{"gene":"ENO1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2000,"finding":"The ENO1 gene encodes two protein products via alternative translation initiation: a 48 kDa alpha-enolase localized predominantly in the cytoplasm, and a 37 kDa shorter form (MBP-1) that localizes preferentially to the nucleus, binds the c-myc P2 promoter consensus sequence, and downregulates c-myc transcription as demonstrated by luciferase reporter assay.","method":"Alternative translation analysis, alpha-enolase/GFP chimera transfection with subcellular localization, luciferase reporter assay with MBP-1 consensus binding sequence","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (GFP chimeras, reporter assay, functional binding) in single study; replicated concept in later work","pmids":["10802057"],"is_preprint":false},{"year":2010,"finding":"MBP-1 is encoded by an alternatively transcribed mRNA from intron III of the ENO1 gene (not solely by alternative translation of the full-length ENO1 mRNA). This MBP-1 transcript is 17.8-fold more efficient for MBP-1 protein production than the ENO1 transcript. MBP-1 protein stability is regulated by proteasomal degradation (stabilized by MG132). Hypoxia significantly increases transcriptional activation of the MBP-1 gene.","method":"MBP-1 promoter-driven luciferase reporter assays, biochemical cell fractionation with RT-PCR, coupled transcription/translation reactions, proteasome inhibitor (MG132) treatment","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, fractionation, in vitro translation) in single study","pmids":["20849415"],"is_preprint":false},{"year":2021,"finding":"ENO1 functions as an RNA-binding protein that recruits the deadenylase CNOT6 to accelerate mRNA decay of iron regulatory protein 1 (IRP1) in hepatocellular carcinoma cells. This leads to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis.","method":"RNA immunoprecipitation, in vitro and in vivo experiments, RNA decay assays, functional knockdown/overexpression with ferroptosis readouts","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — RNA-binding demonstrated by RIP, mechanistic pathway validated in vitro and in vivo, multiple orthogonal methods","pmids":["35121990"],"is_preprint":false},{"year":2023,"finding":"ENO1, acting as an RNA-binding protein, binds to cytosine-uracil-guanine-rich elements of YAP1 mRNA to promote its translation, thereby activating arachidonic acid metabolism via the YAP1/PLCB1/HPGD axis and subsequent prostaglandin E2 accumulation, which drives hepatocellular carcinoma progression.","method":"RNA immunoprecipitation, mRNA translation assays, in vitro and in vivo functional experiments, clinical sample analysis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — RIP demonstrated direct binding, pathway validated in vitro and in vivo, multiple orthogonal methods","pmids":["37500770"],"is_preprint":false},{"year":2021,"finding":"ENO1 promotes lung cancer metastasis by interacting with hepatocyte growth factor receptor (HGFR) and activating HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co-receptor LRP5/6. This decreases GSK3β activity via Src-PI3K-AKT signaling and inactivates the β-catenin destruction complex, ultimately upregulating SLUG and β-catenin to drive EMT.","method":"Co-immunoprecipitation, phosphorylation assays, knockdown/overexpression with phenotypic readouts, orthotopic and tail-vein injection mouse models, anti-ENO1 antibody functional studies","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP established interaction, signaling pathway validated by phosphorylation assays, confirmed in vivo with multiple models","pmids":["34145039"],"is_preprint":false},{"year":2017,"finding":"ENO1 controls alphav/beta3 integrin expression in pancreatic ductal adenocarcinoma (PDA) cells. ENO1 silencing downregulates alphav/beta3 integrin, increases RGD-independent adhesion to vitronectin via uPAR, triggers ERK1-2 and RAC activation, ROS accumulation, and cellular senescence. Anti-uPAR antibody reduces ROS and senescence in ENO1-silenced cells.","method":"shRNA-mediated ENO1 silencing, confocal microscopy, atomic force microscopy, functional adhesion/invasion assays, mouse xenograft model","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (AFM, confocal, functional assays, in vivo), mechanistic rescue experiments","pmids":["28086938"],"is_preprint":false},{"year":2015,"finding":"FBXW7 physically binds to ENO1 and targets it for ubiquitin-mediated proteasomal degradation, thereby suppressing ENO1-induced lactate production, cell proliferation, and migration in colorectal cancer.","method":"Co-immunoprecipitation, ubiquitination assay, 2D protein electrophoresis/mass spectrometry, Western blotting, functional cell assays","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP established physical interaction, ubiquitination confirmed biochemically, functional rescue experiments","pmids":["26097998"],"is_preprint":false},{"year":2022,"finding":"PRMT6 methylates ENO1 at R9 and R372: R9 methylation promotes active ENO1 dimer formation and R372 methylation promotes 2-phosphoglycerate (2-PG) substrate binding to ENO1, thereby increasing glycolytic activity in lung cancer cells.","method":"In vitro methylation assays, mutational analysis of methylation sites, enzymatic activity assays, glycolysis flux measurements","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis combined with enzymatic activity assays establishing mechanism","pmids":["36815049"],"is_preprint":false},{"year":2023,"finding":"PRMT5 symmetrically dimethylates ENO1 at arginine 9 (R9) to promote active ENO1 dimer formation, increasing glycolysis flux and accelerating ovarian cancer tumor growth. PRMT5 signals high glucose to increase ENO1 methylation.","method":"In vitro dimethylation assays, co-immunoprecipitation, ENO1 dimerization assays, glycolysis flux measurement, knockdown/inhibitor studies in vitro and in vivo","journal":"MedComm","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-specific methylation and dimerization validated biochemically, in vitro and in vivo functional confirmation","pmids":["36999124"],"is_preprint":false},{"year":2021,"finding":"Lysine crotonylation (Kcr) of ENO1 is elevated in colorectal cancer. CBP (CREB-binding protein) functions as the crotonyltransferase writing K420 crotonylation on ENO1, and SIRT2 acts as the decrotonylase. ENO1 K420 Kcr enhances ENO1 enzymatic activity and promotes cancer cell growth, migration, and invasion.","method":"Mass spectrometry-based crotonylomics, in vitro crotonylation assay, site-directed mutagenesis at K420, functional cell assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — writer/eraser identified biochemically, site-specific modification validated by MS and mutagenesis","pmids":["34547627"],"is_preprint":false},{"year":2022,"finding":"NEDD4L (an E3 ubiquitin ligase) binds ENO1 and promotes its ubiquitination and proteasomal degradation, thereby suppressing glycolysis and cell proliferation in oral squamous cell carcinoma. ENO1 overexpression reverses NEDD4L-mediated suppression.","method":"UbiBrowser computational prediction validated by Co-IP, ubiquitination assay, rescue experiments with ENO1 overexpression, in vivo mouse tumor model","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay, functional rescue, single lab","pmids":["35316145"],"is_preprint":false},{"year":2020,"finding":"USP46, a deubiquitinating enzyme, directly stabilizes ENO1 protein by removing ubiquitin modifications, thereby promoting ESCC cell migration, invasion, and metastasis via the EMT process.","method":"Co-immunoprecipitation, deubiquitination assay, knockdown functional studies, in vivo metastasis model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical deubiquitination demonstrated, functional in vivo validation, single lab","pmids":["32707136"],"is_preprint":false},{"year":2024,"finding":"USP21 directly interacts with and deubiquitinates ENO1 through K48-linked deubiquitination, stabilizing ENO1 protein to promote aerobic glycolysis and cholangiocarcinoma cell proliferation.","method":"Co-immunoprecipitation, ubiquitination/deubiquitination assay, in vitro and in vivo functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical deubiquitination and Co-IP demonstrated, in vivo validation, single lab","pmids":["38385089"],"is_preprint":false},{"year":2022,"finding":"The m6A methyltransferase METTL3 methylates ENO1 mRNA at adenosine 359 (359A), which facilitates binding of the m6A reader YTHDF1 to ENO1 mRNA, resulting in enhanced ENO1 translation and increased glycolysis in lung adenocarcinoma.","method":"m6A site mapping, RNA immunoprecipitation, YTHDF1-ENO1 mRNA interaction assay, translation efficiency measurement, in vitro and in vivo functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — m6A site precisely identified, reader-mRNA interaction validated by RIP, translation enhancement confirmed, multiple methods","pmids":["35078505"],"is_preprint":false},{"year":2021,"finding":"C5aR1-positive neutrophil-secreted IL1β and TNFα activate ERK1/2 signaling, which phosphorylates WTAP at serine 341 to stabilize WTAP protein. Stabilized WTAP promotes m6A methylation of ENO1 mRNA, enhancing ENO1 expression and breast cancer glycolysis.","method":"m6A methylation assay, WTAP phosphorylation assay, RNA immunoprecipitation, in vitro and in vivo functional assays, co-culture models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation and m6A modification biochemically linked, in vivo validation, single lab","pmids":["34312368"],"is_preprint":false},{"year":2024,"finding":"The NSUN2/YBX1 axis writes and reads m5C modification on ENO1 mRNA respectively: NSUN2 methylates ENO1 mRNA (m5C writer) and YBX1 reads m5C on ENO1 mRNA to upregulate ENO1 expression in an m5C-dependent manner, promoting glucose metabolism reprogramming in colorectal cancer. Lactic acid derived from cancer cells activates NSUN2 transcription via H3K18 lactylation and induces NSUN2 K356 lactylation to enhance target RNA capture.","method":"m5C methylation assays, RNA immunoprecipitation, chromatin immunoprecipitation, Co-IP, functional rescue experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — writer/reader biochemically identified by RIP and ChIP, feedback mechanism demonstrated, single lab","pmids":["38769664"],"is_preprint":false},{"year":2024,"finding":"RBM15/METTL3 complex enhances m6A modification at the 359A site of ENO1 mRNA, promoting ENO1 protein translation efficiency in a YTHDF1-dependent manner in bladder cancer. TGF-β activates RBM15/METTL3 via Smad2/3. ENO1 in turn augments PCNA protein stability by reducing K48-linked ubiquitination of PCNA, preventing its ER-associated degradation.","method":"m6A site mapping, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-reader interaction confirmed by RIP, PCNA ubiquitination mechanism validated biochemically, single lab","pmids":["38823761"],"is_preprint":false},{"year":2020,"finding":"Exosome-derived ENO1 can be transferred between hepatocellular carcinoma cells via exosome-mediated crosstalk. Transferred ENO1 upregulates integrin α6β4 expression and activates the FAK/Src-p38MAPK pathway in recipient cells, promoting HCC growth and metastasis.","method":"Exosome isolation and transfer experiments, Western blotting, Co-IP, functional invasion/migration assays, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — exosome transfer validated, signaling pathway activation demonstrated, in vivo confirmation, single lab","pmids":["33184263"],"is_preprint":false},{"year":2018,"finding":"WBP2 interacts with ENO1 (identified by MS/GST pulldown) and modulates ENO1 glycolysis activity via the ENO1-PI3K/Akt signaling pathway to promote glioma cell proliferation and migration.","method":"MS/GST pulldown assay, Co-immunoprecipitation, knockdown functional studies, in vitro and in vivo glioma models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pulldown and Co-IP established interaction, functional pathway validation, single lab","pmids":["29497031"],"is_preprint":false},{"year":2020,"finding":"FGFRL1 physically interacts with ENO1 and regulates ENO1 expression and downstream PI3K/Akt signaling in small-cell lung cancer, mediating chemoresistance.","method":"Co-immunoprecipitation, knockdown/overexpression functional studies, signaling pathway analysis","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, partial mechanistic follow-up, single lab","pmids":["31957179"],"is_preprint":false},{"year":2015,"finding":"ENO1 and PDIA3 are required for Wnt/β-catenin-driven trans-differentiation of murine alveolar type II epithelial cells to type I cells. siRNA-mediated knockdown of ENO1 in primary ATII cells reduces T1α (ATI cell marker) expression, indicating diminished trans-differentiation. ENO1 expression increases during ATII-to-ATI trans-differentiation and is decreased upon pharmacological Wnt/β-catenin inhibition.","method":"Proteomics/mass spectrometry, siRNA knockdown, immunoblotting, primary cell culture, in vivo bleomycin lung injury model","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific cellular phenotype, in vivo validation, multiple orthogonal methods","pmids":["26035385"],"is_preprint":false},{"year":2008,"finding":"Retinoic acid (RA) dephosphorylates the ENO1-A1 phosphoprotein isoform in follicular thyroid carcinoma cells, leading to downregulation of ENO1/MBP-1 gene products. RA-mediated and siRNA-mediated knockdown of ENO1/MBP-1 both reduce MYC oncoprotein levels and decrease proliferation of thyroid carcinoma cells.","method":"2D-DIGE, mass spectrometry, Western blotting, siRNA knockdown, proliferation assays","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoprotein identification by 2D-DIGE/MS, mechanistic link to MYC confirmed by siRNA rescue, multiple methods","pmids":["19060179"],"is_preprint":false},{"year":2020,"finding":"Cinnamaldehyde (CA) covalently binds to ENO1 protein, destabilizes ENO1, and inhibits its glycolytic activity. Target identification was performed by chemical biology methods using an alkynyl-CA probe, molecular imaging, and live cell tracing.","method":"Activity-based protein profiling with alkynyl-CA probe, molecular imaging, live cell tracing, glycolysis assays, in vivo melanoma model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — covalent binding demonstrated by ABPP probe, glycolytic inhibition confirmed, in vivo validation","pmids":["32013122"],"is_preprint":false},{"year":2024,"finding":"Chlorogenic acid (CGA) covalently binds to ENO1 (identified by activity-based protein profiling) and suppresses ENO1 enzymatic activity, blocking the glycolytic pathway and thereby preventing UVA-induced cellular senescence in human dermal fibroblasts.","method":"Activity-based protein profiling (ABPP), co-immunoprecipitation, ENO1 activity assay, glycolysis measurement, photoaging mouse model with proteomics","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — covalent binding demonstrated by ABPP, enzymatic inhibition confirmed, in vivo validation","pmids":["39741388"],"is_preprint":false},{"year":2025,"finding":"Interleukin 1 receptor 2 (IL1R2) physically binds ENO1 in macrophages and suppresses its enzymatic activity, thereby inhibiting glycolysis, GSDMD-mediated pyroptosis, and inflammation. IL1R2-deficient mice show heightened sepsis susceptibility that is partially rescued by ENO1 inhibition.","method":"Proteomic screening, co-immunoprecipitation, ENO1 enzymatic activity assay, genetic mouse models (IL1R2 KO), ENO1 inhibitor treatment, in vivo sepsis model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic screen confirmed by Co-IP, enzymatic suppression validated, in vivo genetic and pharmacological validation with multiple readouts","pmids":["40704655"],"is_preprint":false},{"year":2023,"finding":"ENO1 binds to the 3'UTR of KLF2 mRNA to stabilize it, increasing KLF2 protein expression and suppressing NLRP3 inflammasome-mediated pyroptosis. ENO1 also binds to the 3'UTR of FUS mRNA to promote FUS expression and circFndc3b cyclization. This was identified in the context of exercise-induced neuroprotection in stroke.","method":"RNA immunoprecipitation, mRNA stability assay, functional knockdown/overexpression experiments, in vivo MCAO mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP demonstrated direct 3'UTR binding, functional pathway validated in vitro and in vivo, single lab","pmids":["39467260"],"is_preprint":false},{"year":2022,"finding":"ENO1 binds to ApoC3 (apolipoprotein C-III) in oral squamous cell carcinoma cells (identified by MS/GST pulldown). This interaction elicits IL-8 production; IL-8 activates STAT3 signaling in T cells, promoting T cell apoptosis and inhibiting T cell proliferation.","method":"MS/GST pulldown assay, cytokine antibody assay, co-culture experiments, Western blot for STAT3/p-STAT3","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown identification, partial mechanistic follow-up, no reciprocal Co-IP, single lab","pmids":["36361568"],"is_preprint":false},{"year":2024,"finding":"ENO1 acts as an RNA-binding protein in gastric cancer cells, stabilizing the mRNAs of SOX9, VEGFA, GPRC5A, and MCL1 by binding to them, and interacting with NEAT1, LINC00511, CD44, and PKM2 to regulate their expression, thereby promoting cell proliferation, migration, and inhibiting apoptosis.","method":"RNA immunoprecipitation sequencing (RIP-seq), RNA sequencing, bioinformatics analysis","journal":"Journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP-seq established genome-wide binding, but functional validation of individual targets is limited, single lab","pmids":["37201055"],"is_preprint":false},{"year":2020,"finding":"ENO1 promotes lung cancer stem cell self-renewal and invasion by inactivating the AMPK pathway and activating the mTOR pathway. ENO1 was identified as the cell-surface target antigen of monoclonal antibody 12C7 by LC-MALDI-TOF/TOF mass spectrometry and immunoprecipitation.","method":"LC-MALDI-TOF/TOF mass spectrometry, immunoprecipitation, immunofluorescence, RNA-seq, KEGG pathway analysis, immunoblot for AMPK/mTOR pathway","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — antigen identified by MS and confirmed by IP, pathway validated by RNA-seq and immunoblot, functional assays","pmids":["33579362"],"is_preprint":false},{"year":2024,"finding":"UCHL3 deubiquitinase stabilizes ENO1 protein through its deubiquitinating enzyme activity in TP53-mutant colorectal cancer. The JAK2-STAT3 pathway controls UCHL3 expression; pacritinib (JAK2 inhibitor) suppresses UCHL3, reducing ENO1 stability and glycolysis.","method":"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression, in vitro and in vivo functional assays, pharmacological inhibition","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — deubiquitination confirmed biochemically, pathway validated pharmacologically and genetically, single lab","pmids":["40487654"],"is_preprint":false},{"year":2023,"finding":"ENO1 upregulates PD-L1 expression in pancreatic ductal adenocarcinoma cells through the HIF-1α signaling pathway, thereby preventing CD8+ T cell infiltration and promoting immune evasion.","method":"CRISPR/Cas9 ENO1 knockout, flow cytometry, in vivo mouse PDAC models, mechanistic pathway analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined immune phenotype, in vivo validation, signaling pathway implicated","pmids":["39752908"],"is_preprint":false},{"year":2019,"finding":"ENO1 silencing in ENO1-deleted glioma cells establishes the concept of collateral lethality: small-molecule enolase inhibitor POMHEX selectively kills ENO1-deleted glioma cells and eradicates intracranial orthotopic ENO1-deleted tumors in mice, demonstrating ENO1 as a glycolytic enzyme whose loss creates dependency on ENO2.","method":"In vitro cell killing assays, intracranial orthotopic xenograft mouse model, pharmacokinetic studies in non-human primates","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro and in vivo proof-of-concept, dose-tolerable in primates, collateral lethality mechanism rigorously validated","pmids":["33230295"],"is_preprint":false},{"year":2022,"finding":"ENO1 promotes OSCC tumor cell migration and invasion through a dual mechanism: (1) tumor cell-derived lactic acid (produced via ENO1-mediated glycolysis) activates macrophages to secrete IL-6, and (2) paracrine ENO1 signals through TLR4 on macrophages to further stimulate IL-6 secretion. IL-6 in turn promotes tumor cell EMT and invasion in a positive feedback loop.","method":"siRNA knockdown, recombinant ENO1 stimulation, conditioned medium experiments, cytokine measurement, EMT marker analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — dual mechanism validated by siRNA and recombinant protein, paracrine signaling confirmed by conditioned medium, single lab","pmids":["36614179"],"is_preprint":false},{"year":2023,"finding":"Extracellular ENO1 (surface or secreted form) enhances glycolysis by upregulating HIF-1α and glycolysis-related gene expression in multiple myeloma cells. ENO1-specific monoclonal antibody blocks these extracellular ENO1-mediated effects and reduces tumor growth in an MM xenograft model.","method":"ENO1 knockdown, addition of recombinant extracellular ENO1 protein, HIF-1α silencing, glycolysis assays, Seahorse analysis, in vivo MM xenograft model with ENO1 mAb","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — extracellular function demonstrated by recombinant protein addition and HIF-1α silencing rescue, in vivo validation, single lab","pmids":["37800625"],"is_preprint":false},{"year":2023,"finding":"In hepatic stellate cells, the FAK/Ras/c-myc/ENO1 pathway promotes aerobic glycolysis and liver fibrosis. Chromatin immunoprecipitation and dual-luciferase reporter assays validated that c-myc binds the ENO1 promoter to drive ENO1 transcription in this context.","method":"ChIP, dual-luciferase reporter assay, FRNK knockout mouse model, in vitro LX-2 cell experiments, glycolysis measurements","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP and reporter assay established c-myc binding at ENO1 promoter, in vivo genetic validation, single lab","pmids":["35125823"],"is_preprint":false},{"year":2024,"finding":"ENO1 mRNA is acetylated at N4-cytidine (ac4C) by NAT10 (N-acetyltransferase 10), which enhances ENO1 mRNA stability and translation. NAT10 inhibition reduces ac4C levels on ENO1 mRNA, decreasing ENO1 expression and thereby inhibiting glycolysis and promoting apoptosis in NSCLC cells.","method":"ac4C-RNA immunoprecipitation (acRIP), dual-luciferase reporter assay, ENO1 overexpression rescue experiments, glycolysis and apoptosis assays","journal":"BMC pulmonary medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C modification confirmed by acRIP, writer identified, functional rescue with ENO1 overexpression, single lab","pmids":["39948547"],"is_preprint":false},{"year":2022,"finding":"The lncRNA AL355338 directly binds ENO1 protein, enhances its stability by modulating ubiquitination and degradation, and enables ENO1/EGFR complex formation to activate EGFR-AKT signaling and promote NSCLC glycolysis and progression.","method":"RNA pull-down, mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation, in situ proximity ligation assay, ubiquitination assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding by RIP/pulldown, ubiquitination modulation demonstrated, ENO1/EGFR complex by PLA, single lab","pmids":["34627260"],"is_preprint":false},{"year":2023,"finding":"ENO1 promotes hypoxia-induced ERK phosphorylation in pancreatic ductal adenocarcinoma cells, thereby inhibiting apoptosis and promoting tumor survival and invasion. Under hypoxic conditions, CoCl2-treated ENO1-knockdown cells show elevated caspase-3 and increased apoptosis, reversing the hypoxia-induced ERK signaling.","method":"Transcriptomic sequencing, ENO1 knockdown, ERK phosphorylation assay, apoptosis assay, in vivo PDAC hindlimb ischemia model","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic and biochemical validation of ERK pathway, in vivo confirmation, single lab","pmids":["36476328"],"is_preprint":false},{"year":2024,"finding":"ENO1 deletion in colorectal cancer cells inactivates AKT/STAT3 signaling, which leads to decreased glycolysis and enhanced ferroptosis. AKT activator SC79 partially reverses the effects of ENO1 deficiency on glycolysis, proliferation, and ferroptosis, placing ENO1 upstream of the AKT/STAT3 axis.","method":"CRISPR-based ENO1 knockdown, AKT activator rescue (SC79), glycolysis measurement, ferroptosis markers, cell proliferation assays","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis via rescue experiment with AKT activator, multiple phenotypic readouts, single lab","pmids":["38414789"],"is_preprint":false},{"year":2023,"finding":"ENO1 promotes gemcitabine resistance in pancreatic cancer by maintaining expression of YAP1 (a Hippo pathway effector), which promotes autophagy and protects cells from gemcitabine-induced apoptosis. YAP1 overexpression attenuates the inhibitory effects of ENO1 silencing.","method":"ENO1 knockdown, YAP1 overexpression rescue, autophagy assays (TEM, flow cytometry), in vivo tumor growth model, immunoblot","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis established by YAP1 overexpression rescue, in vivo validation, single lab","pmids":["38517039"],"is_preprint":false},{"year":2021,"finding":"CircNFKB1 physically interacts with ENO1, and this interaction regulates expression of the parental gene NFKB1 to sustain NF-κB signaling pathway activation in chondrocytes, promoting osteoarthritis progression.","method":"circRNA sequencing, RNA pulldown, co-immunoprecipitation, NF-κB signaling assays, intra-articular injection mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct ENO1-circRNA interaction by RIP/pulldown, in vivo validation, single lab","pmids":["35945200"],"is_preprint":false},{"year":2024,"finding":"LINC00520 lncRNA binds ENO1 protein and blocks FBXW7-mediated ubiquitination and proteasomal degradation of ENO1, thereby stabilizing ENO1 to promote glycolysis and cisplatin resistance in osteosarcoma.","method":"Co-immunoprecipitation, ubiquitination assay, rescue experiments, in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — lncRNA-ENO1 interaction by Co-IP, FBXW7-mediated ubiquitination blocking demonstrated, in vivo validation","pmids":["39168299"],"is_preprint":false},{"year":2019,"finding":"ENO1 expression promotes β-catenin expression in bladder cancer cells. Ectopic β-catenin overexpression rescues proliferation impaired by ENO1 knockdown, and β-catenin knockdown phenocopies ENO1 knockdown, establishing ENO1 as an upstream regulator of β-catenin in bladder cancer.","method":"Lentivirus-mediated knockdown and overexpression, β-catenin rescue experiments, double knockdown, cell proliferation/growth assays","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis by rescue experiment, no biochemical mechanism established, single lab","pmids":["31431517"],"is_preprint":false},{"year":2023,"finding":"Targeting endothelial ENO1 via siRNA or inhibitor restores hypoxia-induced endothelial dysfunction (excessive proliferation, angiogenesis, adhesion). RNA-seq showed ENO1 targets mitochondrion-related genes and the PI3K-Akt signaling pathway in endothelial cells. Adeno-associated virus overexpressing ENO1 worsens hypoxic pulmonary hypertension.","method":"siRNA knockdown, ENO1 inhibitor, AAV-ENO1 delivery in vivo, RNA-seq, Seahorse mitochondrial function analysis, mouse pulmonary hypertension model","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic gain- and loss-of-function with defined phenotype, RNA-seq pathway analysis, multiple methods","pmids":["37075135"],"is_preprint":false},{"year":2024,"finding":"Disturbed shear stress (DS) induces ENO1 expression in vascular endothelial cells. ENO1 silencing represses DS- and TGF-β-induced endothelial inflammation and endothelial-to-mesenchymal transition (EndMT). ENO1 is highly expressed in ECs at the proatherogenic inner curvature of the mouse aortic arch in vivo.","method":"Single-cell RNA sequencing, pseudotime trajectory analysis, ENO1 siRNA knockdown with shear stress/TGF-β stimulation, in vivo mouse aortic arch analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq combined with functional knockdown, in vivo localization, multiple orthogonal approaches","pmids":["38261622"],"is_preprint":false},{"year":2021,"finding":"ENO1 promotes invasion and metastasis in Burkitt lymphoma by acting as a plasminogen receptor that recruits plasminogen (PLG), promoting plasmin generation and TGF-β1 activation, which activates PI3K-AKT and EMT signaling pathways. A natural compound (Ciwujianoside E/L-06) disrupts the ENO1-PLG interaction and reduces tumor growth.","method":"RNA interference, Co-IP/ENO1-PLG interaction assay, plasmin activity assay, TGF-β1 activation measurement, in vitro and in vivo functional assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — plasminogen receptor function biochemically demonstrated, rescue by TGF-β1 addition, in vivo inhibitor validation","pmids":["38897160"],"is_preprint":false},{"year":2023,"finding":"ENO1, acting as an RNA-binding protein, binds to the 3'UTR of Klf2 mRNA to stabilize it; KMT5A (H4K20 methyltransferase) and RFX1 transcription factor associate with the ENO1 promoter to regulate its transcription in diabetic nephropathy. High glucose downregulates KMT5A and increases RFX1, leading to elevated ENO1 expression and endothelial-to-mesenchymal transition.","method":"ChIP, promoter activity assay, siRNA knockdown, Co-immunoprecipitation between KMT5A and RFX1, in vivo DN mouse and patient samples","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrated promoter binding, epistasis by siRNA rescue, in vivo validation","pmids":["34803485"],"is_preprint":false}],"current_model":"ENO1 is a multifunctional glycolytic enzyme (catalyzing 2-phosphoglycerate to phosphoenolpyruvate) that also operates as an RNA-binding protein to regulate mRNA translation and stability (e.g., IRP1 mRNA decay via CNOT6 recruitment, YAP1 mRNA translation, KLF2 mRNA stabilization), produces a nuclear transcriptional repressor of c-myc (MBP-1) via alternative translation/transcription, acts as a cell-surface plasminogen receptor promoting invasion, and is subject to multiple post-translational modifications—including arginine methylation by PRMT5/PRMT6 that promotes active dimer formation, lysine crotonylation by CBP/SIRT2 that enhances enzymatic activity, and ubiquitination/deubiquitination by FBXW7/NEDD4L and USP21/USP46 respectively that controls its protein stability—while its downstream signaling encompasses HGFR-Wnt-SLUG, AKT-STAT3, ERK, and HIF-1α pathways that collectively drive tumor glycolysis, invasion, metastasis, immune evasion, and drug resistance."},"narrative":{"mechanistic_narrative":"ENO1 is a metabolic glycolytic enzyme that converts 2-phosphoglycerate to phosphoenolpyruvate, and whose enzymatic activity, abundance, and moonlighting functions are extensively co-opted to drive aerobic glycolysis, tumor progression, and inflammatory/fibrotic remodeling across diverse tissues [PMID:36815049, PMID:33230295]. The single ENO1 locus generates two functionally distinct products: a cytoplasmic 48 kDa α-enolase and a 37 kDa nuclear form (MBP-1) produced via an alternatively transcribed intron III mRNA, which binds the c-myc P2 promoter and represses c-myc transcription [PMID:10802057, PMID:20849415]. Beyond glycolysis, ENO1 acts as a sequence-selective RNA-binding protein that controls the fate of target transcripts—recruiting the deadenylase CNOT6 to accelerate IRP1 mRNA decay and thereby restrain ferroptosis [PMID:35121990], binding CUG-rich elements of YAP1 mRNA to promote its translation and downstream prostaglandin signaling [PMID:37500770], and stabilizing 3'UTR-bound mRNAs such as KLF2 to limit NLRP3 inflammasome-mediated pyroptosis [PMID:39467260]. ENO1 enzymatic activity is tuned by post-translational modifications: PRMT5/PRMT6 methylation at R9 promotes active dimer formation while R372 methylation enhances substrate binding [PMID:36815049, PMID:36999124], and CBP-written, SIRT2-erased K420 crotonylation augments catalysis [PMID:34547627]. ENO1 protein stability is set by a ubiquitination/deubiquitination balance, with FBXW7 and NEDD4L driving proteasomal degradation [PMID:26097998, PMID:35316145] and USP21, USP46, and UCHL3 stabilizing the protein to sustain glycolysis [PMID:32707136, PMID:38385089, PMID:40487654]. Extracellular and cell-surface ENO1 functions as a plasminogen receptor and interacts with HGFR to engage Wnt/β-catenin, PI3K-AKT, ERK, STAT3, and HIF-1α signaling that collectively drive EMT, invasion, metastasis, immune evasion, and drug resistance [PMID:34145039, PMID:39752908, PMID:38897160]. ENO1 is the target of collateral-lethality therapeutics: in ENO1-deleted glioma, ENO2 dependency renders cells selectively vulnerable to the enolase inhibitor POMHEX [PMID:33230295].","teleology":[{"year":2000,"claim":"Established that the ENO1 locus is functionally bifunctional, encoding both a cytoplasmic glycolytic enzyme and a distinct nuclear transcriptional repressor, reframing ENO1 as more than a metabolic gene.","evidence":"Alternative translation analysis with α-enolase/GFP chimeras, subcellular localization, and luciferase reporter assays of MBP-1 binding the c-myc P2 promoter","pmids":["10802057"],"confidence":"High","gaps":["Did not resolve whether MBP-1 arises from alternative translation versus a separate transcript","Endogenous occupancy of the c-myc promoter not shown"]},{"year":2010,"claim":"Resolved the origin of MBP-1, showing it derives from an alternatively transcribed intron III mRNA that is far more efficient at producing the repressor and is induced by hypoxia.","evidence":"MBP-1 promoter luciferase reporters, cell fractionation with RT-PCR, coupled transcription/translation, and MG132 proteasome inhibition","pmids":["20849415"],"confidence":"High","gaps":["Trans-factors driving hypoxic MBP-1 induction not identified","Relative in vivo contribution of MBP-1 versus full-length ENO1 to c-myc repression unquantified"]},{"year":2008,"claim":"Linked ENO1/MBP-1 abundance to MYC oncoprotein levels and proliferation, providing a regulatable handle (retinoic acid–driven dephosphorylation) on the ENO1-MYC axis.","evidence":"2D-DIGE/MS phosphoprotein identification, siRNA knockdown, and proliferation assays in follicular thyroid carcinoma","pmids":["19060179"],"confidence":"Medium","gaps":["Kinase/phosphatase responsible for ENO1-A1 dephosphorylation not defined","Mechanism connecting phosphostate to product levels unclear"]},{"year":2015,"claim":"Identified the first stability control point for ENO1 protein and a developmental role, showing FBXW7-mediated degradation restrains glycolysis while ENO1 is required for Wnt-driven epithelial trans-differentiation.","evidence":"Reciprocal Co-IP, ubiquitination assays, and functional cell assays (FBXW7); proteomics with siRNA in primary ATII cells and bleomycin lung injury model","pmids":["26097998","26035385"],"confidence":"High","gaps":["Degron/phosphodegron recognized by FBXW7 not mapped","Whether trans-differentiation requires glycolytic versus moonlighting ENO1 unresolved"]},{"year":2017,"claim":"Defined a surface/adhesion role, showing ENO1 governs integrin and uPAR signaling to suppress ROS and senescence, distinct from its enzymatic function.","evidence":"shRNA silencing, confocal and atomic force microscopy, adhesion/invasion assays, and xenografts in pancreatic cancer","pmids":["28086938"],"confidence":"High","gaps":["Direct physical interaction of ENO1 with integrin/uPAR not biochemically demonstrated","Causal step linking ENO1 to integrin transcription unknown"]},{"year":2021,"claim":"Established ENO1 as a sequence-selective RNA-binding protein that actively shapes the transcriptome, recruiting a deadenylase to destabilize a specific mRNA and thereby controlling ferroptosis.","evidence":"RNA immunoprecipitation, RNA decay assays, and in vitro/in vivo ferroptosis readouts in hepatocellular carcinoma (IRP1/CNOT6/Mfrn1)","pmids":["35121990"],"confidence":"High","gaps":["RNA-binding domain/motif within ENO1 not mapped","Generality of CNOT6 recruitment beyond IRP1 untested"]},{"year":2021,"claim":"Defined membrane-receptor and signaling cascades downstream of ENO1, showing it engages HGFR to activate Src-PI3K-AKT-Wnt and drive EMT in metastasis.","evidence":"Co-IP, phosphorylation assays, orthotopic and tail-vein mouse models, and anti-ENO1 antibody studies in lung cancer","pmids":["34145039"],"confidence":"High","gaps":["Stoichiometry and direct binding interface between ENO1 and HGFR unresolved","Whether intracellular versus surface ENO1 mediates HGFR activation unclear"]},{"year":2022,"claim":"Mapped post-translational control of ENO1 catalysis, showing arginine methylation drives active dimer formation and substrate binding while lysine crotonylation enhances enzymatic activity.","evidence":"Site-directed mutagenesis, in vitro methylation/crotonylation assays, enzymatic activity and glycolytic flux measurements (PRMT6 R9/R372; CBP/SIRT2 K420)","pmids":["36815049","34547627"],"confidence":"High","gaps":["Crosstalk between distinct PTMs on the same molecule untested","Structural basis of dimerization change from R9 methylation not solved"]},{"year":2023,"claim":"Extended ENO1 RNA-binding to translational activation, showing it binds CUG-rich elements of YAP1 mRNA to promote translation and arachidonic acid/PGE2 signaling, and reinforced PRMT5-driven dimer activation under high glucose.","evidence":"RIP, translation assays, and in vitro/in vivo functional experiments in hepatocellular carcinoma (YAP1); dimethylation and dimerization assays in ovarian cancer (PRMT5 R9)","pmids":["37500770","36999124"],"confidence":"High","gaps":["How ENO1 switches between mRNA decay and translational activation modes is unknown","Signal coupling glucose to PRMT5-ENO1 methylation incompletely defined"]},{"year":2024,"claim":"Layered upstream mRNA modification control onto ENO1, showing m6A (METTL3/RBM15-YTHDF1), m5C (NSUN2/YBX1), and ac4C (NAT10) marks on ENO1 mRNA enhance its translation/stability to boost glycolysis, and identified a deubiquitinase network (USP21, UCHL3) stabilizing ENO1 protein.","evidence":"m6A/m5C/ac4C site mapping, RIP, reporter and ubiquitination assays, and in vitro/in vivo functional assays across multiple cancers","pmids":["35078505","38769664","39948547","38385089","40487654"],"confidence":"Medium","gaps":["Functional hierarchy among the multiple mRNA modifications unresolved","Several writer/reader links validated in single labs without reciprocal confirmation"]},{"year":2025,"claim":"Demonstrated direct enzymatic regulation of ENO1 by a receptor protein in immune cells, showing IL1R2 binding suppresses ENO1 activity to dampen glycolysis-driven pyroptosis and inflammation.","evidence":"Proteomic screen, Co-IP, enzymatic activity assays, IL1R2-knockout mice, and ENO1 inhibitor rescue in a sepsis model","pmids":["40704655"],"confidence":"High","gaps":["Structural basis of IL1R2-mediated enzymatic inhibition not solved","Whether this regulation operates in tumor settings untested"]},{"year":2019,"claim":"Validated ENO1 as a therapeutic vulnerability via collateral lethality, showing ENO1-deleted tumors depend on ENO2 and are selectively killed by an enolase inhibitor.","evidence":"In vitro killing assays, intracranial orthotopic xenografts, and non-human primate pharmacokinetics (POMHEX)","pmids":["33230295"],"confidence":"High","gaps":["Applicability beyond ENO1-deleted gliomas unestablished","Selectivity for ENO1 versus ENO2 in non-deleted tissues not addressed here"]},{"year":null,"claim":"How ENO1 partitions between its glycolytic, nuclear (MBP-1), RNA-binding, and cell-surface/plasminogen-receptor functions—and what governs the switch—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural definition of the RNA-binding interface","Determinants of cytoplasmic versus nuclear versus surface localization unknown","Integrated model reconciling moonlighting roles in a single cell lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[7,31]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,3,25,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[45]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,28,45]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[17,33]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,31]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,38,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,34]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,38]}],"complexes":[],"partners":["CNOT6","HGFR","FBXW7","NEDD4L","USP21","PRMT5","IL1R2","PLG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06733","full_name":"Alpha-enolase","aliases":["2-phospho-D-glycerate hydro-lyase","C-myc promoter-binding protein","Enolase 1","MBP-1","MPB-1","Non-neural enolase","NNE","Phosphopyruvate hydratase","Plasminogen-binding protein"],"length_aa":434,"mass_kda":47.2,"function":"Enolase that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in glycolysis and the reverse reaction in gluconeogenesis (PubMed:1369209, PubMed:29775581). Also involved in various processes such as growth control, hypoxia tolerance and allergic responses (PubMed:10802057, PubMed:12666133, PubMed:2005901, PubMed:29775581). May also function in the intravascular and pericellular fibrinolytic system due to its ability to serve as a receptor and activator of plasminogen on the cell surface of several cell-types such as leukocytes and neurons (PubMed:12666133). Stimulates immunoglobulin production (PubMed:1369209) Binds to the myc promoter and acts as a transcriptional repressor. May be a tumor suppressor","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P06733/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ENO1","classification":"Not Classified","n_dependent_lines":697,"n_total_lines":1208,"dependency_fraction":0.5769867549668874},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000074800","cell_line_id":"CID000937","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ENO2","stoichiometry":0.2},{"gene":"TMCC3","stoichiometry":0.2},{"gene":"ENO3","stoichiometry":0.2},{"gene":"ACTR3B","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"INPPL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000937","total_profiled":1310},"omim":[{"mim_id":"620472","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2B; TRAPPC2B","url":"https://www.omim.org/entry/620472"},{"mim_id":"612280","title":"FUCOSIDASE, ALPHA-L, 1; FUCA1","url":"https://www.omim.org/entry/612280"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"},{"mim_id":"191710","title":"CYTIDINE MONOPHOSPHATE (UMP-CMP) KINASE 1, CYTOSOLIC; CMPK1","url":"https://www.omim.org/entry/191710"},{"mim_id":"172430","title":"ENOLASE 1; ENO1","url":"https://www.omim.org/entry/172430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ENO1"},"hgnc":{"alias_symbol":["PPH","MBP-1"],"prev_symbol":["ENO1L1","MPB1","ENO1-IT1"]},"alphafold":{"accession":"P06733","domains":[{"cath_id":"3.30.390.10","chopping":"4-127","consensus_level":"high","plddt":97.2897,"start":4,"end":127},{"cath_id":"3.20.20.120","chopping":"146-426","consensus_level":"high","plddt":97.9731,"start":146,"end":426}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06733","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06733-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06733-F1-predicted_aligned_error_v6.png","plddt_mean":97.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ENO1","jax_strain_url":"https://www.jax.org/strain/search?query=ENO1"},"sequence":{"accession":"P06733","fasta_url":"https://rest.uniprot.org/uniprotkb/P06733.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06733/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06733"}},"corpus_meta":[{"pmid":"10802057","id":"PMC_10802057","title":"ENO1 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   \"method\": \"Alternative translation analysis, alpha-enolase/GFP chimera transfection with subcellular localization, luciferase reporter assay with MBP-1 consensus binding sequence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (GFP chimeras, reporter assay, functional binding) in single study; replicated concept in later work\",\n      \"pmids\": [\"10802057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MBP-1 is encoded by an alternatively transcribed mRNA from intron III of the ENO1 gene (not solely by alternative translation of the full-length ENO1 mRNA). This MBP-1 transcript is 17.8-fold more efficient for MBP-1 protein production than the ENO1 transcript. MBP-1 protein stability is regulated by proteasomal degradation (stabilized by MG132). Hypoxia significantly increases transcriptional activation of the MBP-1 gene.\",\n      \"method\": \"MBP-1 promoter-driven luciferase reporter assays, biochemical cell fractionation with RT-PCR, coupled transcription/translation reactions, proteasome inhibitor (MG132) treatment\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (reporter assay, fractionation, in vitro translation) in single study\",\n      \"pmids\": [\"20849415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ENO1 functions as an RNA-binding protein that recruits the deadenylase CNOT6 to accelerate mRNA decay of iron regulatory protein 1 (IRP1) in hepatocellular carcinoma cells. This leads to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis.\",\n      \"method\": \"RNA immunoprecipitation, in vitro and in vivo experiments, RNA decay assays, functional knockdown/overexpression with ferroptosis readouts\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — RNA-binding demonstrated by RIP, mechanistic pathway validated in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35121990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1, acting as an RNA-binding protein, binds to cytosine-uracil-guanine-rich elements of YAP1 mRNA to promote its translation, thereby activating arachidonic acid metabolism via the YAP1/PLCB1/HPGD axis and subsequent prostaglandin E2 accumulation, which drives hepatocellular carcinoma progression.\",\n      \"method\": \"RNA immunoprecipitation, mRNA translation assays, in vitro and in vivo functional experiments, clinical sample analysis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — RIP demonstrated direct binding, pathway validated in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"37500770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ENO1 promotes lung cancer metastasis by interacting with hepatocyte growth factor receptor (HGFR) and activating HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co-receptor LRP5/6. This decreases GSK3β activity via Src-PI3K-AKT signaling and inactivates the β-catenin destruction complex, ultimately upregulating SLUG and β-catenin to drive EMT.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, knockdown/overexpression with phenotypic readouts, orthotopic and tail-vein injection mouse models, anti-ENO1 antibody functional studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP established interaction, signaling pathway validated by phosphorylation assays, confirmed in vivo with multiple models\",\n      \"pmids\": [\"34145039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ENO1 controls alphav/beta3 integrin expression in pancreatic ductal adenocarcinoma (PDA) cells. ENO1 silencing downregulates alphav/beta3 integrin, increases RGD-independent adhesion to vitronectin via uPAR, triggers ERK1-2 and RAC activation, ROS accumulation, and cellular senescence. Anti-uPAR antibody reduces ROS and senescence in ENO1-silenced cells.\",\n      \"method\": \"shRNA-mediated ENO1 silencing, confocal microscopy, atomic force microscopy, functional adhesion/invasion assays, mouse xenograft model\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (AFM, confocal, functional assays, in vivo), mechanistic rescue experiments\",\n      \"pmids\": [\"28086938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXW7 physically binds to ENO1 and targets it for ubiquitin-mediated proteasomal degradation, thereby suppressing ENO1-induced lactate production, cell proliferation, and migration in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, 2D protein electrophoresis/mass spectrometry, Western blotting, functional cell assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP established physical interaction, ubiquitination confirmed biochemically, functional rescue experiments\",\n      \"pmids\": [\"26097998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT6 methylates ENO1 at R9 and R372: R9 methylation promotes active ENO1 dimer formation and R372 methylation promotes 2-phosphoglycerate (2-PG) substrate binding to ENO1, thereby increasing glycolytic activity in lung cancer cells.\",\n      \"method\": \"In vitro methylation assays, mutational analysis of methylation sites, enzymatic activity assays, glycolysis flux measurements\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis combined with enzymatic activity assays establishing mechanism\",\n      \"pmids\": [\"36815049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT5 symmetrically dimethylates ENO1 at arginine 9 (R9) to promote active ENO1 dimer formation, increasing glycolysis flux and accelerating ovarian cancer tumor growth. PRMT5 signals high glucose to increase ENO1 methylation.\",\n      \"method\": \"In vitro dimethylation assays, co-immunoprecipitation, ENO1 dimerization assays, glycolysis flux measurement, knockdown/inhibitor studies in vitro and in vivo\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific methylation and dimerization validated biochemically, in vitro and in vivo functional confirmation\",\n      \"pmids\": [\"36999124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lysine crotonylation (Kcr) of ENO1 is elevated in colorectal cancer. CBP (CREB-binding protein) functions as the crotonyltransferase writing K420 crotonylation on ENO1, and SIRT2 acts as the decrotonylase. ENO1 K420 Kcr enhances ENO1 enzymatic activity and promotes cancer cell growth, migration, and invasion.\",\n      \"method\": \"Mass spectrometry-based crotonylomics, in vitro crotonylation assay, site-directed mutagenesis at K420, functional cell assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — writer/eraser identified biochemically, site-specific modification validated by MS and mutagenesis\",\n      \"pmids\": [\"34547627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NEDD4L (an E3 ubiquitin ligase) binds ENO1 and promotes its ubiquitination and proteasomal degradation, thereby suppressing glycolysis and cell proliferation in oral squamous cell carcinoma. ENO1 overexpression reverses NEDD4L-mediated suppression.\",\n      \"method\": \"UbiBrowser computational prediction validated by Co-IP, ubiquitination assay, rescue experiments with ENO1 overexpression, in vivo mouse tumor model\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay, functional rescue, single lab\",\n      \"pmids\": [\"35316145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP46, a deubiquitinating enzyme, directly stabilizes ENO1 protein by removing ubiquitin modifications, thereby promoting ESCC cell migration, invasion, and metastasis via the EMT process.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, knockdown functional studies, in vivo metastasis model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical deubiquitination demonstrated, functional in vivo validation, single lab\",\n      \"pmids\": [\"32707136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP21 directly interacts with and deubiquitinates ENO1 through K48-linked deubiquitination, stabilizing ENO1 protein to promote aerobic glycolysis and cholangiocarcinoma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination/deubiquitination assay, in vitro and in vivo functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical deubiquitination and Co-IP demonstrated, in vivo validation, single lab\",\n      \"pmids\": [\"38385089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The m6A methyltransferase METTL3 methylates ENO1 mRNA at adenosine 359 (359A), which facilitates binding of the m6A reader YTHDF1 to ENO1 mRNA, resulting in enhanced ENO1 translation and increased glycolysis in lung adenocarcinoma.\",\n      \"method\": \"m6A site mapping, RNA immunoprecipitation, YTHDF1-ENO1 mRNA interaction assay, translation efficiency measurement, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — m6A site precisely identified, reader-mRNA interaction validated by RIP, translation enhancement confirmed, multiple methods\",\n      \"pmids\": [\"35078505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C5aR1-positive neutrophil-secreted IL1β and TNFα activate ERK1/2 signaling, which phosphorylates WTAP at serine 341 to stabilize WTAP protein. Stabilized WTAP promotes m6A methylation of ENO1 mRNA, enhancing ENO1 expression and breast cancer glycolysis.\",\n      \"method\": \"m6A methylation assay, WTAP phosphorylation assay, RNA immunoprecipitation, in vitro and in vivo functional assays, co-culture models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation and m6A modification biochemically linked, in vivo validation, single lab\",\n      \"pmids\": [\"34312368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The NSUN2/YBX1 axis writes and reads m5C modification on ENO1 mRNA respectively: NSUN2 methylates ENO1 mRNA (m5C writer) and YBX1 reads m5C on ENO1 mRNA to upregulate ENO1 expression in an m5C-dependent manner, promoting glucose metabolism reprogramming in colorectal cancer. Lactic acid derived from cancer cells activates NSUN2 transcription via H3K18 lactylation and induces NSUN2 K356 lactylation to enhance target RNA capture.\",\n      \"method\": \"m5C methylation assays, RNA immunoprecipitation, chromatin immunoprecipitation, Co-IP, functional rescue experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — writer/reader biochemically identified by RIP and ChIP, feedback mechanism demonstrated, single lab\",\n      \"pmids\": [\"38769664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15/METTL3 complex enhances m6A modification at the 359A site of ENO1 mRNA, promoting ENO1 protein translation efficiency in a YTHDF1-dependent manner in bladder cancer. TGF-β activates RBM15/METTL3 via Smad2/3. ENO1 in turn augments PCNA protein stability by reducing K48-linked ubiquitination of PCNA, preventing its ER-associated degradation.\",\n      \"method\": \"m6A site mapping, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-reader interaction confirmed by RIP, PCNA ubiquitination mechanism validated biochemically, single lab\",\n      \"pmids\": [\"38823761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Exosome-derived ENO1 can be transferred between hepatocellular carcinoma cells via exosome-mediated crosstalk. Transferred ENO1 upregulates integrin α6β4 expression and activates the FAK/Src-p38MAPK pathway in recipient cells, promoting HCC growth and metastasis.\",\n      \"method\": \"Exosome isolation and transfer experiments, Western blotting, Co-IP, functional invasion/migration assays, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — exosome transfer validated, signaling pathway activation demonstrated, in vivo confirmation, single lab\",\n      \"pmids\": [\"33184263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WBP2 interacts with ENO1 (identified by MS/GST pulldown) and modulates ENO1 glycolysis activity via the ENO1-PI3K/Akt signaling pathway to promote glioma cell proliferation and migration.\",\n      \"method\": \"MS/GST pulldown assay, Co-immunoprecipitation, knockdown functional studies, in vitro and in vivo glioma models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pulldown and Co-IP established interaction, functional pathway validation, single lab\",\n      \"pmids\": [\"29497031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGFRL1 physically interacts with ENO1 and regulates ENO1 expression and downstream PI3K/Akt signaling in small-cell lung cancer, mediating chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression functional studies, signaling pathway analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, partial mechanistic follow-up, single lab\",\n      \"pmids\": [\"31957179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ENO1 and PDIA3 are required for Wnt/β-catenin-driven trans-differentiation of murine alveolar type II epithelial cells to type I cells. siRNA-mediated knockdown of ENO1 in primary ATII cells reduces T1α (ATI cell marker) expression, indicating diminished trans-differentiation. ENO1 expression increases during ATII-to-ATI trans-differentiation and is decreased upon pharmacological Wnt/β-catenin inhibition.\",\n      \"method\": \"Proteomics/mass spectrometry, siRNA knockdown, immunoblotting, primary cell culture, in vivo bleomycin lung injury model\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific cellular phenotype, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"26035385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retinoic acid (RA) dephosphorylates the ENO1-A1 phosphoprotein isoform in follicular thyroid carcinoma cells, leading to downregulation of ENO1/MBP-1 gene products. RA-mediated and siRNA-mediated knockdown of ENO1/MBP-1 both reduce MYC oncoprotein levels and decrease proliferation of thyroid carcinoma cells.\",\n      \"method\": \"2D-DIGE, mass spectrometry, Western blotting, siRNA knockdown, proliferation assays\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoprotein identification by 2D-DIGE/MS, mechanistic link to MYC confirmed by siRNA rescue, multiple methods\",\n      \"pmids\": [\"19060179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cinnamaldehyde (CA) covalently binds to ENO1 protein, destabilizes ENO1, and inhibits its glycolytic activity. Target identification was performed by chemical biology methods using an alkynyl-CA probe, molecular imaging, and live cell tracing.\",\n      \"method\": \"Activity-based protein profiling with alkynyl-CA probe, molecular imaging, live cell tracing, glycolysis assays, in vivo melanoma model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — covalent binding demonstrated by ABPP probe, glycolytic inhibition confirmed, in vivo validation\",\n      \"pmids\": [\"32013122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chlorogenic acid (CGA) covalently binds to ENO1 (identified by activity-based protein profiling) and suppresses ENO1 enzymatic activity, blocking the glycolytic pathway and thereby preventing UVA-induced cellular senescence in human dermal fibroblasts.\",\n      \"method\": \"Activity-based protein profiling (ABPP), co-immunoprecipitation, ENO1 activity assay, glycolysis measurement, photoaging mouse model with proteomics\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — covalent binding demonstrated by ABPP, enzymatic inhibition confirmed, in vivo validation\",\n      \"pmids\": [\"39741388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Interleukin 1 receptor 2 (IL1R2) physically binds ENO1 in macrophages and suppresses its enzymatic activity, thereby inhibiting glycolysis, GSDMD-mediated pyroptosis, and inflammation. IL1R2-deficient mice show heightened sepsis susceptibility that is partially rescued by ENO1 inhibition.\",\n      \"method\": \"Proteomic screening, co-immunoprecipitation, ENO1 enzymatic activity assay, genetic mouse models (IL1R2 KO), ENO1 inhibitor treatment, in vivo sepsis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic screen confirmed by Co-IP, enzymatic suppression validated, in vivo genetic and pharmacological validation with multiple readouts\",\n      \"pmids\": [\"40704655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1 binds to the 3'UTR of KLF2 mRNA to stabilize it, increasing KLF2 protein expression and suppressing NLRP3 inflammasome-mediated pyroptosis. ENO1 also binds to the 3'UTR of FUS mRNA to promote FUS expression and circFndc3b cyclization. This was identified in the context of exercise-induced neuroprotection in stroke.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, functional knockdown/overexpression experiments, in vivo MCAO mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP demonstrated direct 3'UTR binding, functional pathway validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"39467260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ENO1 binds to ApoC3 (apolipoprotein C-III) in oral squamous cell carcinoma cells (identified by MS/GST pulldown). This interaction elicits IL-8 production; IL-8 activates STAT3 signaling in T cells, promoting T cell apoptosis and inhibiting T cell proliferation.\",\n      \"method\": \"MS/GST pulldown assay, cytokine antibody assay, co-culture experiments, Western blot for STAT3/p-STAT3\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown identification, partial mechanistic follow-up, no reciprocal Co-IP, single lab\",\n      \"pmids\": [\"36361568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ENO1 acts as an RNA-binding protein in gastric cancer cells, stabilizing the mRNAs of SOX9, VEGFA, GPRC5A, and MCL1 by binding to them, and interacting with NEAT1, LINC00511, CD44, and PKM2 to regulate their expression, thereby promoting cell proliferation, migration, and inhibiting apoptosis.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq), RNA sequencing, bioinformatics analysis\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP-seq established genome-wide binding, but functional validation of individual targets is limited, single lab\",\n      \"pmids\": [\"37201055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ENO1 promotes lung cancer stem cell self-renewal and invasion by inactivating the AMPK pathway and activating the mTOR pathway. ENO1 was identified as the cell-surface target antigen of monoclonal antibody 12C7 by LC-MALDI-TOF/TOF mass spectrometry and immunoprecipitation.\",\n      \"method\": \"LC-MALDI-TOF/TOF mass spectrometry, immunoprecipitation, immunofluorescence, RNA-seq, KEGG pathway analysis, immunoblot for AMPK/mTOR pathway\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — antigen identified by MS and confirmed by IP, pathway validated by RNA-seq and immunoblot, functional assays\",\n      \"pmids\": [\"33579362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UCHL3 deubiquitinase stabilizes ENO1 protein through its deubiquitinating enzyme activity in TP53-mutant colorectal cancer. The JAK2-STAT3 pathway controls UCHL3 expression; pacritinib (JAK2 inhibitor) suppresses UCHL3, reducing ENO1 stability and glycolysis.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression, in vitro and in vivo functional assays, pharmacological inhibition\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — deubiquitination confirmed biochemically, pathway validated pharmacologically and genetically, single lab\",\n      \"pmids\": [\"40487654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1 upregulates PD-L1 expression in pancreatic ductal adenocarcinoma cells through the HIF-1α signaling pathway, thereby preventing CD8+ T cell infiltration and promoting immune evasion.\",\n      \"method\": \"CRISPR/Cas9 ENO1 knockout, flow cytometry, in vivo mouse PDAC models, mechanistic pathway analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined immune phenotype, in vivo validation, signaling pathway implicated\",\n      \"pmids\": [\"39752908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ENO1 silencing in ENO1-deleted glioma cells establishes the concept of collateral lethality: small-molecule enolase inhibitor POMHEX selectively kills ENO1-deleted glioma cells and eradicates intracranial orthotopic ENO1-deleted tumors in mice, demonstrating ENO1 as a glycolytic enzyme whose loss creates dependency on ENO2.\",\n      \"method\": \"In vitro cell killing assays, intracranial orthotopic xenograft mouse model, pharmacokinetic studies in non-human primates\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro and in vivo proof-of-concept, dose-tolerable in primates, collateral lethality mechanism rigorously validated\",\n      \"pmids\": [\"33230295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ENO1 promotes OSCC tumor cell migration and invasion through a dual mechanism: (1) tumor cell-derived lactic acid (produced via ENO1-mediated glycolysis) activates macrophages to secrete IL-6, and (2) paracrine ENO1 signals through TLR4 on macrophages to further stimulate IL-6 secretion. IL-6 in turn promotes tumor cell EMT and invasion in a positive feedback loop.\",\n      \"method\": \"siRNA knockdown, recombinant ENO1 stimulation, conditioned medium experiments, cytokine measurement, EMT marker analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — dual mechanism validated by siRNA and recombinant protein, paracrine signaling confirmed by conditioned medium, single lab\",\n      \"pmids\": [\"36614179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Extracellular ENO1 (surface or secreted form) enhances glycolysis by upregulating HIF-1α and glycolysis-related gene expression in multiple myeloma cells. ENO1-specific monoclonal antibody blocks these extracellular ENO1-mediated effects and reduces tumor growth in an MM xenograft model.\",\n      \"method\": \"ENO1 knockdown, addition of recombinant extracellular ENO1 protein, HIF-1α silencing, glycolysis assays, Seahorse analysis, in vivo MM xenograft model with ENO1 mAb\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — extracellular function demonstrated by recombinant protein addition and HIF-1α silencing rescue, in vivo validation, single lab\",\n      \"pmids\": [\"37800625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatic stellate cells, the FAK/Ras/c-myc/ENO1 pathway promotes aerobic glycolysis and liver fibrosis. Chromatin immunoprecipitation and dual-luciferase reporter assays validated that c-myc binds the ENO1 promoter to drive ENO1 transcription in this context.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, FRNK knockout mouse model, in vitro LX-2 cell experiments, glycolysis measurements\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP and reporter assay established c-myc binding at ENO1 promoter, in vivo genetic validation, single lab\",\n      \"pmids\": [\"35125823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ENO1 mRNA is acetylated at N4-cytidine (ac4C) by NAT10 (N-acetyltransferase 10), which enhances ENO1 mRNA stability and translation. NAT10 inhibition reduces ac4C levels on ENO1 mRNA, decreasing ENO1 expression and thereby inhibiting glycolysis and promoting apoptosis in NSCLC cells.\",\n      \"method\": \"ac4C-RNA immunoprecipitation (acRIP), dual-luciferase reporter assay, ENO1 overexpression rescue experiments, glycolysis and apoptosis assays\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C modification confirmed by acRIP, writer identified, functional rescue with ENO1 overexpression, single lab\",\n      \"pmids\": [\"39948547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA AL355338 directly binds ENO1 protein, enhances its stability by modulating ubiquitination and degradation, and enables ENO1/EGFR complex formation to activate EGFR-AKT signaling and promote NSCLC glycolysis and progression.\",\n      \"method\": \"RNA pull-down, mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation, in situ proximity ligation assay, ubiquitination assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding by RIP/pulldown, ubiquitination modulation demonstrated, ENO1/EGFR complex by PLA, single lab\",\n      \"pmids\": [\"34627260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1 promotes hypoxia-induced ERK phosphorylation in pancreatic ductal adenocarcinoma cells, thereby inhibiting apoptosis and promoting tumor survival and invasion. Under hypoxic conditions, CoCl2-treated ENO1-knockdown cells show elevated caspase-3 and increased apoptosis, reversing the hypoxia-induced ERK signaling.\",\n      \"method\": \"Transcriptomic sequencing, ENO1 knockdown, ERK phosphorylation assay, apoptosis assay, in vivo PDAC hindlimb ischemia model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic and biochemical validation of ERK pathway, in vivo confirmation, single lab\",\n      \"pmids\": [\"36476328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ENO1 deletion in colorectal cancer cells inactivates AKT/STAT3 signaling, which leads to decreased glycolysis and enhanced ferroptosis. AKT activator SC79 partially reverses the effects of ENO1 deficiency on glycolysis, proliferation, and ferroptosis, placing ENO1 upstream of the AKT/STAT3 axis.\",\n      \"method\": \"CRISPR-based ENO1 knockdown, AKT activator rescue (SC79), glycolysis measurement, ferroptosis markers, cell proliferation assays\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis via rescue experiment with AKT activator, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"38414789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1 promotes gemcitabine resistance in pancreatic cancer by maintaining expression of YAP1 (a Hippo pathway effector), which promotes autophagy and protects cells from gemcitabine-induced apoptosis. YAP1 overexpression attenuates the inhibitory effects of ENO1 silencing.\",\n      \"method\": \"ENO1 knockdown, YAP1 overexpression rescue, autophagy assays (TEM, flow cytometry), in vivo tumor growth model, immunoblot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis established by YAP1 overexpression rescue, in vivo validation, single lab\",\n      \"pmids\": [\"38517039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CircNFKB1 physically interacts with ENO1, and this interaction regulates expression of the parental gene NFKB1 to sustain NF-κB signaling pathway activation in chondrocytes, promoting osteoarthritis progression.\",\n      \"method\": \"circRNA sequencing, RNA pulldown, co-immunoprecipitation, NF-κB signaling assays, intra-articular injection mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct ENO1-circRNA interaction by RIP/pulldown, in vivo validation, single lab\",\n      \"pmids\": [\"35945200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC00520 lncRNA binds ENO1 protein and blocks FBXW7-mediated ubiquitination and proteasomal degradation of ENO1, thereby stabilizing ENO1 to promote glycolysis and cisplatin resistance in osteosarcoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rescue experiments, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — lncRNA-ENO1 interaction by Co-IP, FBXW7-mediated ubiquitination blocking demonstrated, in vivo validation\",\n      \"pmids\": [\"39168299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ENO1 expression promotes β-catenin expression in bladder cancer cells. Ectopic β-catenin overexpression rescues proliferation impaired by ENO1 knockdown, and β-catenin knockdown phenocopies ENO1 knockdown, establishing ENO1 as an upstream regulator of β-catenin in bladder cancer.\",\n      \"method\": \"Lentivirus-mediated knockdown and overexpression, β-catenin rescue experiments, double knockdown, cell proliferation/growth assays\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis by rescue experiment, no biochemical mechanism established, single lab\",\n      \"pmids\": [\"31431517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Targeting endothelial ENO1 via siRNA or inhibitor restores hypoxia-induced endothelial dysfunction (excessive proliferation, angiogenesis, adhesion). RNA-seq showed ENO1 targets mitochondrion-related genes and the PI3K-Akt signaling pathway in endothelial cells. Adeno-associated virus overexpressing ENO1 worsens hypoxic pulmonary hypertension.\",\n      \"method\": \"siRNA knockdown, ENO1 inhibitor, AAV-ENO1 delivery in vivo, RNA-seq, Seahorse mitochondrial function analysis, mouse pulmonary hypertension model\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic gain- and loss-of-function with defined phenotype, RNA-seq pathway analysis, multiple methods\",\n      \"pmids\": [\"37075135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disturbed shear stress (DS) induces ENO1 expression in vascular endothelial cells. ENO1 silencing represses DS- and TGF-β-induced endothelial inflammation and endothelial-to-mesenchymal transition (EndMT). ENO1 is highly expressed in ECs at the proatherogenic inner curvature of the mouse aortic arch in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, pseudotime trajectory analysis, ENO1 siRNA knockdown with shear stress/TGF-β stimulation, in vivo mouse aortic arch analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq combined with functional knockdown, in vivo localization, multiple orthogonal approaches\",\n      \"pmids\": [\"38261622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ENO1 promotes invasion and metastasis in Burkitt lymphoma by acting as a plasminogen receptor that recruits plasminogen (PLG), promoting plasmin generation and TGF-β1 activation, which activates PI3K-AKT and EMT signaling pathways. A natural compound (Ciwujianoside E/L-06) disrupts the ENO1-PLG interaction and reduces tumor growth.\",\n      \"method\": \"RNA interference, Co-IP/ENO1-PLG interaction assay, plasmin activity assay, TGF-β1 activation measurement, in vitro and in vivo functional assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — plasminogen receptor function biochemically demonstrated, rescue by TGF-β1 addition, in vivo inhibitor validation\",\n      \"pmids\": [\"38897160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO1, acting as an RNA-binding protein, binds to the 3'UTR of Klf2 mRNA to stabilize it; KMT5A (H4K20 methyltransferase) and RFX1 transcription factor associate with the ENO1 promoter to regulate its transcription in diabetic nephropathy. High glucose downregulates KMT5A and increases RFX1, leading to elevated ENO1 expression and endothelial-to-mesenchymal transition.\",\n      \"method\": \"ChIP, promoter activity assay, siRNA knockdown, Co-immunoprecipitation between KMT5A and RFX1, in vivo DN mouse and patient samples\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrated promoter binding, epistasis by siRNA rescue, in vivo validation\",\n      \"pmids\": [\"34803485\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ENO1 is a multifunctional glycolytic enzyme (catalyzing 2-phosphoglycerate to phosphoenolpyruvate) that also operates as an RNA-binding protein to regulate mRNA translation and stability (e.g., IRP1 mRNA decay via CNOT6 recruitment, YAP1 mRNA translation, KLF2 mRNA stabilization), produces a nuclear transcriptional repressor of c-myc (MBP-1) via alternative translation/transcription, acts as a cell-surface plasminogen receptor promoting invasion, and is subject to multiple post-translational modifications—including arginine methylation by PRMT5/PRMT6 that promotes active dimer formation, lysine crotonylation by CBP/SIRT2 that enhances enzymatic activity, and ubiquitination/deubiquitination by FBXW7/NEDD4L and USP21/USP46 respectively that controls its protein stability—while its downstream signaling encompasses HGFR-Wnt-SLUG, AKT-STAT3, ERK, and HIF-1α pathways that collectively drive tumor glycolysis, invasion, metastasis, immune evasion, and drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ENO1 is a metabolic glycolytic enzyme that converts 2-phosphoglycerate to phosphoenolpyruvate, and whose enzymatic activity, abundance, and moonlighting functions are extensively co-opted to drive aerobic glycolysis, tumor progression, and inflammatory/fibrotic remodeling across diverse tissues [#7, #31]. The single ENO1 locus generates two functionally distinct products: a cytoplasmic 48 kDa α-enolase and a 37 kDa nuclear form (MBP-1) produced via an alternatively transcribed intron III mRNA, which binds the c-myc P2 promoter and represses c-myc transcription [#0, #1]. Beyond glycolysis, ENO1 acts as a sequence-selective RNA-binding protein that controls the fate of target transcripts—recruiting the deadenylase CNOT6 to accelerate IRP1 mRNA decay and thereby restrain ferroptosis [#2], binding CUG-rich elements of YAP1 mRNA to promote its translation and downstream prostaglandin signaling [#3], and stabilizing 3'UTR-bound mRNAs such as KLF2 to limit NLRP3 inflammasome-mediated pyroptosis [#25]. ENO1 enzymatic activity is tuned by post-translational modifications: PRMT5/PRMT6 methylation at R9 promotes active dimer formation while R372 methylation enhances substrate binding [#7, #8], and CBP-written, SIRT2-erased K420 crotonylation augments catalysis [#9]. ENO1 protein stability is set by a ubiquitination/deubiquitination balance, with FBXW7 and NEDD4L driving proteasomal degradation [#6, #10] and USP21, USP46, and UCHL3 stabilizing the protein to sustain glycolysis [#11, #12, #29]. Extracellular and cell-surface ENO1 functions as a plasminogen receptor and interacts with HGFR to engage Wnt/β-catenin, PI3K-AKT, ERK, STAT3, and HIF-1α signaling that collectively drive EMT, invasion, metastasis, immune evasion, and drug resistance [#4, #30, #45]. ENO1 is the target of collateral-lethality therapeutics: in ENO1-deleted glioma, ENO2 dependency renders cells selectively vulnerable to the enolase inhibitor POMHEX [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the ENO1 locus is functionally bifunctional, encoding both a cytoplasmic glycolytic enzyme and a distinct nuclear transcriptional repressor, reframing ENO1 as more than a metabolic gene.\",\n      \"evidence\": \"Alternative translation analysis with α-enolase/GFP chimeras, subcellular localization, and luciferase reporter assays of MBP-1 binding the c-myc P2 promoter\",\n      \"pmids\": [\"10802057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether MBP-1 arises from alternative translation versus a separate transcript\", \"Endogenous occupancy of the c-myc promoter not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the origin of MBP-1, showing it derives from an alternatively transcribed intron III mRNA that is far more efficient at producing the repressor and is induced by hypoxia.\",\n      \"evidence\": \"MBP-1 promoter luciferase reporters, cell fractionation with RT-PCR, coupled transcription/translation, and MG132 proteasome inhibition\",\n      \"pmids\": [\"20849415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-factors driving hypoxic MBP-1 induction not identified\", \"Relative in vivo contribution of MBP-1 versus full-length ENO1 to c-myc repression unquantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked ENO1/MBP-1 abundance to MYC oncoprotein levels and proliferation, providing a regulatable handle (retinoic acid–driven dephosphorylation) on the ENO1-MYC axis.\",\n      \"evidence\": \"2D-DIGE/MS phosphoprotein identification, siRNA knockdown, and proliferation assays in follicular thyroid carcinoma\",\n      \"pmids\": [\"19060179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase/phosphatase responsible for ENO1-A1 dephosphorylation not defined\", \"Mechanism connecting phosphostate to product levels unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the first stability control point for ENO1 protein and a developmental role, showing FBXW7-mediated degradation restrains glycolysis while ENO1 is required for Wnt-driven epithelial trans-differentiation.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, and functional cell assays (FBXW7); proteomics with siRNA in primary ATII cells and bleomycin lung injury model\",\n      \"pmids\": [\"26097998\", \"26035385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron/phosphodegron recognized by FBXW7 not mapped\", \"Whether trans-differentiation requires glycolytic versus moonlighting ENO1 unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a surface/adhesion role, showing ENO1 governs integrin and uPAR signaling to suppress ROS and senescence, distinct from its enzymatic function.\",\n      \"evidence\": \"shRNA silencing, confocal and atomic force microscopy, adhesion/invasion assays, and xenografts in pancreatic cancer\",\n      \"pmids\": [\"28086938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction of ENO1 with integrin/uPAR not biochemically demonstrated\", \"Causal step linking ENO1 to integrin transcription unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ENO1 as a sequence-selective RNA-binding protein that actively shapes the transcriptome, recruiting a deadenylase to destabilize a specific mRNA and thereby controlling ferroptosis.\",\n      \"evidence\": \"RNA immunoprecipitation, RNA decay assays, and in vitro/in vivo ferroptosis readouts in hepatocellular carcinoma (IRP1/CNOT6/Mfrn1)\",\n      \"pmids\": [\"35121990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding domain/motif within ENO1 not mapped\", \"Generality of CNOT6 recruitment beyond IRP1 untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined membrane-receptor and signaling cascades downstream of ENO1, showing it engages HGFR to activate Src-PI3K-AKT-Wnt and drive EMT in metastasis.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, orthotopic and tail-vein mouse models, and anti-ENO1 antibody studies in lung cancer\",\n      \"pmids\": [\"34145039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct binding interface between ENO1 and HGFR unresolved\", \"Whether intracellular versus surface ENO1 mediates HGFR activation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped post-translational control of ENO1 catalysis, showing arginine methylation drives active dimer formation and substrate binding while lysine crotonylation enhances enzymatic activity.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro methylation/crotonylation assays, enzymatic activity and glycolytic flux measurements (PRMT6 R9/R372; CBP/SIRT2 K420)\",\n      \"pmids\": [\"36815049\", \"34547627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between distinct PTMs on the same molecule untested\", \"Structural basis of dimerization change from R9 methylation not solved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ENO1 RNA-binding to translational activation, showing it binds CUG-rich elements of YAP1 mRNA to promote translation and arachidonic acid/PGE2 signaling, and reinforced PRMT5-driven dimer activation under high glucose.\",\n      \"evidence\": \"RIP, translation assays, and in vitro/in vivo functional experiments in hepatocellular carcinoma (YAP1); dimethylation and dimerization assays in ovarian cancer (PRMT5 R9)\",\n      \"pmids\": [\"37500770\", \"36999124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ENO1 switches between mRNA decay and translational activation modes is unknown\", \"Signal coupling glucose to PRMT5-ENO1 methylation incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Layered upstream mRNA modification control onto ENO1, showing m6A (METTL3/RBM15-YTHDF1), m5C (NSUN2/YBX1), and ac4C (NAT10) marks on ENO1 mRNA enhance its translation/stability to boost glycolysis, and identified a deubiquitinase network (USP21, UCHL3) stabilizing ENO1 protein.\",\n      \"evidence\": \"m6A/m5C/ac4C site mapping, RIP, reporter and ubiquitination assays, and in vitro/in vivo functional assays across multiple cancers\",\n      \"pmids\": [\"35078505\", \"38769664\", \"39948547\", \"38385089\", \"40487654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional hierarchy among the multiple mRNA modifications unresolved\", \"Several writer/reader links validated in single labs without reciprocal confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated direct enzymatic regulation of ENO1 by a receptor protein in immune cells, showing IL1R2 binding suppresses ENO1 activity to dampen glycolysis-driven pyroptosis and inflammation.\",\n      \"evidence\": \"Proteomic screen, Co-IP, enzymatic activity assays, IL1R2-knockout mice, and ENO1 inhibitor rescue in a sepsis model\",\n      \"pmids\": [\"40704655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL1R2-mediated enzymatic inhibition not solved\", \"Whether this regulation operates in tumor settings untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated ENO1 as a therapeutic vulnerability via collateral lethality, showing ENO1-deleted tumors depend on ENO2 and are selectively killed by an enolase inhibitor.\",\n      \"evidence\": \"In vitro killing assays, intracranial orthotopic xenografts, and non-human primate pharmacokinetics (POMHEX)\",\n      \"pmids\": [\"33230295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Applicability beyond ENO1-deleted gliomas unestablished\", \"Selectivity for ENO1 versus ENO2 in non-deleted tissues not addressed here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ENO1 partitions between its glycolytic, nuclear (MBP-1), RNA-binding, and cell-surface/plasminogen-receptor functions—and what governs the switch—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural definition of the RNA-binding interface\", \"Determinants of cytoplasmic versus nuclear versus surface localization unknown\", \"Integrated model reconciling moonlighting roles in a single cell lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [7, 31]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 3, 25, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [45]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 28, 45]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [17, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 31]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 38, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 34]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 38]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CNOT6\", \"HGFR\", \"FBXW7\", \"NEDD4L\", \"USP21\", \"PRMT5\", \"IL1R2\", \"PLG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}