"AOEB166 (PRDX5) localizes to mitochondria and peroxisomes in HepG2 cells, as shown by GFP fusion protein sorting to both organelles; N- and C-terminal domains contain mitochondrial and peroxisomal targeting sequences.","method":"GFP fusion protein expression and fluorescence microscopy in HepG2 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by live-cell imaging, single lab, one method but consistent with domain analysis","pmids":["10521424"],"is_preprint":false},{"year":1999,"finding":"Human PMP20 (PRDX5) is imported into the peroxisomal matrix via the PTS1 receptor PEX5; the C-terminal tripeptide SQL is necessary and sufficient for binding to HsPEX5, as shown by direct binding assay and mutagenesis of the SQL sequence.","method":"Direct binding assay (PMP20 to HsPEX5), mutagenesis of C-terminal SQL tripeptide, subcellular fractionation, double-staining immunofluorescence co-localization with thiolase","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding assay with mutagenesis plus subcellular fractionation and co-localization, multiple orthogonal methods in one study","pmids":["10514471"],"is_preprint":false},{"year":1999,"finding":"Human PMP20 (PRDX5) exhibits thiol-specific antioxidant activity (inhibits glutamine synthetase inactivation in thiol-metal-catalyzed but not non-thiol metal-catalyzed oxidation) and thiol-peroxidase activity (removes hydrogen peroxide).","method":"In vitro glutamine synthetase protection assay (thiol vs. non-thiol MCO systems), thiol-peroxidase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — two orthogonal in vitro enzymatic assays distinguishing thiol-specific vs. non-thiol activity, rigorous controls","pmids":["10514471"],"is_preprint":false},{"year":2014,"finding":"Small-molecule fragments bind to PRDX5 at defined sites; NMR methods (STD-epitope mapping, 15N-HSQC chemical shift perturbation) were used to compare binding modes of analogous fragments, validating PRDX5 as a druggable target with structurally distinct binding pockets.","method":"Ligand-observed STD NMR, protein-observed 15N-HSQC NMR, CSP analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR-based structural/binding study, single lab, focused on fragment binding mode characterization","pmids":["25025339"],"is_preprint":false},{"year":2020,"finding":"PRDX5 physically interacts with Nrf2 in H2O2-stimulated NSCLC cells, and this interaction promotes NQO1 protein expression; the interaction was detected by co-immunoprecipitation.","method":"Co-immunoprecipitation in H2O2-stimulated NSCLC cells, western blot for NQO1","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single co-IP, single lab, limited mechanistic follow-up","pmids":["31899687"],"is_preprint":false},{"year":2020,"finding":"STAT3 binds to two specific sites in the PRDX5 promoter (site 1: −444 to −434 bp; site 4: −1,417 to −1,407 bp) and transcriptionally activates PRDX5 expression; ROS-mediated demethylation of the PRDX5 promoter enhances STAT3 binding affinity.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, bisulfite sequencing PCR, STAT3 knockdown/overexpression with western blot","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay plus loss/gain-of-function, single lab, two orthogonal methods","pmids":["33416106"],"is_preprint":false},{"year":2020,"finding":"PRDX5 overexpression in NSCLC cells under oxidative stress promotes epithelial-mesenchymal transition (decreases E-cadherin, increases vimentin) and activates the Nrf2 signaling pathway, while PRDX5 knockdown has the opposite effects.","method":"siRNA knockdown and pcDNA3.1 overexpression, western blot for EMT markers and Nrf2 pathway components in H1299 cells pretreated with H2O2","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts, single lab","pmids":["33416106"],"is_preprint":false},{"year":2023,"finding":"Prdx5 regulates DNA damage response (DDR) through: (1) Plk1-mediated phosphorylation of ATM kinase activating downstream Chek1/Chek2; (2) increasing p53 acetylation at K382, stabilizing nuclear p53 and enhancing transcription; (3) induction of autophagy that regulates recycling of DDR molecules. Sirt2 was identified as a novel deacetylase of p53 at K382, acting in a Prdx5-dependent manner.","method":"Prdx5 knockdown (γ-H2AX and 53BP1 induction), western blot for ATM phosphorylation/Chek1/Chek2, p53 acetylation assays, autophagy induction assays, Sirt2 deacetylase identification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple downstream readouts and pathway placement, single lab but multiple orthogonal methods","pmids":["36067023"],"is_preprint":false},{"year":2023,"finding":"PRDX5 and Nrf2 form a protein complex (confirmed by Co-IP), and their synergistic interaction increases proliferation and drug resistance of NSCLC cells; oxidative stress enhances the PRDX5–Nrf2 interaction.","method":"Co-immunoprecipitation, western blotting, immunohistochemistry, zebrafish xenograft models","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional zebrafish models, replicated across two NSCLC papers but same context","pmids":["37305326"],"is_preprint":false},{"year":2025,"finding":"PRDX5 directly binds TFAM; PRDX5 overexpression enhances TFAM-mediated mitochondrial function, and TFAM knockdown reverses the mitochondrial functional improvements achieved through PRDX5 overexpression, placing PRDX5 upstream of TFAM in mitochondrial homeostasis.","method":"Protein binding assay (PRDX5–TFAM interaction), TFAM knockdown rescue experiment, in vitro and in vivo CKD models with PRDX5 overexpression","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein binding assay plus epistasis by TFAM knockdown rescue, single lab","pmids":["39955823"],"is_preprint":false},{"year":2025,"finding":"IER3 interacts with the presenilin-associated rhomboid-like protein (PARL) and reduces its shear activity, thereby inhibiting cleavage and mitochondrial translocation of cytoplasmic PRDX5. Reduced mitochondrial PRDX5 impairs antioxidant capacity, causes oxidative mitochondrial damage, and promotes stress-induced cellular senescence driving AKI-to-CKD transition.","method":"IER3 knockout mouse RNA-seq identifying PRDX5 upregulation, co-IP of IER3–PARL interaction, PRDX5 inhibition epistasis experiments, mitochondrial fractionation","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus Co-IP plus epistasis, single lab, multiple orthogonal methods","pmids":["41359162"],"is_preprint":false},{"year":2025,"finding":"SIRT3 promotes PRDX5 function downstream in a SIRT3–PRDX5 axis in spinal cord neurons; SIRT3 and PRDX5 co-localize within neurons of the anterior horn of the spinal cord, and genetic silencing of PRDX5 partially abrogates SIRT3's neuroprotective effects against apoptosis and oxidative stress after spinal cord injury.","method":"Transcriptome analysis of Sirt3-/- renal tissues, immunofluorescence co-localization, PRDX5 genetic silencing epistasis experiment in SCI mouse model","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-guided discovery plus co-localization plus genetic epistasis, single lab","pmids":["40818507"],"is_preprint":false},{"year":2025,"finding":"Acetylation of PRDX5 inhibits its antioxidant and anti-apoptotic functions in retinal neurons under ischemia-reperfusion: OGD/R increases PRDX5 acetylation; increasing acetylation (NAM treatment) elevates ROS and apoptosis, while decreasing acetylation (NRC treatment) reduces ROS and apoptosis; inhibiting deacetylation abolishes the protective effect of PRDX5 overexpression.","method":"OGD/R cell model, pharmacological manipulation of acetylation (NAM/NRC), PRDX5 overexpression/knockdown, ROS assay, apoptosis assay (TUNEL, PI staining), western blot","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function plus PTM manipulation with multiple functional readouts, single lab","pmids":["41740330"],"is_preprint":false},{"year":2025,"finding":"Salvianolic acid B (SAB) directly binds PRDX5 (confirmed by DARTS, CETSA, and molecular docking) and enhances its redox activity, which in turn potentiates SLC7A11 and GPX4 inhibitory effects on ferroptosis; PRDX5 silencing partially abrogates SAB's renoprotective effects in AKI models.","method":"DARTS assay, CETSA, molecular docking, PRDX5 knockdown rescue in cisplatin-induced AKI model, in vivo mouse AKI models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal target engagement assays plus genetic epistasis, single lab","pmids":["40654183"],"is_preprint":false},{"year":2025,"finding":"PRDX5 loss-of-function during myogenesis causes myonuclear clustering (impaired nuclear spreading) and reduced mitochondrial ATP production. PRDX5 facilitates mitochondrial transport and nuclear positioning at least in part through transcriptional regulation of Rhot1 and Trak1; knockdown of Rhot1 or Trak1 in WT myotubes phenocopies Prdx5 deficiency.","method":"Prdx5-/- mouse myotube analysis, Seahorse OCR mitochondrial function assay, confocal and super-resolution SIM microscopy, Rhot1/Trak1 knockdown epistasis, in vivo muscle function and histology","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse plus multiple orthogonal methods (Seahorse, super-resolution imaging, epistasis knockdown), in vitro and in vivo validation","pmids":["41147088"],"is_preprint":false},{"year":2025,"finding":"Prdx5 regulates macrophage polarization toward M1 phenotype in an ROS-dependent manner via the TLR4/NF-κB pathway; Prdx5 silencing suppresses M1 polarization and reduces prostate epithelial cell apoptosis in an experimental autoimmune prostatitis model.","method":"siRNA knockdown of Prdx5, western blot, RT-qPCR, flow cytometry, immunofluorescence, immunohistochemistry, cell co-culture, EAP mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway analysis in vitro and in vivo, single lab, multiple readouts","pmids":["40015209"],"is_preprint":false},{"year":2025,"finding":"Under cryopreservation-induced oxidative stress, PRDX5 translocates intracellularly in bull sperm and forms high-molecular-weight oligomers detected by PAGE; oligomerization may shift PRDX5 function from peroxidase to chaperone. PRDX5 interaction with TLR4 may be key to its intracellular transport, and PRDX5 was detected in exosomal vesicles.","method":"Imaging Flow Cytometry, native and denaturing PAGE, fluorescence microscopy, ROS/NO measurement","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, descriptive oligomerization and localization data, TLR4 interaction proposed but not directly demonstrated by Co-IP","pmids":["39780184"],"is_preprint":false},{"year":2024,"finding":"Stachyose (STA) and its derivative C6-STA inhibit PRDX5 enzymatic activity and disrupt PRDX5–NRF2 protein–protein interaction, leading to decreased NQO1 levels and quinone radical accumulation that induces apoptosis of drug-tolerant persister cells in CRPC.","method":"PRDX5 enzyme activity assay, Co-IP (PRDX5–NRF2 interaction), western blot for NQO1, pharmacokinetic analysis, in vitro and in vivo CRPC models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme activity inhibition assay plus Co-IP disruption assay with downstream readouts, single lab","pmids":["39168191"],"is_preprint":false},{"year":2022,"finding":"Porcine PRDX5 anti-inflammatory activity depends on its peroxidase activity; recombinant pPRDX5 inhibits TNF-α- and PRRSV-induced inflammatory responses in alveolar macrophages, while siRNA knockdown enhances inflammation. Peroxidase activity is required for the anti-inflammatory effect.","method":"Recombinant protein treatment, siRNA knockdown in porcine alveolar macrophages, inflammatory cytokine measurement, peroxidase activity assay","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function plus peroxidase activity requirement established, single lab","pmids":["35985565"],"is_preprint":false}],"current_model":"PRDX5 is a thiol-dependent peroxidase (atypical 2-Cys subfamily of peroxiredoxins) that localizes to mitochondria and peroxisomes via N-terminal targeting sequences and a C-terminal SQL peroxisomal targeting signal recognized by PEX5; it directly scavenges H2O2 and alkyl hydroperoxides, and its enzymatic activity underlies its roles in DNA damage response (through the Plk1-ATM-Chek1/2 and Sirt2-p53 axes), regulation of macrophage M1 polarization via TLR4/NF-κB, mitochondrial transport and myonuclear positioning (through transcriptional regulation of Rhot1/Trak1), protection from ferroptosis, and CRPC drug resistance; PRDX5 also physically interacts with Nrf2 to promote NQO1 expression, with TFAM to maintain mitochondrial homeostasis, and its function is negatively regulated by acetylation and positively by the SIRT3 deacetylase axis."},"narrative":{"mechanistic_narrative":"PRDX5 is a thiol-dependent peroxiredoxin antioxidant enzyme that scavenges hydrogen peroxide and alkyl hydroperoxides through a thiol-specific catalytic mechanism, providing antioxidant protection comparable to catalase in vitro [PMID:10521424, PMID:10514471]. It is dually targeted to mitochondria and peroxisomes, with N- and C-terminal targeting determinants directing organellar sorting; peroxisomal import depends on a C-terminal SQL tripeptide that is necessary and sufficient for recognition by the PTS1 receptor PEX5 [PMID:10521424, PMID:10514471]. Its peroxidase activity is the basis of its cytoprotective functions: recombinant enzyme requires intact peroxidase activity for anti-inflammatory effects in macrophages [PMID:35985565], and its antioxidant and anti-apoptotic outputs are negatively regulated by acetylation, such that increasing PRDX5 acetylation elevates ROS and apoptosis while deacetylation is protective [PMID:41740330]. PRDX5 supports mitochondrial homeostasis by binding TFAM and acting upstream of TFAM-mediated mitochondrial function [PMID:39955823], and during myogenesis it promotes mitochondrial transport and myonuclear positioning through transcriptional regulation of Rhot1 and Trak1, with mitochondrial ATP production reduced upon its loss [PMID:41147088]. In oxidative-stress and cancer contexts PRDX5 physically interacts with Nrf2 to promote NQO1 expression and drug resistance [PMID:31899687, PMID:37305326, PMID:39168191], regulates the DNA damage response via Plk1–ATM–Chek1/2 signaling and Sirt2-dependent p53 acetylation [PMID:36067023], drives ROS-dependent M1 macrophage polarization through TLR4/NF-κB [PMID:40015209], and protects against ferroptosis by potentiating SLC7A11/GPX4 [PMID:40654183]. PRDX5 expression is transcriptionally activated by STAT3 binding to its promoter, an interaction enhanced by ROS-mediated promoter demethylation [PMID:33416106].","teleology":[{"year":1999,"claim":"Established that PRDX5 is a bona fide antioxidant enzyme, defining its core biochemical identity as a thiol-dependent peroxidase rather than an inferred family member.","evidence":"Recombinant E. coli protein with in vitro peroxidase and glutamine synthetase protection assays distinguishing thiol-specific from non-thiol activity","pmids":["10521424","10514471"],"confidence":"High","gaps":["Catalytic cysteine residues and regeneration mechanism not resolved in these assays","Physiological substrate spectrum beyond H2O2 not delimited"]},{"year":1999,"claim":"Resolved how PRDX5 reaches its sites of action, showing dual mitochondrial/peroxisomal targeting and defining the molecular import determinant for peroxisomes.","evidence":"GFP fusion live-cell imaging in HepG2 cells plus direct PMP20–PEX5 binding assay with SQL mutagenesis, fractionation, and thiolase co-localization","pmids":["10521424","10514471"],"confidence":"High","gaps":["Mitochondrial targeting sequence not mapped at residue resolution","Determinants partitioning the protein between the two organelles not defined"]},{"year":2014,"claim":"Demonstrated PRDX5 is structurally druggable, identifying distinct ligand-binding pockets to guide small-molecule modulation.","evidence":"Ligand-observed STD NMR and protein-observed 15N-HSQC chemical shift perturbation fragment mapping","pmids":["25025339"],"confidence":"Medium","gaps":["No functional consequence of fragment binding established","Binding sites not linked to catalytic regulation"]},{"year":2020,"claim":"Connected PRDX5 to redox-responsive transcriptional programs, showing it both interacts with Nrf2 to drive NQO1 and is itself a STAT3 target under ROS-modulated epigenetic control.","evidence":"Co-IP in H2O2-stimulated NSCLC cells; ChIP, luciferase reporter, bisulfite sequencing, and STAT3 loss/gain-of-function","pmids":["31899687","33416106"],"confidence":"Medium","gaps":["Whether PRDX5–Nrf2 interaction is direct not established by reciprocal/structural validation","Functional link between PRDX5 peroxidase activity and Nrf2 stabilization not mechanistically resolved"]},{"year":2023,"claim":"Placed PRDX5 within DNA damage response signaling and as a stable Nrf2 complex partner driving tumor cell proliferation and drug resistance.","evidence":"Prdx5 knockdown with γ-H2AX/53BP1, ATM phosphorylation and p53 acetylation readouts, Sirt2 deacetylase identification; Co-IP plus zebrafish xenografts","pmids":["36067023","37305326"],"confidence":"Medium","gaps":["Direct biochemical link between PRDX5 enzymatic activity and Plk1–ATM axis not reconstituted","Stoichiometry and interface of the PRDX5–Nrf2 complex undefined"]},{"year":2025,"claim":"Defined non-classical, structural and trafficking roles for PRDX5 in mitochondrial biology, linking it to TFAM-dependent mitochondrial homeostasis and to Rhot1/Trak1-mediated mitochondrial transport and myonuclear positioning.","evidence":"PRDX5–TFAM binding assay with TFAM knockdown rescue in CKD models; Prdx5-/- myotube Seahorse, super-resolution SIM, and Rhot1/Trak1 knockdown epistasis","pmids":["39955823","41147088"],"confidence":"High","gaps":["Mechanism by which PRDX5 transcriptionally controls Rhot1/Trak1 unknown","Whether TFAM binding is direct and how it modulates TFAM function not structurally resolved"]},{"year":2025,"claim":"Established acetylation as a key negative regulatory switch on PRDX5 antioxidant function, integrated within SIRT3/SIRT2 deacetylase axes governing neuroprotection.","evidence":"OGD/R retinal model with pharmacological acetylation manipulation (NAM/NRC) and PRDX5 over/knockdown; SIRT3-PRDX5 co-localization and genetic epistasis in SCI model","pmids":["41740330","40818507"],"confidence":"Medium","gaps":["Specific acetylated lysine residues on PRDX5 not mapped","Direct deacetylase–substrate biochemistry not demonstrated"]},{"year":2025,"claim":"Extended PRDX5 cytoprotective output to ferroptosis defense and immune/inflammatory regulation, and identified its regulation by upstream IER3–PARL-controlled mitochondrial translocation.","evidence":"SAB target engagement (DARTS, CETSA, docking) with SLC7A11/GPX4 readouts; TLR4/NF-κB macrophage polarization with siRNA; IER3 knockout RNA-seq, IER3–PARL Co-IP, and mitochondrial fractionation","pmids":["40654183","40015209","41359162"],"confidence":"Medium","gaps":["Direct molecular link between PRDX5 redox activity and GPX4/SLC7A11 not established","PARL cleavage site on PRDX5 not mapped"]},{"year":2025,"claim":"Raised the possibility of a peroxidase-to-chaperone functional switch via oxidative-stress-induced oligomerization and extracellular/exosomal trafficking.","evidence":"Imaging flow cytometry, native/denaturing PAGE, and fluorescence microscopy in cryopreserved bull sperm","pmids":["39780184"],"confidence":"Low","gaps":["TLR4 interaction proposed but not demonstrated by Co-IP","Chaperone activity of oligomers not biochemically confirmed","Single descriptive study in one model system"]},{"year":null,"claim":"How a single peroxidase coordinates its many divergent roles — organellar antioxidant catalysis, transcriptional control of mitochondrial transport, protein-complex scaffolding with Nrf2 and TFAM, and putative chaperone activity — through shared structural and regulatory determinants remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking catalytic state to interaction partners","Mechanism converting enzymatic activity into transcriptional regulation of Rhot1/Trak1 unknown","Tissue-specific determinants of which PRDX5 function dominates not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,3,19]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,10,11]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,3,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,19]}],"complexes":[],"partners":["NFE2L2","TFAM","PEX5","PARL","TLR4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30044","full_name":"Peroxiredoxin-5, mitochondrial","aliases":["Alu corepressor 1","Antioxidant enzyme B166","AOEB166","Liver tissue 2D-page spot 71B","PLP","Peroxiredoxin V","Prx-V","Peroxisomal antioxidant enzyme","TPx type VI","Thioredoxin peroxidase PMP20","Thioredoxin-dependent peroxiredoxin 5"],"length_aa":214,"mass_kda":22.1,"function":"Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events","subcellular_location":"Cytoplasm; Peroxisome matrix","url":"https://www.uniprot.org/uniprotkb/P30044/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRDX5","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRDX5","total_profiled":1310},"omim":[{"mim_id":"619862","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 32; SCAR32","url":"https://www.omim.org/entry/619862"},{"mim_id":"618756","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 10, DEPALMITOYLASE; ABHD10","url":"https://www.omim.org/entry/618756"},{"mim_id":"606583","title":"PEROXIREDOXIN 5; PRDX5","url":"https://www.omim.org/entry/606583"},{"mim_id":"604769","title":"PEROXIREDOXIN 3; PRDX3","url":"https://www.omim.org/entry/604769"},{"mim_id":"601244","title":"GUANYLATE CYCLASE 1, SOLUBLE, ALPHA-2; GUCY1A2","url":"https://www.omim.org/entry/601244"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":1322.0}],"url":"https://www.proteinatlas.org/search/PRDX5"},"hgnc":{"alias_symbol":["ACR1","AOEB166","MGC142285","PRXV","PMP20","B166","PRDX6","PLP","SBBI10","MGC117264","MGC142283"],"prev_symbol":[]},"alphafold":{"accession":"P30044","domains":[{"cath_id":"3.40.30.10","chopping":"63-214","consensus_level":"high","plddt":98.2612,"start":63,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30044","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30044-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30044-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRDX5","jax_strain_url":"https://www.jax.org/strain/search?query=PRDX5"},"sequence":{"accession":"P30044","fasta_url":"https://rest.uniprot.org/uniprotkb/P30044.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30044/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30044"}},"corpus_meta":[{"pmid":"10521424","id":"PMC_10521424","title":"Cloning 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CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39780184","citation_count":4,"is_preprint":false},{"pmid":"40015209","id":"PMC_40015209","title":"Prdx5 regulates macrophage polarization by modulating the TLR4/NF-κB pathway to promote apoptosis in chronic prostatitis.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40015209","citation_count":4,"is_preprint":false},{"pmid":"38880456","id":"PMC_38880456","title":"A novel strategy to elicit enduring anti-morphine immunity and relief from addiction by targeting Acr1 protein nano vaccine through TLR-2 to dendritic cells.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38880456","citation_count":4,"is_preprint":false},{"pmid":"39900986","id":"PMC_39900986","title":"Elevated serum levels of GPX4, NDUFS4, PRDX5, and TXNRD2 as predictive biomarkers for castration resistance in prostate cancer patients: an exploratory study.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39900986","citation_count":4,"is_preprint":false},{"pmid":"40122834","id":"PMC_40122834","title":"Single-cell sequencing combined with urinary multi-omics analysis reveals that the non-invasive biomarker PRDX5 regulates bladder cancer progression through ferroptosis signaling.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40122834","citation_count":3,"is_preprint":false},{"pmid":"39571926","id":"PMC_39571926","title":"First report of Peroxiredoxin-5 (PRDX5) in starry flounder (Platichthys stellatus): Molecular features and expression analysis.","date":"2024","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39571926","citation_count":3,"is_preprint":false},{"pmid":"40798978","id":"PMC_40798978","title":"F18 Promiscuous Epitope of Acr1 Protein of Mycobacterium tuberculosis Induces the Secretion of IL-10 and Tregs but Not IL-6.","date":"2025","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/40798978","citation_count":3,"is_preprint":false},{"pmid":"41147088","id":"PMC_41147088","title":"PRDX5 Regulates Mitochondrial Function and Nuclear Spreading in Myogenesis and Acts With PRDX3 to Delay Muscle Aging.","date":"2025","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/41147088","citation_count":2,"is_preprint":false},{"pmid":"39168191","id":"PMC_39168191","title":"Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39168191","citation_count":2,"is_preprint":false},{"pmid":"37443747","id":"PMC_37443747","title":"Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling 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demonstrated peroxidase activity in vitro; recombinant protein expressed in E. coli exhibits peroxidase activity and antioxidant activity comparable to catalase in a glutamine synthetase protection assay against DTT/Fe3+/O2 oxidation.\",\n      \"method\": \"Recombinant protein expression in E. coli, in vitro peroxidase assay, glutamine synthetase protection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution with two orthogonal activity assays, replicated in initial characterization paper\",\n      \"pmids\": [\"10521424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"AOEB166 (PRDX5) localizes to mitochondria and peroxisomes in HepG2 cells, as shown by GFP fusion protein sorting to both organelles; N- and C-terminal domains contain mitochondrial and peroxisomal targeting sequences.\",\n      \"method\": \"GFP fusion protein expression and fluorescence microscopy in HepG2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by live-cell imaging, single lab, one method but consistent with domain analysis\",\n      \"pmids\": [\"10521424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human PMP20 (PRDX5) is imported into the peroxisomal matrix via the PTS1 receptor PEX5; the C-terminal tripeptide SQL is necessary and sufficient for binding to HsPEX5, as shown by direct binding assay and mutagenesis of the SQL sequence.\",\n      \"method\": \"Direct binding assay (PMP20 to HsPEX5), mutagenesis of C-terminal SQL tripeptide, subcellular fractionation, double-staining immunofluorescence co-localization with thiolase\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding assay with mutagenesis plus subcellular fractionation and co-localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10514471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human PMP20 (PRDX5) exhibits thiol-specific antioxidant activity (inhibits glutamine synthetase inactivation in thiol-metal-catalyzed but not non-thiol metal-catalyzed oxidation) and thiol-peroxidase activity (removes hydrogen peroxide).\",\n      \"method\": \"In vitro glutamine synthetase protection assay (thiol vs. non-thiol MCO systems), thiol-peroxidase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two orthogonal in vitro enzymatic assays distinguishing thiol-specific vs. non-thiol activity, rigorous controls\",\n      \"pmids\": [\"10514471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Small-molecule fragments bind to PRDX5 at defined sites; NMR methods (STD-epitope mapping, 15N-HSQC chemical shift perturbation) were used to compare binding modes of analogous fragments, validating PRDX5 as a druggable target with structurally distinct binding pockets.\",\n      \"method\": \"Ligand-observed STD NMR, protein-observed 15N-HSQC NMR, CSP analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR-based structural/binding study, single lab, focused on fragment binding mode characterization\",\n      \"pmids\": [\"25025339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX5 physically interacts with Nrf2 in H2O2-stimulated NSCLC cells, and this interaction promotes NQO1 protein expression; the interaction was detected by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation in H2O2-stimulated NSCLC cells, western blot for NQO1\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"31899687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STAT3 binds to two specific sites in the PRDX5 promoter (site 1: −444 to −434 bp; site 4: −1,417 to −1,407 bp) and transcriptionally activates PRDX5 expression; ROS-mediated demethylation of the PRDX5 promoter enhances STAT3 binding affinity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, bisulfite sequencing PCR, STAT3 knockdown/overexpression with western blot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay plus loss/gain-of-function, single lab, two orthogonal methods\",\n      \"pmids\": [\"33416106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRDX5 overexpression in NSCLC cells under oxidative stress promotes epithelial-mesenchymal transition (decreases E-cadherin, increases vimentin) and activates the Nrf2 signaling pathway, while PRDX5 knockdown has the opposite effects.\",\n      \"method\": \"siRNA knockdown and pcDNA3.1 overexpression, western blot for EMT markers and Nrf2 pathway components in H1299 cells pretreated with H2O2\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readouts, single lab\",\n      \"pmids\": [\"33416106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Prdx5 regulates DNA damage response (DDR) through: (1) Plk1-mediated phosphorylation of ATM kinase activating downstream Chek1/Chek2; (2) increasing p53 acetylation at K382, stabilizing nuclear p53 and enhancing transcription; (3) induction of autophagy that regulates recycling of DDR molecules. Sirt2 was identified as a novel deacetylase of p53 at K382, acting in a Prdx5-dependent manner.\",\n      \"method\": \"Prdx5 knockdown (γ-H2AX and 53BP1 induction), western blot for ATM phosphorylation/Chek1/Chek2, p53 acetylation assays, autophagy induction assays, Sirt2 deacetylase identification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple downstream readouts and pathway placement, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36067023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRDX5 and Nrf2 form a protein complex (confirmed by Co-IP), and their synergistic interaction increases proliferation and drug resistance of NSCLC cells; oxidative stress enhances the PRDX5–Nrf2 interaction.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, immunohistochemistry, zebrafish xenograft models\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional zebrafish models, replicated across two NSCLC papers but same context\",\n      \"pmids\": [\"37305326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRDX5 directly binds TFAM; PRDX5 overexpression enhances TFAM-mediated mitochondrial function, and TFAM knockdown reverses the mitochondrial functional improvements achieved through PRDX5 overexpression, placing PRDX5 upstream of TFAM in mitochondrial homeostasis.\",\n      \"method\": \"Protein binding assay (PRDX5–TFAM interaction), TFAM knockdown rescue experiment, in vitro and in vivo CKD models with PRDX5 overexpression\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein binding assay plus epistasis by TFAM knockdown rescue, single lab\",\n      \"pmids\": [\"39955823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IER3 interacts with the presenilin-associated rhomboid-like protein (PARL) and reduces its shear activity, thereby inhibiting cleavage and mitochondrial translocation of cytoplasmic PRDX5. Reduced mitochondrial PRDX5 impairs antioxidant capacity, causes oxidative mitochondrial damage, and promotes stress-induced cellular senescence driving AKI-to-CKD transition.\",\n      \"method\": \"IER3 knockout mouse RNA-seq identifying PRDX5 upregulation, co-IP of IER3–PARL interaction, PRDX5 inhibition epistasis experiments, mitochondrial fractionation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus Co-IP plus epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41359162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT3 promotes PRDX5 function downstream in a SIRT3–PRDX5 axis in spinal cord neurons; SIRT3 and PRDX5 co-localize within neurons of the anterior horn of the spinal cord, and genetic silencing of PRDX5 partially abrogates SIRT3's neuroprotective effects against apoptosis and oxidative stress after spinal cord injury.\",\n      \"method\": \"Transcriptome analysis of Sirt3-/- renal tissues, immunofluorescence co-localization, PRDX5 genetic silencing epistasis experiment in SCI mouse model\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-guided discovery plus co-localization plus genetic epistasis, single lab\",\n      \"pmids\": [\"40818507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Acetylation of PRDX5 inhibits its antioxidant and anti-apoptotic functions in retinal neurons under ischemia-reperfusion: OGD/R increases PRDX5 acetylation; increasing acetylation (NAM treatment) elevates ROS and apoptosis, while decreasing acetylation (NRC treatment) reduces ROS and apoptosis; inhibiting deacetylation abolishes the protective effect of PRDX5 overexpression.\",\n      \"method\": \"OGD/R cell model, pharmacological manipulation of acetylation (NAM/NRC), PRDX5 overexpression/knockdown, ROS assay, apoptosis assay (TUNEL, PI staining), western blot\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function plus PTM manipulation with multiple functional readouts, single lab\",\n      \"pmids\": [\"41740330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Salvianolic acid B (SAB) directly binds PRDX5 (confirmed by DARTS, CETSA, and molecular docking) and enhances its redox activity, which in turn potentiates SLC7A11 and GPX4 inhibitory effects on ferroptosis; PRDX5 silencing partially abrogates SAB's renoprotective effects in AKI models.\",\n      \"method\": \"DARTS assay, CETSA, molecular docking, PRDX5 knockdown rescue in cisplatin-induced AKI model, in vivo mouse AKI models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal target engagement assays plus genetic epistasis, single lab\",\n      \"pmids\": [\"40654183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRDX5 loss-of-function during myogenesis causes myonuclear clustering (impaired nuclear spreading) and reduced mitochondrial ATP production. PRDX5 facilitates mitochondrial transport and nuclear positioning at least in part through transcriptional regulation of Rhot1 and Trak1; knockdown of Rhot1 or Trak1 in WT myotubes phenocopies Prdx5 deficiency.\",\n      \"method\": \"Prdx5-/- mouse myotube analysis, Seahorse OCR mitochondrial function assay, confocal and super-resolution SIM microscopy, Rhot1/Trak1 knockdown epistasis, in vivo muscle function and histology\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse plus multiple orthogonal methods (Seahorse, super-resolution imaging, epistasis knockdown), in vitro and in vivo validation\",\n      \"pmids\": [\"41147088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Prdx5 regulates macrophage polarization toward M1 phenotype in an ROS-dependent manner via the TLR4/NF-κB pathway; Prdx5 silencing suppresses M1 polarization and reduces prostate epithelial cell apoptosis in an experimental autoimmune prostatitis model.\",\n      \"method\": \"siRNA knockdown of Prdx5, western blot, RT-qPCR, flow cytometry, immunofluorescence, immunohistochemistry, cell co-culture, EAP mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway analysis in vitro and in vivo, single lab, multiple readouts\",\n      \"pmids\": [\"40015209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under cryopreservation-induced oxidative stress, PRDX5 translocates intracellularly in bull sperm and forms high-molecular-weight oligomers detected by PAGE; oligomerization may shift PRDX5 function from peroxidase to chaperone. PRDX5 interaction with TLR4 may be key to its intracellular transport, and PRDX5 was detected in exosomal vesicles.\",\n      \"method\": \"Imaging Flow Cytometry, native and denaturing PAGE, fluorescence microscopy, ROS/NO measurement\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, descriptive oligomerization and localization data, TLR4 interaction proposed but not directly demonstrated by Co-IP\",\n      \"pmids\": [\"39780184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Stachyose (STA) and its derivative C6-STA inhibit PRDX5 enzymatic activity and disrupt PRDX5–NRF2 protein–protein interaction, leading to decreased NQO1 levels and quinone radical accumulation that induces apoptosis of drug-tolerant persister cells in CRPC.\",\n      \"method\": \"PRDX5 enzyme activity assay, Co-IP (PRDX5–NRF2 interaction), western blot for NQO1, pharmacokinetic analysis, in vitro and in vivo CRPC models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme activity inhibition assay plus Co-IP disruption assay with downstream readouts, single lab\",\n      \"pmids\": [\"39168191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Porcine PRDX5 anti-inflammatory activity depends on its peroxidase activity; recombinant pPRDX5 inhibits TNF-α- and PRRSV-induced inflammatory responses in alveolar macrophages, while siRNA knockdown enhances inflammation. Peroxidase activity is required for the anti-inflammatory effect.\",\n      \"method\": \"Recombinant protein treatment, siRNA knockdown in porcine alveolar macrophages, inflammatory cytokine measurement, peroxidase activity assay\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function plus peroxidase activity requirement established, single lab\",\n      \"pmids\": [\"35985565\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRDX5 is a thiol-dependent peroxidase (atypical 2-Cys subfamily of peroxiredoxins) that localizes to mitochondria and peroxisomes via N-terminal targeting sequences and a C-terminal SQL peroxisomal targeting signal recognized by PEX5; it directly scavenges H2O2 and alkyl hydroperoxides, and its enzymatic activity underlies its roles in DNA damage response (through the Plk1-ATM-Chek1/2 and Sirt2-p53 axes), regulation of macrophage M1 polarization via TLR4/NF-κB, mitochondrial transport and myonuclear positioning (through transcriptional regulation of Rhot1/Trak1), protection from ferroptosis, and CRPC drug resistance; PRDX5 also physically interacts with Nrf2 to promote NQO1 expression, with TFAM to maintain mitochondrial homeostasis, and its function is negatively regulated by acetylation and positively by the SIRT3 deacetylase axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRDX5 is a thiol-dependent peroxiredoxin antioxidant enzyme that scavenges hydrogen peroxide and alkyl hydroperoxides through a thiol-specific catalytic mechanism, providing antioxidant protection comparable to catalase in vitro [#0, #3]. It is dually targeted to mitochondria and peroxisomes, with N- and C-terminal targeting determinants directing organellar sorting; peroxisomal import depends on a C-terminal SQL tripeptide that is necessary and sufficient for recognition by the PTS1 receptor PEX5 [#1, #2]. Its peroxidase activity is the basis of its cytoprotective functions: recombinant enzyme requires intact peroxidase activity for anti-inflammatory effects in macrophages [#19], and its antioxidant and anti-apoptotic outputs are negatively regulated by acetylation, such that increasing PRDX5 acetylation elevates ROS and apoptosis while deacetylation is protective [#13]. PRDX5 supports mitochondrial homeostasis by binding TFAM and acting upstream of TFAM-mediated mitochondrial function [#10], and during myogenesis it promotes mitochondrial transport and myonuclear positioning through transcriptional regulation of Rhot1 and Trak1, with mitochondrial ATP production reduced upon its loss [#15]. In oxidative-stress and cancer contexts PRDX5 physically interacts with Nrf2 to promote NQO1 expression and drug resistance [#5, #9, #18], regulates the DNA damage response via Plk1–ATM–Chek1/2 signaling and Sirt2-dependent p53 acetylation [#8], drives ROS-dependent M1 macrophage polarization through TLR4/NF-κB [#16], and protects against ferroptosis by potentiating SLC7A11/GPX4 [#14]. PRDX5 expression is transcriptionally activated by STAT3 binding to its promoter, an interaction enhanced by ROS-mediated promoter demethylation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that PRDX5 is a bona fide antioxidant enzyme, defining its core biochemical identity as a thiol-dependent peroxidase rather than an inferred family member.\",\n      \"evidence\": \"Recombinant E. coli protein with in vitro peroxidase and glutamine synthetase protection assays distinguishing thiol-specific from non-thiol activity\",\n      \"pmids\": [\"10521424\", \"10514471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic cysteine residues and regeneration mechanism not resolved in these assays\", \"Physiological substrate spectrum beyond H2O2 not delimited\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved how PRDX5 reaches its sites of action, showing dual mitochondrial/peroxisomal targeting and defining the molecular import determinant for peroxisomes.\",\n      \"evidence\": \"GFP fusion live-cell imaging in HepG2 cells plus direct PMP20–PEX5 binding assay with SQL mutagenesis, fractionation, and thiolase co-localization\",\n      \"pmids\": [\"10521424\", \"10514471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitochondrial targeting sequence not mapped at residue resolution\", \"Determinants partitioning the protein between the two organelles not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated PRDX5 is structurally druggable, identifying distinct ligand-binding pockets to guide small-molecule modulation.\",\n      \"evidence\": \"Ligand-observed STD NMR and protein-observed 15N-HSQC chemical shift perturbation fragment mapping\",\n      \"pmids\": [\"25025339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of fragment binding established\", \"Binding sites not linked to catalytic regulation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PRDX5 to redox-responsive transcriptional programs, showing it both interacts with Nrf2 to drive NQO1 and is itself a STAT3 target under ROS-modulated epigenetic control.\",\n      \"evidence\": \"Co-IP in H2O2-stimulated NSCLC cells; ChIP, luciferase reporter, bisulfite sequencing, and STAT3 loss/gain-of-function\",\n      \"pmids\": [\"31899687\", \"33416106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PRDX5–Nrf2 interaction is direct not established by reciprocal/structural validation\", \"Functional link between PRDX5 peroxidase activity and Nrf2 stabilization not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed PRDX5 within DNA damage response signaling and as a stable Nrf2 complex partner driving tumor cell proliferation and drug resistance.\",\n      \"evidence\": \"Prdx5 knockdown with γ-H2AX/53BP1, ATM phosphorylation and p53 acetylation readouts, Sirt2 deacetylase identification; Co-IP plus zebrafish xenografts\",\n      \"pmids\": [\"36067023\", \"37305326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between PRDX5 enzymatic activity and Plk1–ATM axis not reconstituted\", \"Stoichiometry and interface of the PRDX5–Nrf2 complex undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined non-classical, structural and trafficking roles for PRDX5 in mitochondrial biology, linking it to TFAM-dependent mitochondrial homeostasis and to Rhot1/Trak1-mediated mitochondrial transport and myonuclear positioning.\",\n      \"evidence\": \"PRDX5–TFAM binding assay with TFAM knockdown rescue in CKD models; Prdx5-/- myotube Seahorse, super-resolution SIM, and Rhot1/Trak1 knockdown epistasis\",\n      \"pmids\": [\"39955823\", \"41147088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PRDX5 transcriptionally controls Rhot1/Trak1 unknown\", \"Whether TFAM binding is direct and how it modulates TFAM function not structurally resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established acetylation as a key negative regulatory switch on PRDX5 antioxidant function, integrated within SIRT3/SIRT2 deacetylase axes governing neuroprotection.\",\n      \"evidence\": \"OGD/R retinal model with pharmacological acetylation manipulation (NAM/NRC) and PRDX5 over/knockdown; SIRT3-PRDX5 co-localization and genetic epistasis in SCI model\",\n      \"pmids\": [\"41740330\", \"40818507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific acetylated lysine residues on PRDX5 not mapped\", \"Direct deacetylase–substrate biochemistry not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PRDX5 cytoprotective output to ferroptosis defense and immune/inflammatory regulation, and identified its regulation by upstream IER3–PARL-controlled mitochondrial translocation.\",\n      \"evidence\": \"SAB target engagement (DARTS, CETSA, docking) with SLC7A11/GPX4 readouts; TLR4/NF-κB macrophage polarization with siRNA; IER3 knockout RNA-seq, IER3–PARL Co-IP, and mitochondrial fractionation\",\n      \"pmids\": [\"40654183\", \"40015209\", \"41359162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PRDX5 redox activity and GPX4/SLC7A11 not established\", \"PARL cleavage site on PRDX5 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Raised the possibility of a peroxidase-to-chaperone functional switch via oxidative-stress-induced oligomerization and extracellular/exosomal trafficking.\",\n      \"evidence\": \"Imaging flow cytometry, native/denaturing PAGE, and fluorescence microscopy in cryopreserved bull sperm\",\n      \"pmids\": [\"39780184\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TLR4 interaction proposed but not demonstrated by Co-IP\", \"Chaperone activity of oligomers not biochemically confirmed\", \"Single descriptive study in one model system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single peroxidase coordinates its many divergent roles — organellar antioxidant catalysis, transcriptional control of mitochondrial transport, protein-complex scaffolding with Nrf2 and TFAM, and putative chaperone activity — through shared structural and regulatory determinants remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking catalytic state to interaction partners\", \"Mechanism converting enzymatic activity into transcriptional regulation of Rhot1/Trak1 unknown\", \"Tissue-specific determinants of which PRDX5 function dominates not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 3, 19]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 10, 11]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NFE2L2\", \"TFAM\", \"PEX5\", \"PARL\", \"TLR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}