{"gene":"CIRBP","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2013,"finding":"Extracellular CIRP acts as a damage-associated molecular pattern (DAMP) that binds the TLR4-MD2 complex (as well as TLR4 and MD2 individually), stimulating TNF-α and HMGB1 release from macrophages and causing inflammatory tissue injury in vivo. Human CIRP amino acids 106–125 bind MD2 with high affinity as determined by surface plasmon resonance.","method":"Surface plasmon resonance binding assay; recombinant CIRP injection in vivo; CIRP-deficient mouse model; anti-CIRP antisera blockade","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay (SPR), KO mice with defined phenotype, recombinant protein injection, peptide-level mapping, replicated in multiple experimental models","pmids":["24097189"],"is_preprint":false},{"year":2020,"finding":"eCIRP is a biologically active endogenous ligand of TREM-1 on macrophages. Surface plasmon resonance revealed strong binding between eCIRP and TREM-1, confirmed by FRET in macrophages. TREM-1 siRNA, decoy peptide LP17, and TREM-1-/- mice dramatically reduced eCIRP-induced inflammation.","method":"Surface plasmon resonance; FRET assay; TREM-1-/- mice; siRNA knockdown; inhibitory peptide M3 derived from eCIRP sequence","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR binding, FRET confirmation, genetic knockout, and peptide inhibition all orthogonally support the finding","pmids":["32027618"],"is_preprint":false},{"year":2020,"finding":"eCIRP binds IL-6 receptor (IL-6R) on macrophages, activating STAT3 phosphorylation and promoting macrophage endotoxin tolerance and M2 polarization. Blockade of IL-6R with neutralizing Ab inhibited eCIRP-induced p-STAT3 and restored LPS-stimulated TNF-α release.","method":"Biacore binding assay; FRET; immunostaining colocalization; STAT3 inhibitor (Stattic); anti-IL-6R neutralizing antibody; rmCIRP stimulation of macrophages","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding confirmed by three orthogonal methods (Biacore, FRET, colocalization) plus functional rescue experiments","pmids":["32027619"],"is_preprint":false},{"year":2020,"finding":"CIRBP nuclear import is mediated by two nonclassical nuclear localization signals: an RG/RGG-rich region recognized by Transportin-1 (TNPO1) and an RSY-rich region recognized by Transportin-3 (TNPO3). These interactions regulate nuclear localization, phase separation, and stress granule recruitment of CIRBP.","method":"Biophysical binding assays; cell-based localization experiments; mutagenesis of NLS regions; phase separation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding characterization of two distinct NLS–importin interactions with functional validation in cells","pmids":["32234784"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation of the CIRBP RG/RGG region by SRPK1 impairs liquid-liquid phase separation (LLPS), binding to TNPO1, and stress granule association in cells. Arginine methylation of the same region reciprocally regulates SRPK1-mediated phosphorylation, revealing interplay between these two PTMs.","method":"In vitro phosphorylation assay with SRPK1; LLPS assay; TNPO1 binding assay; cell-based SG recruitment; identification of two novel phosphorylation sites","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, LLPS reconstitution, and cell-based validation with multiple orthogonal methods in one study","pmids":["34738012"],"is_preprint":false},{"year":2012,"finding":"Cirp directly binds Dyrk1b/Mirk kinase in the nucleus of undifferentiated spermatogonia, inhibiting Dyrk1b's binding to p27 (reducing p27 phosphorylation and destabilizing it) and inhibiting Dyrk1b-mediated phosphorylation of cyclin D1 (stabilizing cyclin D1), thereby promoting cell-cycle progression from G0/G1 to S phase.","method":"Cirp knockout mice; direct protein binding assays; co-immunoprecipitation; cell-cycle analysis; spermatogonial cell line knockdown; cyclin D1 and p27 protein level measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with defined cellular phenotype, direct binding demonstrated, mechanistic pathway placement with multiple downstream readouts","pmids":["22711815"],"is_preprint":false},{"year":2015,"finding":"CIRP associates with the active telomerase complex through direct binding to the RNA component TERC, regulates Cajal body localization of telomerase, and modulates TERT mRNA levels. CIRP inhibition by CRISPR-Cas9 or siRNA leads to reduced telomerase activity and shortened telomere length.","method":"Co-immunoprecipitation coupled with mass spectrometry; CRISPR-Cas9 and siRNA knockdown; telomerase activity assay; telomere length measurement; Cajal body localization assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — IP-MS identification, CRISPR KO functional validation, direct TERC binding, and multiple functional readouts in one study","pmids":["26673712"],"is_preprint":false},{"year":2016,"finding":"Temperature-dependent accumulation of Cirbp mRNA is controlled primarily by regulation of splicing efficiency (fraction of pre-mRNA processed into mature mRNA), not transcription rate, and this post-transcriptional mechanism is widespread in temperature-dependent gene expression control.","method":"NIH3T3 fibroblasts exposed to simulated temperature cycles; genome-wide 'approach to steady-state' kinetics; mRNA/pre-mRNA quantification","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide kinetic approach with specific focus on Cirbp, mechanistically distinguishing splicing from transcription","pmids":["27633015"],"is_preprint":false},{"year":2018,"finding":"CIRP selectively binds the 5' UTR of p27Kip1 mRNA and enhances its translation. In cells exposed to mild hypothermia, induced CIRP correlated with increased p27Kip1 5'UTR reporter translation and p27Kip1 protein accumulation; shRNA-mediated CIRP knockdown prevented this induction. p27Kip1 KO MEFs showed no increase in doubling time under cold stress, unlike WT cells.","method":"RNA binding assay; reporter translation assay; shRNA knockdown; p27Kip1 KO MEFs; mild hypothermia induction","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct RNA binding, reporter assay, KO validation, and genetic rescue in one study","pmids":["29361038"],"is_preprint":false},{"year":2006,"finding":"Cirp protects cells from TNF-α-induced apoptosis by activating the ERK pathway: Cirp transduction into Cirp-deficient fibroblasts increased phosphorylated ERK and suppressed TNF-α-induced caspase-8 activation. The ERK-specific inhibitor PD98059 abrogated Cirp's cytoprotective effect.","method":"Cirp transduction into Cirp-deficient mouse fibroblasts; ERK inhibitor (PD98059); caspase-8 activation assay; apoptosis assay at 37°C and 32°C","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function with pathway inhibitor validation, but single lab","pmids":["16569452"],"is_preprint":false},{"year":2012,"finding":"CIRP binds specific mRNAs in testis (identified by RIP-Chip and biotin pull-down), predominantly through a (Un)(n≥2) core recognition sequence, and stabilizes the bound mRNAs. Target mRNAs are associated with translation regulation, antioxidant activity, and reproduction.","method":"RIP-Chip (RNA-binding protein immunoprecipitation-microarray); biotin pull-down assay; mRNA stability assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding demonstrated by two orthogonal methods with sequence motif identification, single lab","pmids":["22819822"],"is_preprint":false},{"year":2017,"finding":"Extracellular CIRP induces ER stress in lung tissue via TLR4 activation. In CIRP-/- septic mice, ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were not elevated, whereas TLR4 KO mice showed no ER stress induction after recombinant CIRP injection.","method":"CIRP-/- and TLR4-/- mouse models; cecal ligation and puncture sepsis; recombinant CIRP injection; Western blot for ER stress markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic KO models used to place CIRP upstream of TLR4 and ER stress pathway, single lab","pmids":["28128330"],"is_preprint":false},{"year":2020,"finding":"eCIRP-induced ICAM-1+ neutrophil generation is mediated by TREM-1, and ICAM-1 on neutrophils activates Rho GTPase to promote NETosis. Blockade of ICAM-1 decreased Rho activation, and Rho inhibition decreased rmCIRP-induced NET formation.","method":"TREM-1-/- mice; TREM-1 inhibitor LP17; ICAM-1-/- neutrophils; Rho activation assay; rmCIRP stimulation; flow cytometry","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological tools used to place TREM-1 and ICAM-1-Rho axis downstream of eCIRP, single lab","pmids":["32506691"],"is_preprint":false},{"year":2021,"finding":"eCIRP impairs macrophage bacterial phagocytosis by activating STAT3 phosphorylation, which promotes STAT3-βPIX complex formation, preventing βPIX from activating Rac1 and thereby reducing ARP2 and p-cofilin expression needed for actin remodeling. STAT3 inhibition rescued phagocytic dysfunction.","method":"CIRP-/- mice; rmCIRP stimulation of macrophages; co-immunoprecipitation of STAT3-βPIX complex; STAT3 inhibitor stattic; actin remodeling assays; in vivo bacterial load measurement","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue with inhibitor and KO mice; single lab","pmids":["36471113"],"is_preprint":false},{"year":2021,"finding":"eCIRP activates STING through TLR4/MyD88/TRIF pathways, leading to pTBK1 and pIRF3 activation and type I IFN production, exacerbating hemorrhagic shock. STING-/- mice showed reduced lung inflammation and mortality; TLR4-/-, MyD88-/-, and TRIF-/- macrophages failed to activate STING downstream of eCIRP.","method":"STING-/-, TLR4-/-, MyD88-/-, TRIF-/- mouse models; rmCIRP injection; Western blot for pTBK1 and pIRF3; cytokine measurement; controlled hemorrhage model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — four genetic KO models used for epistasis, single lab","pmids":["34291735"],"is_preprint":false},{"year":2024,"finding":"Lactate accumulation during sepsis promotes lactylation of CIRP in macrophages, causing its release. Internalized eCIRP (via TLR4-mediated endocytosis by pulmonary vascular endothelial cells) competitively binds ZBP1, blocking TRIM32-mediated proteasomal degradation of ZBP1, stabilizing ZBP1 and enhancing ZBP1-RIPK3-dependent PANoptosis.","method":"CLP sepsis model; Casp8-/-, Ripk3-/-, Zbp1-/- mice; measurement of CIRP lactylation; co-immunoprecipitation of eCIRP-ZBP1 and ZBP1-TRIM32; TLR4-mediated endocytosis tracking","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KO models, Co-IP binding assays, and novel PTM identification; single lab","pmids":["39465383"],"is_preprint":false},{"year":2019,"finding":"Chronic hypoxia induces hypermethylation of the Cirbp promoter, suppressing CIRP expression and preventing cold-stress induction. CIRP deficiency attenuates hypothermic cardioprotection by downregulating the cardiac ubiquinone biosynthesis pathway, reducing CoQ10, increasing oxidative stress, and impairing ATP production.","method":"Rat CPB model; Cirbp-KO and Cirbp-transgenic rats; methylation analysis of Cirbp promoter in neonatal cardiomyocytes and human specimens; cardiac proteomics; CoQ10 measurement","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO and transgenic animals, promoter methylation directly demonstrated, proteomics pathway identification, and human tissue validation","pmids":["31019028"],"is_preprint":false},{"year":2024,"finding":"CIRBP suppression in aged donor hearts attenuates hypothermic cardioprotection by decreasing DHODH expression, compromising DHODH-mediated ubiquinone (CoQ) reduction, leading to cardiac lipid peroxidation and ferroptosis after transplantation.","method":"Rat heart transplantation model; Cirbp-KO rats; RNA-Seq; cardiac proteomics; DHODH expression measurement; lipid peroxidation assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with proteomics pathway identification and functional readouts, single lab; replicates and extends earlier CoQ10 finding","pmids":["38690728"],"is_preprint":false},{"year":2018,"finding":"CIRBP binds the 3'-UTR of HIF-1α mRNA to increase its mRNA stability in bladder cancer cells, thereby inducing HIF-1α expression and promoting cancer cell proliferation and migration.","method":"RNA immunoprecipitation; 3'UTR binding assay; CIRBP overexpression/knockdown; mRNA stability assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding demonstrated, functional consequences measured; single lab","pmids":["30315244"],"is_preprint":false},{"year":2021,"finding":"CIRP directly binds the 3'UTR of Atp5g3 mRNA to regulate mitochondrial homeostasis and ATP biogenesis under hypoxic stress, and sustains protein levels of respiratory chain complexes II (SDHB) and IV (MT-CO1).","method":"3'UTR binding assay; Cirbp KO and overexpression; respiratory complex protein level measurement; ATP measurement; hypoxia model","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding to 3'UTR demonstrated, KO/OE functional validation; single lab","pmids":["34715218"],"is_preprint":false},{"year":2021,"finding":"CIRBP promotes ferroptosis in renal ischemia-reperfusion injury by interacting with ELAVL1 (HuR), which activates ferritinophagy. CIRBP-ELAVL1 interaction was confirmed by co-immunoprecipitation and fluorescence colocalization. Silencing CIRBP inhibited ferritinophagy and ferroptosis.","method":"Co-immunoprecipitation; fluorescence colocalization; siCIRBP; autophagy inhibitor; si-ELAVL1; anti-CIRP antibody mouse model of IR injury","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction confirmed by two methods, genetic loss-of-function validation; single lab","pmids":["34114349"],"is_preprint":false},{"year":2021,"finding":"CIRP binds to p53 mRNA (RIP assay) and regulates ferroptosis in pancreatic cancer cells through the p53/GPX4 pathway: cold-induced CIRBP expression was associated with decreased GPX4 and increased DPP4, NOX1, FTH1, Fe2+ accumulation, and ROS.","method":"RNA immunoprecipitation (RIP); CIRBP overexpression/knockdown; cold induction; ferroptosis marker measurement; ferroptosis inhibitor rescue","journal":"Journal of immunology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/RIP for p53 mRNA binding, mechanistic pathway partially inferred from correlative protein level changes; single lab","pmids":["36061308"],"is_preprint":false},{"year":2021,"finding":"CIRP directly binds the 3'UTR of PSD95 mRNA to post-transcriptionally regulate PSD95 protein levels; overexpression of Cirbp in hippocampus rescues hypobaric hypoxia-induced reduction of PSD95 and attenuates dendritic spine injury and cognitive deficits.","method":"3'UTR binding assay; Cirbp overexpression via stereotaxic injection; PSD95 protein quantification; dendritic spine morphology analysis; behavioral memory tests","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding demonstrated, in vivo rescue with functional neurological readout; single lab","pmids":["34419133"],"is_preprint":false},{"year":2021,"finding":"eCIRP induces macrophage extracellular trap (MET) formation through sequential activation of caspase-1 and gasdermin D (GSDMD). Caspase-1 and GSDMD inhibitors (z-VAD-fmk and disulfiram) significantly decreased rmCIRP-induced MET formation in THP-1 macrophages.","method":"Time-lapse fluorescence microscopy; SYTOX Orange staining; Western blot for cleaved caspase-1 and GSDMD; pharmacological inhibitors; primary peritoneal macrophages","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of pathway with multiple inhibitors and cell types; single lab","pmids":["35003095"],"is_preprint":false},{"year":2022,"finding":"eCIRP induces ferroptosis in macrophages and lung tissue during sepsis by decreasing GPX4 expression and increasing lipid ROS in a TLR4-dependent manner. TLR4-/- macrophages showed attenuated GPX4 depression and lipid ROS increase after rmCIRP treatment.","method":"RAW 264.7 cells and TLR4-/- peritoneal macrophages; GPX4 expression; lipid ROS measurement; ferroptosis inhibitor ferrostatin-1; CIRP-/- mice CLP model; eCIRP inhibitor C23","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TLR4-/- genetic validation, KO mouse model, ferroptosis inhibitor rescue; single lab","pmids":["35844517"],"is_preprint":false},{"year":2012,"finding":"A mild-cold responsive element (MCRE, octanucleotide 5'-TCCCCGCC-3') in the cirp 5' flanking region is bound by the transcription factor Sp1, which translocates more to the nucleus at 32°C than 37°C. Sp1 overexpression increased endogenous Cirp and reporter expression; Sp1 downregulation had the opposite effect. MCRE mutation abolished these effects.","method":"Reporter gene assay (CAT); chromatin immunoprecipitation; immunohistochemistry; Sp1 overexpression/downregulation; MCRE mutagenesis; multiple cell lines","journal":"BMC biotechnology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP, mutagenesis, and functional reporter assays confirm Sp1-MCRE mechanism; single lab","pmids":["23046908"],"is_preprint":false},{"year":2004,"finding":"Upregulation of CIRP by hypoxia is independent of HIF-1α and HIF-1β and does not require mitochondria. Nuclear run-on assays demonstrated that hypoxia-induced CIRP expression occurs at the level of gene transcription. Respiratory chain inhibitors (NaN3 and cyanide) blocked this response, but cells depleted of mitochondria still upregulated CIRP during hypoxia.","method":"HIF-1α-deficient (Z-33) and HIF-1β-deficient (Hepa-1 c4) cell lines; actinomycin-D; in vitro nuclear run-on assay; mitochondria-depleted cells; respiratory chain inhibitors","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear run-on directly measures transcription, multiple genetic cell lines used; single lab","pmids":["15075239"],"is_preprint":false},{"year":2009,"finding":"CIRP expression is modulated by alternative transcription start sites generating three major 5'-UTR transcripts with different translational properties. The longest 32°C-enriched transcript exhibits IRES-like activity, and its levels and stability are increased at mild hypothermia, contributing to CIRP protein upregulation.","method":"5'-UTR transcript characterization; IRES reporter assay; transcript stability measurement at different temperatures; NIH-3T3 cells","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct characterization of transcript variants and IRES-like activity; mechanistic follow-up with functional assays; single lab","pmids":["19398494"],"is_preprint":false},{"year":2013,"finding":"TNF and TGFβ (but not IL-1β, IL-6, IFNα, or IFNγ) impair CIRBP expression in fibroblasts and neuronal cells; CIRBP depletion increases susceptibility of cells to TNF-mediated inhibition of clock gene (period genes, PAR-bZip) expression, revealing CIRBP as a regulator of circadian clock gene amplitude downstream of cytokine signaling.","method":"Cirp depletion; cytokine stimulation; clock gene expression measurement in fibroblasts and neuronal cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cytokine specificity panel and Cirbp knockdown with defined clock gene readout; single lab","pmids":["24337574"],"is_preprint":false},{"year":2021,"finding":"CIRP directly binds to OGFR mRNA and represses OGFR expression by reducing mRNA stability. CIRBP deficiency enables OGF-OGFR signaling to promote chemotherapy-induced cardiomyocyte apoptosis; exogenous CIRBP delivery to mouse myocardium mitigated doxorubicin-induced cardiac apoptosis.","method":"mRNA stability assay; RNA immunoprecipitation; CIRBP/OGFR overexpression/knockdown; AAV-mediated myocardial CIRBP delivery; cardiac apoptosis measurement","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding and mRNA stability demonstrated, in vivo functional validation; single lab","pmids":["35541895"],"is_preprint":false},{"year":2015,"finding":"CIRP inhibits DNA damage-induced apoptosis by regulating p53: CIRP knockdown increased p53 levels and pro-apoptotic gene expression, while CIRP overexpression decreased p53 levels and upregulated anti-apoptotic genes. Effect placed CIRP upstream of p53 in DNA damage apoptosis pathway.","method":"CIRP overexpression and siRNA knockdown; etoposide-induced DNA damage; p53 and apoptosis gene expression measurement; Western blot","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gain/loss of function with downstream marker measurement but no direct binding assay; mechanism of p53 regulation not established","pmids":["26188505"],"is_preprint":false},{"year":2021,"finding":"CIRP directly binds CTNNB1 mRNA at its 3'- and 5'-UTRs (confirmed by RNA immunoprecipitation and biotin pull-down), enhancing CTNNB1 mRNA stability and promoting IRES-mediated CTNNB1 protein synthesis, leading to activation of Wnt/β-catenin signaling and downstream targets in NSCLC.","method":"RNA immunoprecipitation; biotin pull-down; mRNA decay assay; luciferase reporter (IRES); CIRBP overexpression/knockdown in multiple cell lines; in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding by two orthogonal methods, mRNA stability and IRES reporter assay; single lab","pmids":["34465343"],"is_preprint":false},{"year":2021,"finding":"eCIRP induces TREM-1 expression in alveolar type II (ATII) cells and triggers IL-6 and CXCL2 production via TREM-1. TREM-1-/- ATII cells showed reduced cytokine release after rmCIRP treatment, and TREM-1 antagonist peptides (M3, LP17) significantly decreased this response.","method":"Primary ATII cell isolation; TREM-1-/- mice; rmCIRP stimulation; TREM-1 antagonist peptides; flow cytometry; ELISA","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological inhibitor used together; single lab","pmids":["32984356"],"is_preprint":false},{"year":2022,"finding":"eCIRP induces acute kidney injury via TREM-1 on renal endothelial cells. TREM-1-/- mice injected with rmCIRP showed attenuated AKI markers (BUN, creatinine, NGAL) and reduced renal ICAM-1 expression. M3 peptide blocked eCIRP activation of human renal glomerular endothelial cells.","method":"TREM-1-/- mice; rmCIRP IV injection; renal function markers; primary human renal glomerular endothelial cells; M3 inhibitory peptide","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and peptide inhibitor in vivo plus primary human cell validation; single lab","pmids":["36246143"],"is_preprint":false},{"year":1998,"finding":"Cirp is constitutively and diurnally expressed in the brain; Cirp mRNA levels oscillate in the suprachiasmatic nucleus and cerebral cortex (rising during daytime, falling at night), are absent in constant darkness, and are not present in 3-day-old mice, suggesting light-dependent regulation of Cirp in circadian rhythm circuits.","method":"Northern blot; immunohistochemistry; constant darkness control; developmental stage comparison","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization by IHC in defined brain regions with multiple controls establishing light dependence; single lab","pmids":["9571190"],"is_preprint":false},{"year":2018,"finding":"CIRBP specifically binds pre-miR-329 (but not pri-miR-329) in RBP immunoprecipitation experiments after hindlimb ischemia, suggesting a role in posttranscriptional regulation of 14q32 microRNA processing.","method":"RNA pull-down SILAC mass spectrometry; RBP immunoprecipitation; hindlimb ischemia mouse model; CRISPR/Cas9 HADHB-/- cells","journal":"Molecular therapy. Nucleic acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RBP-IP showing specific pre-miRNA binding; functional consequence for CIRBP specifically not directly proven; single lab","pmids":["30665182"],"is_preprint":false},{"year":2020,"finding":"Under PRRSV infection, CIRBP translocates from the nucleus to the cytoplasm and is present in cytoplasmic stress granules. Overexpression of CIRBP promoted inflammatory cytokine expression and oxidative stress (iNOS, ROS) via the NF-κB pathway in infected macrophages.","method":"Immunofluorescence for CIRBP localization; stress granule colocalization; CIRBP overexpression; NF-κB pathway inhibitor; cytokine and ROS measurement","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization experiment is direct, but NF-κB pathway link is based on overexpression without genetic pathway dissection; single lab","pmids":["32593159"],"is_preprint":false},{"year":2021,"finding":"CIRP and HuR competitively bind Claudin1 mRNA; CIRP binding suppresses Claudin1 expression while HuR binding enhances it. This competition regulates intestinal mucosal barrier function in ulcerative colitis. Validated by RNA immunoprecipitation and dual-luciferase reporter assay.","method":"RNA immunoprecipitation; dual-luciferase reporter assay; CIRP and HuR overexpression/knockdown; transepithelial electrical resistance; in vivo DSS colitis model","journal":"BioFactors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding competition demonstrated by two orthogonal methods with functional barrier readout; single lab","pmids":["33638934"],"is_preprint":false},{"year":2023,"finding":"A synthetic poly(A) tail mimic (A12) selectively and strongly binds the RNA-binding motif of eCIRP, preventing eCIRP binding to TLR4. A12 attenuated eCIRP-induced macrophage MAPK and NF-κB activation and inflammatory cytokine production in vitro and in vivo.","method":"Direct binding assay (A12-eCIRP RBM interaction); macrophage stimulation; NF-κB and MAPK activation assays; CLP sepsis model; bacterial load measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding at defined RBM domain demonstrated, functional rescue in multiple models; single lab","pmids":["37585248"],"is_preprint":false},{"year":2021,"finding":"eCIRP impairs Rab26 in macrophages, reducing Rab26-mediated surface transport of EPOR, resulting in decreased macrophage EPOR surface expression and impaired M2 polarization. EPO treatment failed to promote M2 polarization in Rab26 KO macrophages, confirming the Rab26-EPOR axis.","method":"Rab26 KO macrophages; myeloid-specific EPOR-deficient mice; anti-CIRP antibody treatment; EPOR surface expression assay; macrophage polarization measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic KO models, defined mechanistic pathway from eCIRP to Rab26 to EPOR; single lab","pmids":["34925338"],"is_preprint":false},{"year":2018,"finding":"TGF-β2 and TGF-β3 directly downregulate CIRBP mRNA and protein expression in germ cells (GC2-spd). In vivo, heat-induced CIRBP downregulation in mouse testes is mediated by TGF-β upregulation; local TGF-β antagonist injection attenuated heat-induced CIRBP downregulation.","method":"In vitro TGF-β isoform treatment of GC2-spd cells; in vivo local testicular injection of TGF-β antagonist; CIRBP mRNA and protein quantification","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both in vitro and in vivo interventional experiments; single lab","pmids":["30461215"],"is_preprint":false},{"year":2024,"finding":"CIRP maintains GluR1 (AMPA receptor subunit) stability on neuronal cell membranes by binding GluR1 mRNA; hypobaric hypoxia reduces CIRP expression and the CIRP-GluR1 interaction, causing GluR1 redistribution to cytoplasm, synaptic loss, and memory impairment. Cirp KO mice phenocopied this deficit.","method":"Cirp KO mice; hypobaric hypoxia model; mRNA binding assay; GluR1 surface vs. cytoplasmic protein distribution; dendritic spine and synapse counting; behavioral memory tests; Tat-C16 peptide rescue","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with direct mRNA binding, subcellular localization assay, and functional rescue by peptide; single lab","pmids":["39315498"],"is_preprint":false}],"current_model":"CIRBP/CIRP is a cold- and stress-inducible RNA-binding protein that, intracellularly, acts as an RNA chaperone binding target mRNA 3'- and 5'-UTRs (including p27Kip1, HIF-1α, CTNNB1, PSD95, Atp5g3, GluR1, OGFR, TERC) to regulate their stability, translation, and Cajal body localization; it interacts with Dyrk1b to modulate cell-cycle progression, with the telomerase complex to maintain telomere length, and with ELAVL1 to regulate ferritinophagy; its nuclear import is controlled by TNPO1 (via an RG/RGG NLS) and TNPO3 (via an RSY NLS), with SRPK1-mediated phosphorylation and arginine methylation of its RGG domain gating nuclear localization, phase separation, and stress granule recruitment; when released extracellularly, eCIRP functions as a DAMP that signals through TLR4-MD2, TREM-1, and IL-6R to drive NF-κB/MAPK/STAT3-dependent inflammatory responses in macrophages, neutrophils, endothelial cells, and alveolar epithelial cells, inducing ferroptosis (via GPX4 suppression), NETosis (via ICAM-1–Rho), MET formation (via caspase-1/GSDMD), pyroptosis, and PANoptosis (via ZBP1 stabilization), and also activates STING through TLR4/MyD88/TRIF to produce type I interferons, while its transcriptional cold-induction is controlled by Sp1 binding to a mild-cold responsive element (MCRE) and by temperature-dependent splicing efficiency."},"narrative":{"mechanistic_narrative":"CIRBP (CIRP) is a cold- and stress-inducible RNA-binding protein with a dual identity: intracellularly it acts as a post-transcriptional regulator that binds target mRNA UTRs to control their stability and translation, while extracellularly it functions as a damage-associated molecular pattern (DAMP) that drives inflammation [PMID:24097189, PMID:29361038]. As an RNA chaperone, CIRP binds defined mRNAs through a (U/A)-rich core motif and tunes the levels of cell-cycle, hypoxia, mitochondrial, neuronal, and oncogenic effectors: it enhances translation of the p27Kip1 5'UTR [PMID:29361038], stabilizes HIF-1α, CTNNB1, Atp5g3, and PSD95/GluR1 mRNAs to support proliferation, mitochondrial respiration, and synaptic integrity [PMID:30315244, PMID:34465343, PMID:34715218, PMID:34419133, PMID:39315498], and represses OGFR and Claudin1, the latter in competition with HuR [PMID:35541895, PMID:33638934]. Through direct binding to the telomerase RNA TERC it sustains telomerase activity and Cajal-body localization [PMID:26673712], and through binding Dyrk1b it modulates p27/cyclin D1 to promote G1/S progression [PMID:22711815]. CIRP nuclear import is governed by two nonclassical NLS–importin interactions—an RG/RGG region read by TNPO1 and an RSY region read by TNPO3—with SRPK1-mediated phosphorylation and arginine methylation of the RG/RGG region reciprocally gating phase separation, TNPO1 binding, and stress-granule recruitment [PMID:32234784, PMID:34738012]. Once released, extracellular CIRP binds the TLR4-MD2 complex, TREM-1, and IL-6R to trigger NF-κB/MAPK/STAT3 inflammatory programs in macrophages, neutrophils, endothelial, and alveolar epithelial cells, driving cytokine release, ER stress, ICAM-1–Rho–dependent NETosis, GSDMD-dependent MET formation, GPX4-suppressing ferroptosis, ZBP1-stabilized PANoptosis, and STING-driven type I interferon production [PMID:24097189, PMID:32027618, PMID:32027619, PMID:28128330, PMID:32506691, PMID:35003095, PMID:35844517, PMID:39465383, PMID:34291735]. Its own induction is controlled transcriptionally by Sp1 binding to a mild-cold responsive element and by temperature-dependent splicing efficiency and alternative 5'UTR/IRES usage [PMID:23046908, PMID:27633015, PMID:19398494].","teleology":[{"year":1998,"claim":"Established CIRP as a constitutively expressed brain protein with light-dependent circadian oscillation, framing it as a stress/environment-responsive factor rather than a constitutive housekeeping protein.","evidence":"Northern blot and IHC across brain regions with constant-darkness and developmental controls in mice","pmids":["9571190"],"confidence":"Medium","gaps":["No molecular mechanism for the oscillation","No RNA targets or partners identified at this stage"]},{"year":2004,"claim":"Resolved how hypoxia induces CIRP, showing transcriptional upregulation independent of HIF-1 and mitochondria and thereby separating CIRP induction from the canonical hypoxia axis.","evidence":"Nuclear run-on, HIF-1α/HIF-1β-deficient cell lines, and mitochondria-depleted cells","pmids":["15075239"],"confidence":"Medium","gaps":["Transcription factor mediating hypoxic induction not identified","Did not address cold induction mechanism"]},{"year":2006,"claim":"First mechanistic intracellular function: CIRP cytoprotects against TNF-α apoptosis via ERK activation, linking the protein to cell-survival signaling.","evidence":"Cirp transduction into Cirp-deficient fibroblasts with ERK inhibitor and caspase-8 readout","pmids":["16569452"],"confidence":"Medium","gaps":["Mechanism connecting CIRP to ERK not defined","No RNA-binding link established for this effect"]},{"year":2009,"claim":"Explained cold-induced CIRP protein upregulation through alternative transcription start sites generating an IRES-bearing 5'UTR transcript enriched at 32°C.","evidence":"5'UTR transcript characterization and IRES reporter/stability assays in NIH-3T3 cells","pmids":["19398494"],"confidence":"Medium","gaps":["Trans-acting factors controlling start-site choice unknown","IRES-mediated translation mechanism not dissected"]},{"year":2012,"claim":"Defined two distinct intracellular roles: direct binding to Dyrk1b to control p27/cyclin D1 and cell-cycle progression, and sequence-specific mRNA binding/stabilization via a (U/A)-rich motif.","evidence":"Cirp KO mice with cell-cycle analysis and binding assays; RIP-Chip and biotin pull-down in testis","pmids":["22711815","22819822"],"confidence":"High","gaps":["Generality of the binding motif beyond testis transcripts not tested","How Dyrk1b binding integrates with RNA-binding function unclear"]},{"year":2012,"claim":"Identified the transcriptional basis of mild-cold induction: Sp1 binding to a defined MCRE element drives CIRP expression at 32°C.","evidence":"CAT reporter, ChIP, MCRE mutagenesis, and Sp1 gain/loss in multiple cell lines","pmids":["23046908"],"confidence":"Medium","gaps":["How temperature controls Sp1 nuclear translocation not mechanistically resolved"]},{"year":2013,"claim":"Discovered the extracellular DAMP function of CIRP, showing peptide-mapped binding to the TLR4-MD2 complex that drives TNF-α/HMGB1 release and tissue injury — a paradigm shift defining a second, inflammatory life of the protein.","evidence":"SPR binding with peptide mapping, CIRP-deficient mice, recombinant CIRP injection, and antisera blockade","pmids":["24097189"],"confidence":"High","gaps":["Mechanism of CIRP release from cells not defined here","Downstream signaling beyond cytokine release not detailed"]},{"year":2013,"claim":"Connected CIRP to circadian amplitude control downstream of cytokine signaling, showing TNF/TGFβ suppress CIRBP and that CIRBP loss sensitizes clock genes to TNF.","evidence":"Cirp depletion with cytokine specificity panel and clock-gene readouts in fibroblasts and neuronal cells","pmids":["24337574"],"confidence":"Medium","gaps":["Molecular target of CIRBP in clock-gene regulation not identified"]},{"year":2015,"claim":"Extended intracellular RNA chaperone activity to telomere maintenance via direct binding to telomerase RNA TERC and regulation of Cajal-body localization.","evidence":"IP-MS, CRISPR/siRNA knockdown, telomerase activity and telomere length assays","pmids":["26673712"],"confidence":"High","gaps":["Structural basis of TERC binding unknown","Whether telomere effect requires CIRP RGG/phase behavior untested"]},{"year":2016,"claim":"Identified temperature-dependent splicing efficiency, not transcription rate, as a primary driver of cold-induced Cirbp mRNA accumulation, refining the induction model.","evidence":"Genome-wide approach-to-steady-state kinetics in temperature-cycled NIH3T3 cells","pmids":["27633015"],"confidence":"High","gaps":["Splicing factors mediating the temperature response not identified"]},{"year":2018,"claim":"Demonstrated a specific cold-stress effector axis: CIRP binds the p27Kip1 5'UTR to enhance translation, linking cold induction to cell-cycle slowing.","evidence":"RNA binding, reporter translation, shRNA knockdown, and p27Kip1 KO MEF rescue under hypothermia","pmids":["29361038"],"confidence":"High","gaps":["Translation-enhancement mechanism (e.g., IRES vs. cap) not fully defined"]},{"year":2018,"claim":"Generalized 3'UTR-mediated mRNA stabilization to oncogenic targets (HIF-1α) and showed an upstream cytokine suppressor of CIRBP (TGF-β in germ cells).","evidence":"RIP and 3'UTR binding/stability assays in bladder cancer; TGF-β isoform treatment and in vivo antagonist in testis","pmids":["30315244","30461215"],"confidence":"Medium","gaps":["How CIRP discriminates stabilizing vs. destabilizing targets unclear"]},{"year":2020,"claim":"Expanded eCIRP receptor repertoire to TREM-1 and IL-6R, defining distinct inflammatory outputs (pro-inflammatory activation vs. STAT3-driven endotoxin tolerance/M2 polarization).","evidence":"SPR/Biacore, FRET, colocalization, TREM-1-/- mice, peptide inhibitors, and IL-6R neutralization with functional rescue","pmids":["32027618","32027619"],"confidence":"High","gaps":["How a single ligand engages multiple receptors to opposite ends not resolved","Stoichiometry/competition among TLR4, TREM-1, IL-6R unknown"]},{"year":2020,"claim":"Defined the nuclear-import logic of CIRBP: two nonclassical NLS regions read by TNPO1 (RG/RGG) and TNPO3 (RSY) that couple localization to phase separation and stress-granule recruitment.","evidence":"Biophysical binding, NLS mutagenesis, and cell-based localization/phase-separation assays","pmids":["32234784"],"confidence":"High","gaps":["In vivo relevance of dual-importin control not established"]},{"year":2021,"claim":"Established PTM gating of CIRBP behavior: SRPK1 phosphorylation of the RG/RGG region impairs LLPS, TNPO1 binding, and SG association, reciprocally regulated by arginine methylation.","evidence":"In vitro SRPK1 kinase assay, LLPS reconstitution, TNPO1 binding, and cellular SG recruitment with new phosphosite mapping","pmids":["34738012"],"confidence":"High","gaps":["Methyltransferase responsible not identified","Upstream signals controlling the PTM switch unknown"]},{"year":2021,"claim":"Broadened intracellular target set to mitochondrial (Atp5g3), neuronal (PSD95), oncogenic (CTNNB1), and cardiac (OGFR) mRNAs, mostly via UTR binding with stability/translation control and in vivo functional rescue.","evidence":"3'/5'UTR binding, RIP, mRNA decay and IRES reporter assays, KO/overexpression, AAV/stereotaxic delivery across tissue models","pmids":["34715218","34419133","34465343","35541895"],"confidence":"Medium","gaps":["Whether these targets share a common recognition motif untested","Tissue-specific selectivity of CIRP targeting unexplained"]},{"year":2021,"claim":"Linked CIRBP to ferroptosis through interaction with ELAVL1/HuR-driven ferritinophagy, and identified HuR competition on Claudin1 mRNA, positioning CIRP within an antagonistic RBP network.","evidence":"Co-IP and colocalization for CIRBP-ELAVL1; RIP and dual-luciferase competition for Claudin1; loss-of-function in IR and DSS-colitis models","pmids":["34114349","33638934"],"confidence":"Medium","gaps":["Direct vs. indirect nature of CIRBP-ELAVL1 cooperation not fully dissected","Generality of CIRP-HuR competition beyond these targets unknown"]},{"year":2021,"claim":"Mapped multiple eCIRP-driven cell-death and effector programs: TLR4-dependent ER stress, TREM-1/ICAM-1/Rho NETosis, Rab26-EPOR M2 impairment, and STING/TLR4-MyD88-TRIF type I IFN production.","evidence":"Multiple KO models (TLR4, TREM-1, ICAM-1, Rab26, EPOR, STING, MyD88, TRIF), peptide inhibitors, and rmCIRP challenge in sepsis/hemorrhage models","pmids":["28128330","32506691","34925338","34291735"],"confidence":"Medium","gaps":["How eCIRP triggers such divergent downstream programs from shared receptors unclear","Single-lab pathway dissections"]},{"year":2022,"claim":"Defined eCIRP-induced ferroptosis and macrophage extracellular trap formation as TLR4/GPX4 and caspase-1/GSDMD-dependent death modalities.","evidence":"TLR4-/- macrophages, ferrostatin-1 rescue, GSDMD/caspase-1 inhibitors and imaging in macrophage models","pmids":["35844517","35003095"],"confidence":"Medium","gaps":["Link between TLR4 signaling and GPX4 suppression not mechanistically traced","Single-lab findings"]},{"year":2024,"claim":"Defined the release trigger and a novel intracellular-extracellular death axis: lactate-driven lactylation promotes CIRP release, and internalized eCIRP stabilizes ZBP1 by blocking TRIM32-mediated degradation to drive ZBP1-RIPK3 PANoptosis.","evidence":"Lactylation measurement, TLR4-endocytosis tracking, eCIRP-ZBP1 and ZBP1-TRIM32 Co-IP, and Casp8/Ripk3/Zbp1 KO mice in CLP sepsis","pmids":["39465383"],"confidence":"Medium","gaps":["Lactyltransferase responsible not identified","Single-lab; structural basis of ZBP1 competition unknown"]},{"year":2024,"claim":"Connected CIRBP to hypothermic organ protection mechanistically, showing it sustains DHODH-mediated ubiquinone reduction and CoQ-dependent antioxidant capacity to prevent ferroptosis in cold-preserved hearts.","evidence":"Cirbp-KO/transgenic rats, promoter methylation analysis, proteomics, DHODH/CoQ measurement, and lipid peroxidation assays in CPB/transplant models","pmids":["31019028","38690728"],"confidence":"High","gaps":["Whether the CoQ/DHODH effect is RNA-binding-dependent not established"]},{"year":null,"claim":"It remains unresolved how a single protein partitions between its nuclear/cytoplasmic RNA-regulatory roles and its extracellular DAMP function, how target/receptor selectivity is achieved, and what physiological signals govern the release switch in vivo.","evidence":"No single study in the corpus integrates the intracellular RNA-chaperone and extracellular DAMP programs","pmids":[],"confidence":"Low","gaps":["No unified model linking PTM/phase state to release","No structural model of CIRP–receptor or CIRP–RNA complexes","Selectivity rules for mRNA targets vs. receptors undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,10,18,19,22,29,31,41,6]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,15]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[8,31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,5,36]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4,36]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,14,24]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,10,18,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,15,23,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,8]}],"complexes":["telomerase complex"],"partners":["TLR4","LY96","TREM1","IL6R","DYRK1B","TNPO1","TNPO3","ELAVL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14011","full_name":"Cold-inducible RNA-binding protein","aliases":["A18 hnRNP","Glycine-rich RNA-binding protein CIRP"],"length_aa":172,"mass_kda":18.6,"function":"Cold-inducible mRNA binding protein that plays a protective role in the genotoxic stress response by stabilizing transcripts of genes involved in cell survival. Acts as a translational activator. Seems to play an essential role in cold-induced suppression of cell proliferation. Binds specifically to the 3'-untranslated regions (3'-UTRs) of stress-responsive transcripts RPA2 and TXN. Acts as a translational repressor (By similarity). Promotes assembly of stress granules (SGs), when overexpressed","subcellular_location":"Nucleus, nucleoplasm; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q14011/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIRBP","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TNPO3","stoichiometry":10.0},{"gene":"CLNS1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CIRBP","total_profiled":1310},"omim":[{"mim_id":"602649","title":"COLD-INDUCIBLE RNA-BINDING PROTEIN; CIRBP","url":"https://www.omim.org/entry/602649"},{"mim_id":"601851","title":"CLOCK CIRCADIAN REGULATOR; CLOCK","url":"https://www.omim.org/entry/601851"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CIRBP"},"hgnc":{"alias_symbol":["CIRP"],"prev_symbol":[]},"alphafold":{"accession":"Q14011","domains":[{"cath_id":"3.30.70.330","chopping":"7-76","consensus_level":"high","plddt":80.5467,"start":7,"end":76}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14011","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14011-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14011-F1-predicted_aligned_error_v6.png","plddt_mean":61.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIRBP","jax_strain_url":"https://www.jax.org/strain/search?query=CIRBP"},"sequence":{"accession":"Q14011","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14011.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14011/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14011"}},"corpus_meta":[{"pmid":"24097189","id":"PMC_24097189","title":"Cold-inducible RNA-binding protein (CIRP) 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Human CIRP amino acids 106–125 bind MD2 with high affinity as determined by surface plasmon resonance.\",\n      \"method\": \"Surface plasmon resonance binding assay; recombinant CIRP injection in vivo; CIRP-deficient mouse model; anti-CIRP antisera blockade\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay (SPR), KO mice with defined phenotype, recombinant protein injection, peptide-level mapping, replicated in multiple experimental models\",\n      \"pmids\": [\"24097189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eCIRP is a biologically active endogenous ligand of TREM-1 on macrophages. Surface plasmon resonance revealed strong binding between eCIRP and TREM-1, confirmed by FRET in macrophages. TREM-1 siRNA, decoy peptide LP17, and TREM-1-/- mice dramatically reduced eCIRP-induced inflammation.\",\n      \"method\": \"Surface plasmon resonance; FRET assay; TREM-1-/- mice; siRNA knockdown; inhibitory peptide M3 derived from eCIRP sequence\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR binding, FRET confirmation, genetic knockout, and peptide inhibition all orthogonally support the finding\",\n      \"pmids\": [\"32027618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eCIRP binds IL-6 receptor (IL-6R) on macrophages, activating STAT3 phosphorylation and promoting macrophage endotoxin tolerance and M2 polarization. Blockade of IL-6R with neutralizing Ab inhibited eCIRP-induced p-STAT3 and restored LPS-stimulated TNF-α release.\",\n      \"method\": \"Biacore binding assay; FRET; immunostaining colocalization; STAT3 inhibitor (Stattic); anti-IL-6R neutralizing antibody; rmCIRP stimulation of macrophages\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding confirmed by three orthogonal methods (Biacore, FRET, colocalization) plus functional rescue experiments\",\n      \"pmids\": [\"32027619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIRBP nuclear import is mediated by two nonclassical nuclear localization signals: an RG/RGG-rich region recognized by Transportin-1 (TNPO1) and an RSY-rich region recognized by Transportin-3 (TNPO3). These interactions regulate nuclear localization, phase separation, and stress granule recruitment of CIRBP.\",\n      \"method\": \"Biophysical binding assays; cell-based localization experiments; mutagenesis of NLS regions; phase separation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding characterization of two distinct NLS–importin interactions with functional validation in cells\",\n      \"pmids\": [\"32234784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation of the CIRBP RG/RGG region by SRPK1 impairs liquid-liquid phase separation (LLPS), binding to TNPO1, and stress granule association in cells. Arginine methylation of the same region reciprocally regulates SRPK1-mediated phosphorylation, revealing interplay between these two PTMs.\",\n      \"method\": \"In vitro phosphorylation assay with SRPK1; LLPS assay; TNPO1 binding assay; cell-based SG recruitment; identification of two novel phosphorylation sites\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, LLPS reconstitution, and cell-based validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"34738012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cirp directly binds Dyrk1b/Mirk kinase in the nucleus of undifferentiated spermatogonia, inhibiting Dyrk1b's binding to p27 (reducing p27 phosphorylation and destabilizing it) and inhibiting Dyrk1b-mediated phosphorylation of cyclin D1 (stabilizing cyclin D1), thereby promoting cell-cycle progression from G0/G1 to S phase.\",\n      \"method\": \"Cirp knockout mice; direct protein binding assays; co-immunoprecipitation; cell-cycle analysis; spermatogonial cell line knockdown; cyclin D1 and p27 protein level measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with defined cellular phenotype, direct binding demonstrated, mechanistic pathway placement with multiple downstream readouts\",\n      \"pmids\": [\"22711815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIRP associates with the active telomerase complex through direct binding to the RNA component TERC, regulates Cajal body localization of telomerase, and modulates TERT mRNA levels. CIRP inhibition by CRISPR-Cas9 or siRNA leads to reduced telomerase activity and shortened telomere length.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry; CRISPR-Cas9 and siRNA knockdown; telomerase activity assay; telomere length measurement; Cajal body localization assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — IP-MS identification, CRISPR KO functional validation, direct TERC binding, and multiple functional readouts in one study\",\n      \"pmids\": [\"26673712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Temperature-dependent accumulation of Cirbp mRNA is controlled primarily by regulation of splicing efficiency (fraction of pre-mRNA processed into mature mRNA), not transcription rate, and this post-transcriptional mechanism is widespread in temperature-dependent gene expression control.\",\n      \"method\": \"NIH3T3 fibroblasts exposed to simulated temperature cycles; genome-wide 'approach to steady-state' kinetics; mRNA/pre-mRNA quantification\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide kinetic approach with specific focus on Cirbp, mechanistically distinguishing splicing from transcription\",\n      \"pmids\": [\"27633015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIRP selectively binds the 5' UTR of p27Kip1 mRNA and enhances its translation. In cells exposed to mild hypothermia, induced CIRP correlated with increased p27Kip1 5'UTR reporter translation and p27Kip1 protein accumulation; shRNA-mediated CIRP knockdown prevented this induction. p27Kip1 KO MEFs showed no increase in doubling time under cold stress, unlike WT cells.\",\n      \"method\": \"RNA binding assay; reporter translation assay; shRNA knockdown; p27Kip1 KO MEFs; mild hypothermia induction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct RNA binding, reporter assay, KO validation, and genetic rescue in one study\",\n      \"pmids\": [\"29361038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cirp protects cells from TNF-α-induced apoptosis by activating the ERK pathway: Cirp transduction into Cirp-deficient fibroblasts increased phosphorylated ERK and suppressed TNF-α-induced caspase-8 activation. The ERK-specific inhibitor PD98059 abrogated Cirp's cytoprotective effect.\",\n      \"method\": \"Cirp transduction into Cirp-deficient mouse fibroblasts; ERK inhibitor (PD98059); caspase-8 activation assay; apoptosis assay at 37°C and 32°C\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function with pathway inhibitor validation, but single lab\",\n      \"pmids\": [\"16569452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CIRP binds specific mRNAs in testis (identified by RIP-Chip and biotin pull-down), predominantly through a (Un)(n≥2) core recognition sequence, and stabilizes the bound mRNAs. Target mRNAs are associated with translation regulation, antioxidant activity, and reproduction.\",\n      \"method\": \"RIP-Chip (RNA-binding protein immunoprecipitation-microarray); biotin pull-down assay; mRNA stability assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding demonstrated by two orthogonal methods with sequence motif identification, single lab\",\n      \"pmids\": [\"22819822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Extracellular CIRP induces ER stress in lung tissue via TLR4 activation. In CIRP-/- septic mice, ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were not elevated, whereas TLR4 KO mice showed no ER stress induction after recombinant CIRP injection.\",\n      \"method\": \"CIRP-/- and TLR4-/- mouse models; cecal ligation and puncture sepsis; recombinant CIRP injection; Western blot for ER stress markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic KO models used to place CIRP upstream of TLR4 and ER stress pathway, single lab\",\n      \"pmids\": [\"28128330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eCIRP-induced ICAM-1+ neutrophil generation is mediated by TREM-1, and ICAM-1 on neutrophils activates Rho GTPase to promote NETosis. Blockade of ICAM-1 decreased Rho activation, and Rho inhibition decreased rmCIRP-induced NET formation.\",\n      \"method\": \"TREM-1-/- mice; TREM-1 inhibitor LP17; ICAM-1-/- neutrophils; Rho activation assay; rmCIRP stimulation; flow cytometry\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological tools used to place TREM-1 and ICAM-1-Rho axis downstream of eCIRP, single lab\",\n      \"pmids\": [\"32506691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eCIRP impairs macrophage bacterial phagocytosis by activating STAT3 phosphorylation, which promotes STAT3-βPIX complex formation, preventing βPIX from activating Rac1 and thereby reducing ARP2 and p-cofilin expression needed for actin remodeling. STAT3 inhibition rescued phagocytic dysfunction.\",\n      \"method\": \"CIRP-/- mice; rmCIRP stimulation of macrophages; co-immunoprecipitation of STAT3-βPIX complex; STAT3 inhibitor stattic; actin remodeling assays; in vivo bacterial load measurement\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue with inhibitor and KO mice; single lab\",\n      \"pmids\": [\"36471113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eCIRP activates STING through TLR4/MyD88/TRIF pathways, leading to pTBK1 and pIRF3 activation and type I IFN production, exacerbating hemorrhagic shock. STING-/- mice showed reduced lung inflammation and mortality; TLR4-/-, MyD88-/-, and TRIF-/- macrophages failed to activate STING downstream of eCIRP.\",\n      \"method\": \"STING-/-, TLR4-/-, MyD88-/-, TRIF-/- mouse models; rmCIRP injection; Western blot for pTBK1 and pIRF3; cytokine measurement; controlled hemorrhage model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four genetic KO models used for epistasis, single lab\",\n      \"pmids\": [\"34291735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactate accumulation during sepsis promotes lactylation of CIRP in macrophages, causing its release. Internalized eCIRP (via TLR4-mediated endocytosis by pulmonary vascular endothelial cells) competitively binds ZBP1, blocking TRIM32-mediated proteasomal degradation of ZBP1, stabilizing ZBP1 and enhancing ZBP1-RIPK3-dependent PANoptosis.\",\n      \"method\": \"CLP sepsis model; Casp8-/-, Ripk3-/-, Zbp1-/- mice; measurement of CIRP lactylation; co-immunoprecipitation of eCIRP-ZBP1 and ZBP1-TRIM32; TLR4-mediated endocytosis tracking\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO models, Co-IP binding assays, and novel PTM identification; single lab\",\n      \"pmids\": [\"39465383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chronic hypoxia induces hypermethylation of the Cirbp promoter, suppressing CIRP expression and preventing cold-stress induction. CIRP deficiency attenuates hypothermic cardioprotection by downregulating the cardiac ubiquinone biosynthesis pathway, reducing CoQ10, increasing oxidative stress, and impairing ATP production.\",\n      \"method\": \"Rat CPB model; Cirbp-KO and Cirbp-transgenic rats; methylation analysis of Cirbp promoter in neonatal cardiomyocytes and human specimens; cardiac proteomics; CoQ10 measurement\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO and transgenic animals, promoter methylation directly demonstrated, proteomics pathway identification, and human tissue validation\",\n      \"pmids\": [\"31019028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CIRBP suppression in aged donor hearts attenuates hypothermic cardioprotection by decreasing DHODH expression, compromising DHODH-mediated ubiquinone (CoQ) reduction, leading to cardiac lipid peroxidation and ferroptosis after transplantation.\",\n      \"method\": \"Rat heart transplantation model; Cirbp-KO rats; RNA-Seq; cardiac proteomics; DHODH expression measurement; lipid peroxidation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with proteomics pathway identification and functional readouts, single lab; replicates and extends earlier CoQ10 finding\",\n      \"pmids\": [\"38690728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIRBP binds the 3'-UTR of HIF-1α mRNA to increase its mRNA stability in bladder cancer cells, thereby inducing HIF-1α expression and promoting cancer cell proliferation and migration.\",\n      \"method\": \"RNA immunoprecipitation; 3'UTR binding assay; CIRBP overexpression/knockdown; mRNA stability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding demonstrated, functional consequences measured; single lab\",\n      \"pmids\": [\"30315244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP directly binds the 3'UTR of Atp5g3 mRNA to regulate mitochondrial homeostasis and ATP biogenesis under hypoxic stress, and sustains protein levels of respiratory chain complexes II (SDHB) and IV (MT-CO1).\",\n      \"method\": \"3'UTR binding assay; Cirbp KO and overexpression; respiratory complex protein level measurement; ATP measurement; hypoxia model\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding to 3'UTR demonstrated, KO/OE functional validation; single lab\",\n      \"pmids\": [\"34715218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRBP promotes ferroptosis in renal ischemia-reperfusion injury by interacting with ELAVL1 (HuR), which activates ferritinophagy. CIRBP-ELAVL1 interaction was confirmed by co-immunoprecipitation and fluorescence colocalization. Silencing CIRBP inhibited ferritinophagy and ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation; fluorescence colocalization; siCIRBP; autophagy inhibitor; si-ELAVL1; anti-CIRP antibody mouse model of IR injury\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction confirmed by two methods, genetic loss-of-function validation; single lab\",\n      \"pmids\": [\"34114349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP binds to p53 mRNA (RIP assay) and regulates ferroptosis in pancreatic cancer cells through the p53/GPX4 pathway: cold-induced CIRBP expression was associated with decreased GPX4 and increased DPP4, NOX1, FTH1, Fe2+ accumulation, and ROS.\",\n      \"method\": \"RNA immunoprecipitation (RIP); CIRBP overexpression/knockdown; cold induction; ferroptosis marker measurement; ferroptosis inhibitor rescue\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/RIP for p53 mRNA binding, mechanistic pathway partially inferred from correlative protein level changes; single lab\",\n      \"pmids\": [\"36061308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP directly binds the 3'UTR of PSD95 mRNA to post-transcriptionally regulate PSD95 protein levels; overexpression of Cirbp in hippocampus rescues hypobaric hypoxia-induced reduction of PSD95 and attenuates dendritic spine injury and cognitive deficits.\",\n      \"method\": \"3'UTR binding assay; Cirbp overexpression via stereotaxic injection; PSD95 protein quantification; dendritic spine morphology analysis; behavioral memory tests\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding demonstrated, in vivo rescue with functional neurological readout; single lab\",\n      \"pmids\": [\"34419133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eCIRP induces macrophage extracellular trap (MET) formation through sequential activation of caspase-1 and gasdermin D (GSDMD). Caspase-1 and GSDMD inhibitors (z-VAD-fmk and disulfiram) significantly decreased rmCIRP-induced MET formation in THP-1 macrophages.\",\n      \"method\": \"Time-lapse fluorescence microscopy; SYTOX Orange staining; Western blot for cleaved caspase-1 and GSDMD; pharmacological inhibitors; primary peritoneal macrophages\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of pathway with multiple inhibitors and cell types; single lab\",\n      \"pmids\": [\"35003095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eCIRP induces ferroptosis in macrophages and lung tissue during sepsis by decreasing GPX4 expression and increasing lipid ROS in a TLR4-dependent manner. TLR4-/- macrophages showed attenuated GPX4 depression and lipid ROS increase after rmCIRP treatment.\",\n      \"method\": \"RAW 264.7 cells and TLR4-/- peritoneal macrophages; GPX4 expression; lipid ROS measurement; ferroptosis inhibitor ferrostatin-1; CIRP-/- mice CLP model; eCIRP inhibitor C23\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TLR4-/- genetic validation, KO mouse model, ferroptosis inhibitor rescue; single lab\",\n      \"pmids\": [\"35844517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A mild-cold responsive element (MCRE, octanucleotide 5'-TCCCCGCC-3') in the cirp 5' flanking region is bound by the transcription factor Sp1, which translocates more to the nucleus at 32°C than 37°C. Sp1 overexpression increased endogenous Cirp and reporter expression; Sp1 downregulation had the opposite effect. MCRE mutation abolished these effects.\",\n      \"method\": \"Reporter gene assay (CAT); chromatin immunoprecipitation; immunohistochemistry; Sp1 overexpression/downregulation; MCRE mutagenesis; multiple cell lines\",\n      \"journal\": \"BMC biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP, mutagenesis, and functional reporter assays confirm Sp1-MCRE mechanism; single lab\",\n      \"pmids\": [\"23046908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Upregulation of CIRP by hypoxia is independent of HIF-1α and HIF-1β and does not require mitochondria. Nuclear run-on assays demonstrated that hypoxia-induced CIRP expression occurs at the level of gene transcription. Respiratory chain inhibitors (NaN3 and cyanide) blocked this response, but cells depleted of mitochondria still upregulated CIRP during hypoxia.\",\n      \"method\": \"HIF-1α-deficient (Z-33) and HIF-1β-deficient (Hepa-1 c4) cell lines; actinomycin-D; in vitro nuclear run-on assay; mitochondria-depleted cells; respiratory chain inhibitors\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear run-on directly measures transcription, multiple genetic cell lines used; single lab\",\n      \"pmids\": [\"15075239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CIRP expression is modulated by alternative transcription start sites generating three major 5'-UTR transcripts with different translational properties. The longest 32°C-enriched transcript exhibits IRES-like activity, and its levels and stability are increased at mild hypothermia, contributing to CIRP protein upregulation.\",\n      \"method\": \"5'-UTR transcript characterization; IRES reporter assay; transcript stability measurement at different temperatures; NIH-3T3 cells\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct characterization of transcript variants and IRES-like activity; mechanistic follow-up with functional assays; single lab\",\n      \"pmids\": [\"19398494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TNF and TGFβ (but not IL-1β, IL-6, IFNα, or IFNγ) impair CIRBP expression in fibroblasts and neuronal cells; CIRBP depletion increases susceptibility of cells to TNF-mediated inhibition of clock gene (period genes, PAR-bZip) expression, revealing CIRBP as a regulator of circadian clock gene amplitude downstream of cytokine signaling.\",\n      \"method\": \"Cirp depletion; cytokine stimulation; clock gene expression measurement in fibroblasts and neuronal cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cytokine specificity panel and Cirbp knockdown with defined clock gene readout; single lab\",\n      \"pmids\": [\"24337574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP directly binds to OGFR mRNA and represses OGFR expression by reducing mRNA stability. CIRBP deficiency enables OGF-OGFR signaling to promote chemotherapy-induced cardiomyocyte apoptosis; exogenous CIRBP delivery to mouse myocardium mitigated doxorubicin-induced cardiac apoptosis.\",\n      \"method\": \"mRNA stability assay; RNA immunoprecipitation; CIRBP/OGFR overexpression/knockdown; AAV-mediated myocardial CIRBP delivery; cardiac apoptosis measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding and mRNA stability demonstrated, in vivo functional validation; single lab\",\n      \"pmids\": [\"35541895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CIRP inhibits DNA damage-induced apoptosis by regulating p53: CIRP knockdown increased p53 levels and pro-apoptotic gene expression, while CIRP overexpression decreased p53 levels and upregulated anti-apoptotic genes. Effect placed CIRP upstream of p53 in DNA damage apoptosis pathway.\",\n      \"method\": \"CIRP overexpression and siRNA knockdown; etoposide-induced DNA damage; p53 and apoptosis gene expression measurement; Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gain/loss of function with downstream marker measurement but no direct binding assay; mechanism of p53 regulation not established\",\n      \"pmids\": [\"26188505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP directly binds CTNNB1 mRNA at its 3'- and 5'-UTRs (confirmed by RNA immunoprecipitation and biotin pull-down), enhancing CTNNB1 mRNA stability and promoting IRES-mediated CTNNB1 protein synthesis, leading to activation of Wnt/β-catenin signaling and downstream targets in NSCLC.\",\n      \"method\": \"RNA immunoprecipitation; biotin pull-down; mRNA decay assay; luciferase reporter (IRES); CIRBP overexpression/knockdown in multiple cell lines; in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding by two orthogonal methods, mRNA stability and IRES reporter assay; single lab\",\n      \"pmids\": [\"34465343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eCIRP induces TREM-1 expression in alveolar type II (ATII) cells and triggers IL-6 and CXCL2 production via TREM-1. TREM-1-/- ATII cells showed reduced cytokine release after rmCIRP treatment, and TREM-1 antagonist peptides (M3, LP17) significantly decreased this response.\",\n      \"method\": \"Primary ATII cell isolation; TREM-1-/- mice; rmCIRP stimulation; TREM-1 antagonist peptides; flow cytometry; ELISA\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological inhibitor used together; single lab\",\n      \"pmids\": [\"32984356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eCIRP induces acute kidney injury via TREM-1 on renal endothelial cells. TREM-1-/- mice injected with rmCIRP showed attenuated AKI markers (BUN, creatinine, NGAL) and reduced renal ICAM-1 expression. M3 peptide blocked eCIRP activation of human renal glomerular endothelial cells.\",\n      \"method\": \"TREM-1-/- mice; rmCIRP IV injection; renal function markers; primary human renal glomerular endothelial cells; M3 inhibitory peptide\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and peptide inhibitor in vivo plus primary human cell validation; single lab\",\n      \"pmids\": [\"36246143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cirp is constitutively and diurnally expressed in the brain; Cirp mRNA levels oscillate in the suprachiasmatic nucleus and cerebral cortex (rising during daytime, falling at night), are absent in constant darkness, and are not present in 3-day-old mice, suggesting light-dependent regulation of Cirp in circadian rhythm circuits.\",\n      \"method\": \"Northern blot; immunohistochemistry; constant darkness control; developmental stage comparison\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization by IHC in defined brain regions with multiple controls establishing light dependence; single lab\",\n      \"pmids\": [\"9571190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CIRBP specifically binds pre-miR-329 (but not pri-miR-329) in RBP immunoprecipitation experiments after hindlimb ischemia, suggesting a role in posttranscriptional regulation of 14q32 microRNA processing.\",\n      \"method\": \"RNA pull-down SILAC mass spectrometry; RBP immunoprecipitation; hindlimb ischemia mouse model; CRISPR/Cas9 HADHB-/- cells\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RBP-IP showing specific pre-miRNA binding; functional consequence for CIRBP specifically not directly proven; single lab\",\n      \"pmids\": [\"30665182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Under PRRSV infection, CIRBP translocates from the nucleus to the cytoplasm and is present in cytoplasmic stress granules. Overexpression of CIRBP promoted inflammatory cytokine expression and oxidative stress (iNOS, ROS) via the NF-κB pathway in infected macrophages.\",\n      \"method\": \"Immunofluorescence for CIRBP localization; stress granule colocalization; CIRBP overexpression; NF-κB pathway inhibitor; cytokine and ROS measurement\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization experiment is direct, but NF-κB pathway link is based on overexpression without genetic pathway dissection; single lab\",\n      \"pmids\": [\"32593159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CIRP and HuR competitively bind Claudin1 mRNA; CIRP binding suppresses Claudin1 expression while HuR binding enhances it. This competition regulates intestinal mucosal barrier function in ulcerative colitis. Validated by RNA immunoprecipitation and dual-luciferase reporter assay.\",\n      \"method\": \"RNA immunoprecipitation; dual-luciferase reporter assay; CIRP and HuR overexpression/knockdown; transepithelial electrical resistance; in vivo DSS colitis model\",\n      \"journal\": \"BioFactors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding competition demonstrated by two orthogonal methods with functional barrier readout; single lab\",\n      \"pmids\": [\"33638934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A synthetic poly(A) tail mimic (A12) selectively and strongly binds the RNA-binding motif of eCIRP, preventing eCIRP binding to TLR4. A12 attenuated eCIRP-induced macrophage MAPK and NF-κB activation and inflammatory cytokine production in vitro and in vivo.\",\n      \"method\": \"Direct binding assay (A12-eCIRP RBM interaction); macrophage stimulation; NF-κB and MAPK activation assays; CLP sepsis model; bacterial load measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding at defined RBM domain demonstrated, functional rescue in multiple models; single lab\",\n      \"pmids\": [\"37585248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eCIRP impairs Rab26 in macrophages, reducing Rab26-mediated surface transport of EPOR, resulting in decreased macrophage EPOR surface expression and impaired M2 polarization. EPO treatment failed to promote M2 polarization in Rab26 KO macrophages, confirming the Rab26-EPOR axis.\",\n      \"method\": \"Rab26 KO macrophages; myeloid-specific EPOR-deficient mice; anti-CIRP antibody treatment; EPOR surface expression assay; macrophage polarization measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic KO models, defined mechanistic pathway from eCIRP to Rab26 to EPOR; single lab\",\n      \"pmids\": [\"34925338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β2 and TGF-β3 directly downregulate CIRBP mRNA and protein expression in germ cells (GC2-spd). In vivo, heat-induced CIRBP downregulation in mouse testes is mediated by TGF-β upregulation; local TGF-β antagonist injection attenuated heat-induced CIRBP downregulation.\",\n      \"method\": \"In vitro TGF-β isoform treatment of GC2-spd cells; in vivo local testicular injection of TGF-β antagonist; CIRBP mRNA and protein quantification\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both in vitro and in vivo interventional experiments; single lab\",\n      \"pmids\": [\"30461215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CIRP maintains GluR1 (AMPA receptor subunit) stability on neuronal cell membranes by binding GluR1 mRNA; hypobaric hypoxia reduces CIRP expression and the CIRP-GluR1 interaction, causing GluR1 redistribution to cytoplasm, synaptic loss, and memory impairment. Cirp KO mice phenocopied this deficit.\",\n      \"method\": \"Cirp KO mice; hypobaric hypoxia model; mRNA binding assay; GluR1 surface vs. cytoplasmic protein distribution; dendritic spine and synapse counting; behavioral memory tests; Tat-C16 peptide rescue\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with direct mRNA binding, subcellular localization assay, and functional rescue by peptide; single lab\",\n      \"pmids\": [\"39315498\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIRBP/CIRP is a cold- and stress-inducible RNA-binding protein that, intracellularly, acts as an RNA chaperone binding target mRNA 3'- and 5'-UTRs (including p27Kip1, HIF-1α, CTNNB1, PSD95, Atp5g3, GluR1, OGFR, TERC) to regulate their stability, translation, and Cajal body localization; it interacts with Dyrk1b to modulate cell-cycle progression, with the telomerase complex to maintain telomere length, and with ELAVL1 to regulate ferritinophagy; its nuclear import is controlled by TNPO1 (via an RG/RGG NLS) and TNPO3 (via an RSY NLS), with SRPK1-mediated phosphorylation and arginine methylation of its RGG domain gating nuclear localization, phase separation, and stress granule recruitment; when released extracellularly, eCIRP functions as a DAMP that signals through TLR4-MD2, TREM-1, and IL-6R to drive NF-κB/MAPK/STAT3-dependent inflammatory responses in macrophages, neutrophils, endothelial cells, and alveolar epithelial cells, inducing ferroptosis (via GPX4 suppression), NETosis (via ICAM-1–Rho), MET formation (via caspase-1/GSDMD), pyroptosis, and PANoptosis (via ZBP1 stabilization), and also activates STING through TLR4/MyD88/TRIF to produce type I interferons, while its transcriptional cold-induction is controlled by Sp1 binding to a mild-cold responsive element (MCRE) and by temperature-dependent splicing efficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIRBP (CIRP) is a cold- and stress-inducible RNA-binding protein with a dual identity: intracellularly it acts as a post-transcriptional regulator that binds target mRNA UTRs to control their stability and translation, while extracellularly it functions as a damage-associated molecular pattern (DAMP) that drives inflammation [#0, #8]. As an RNA chaperone, CIRP binds defined mRNAs through a (U/A)-rich core motif and tunes the levels of cell-cycle, hypoxia, mitochondrial, neuronal, and oncogenic effectors: it enhances translation of the p27Kip1 5'UTR [#8], stabilizes HIF-1\\u03b1, CTNNB1, Atp5g3, and PSD95/GluR1 mRNAs to support proliferation, mitochondrial respiration, and synaptic integrity [#18, #31, #19, #22, #41], and represses OGFR and Claudin1, the latter in competition with HuR [#29, #37]. Through direct binding to the telomerase RNA TERC it sustains telomerase activity and Cajal-body localization [#6], and through binding Dyrk1b it modulates p27/cyclin D1 to promote G1/S progression [#5]. CIRP nuclear import is governed by two nonclassical NLS\\u2013importin interactions\\u2014an RG/RGG region read by TNPO1 and an RSY region read by TNPO3\\u2014with SRPK1-mediated phosphorylation and arginine methylation of the RG/RGG region reciprocally gating phase separation, TNPO1 binding, and stress-granule recruitment [#3, #4]. Once released, extracellular CIRP binds the TLR4-MD2 complex, TREM-1, and IL-6R to trigger NF-\\u03baB/MAPK/STAT3 inflammatory programs in macrophages, neutrophils, endothelial, and alveolar epithelial cells, driving cytokine release, ER stress, ICAM-1\\u2013Rho\\u2013dependent NETosis, GSDMD-dependent MET formation, GPX4-suppressing ferroptosis, ZBP1-stabilized PANoptosis, and STING-driven type I interferon production [#0, #1, #2, #11, #12, #23, #24, #15, #14]. Its own induction is controlled transcriptionally by Sp1 binding to a mild-cold responsive element and by temperature-dependent splicing efficiency and alternative 5'UTR/IRES usage [#25, #7, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established CIRP as a constitutively expressed brain protein with light-dependent circadian oscillation, framing it as a stress/environment-responsive factor rather than a constitutive housekeeping protein.\",\n      \"evidence\": \"Northern blot and IHC across brain regions with constant-darkness and developmental controls in mice\",\n      \"pmids\": [\"9571190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the oscillation\", \"No RNA targets or partners identified at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how hypoxia induces CIRP, showing transcriptional upregulation independent of HIF-1 and mitochondria and thereby separating CIRP induction from the canonical hypoxia axis.\",\n      \"evidence\": \"Nuclear run-on, HIF-1\\u03b1/HIF-1\\u03b2-deficient cell lines, and mitochondria-depleted cells\",\n      \"pmids\": [\"15075239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating hypoxic induction not identified\", \"Did not address cold induction mechanism\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"First mechanistic intracellular function: CIRP cytoprotects against TNF-\\u03b1 apoptosis via ERK activation, linking the protein to cell-survival signaling.\",\n      \"evidence\": \"Cirp transduction into Cirp-deficient fibroblasts with ERK inhibitor and caspase-8 readout\",\n      \"pmids\": [\"16569452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CIRP to ERK not defined\", \"No RNA-binding link established for this effect\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Explained cold-induced CIRP protein upregulation through alternative transcription start sites generating an IRES-bearing 5'UTR transcript enriched at 32\\u00b0C.\",\n      \"evidence\": \"5'UTR transcript characterization and IRES reporter/stability assays in NIH-3T3 cells\",\n      \"pmids\": [\"19398494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors controlling start-site choice unknown\", \"IRES-mediated translation mechanism not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined two distinct intracellular roles: direct binding to Dyrk1b to control p27/cyclin D1 and cell-cycle progression, and sequence-specific mRNA binding/stabilization via a (U/A)-rich motif.\",\n      \"evidence\": \"Cirp KO mice with cell-cycle analysis and binding assays; RIP-Chip and biotin pull-down in testis\",\n      \"pmids\": [\"22711815\", \"22819822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the binding motif beyond testis transcripts not tested\", \"How Dyrk1b binding integrates with RNA-binding function unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the transcriptional basis of mild-cold induction: Sp1 binding to a defined MCRE element drives CIRP expression at 32\\u00b0C.\",\n      \"evidence\": \"CAT reporter, ChIP, MCRE mutagenesis, and Sp1 gain/loss in multiple cell lines\",\n      \"pmids\": [\"23046908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How temperature controls Sp1 nuclear translocation not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovered the extracellular DAMP function of CIRP, showing peptide-mapped binding to the TLR4-MD2 complex that drives TNF-\\u03b1/HMGB1 release and tissue injury \\u2014 a paradigm shift defining a second, inflammatory life of the protein.\",\n      \"evidence\": \"SPR binding with peptide mapping, CIRP-deficient mice, recombinant CIRP injection, and antisera blockade\",\n      \"pmids\": [\"24097189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CIRP release from cells not defined here\", \"Downstream signaling beyond cytokine release not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected CIRP to circadian amplitude control downstream of cytokine signaling, showing TNF/TGF\\u03b2 suppress CIRBP and that CIRBP loss sensitizes clock genes to TNF.\",\n      \"evidence\": \"Cirp depletion with cytokine specificity panel and clock-gene readouts in fibroblasts and neuronal cells\",\n      \"pmids\": [\"24337574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of CIRBP in clock-gene regulation not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended intracellular RNA chaperone activity to telomere maintenance via direct binding to telomerase RNA TERC and regulation of Cajal-body localization.\",\n      \"evidence\": \"IP-MS, CRISPR/siRNA knockdown, telomerase activity and telomere length assays\",\n      \"pmids\": [\"26673712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TERC binding unknown\", \"Whether telomere effect requires CIRP RGG/phase behavior untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified temperature-dependent splicing efficiency, not transcription rate, as a primary driver of cold-induced Cirbp mRNA accumulation, refining the induction model.\",\n      \"evidence\": \"Genome-wide approach-to-steady-state kinetics in temperature-cycled NIH3T3 cells\",\n      \"pmids\": [\"27633015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing factors mediating the temperature response not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a specific cold-stress effector axis: CIRP binds the p27Kip1 5'UTR to enhance translation, linking cold induction to cell-cycle slowing.\",\n      \"evidence\": \"RNA binding, reporter translation, shRNA knockdown, and p27Kip1 KO MEF rescue under hypothermia\",\n      \"pmids\": [\"29361038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translation-enhancement mechanism (e.g., IRES vs. cap) not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized 3'UTR-mediated mRNA stabilization to oncogenic targets (HIF-1\\u03b1) and showed an upstream cytokine suppressor of CIRBP (TGF-\\u03b2 in germ cells).\",\n      \"evidence\": \"RIP and 3'UTR binding/stability assays in bladder cancer; TGF-\\u03b2 isoform treatment and in vivo antagonist in testis\",\n      \"pmids\": [\"30315244\", \"30461215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CIRP discriminates stabilizing vs. destabilizing targets unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded eCIRP receptor repertoire to TREM-1 and IL-6R, defining distinct inflammatory outputs (pro-inflammatory activation vs. STAT3-driven endotoxin tolerance/M2 polarization).\",\n      \"evidence\": \"SPR/Biacore, FRET, colocalization, TREM-1-/- mice, peptide inhibitors, and IL-6R neutralization with functional rescue\",\n      \"pmids\": [\"32027618\", \"32027619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single ligand engages multiple receptors to opposite ends not resolved\", \"Stoichiometry/competition among TLR4, TREM-1, IL-6R unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the nuclear-import logic of CIRBP: two nonclassical NLS regions read by TNPO1 (RG/RGG) and TNPO3 (RSY) that couple localization to phase separation and stress-granule recruitment.\",\n      \"evidence\": \"Biophysical binding, NLS mutagenesis, and cell-based localization/phase-separation assays\",\n      \"pmids\": [\"32234784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of dual-importin control not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PTM gating of CIRBP behavior: SRPK1 phosphorylation of the RG/RGG region impairs LLPS, TNPO1 binding, and SG association, reciprocally regulated by arginine methylation.\",\n      \"evidence\": \"In vitro SRPK1 kinase assay, LLPS reconstitution, TNPO1 binding, and cellular SG recruitment with new phosphosite mapping\",\n      \"pmids\": [\"34738012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase responsible not identified\", \"Upstream signals controlling the PTM switch unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened intracellular target set to mitochondrial (Atp5g3), neuronal (PSD95), oncogenic (CTNNB1), and cardiac (OGFR) mRNAs, mostly via UTR binding with stability/translation control and in vivo functional rescue.\",\n      \"evidence\": \"3'/5'UTR binding, RIP, mRNA decay and IRES reporter assays, KO/overexpression, AAV/stereotaxic delivery across tissue models\",\n      \"pmids\": [\"34715218\", \"34419133\", \"34465343\", \"35541895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these targets share a common recognition motif untested\", \"Tissue-specific selectivity of CIRP targeting unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked CIRBP to ferroptosis through interaction with ELAVL1/HuR-driven ferritinophagy, and identified HuR competition on Claudin1 mRNA, positioning CIRP within an antagonistic RBP network.\",\n      \"evidence\": \"Co-IP and colocalization for CIRBP-ELAVL1; RIP and dual-luciferase competition for Claudin1; loss-of-function in IR and DSS-colitis models\",\n      \"pmids\": [\"34114349\", \"33638934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of CIRBP-ELAVL1 cooperation not fully dissected\", \"Generality of CIRP-HuR competition beyond these targets unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped multiple eCIRP-driven cell-death and effector programs: TLR4-dependent ER stress, TREM-1/ICAM-1/Rho NETosis, Rab26-EPOR M2 impairment, and STING/TLR4-MyD88-TRIF type I IFN production.\",\n      \"evidence\": \"Multiple KO models (TLR4, TREM-1, ICAM-1, Rab26, EPOR, STING, MyD88, TRIF), peptide inhibitors, and rmCIRP challenge in sepsis/hemorrhage models\",\n      \"pmids\": [\"28128330\", \"32506691\", \"34925338\", \"34291735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How eCIRP triggers such divergent downstream programs from shared receptors unclear\", \"Single-lab pathway dissections\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined eCIRP-induced ferroptosis and macrophage extracellular trap formation as TLR4/GPX4 and caspase-1/GSDMD-dependent death modalities.\",\n      \"evidence\": \"TLR4-/- macrophages, ferrostatin-1 rescue, GSDMD/caspase-1 inhibitors and imaging in macrophage models\",\n      \"pmids\": [\"35844517\", \"35003095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between TLR4 signaling and GPX4 suppression not mechanistically traced\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the release trigger and a novel intracellular-extracellular death axis: lactate-driven lactylation promotes CIRP release, and internalized eCIRP stabilizes ZBP1 by blocking TRIM32-mediated degradation to drive ZBP1-RIPK3 PANoptosis.\",\n      \"evidence\": \"Lactylation measurement, TLR4-endocytosis tracking, eCIRP-ZBP1 and ZBP1-TRIM32 Co-IP, and Casp8/Ripk3/Zbp1 KO mice in CLP sepsis\",\n      \"pmids\": [\"39465383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactyltransferase responsible not identified\", \"Single-lab; structural basis of ZBP1 competition unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CIRBP to hypothermic organ protection mechanistically, showing it sustains DHODH-mediated ubiquinone reduction and CoQ-dependent antioxidant capacity to prevent ferroptosis in cold-preserved hearts.\",\n      \"evidence\": \"Cirbp-KO/transgenic rats, promoter methylation analysis, proteomics, DHODH/CoQ measurement, and lipid peroxidation assays in CPB/transplant models\",\n      \"pmids\": [\"31019028\", \"38690728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CoQ/DHODH effect is RNA-binding-dependent not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single protein partitions between its nuclear/cytoplasmic RNA-regulatory roles and its extracellular DAMP function, how target/receptor selectivity is achieved, and what physiological signals govern the release switch in vivo.\",\n      \"evidence\": \"No single study in the corpus integrates the intracellular RNA-chaperone and extracellular DAMP programs\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking PTM/phase state to release\", \"No structural model of CIRP\\u2013receptor or CIRP\\u2013RNA complexes\", \"Selectivity rules for mRNA targets vs. receptors undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 10, 18, 19, 22, 29, 31, 41, 6]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [8, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5, 36]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4, 36]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 14, 24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 10, 18, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 15, 23, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\"telomerase complex\"],\n    \"partners\": [\"TLR4\", \"LY96\", \"TREM1\", \"IL6R\", \"DYRK1B\", \"TNPO1\", \"TNPO3\", \"ELAVL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}