{"gene":"FBP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2013,"finding":"The Snail-G9a-Dnmt1 complex mediates promoter methylation and transcriptional repression of FBP1 in basal-like breast cancer. Loss of FBP1 induces glycolysis, increases glucose uptake, promotes tetrameric PKM2 formation, maintains ATP production under hypoxia, suppresses mitochondrial complex I activity and ROS production, and enhances β-catenin/TCF interaction to confer cancer stem cell-like properties.","method":"Promoter methylation analysis, ChIP, metabolic assays (glucose uptake, ATP, ROS, oxygen consumption), co-immunoprecipitation of β-catenin/TCF, loss-of-function and gain-of-function experiments in BLBC cells","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, metabolic flux, co-IP, functional rescue), replicated across multiple cell lines and in vivo","pmids":["23453623"],"is_preprint":false},{"year":2018,"finding":"Aberrant FBP1 expression in NK cells inhibits glycolysis and impairs NK cell viability and antitumor function during lung cancer progression.","method":"FBP1 manipulation in primary NK cells, glycolysis assays (glucose uptake, lactate production, ECAR), functional cytotoxicity assays, in vivo Kras-driven lung cancer model","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype (glycolysis inhibition, viability impairment), multiple orthogonal methods, in vivo validation","pmids":["30033198"],"is_preprint":false},{"year":2020,"finding":"Hepatocyte-specific loss of FBP1 causes liver steatosis and promotes hepatic stellate cell (HSC) activation and senescence via HMGB1 release from FBP1-deficient hepatocytes. Blocking HMGB1 with inflachromene limits FBP1-dependent HSC activation and the subsequent senescence-associated secretory phenotype (SASP), establishing FBP1 as a metabolic tumor suppressor in liver cancer.","method":"Hepatocyte-specific Fbp1 conditional knockout mice, senolytic drug treatment (dasatinib/quercetin, ABT-263), HMGB1 inhibition with inflachromene, co-culture experiments, tumor progression assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic in vivo model, multiple pharmacological interventions, mechanistic HMGB1 release assay, replicated in human and murine tumors","pmids":["32367049"],"is_preprint":false},{"year":2017,"finding":"MAGE-A3/C2-TRIM28 ubiquitin ligase complexes bind directly to FBP1 and promote its ubiquitination and proteasomal degradation, thereby enhancing the Warburg effect and hepatocellular carcinoma growth.","method":"Co-immunoprecipitation (direct binding of TRIM28 to FBP1), in vivo ubiquitination assays, glucose consumption/lactate production assays, xenograft mouse models, bortezomib proteasome inhibition rescue","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated by Co-IP, ubiquitination confirmed in vivo, functional metabolic and tumor growth rescue, multiple orthogonal methods in one study","pmids":["28394358"],"is_preprint":false},{"year":2011,"finding":"USP22 deubiquitinates FBP1 (FUSE-binding protein 1); loss of USP22 increases FBP1 polyubiquitination without affecting its protein stability, but instead reduces FBP1 occupancy at the p21 gene promoter, thereby decreasing p21 expression and promoting cell proliferation.","method":"USP22 knockdown, ubiquitination assays, chromatin immunoprecipitation (ChIP) for FBP1 at p21 locus, p21 expression analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — deubiquitination assay combined with ChIP and functional gene expression readout, multiple orthogonal methods establishing a non-canonical (non-degradative) ubiquitination role","pmids":["21779003"],"is_preprint":false},{"year":2020,"finding":"E3 ubiquitin ligase UBR5 promotes FBP1 downregulation by directly binding to and ubiquitinating/degrading the transcription factor C/EBPα, which is required for FBP1 transcription, thereby activating aerobic glycolysis and pancreatic cancer growth.","method":"Co-immunoprecipitation (UBR5 binding to C/EBPα), ubiquitination assays, UBR5 knockdown/overexpression, FBP1 rescue experiments, in vivo xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and ubiquitination demonstrated, mechanistic chain from UBR5→C/EBPα→FBP1 validated by rescue, multiple methods","pmids":["33122826"],"is_preprint":false},{"year":2021,"finding":"TRIM47 directly binds to and ubiquitinates FBP1, promoting its degradation and thereby accelerating aerobic glycolysis and pancreatic cancer progression.","method":"Co-immunoprecipitation (TRIM47 direct binding to FBP1), ubiquitination assays, TRIM47 knockdown/overexpression, FBP1 overexpression rescue, in vivo xenograft assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and ubiquitination shown, FBP1 rescue validates axis, single lab","pmids":["33529753"],"is_preprint":false},{"year":2019,"finding":"USP44 binds to FBP1 and promotes its deubiquitination, stabilizing FBP1 protein levels and suppressing pancreatic cancer progression and gemcitabine resistance.","method":"Co-immunoprecipitation, deubiquitination assays, USP44 knockdown/overexpression, FBP1 protein stability analysis","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and deubiquitination shown by Co-IP and functional assays, single lab","pmids":["31497353"],"is_preprint":false},{"year":2021,"finding":"USP7 binds to and deubiquitinates FBP1, preventing its translocation to the nucleus. Nuclear FBP1 interacts with DNMT1 and traps PARP1 on chromatin, sensitizing pancreatic cancer cells to PARP inhibitors. USP7 inhibitors enhance PARP inhibitor antitumor effects in an FBP1-dependent manner.","method":"Co-immunoprecipitation (USP7-FBP1 and FBP1-DNMT1 interactions), deubiquitination assays, nuclear fractionation, chromatin-bound PARP1 assays, USP7 inhibitor functional assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and functional assays in single lab establishing USP7-FBP1-DNMT1 axis","pmids":["34854226"],"is_preprint":false},{"year":2022,"finding":"PTEN loss activates PI3K/AKT signaling, which promotes CDK-mediated phosphorylation of FBP1 at serine 271, enabling SKP2 E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation of FBP1, thus enhancing the Warburg effect and prostate cancer growth.","method":"Co-immunoprecipitation (SKP2-FBP1), in vivo ubiquitination assays, phospho-site mutagenesis (S271), PTEN-null cell lines and xenograft models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis of phospho-site, ubiquitination assay, in vivo validation; single lab","pmids":["36237339"],"is_preprint":false},{"year":2017,"finding":"HDAC1/HDAC2 repress FBP1 expression in hepatocellular carcinoma by reducing histone H3 lysine 27 acetylation (H3K27Ac) at the FBP1 enhancer. HDAC inhibitor treatment or HDAC1/2 knockdown restores FBP1 expression and suppresses HCC cell growth.","method":"ChIP for H3K27Ac at FBP1 enhancer, HDAC1/2 knockdown and inhibitor treatment, FBP1 expression and glycolysis assays, in vitro and in vivo tumor growth assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay establishing epigenetic mechanism, knockdown validation, single lab","pmids":["28262837"],"is_preprint":false},{"year":2018,"finding":"FOXC1 binds directly to the FBP1 gene promoter and negatively regulates its transcriptional activity, thereby promoting glycolysis and colorectal cancer proliferation.","method":"ChIP assay (FOXC1 binding to FBP1 promoter), luciferase reporter assay, FOXC1 knockdown/overexpression, glycolysis assays, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter demonstrate direct promoter binding, functional metabolic rescue, single lab","pmids":["30171256"],"is_preprint":false},{"year":2020,"finding":"FBP1 physically interacts with BRD4, binding to its BD2 bromodomain in an acetylation-dependent manner. Tip60 acetylates FBP1 at K110 and K113, and HDAC3 removes these marks; this acetylation is critical for FBP1-BRD4 binding in pancreatic cancer cells. FBP1-BRD4 interaction decreases expression of BRD4 target genes to inhibit pancreatic cancer progression.","method":"Co-immunoprecipitation (FBP1-BRD4), domain mapping (BD2), acetylation-site mutagenesis (K110/K113), Tip60 and HDAC3 functional assays, downstream gene expression analysis","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with domain mapping and acetylation mutagenesis, multiple Co-IPs; single lab","pmids":["32195024"],"is_preprint":false},{"year":2024,"finding":"FBP1 interacts with NICD1 (Notch1 intracellular domain) and the E3 ubiquitin ligase FBXW7 to facilitate ubiquitin-proteasome-dependent degradation of NICD1, inhibiting Notch signaling and NSCLC stemness. This function is independent of FBP1's metabolic enzymatic activity.","method":"Co-immunoprecipitation (FBP1-NICD1-FBXW7 complex), ubiquitination assays, enzymatic activity mutant of FBP1, CD133+ stem cell proportion analysis, tumorigenicity assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex Co-IP with enzymatic activity separation, functional stemness readout; single lab","pmids":["38349431"],"is_preprint":false},{"year":2021,"finding":"FBP1 physically interacts with STAT3 and suppresses nuclear translocation of STAT3, exerting non-enzymatic activity to impair STAT3 function in ovarian cancer cells. C-MYC binding to the FBP1 promoter inhibits FBP1 transcription (alongside DNA methylation).","method":"Co-immunoprecipitation (FBP1-STAT3), nuclear fractionation, ChIP (C-MYC at FBP1 promoter), FBP1 overexpression functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP for protein-protein interaction, ChIP for transcriptional repression, single lab","pmids":["34363022"],"is_preprint":false},{"year":2024,"finding":"FBP1 promotes FBP1 radiosensitivity in nasopharyngeal carcinoma by stabilizing FBXW7 protein (through suppressing FBXW7 auto-ubiquitination), which in turn promotes ubiquitination and degradation of mTOR, thereby suppressing glycolysis.","method":"Co-immunoprecipitation (FBXW7-FBP1 and FBXW7-mTOR), ubiquitination assays, FBP1 gain/loss-of-function, glycolysis assays, xenograft models","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays establish mechanistic chain FBP1→FBXW7→mTOR; single lab","pmids":["34298040"],"is_preprint":false},{"year":2019,"finding":"Ets1 transcription factor is overexpressed in irradiation-induced glioblastoma and acts as a transcriptional repressor of FBP1, leading to decreased FBP1 expression, elevated glycolysis, and increased GBM invasiveness after radiation.","method":"FBP1 expression analysis post-irradiation, Ets1 ChIP/promoter analysis, glycolysis assays (glucose uptake, ECAR), orthotopic xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional repressor identified by ChIP, functional metabolic and invasion phenotype validated in vivo; single lab","pmids":["31444412"],"is_preprint":false},{"year":2018,"finding":"C/EBPα binds to two overlapping sites at nucleotide -228/-208 of the FBP1 promoter, and HNF4α binds to H4-SBM and DR3 sites at -566/-554 and -212/-198, respectively, to activate FBP1 transcription in hepatoma HepG2 cells. Mutation of these sites markedly reduces transcriptional activation.","method":"Luciferase reporter assays with promoter mutations, electrophoretic mobility shift assay (EMSA), siRNA knockdown of C/EBPα and HNF4α","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — EMSA and promoter mutagenesis define binding sites, functional reporter assays confirm transcriptional control; single lab","pmids":["29566023"],"is_preprint":false},{"year":2024,"finding":"FBP1 loss in keratinocytes facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 lysine 9 acetylation (H3K9Ac), leading to enhanced transcription of proliferation genes. This mechanism promotes keratinocyte proliferation while inhibiting differentiation and exacerbates psoriasis-like phenotypes.","method":"Fbp1 heterozygous mice (epidermis phenotyping), in vitro keratinocyte FBP1 loss-of-function, acetyl-CoA measurement, H3K9Ac ChIP, transcriptome sequencing, imiquimod psoriasis mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic-epigenetic link established by acetyl-CoA measurement and ChIP, in vivo genetic and pharmacological models; single lab","pmids":["38834617"],"is_preprint":false},{"year":2025,"finding":"FBP1 is a p53 transcriptional target elevated in senescent MASH hepatocytes. FBP1 is suppressed in HCC progenitor cells through promoter hypermethylation and proteasomal degradation driven by AKT and NRF2 activation. AKT and NRF2 accelerate both FBP1 and p53 degradation, reversing senescence and enabling proliferation and metabolic reprogramming needed for MASH-to-HCC progression.","method":"p53 ChIP (FBP1 as p53 target), AKT/NRF2 gain/loss-of-function, proteasomal degradation assays, promoter methylation analysis, mouse MASH-HCC models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP identifies FBP1 as p53 target, multiple genetic models in mice and human validation, mechanistic degradation assays; multiple orthogonal methods","pmids":["39743585"],"is_preprint":false},{"year":2023,"finding":"Hepatic but not intestinal FBP1 is required for fructose metabolism and tolerance. Liver-specific Fbp1 deletion in mice leads to fructose-1-phosphate accumulation (indicative of defective fructolysis, likely due to competitive inhibition by fructose-1,6-bisphosphate), hepatomegaly, and liver injury under high-fructose diet, while intestine-specific deletion has no effect.","method":"Inducible tissue-specific Fbp1 conditional knockout mice (liver vs. intestine), high-fructose diet challenge, metabolite (fructose-1-phosphate) measurement, liver histology and injury assays","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic in vivo tissue-specific KO with mechanistic metabolite accumulation measurement, organ-specific functional dissection","pmids":["36964915"],"is_preprint":false},{"year":2020,"finding":"CELF6 binds the 3'UTR of FBP1 mRNA and stabilizes it, increasing FBP1 protein expression and suppressing triple-negative breast cancer progression.","method":"Luciferase reporter assay (3'UTR binding), RNA immunoprecipitation (RIP), RNA pull-down, CELF6 overexpression/knockdown with FBP1 rescue","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein binding by RIP and pull-down confirmed, functional rescue validates axis; single lab","pmids":["32601971"],"is_preprint":false},{"year":2019,"finding":"HSF2 interacts with EHMT2 (G9a) to epigenetically silence FBP1 expression in hepatocellular carcinoma, thereby promoting aerobic glycolysis and cell proliferation.","method":"Co-immunoprecipitation (HSF2-EHMT2), HSF2 knockdown/overexpression, glycolysis assays, FBP1 expression analysis","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes HSF2-EHMT2 interaction, functional FBP1-glycolysis linkage shown; single lab","pmids":["31497345"],"is_preprint":false},{"year":2020,"finding":"LOXL2 intracellular enzymatic activity (not extracellular) upregulates Snail expression, which represses FBP1, thereby enhancing glycolysis and HIF-1α/VEGF signaling in hepatocellular carcinoma cells. The catalytically inactive LOXL2(Y689F) mutant does not affect Snail or FBP1.","method":"LOXL2 wild-type vs. catalytic mutant (Y689F) overexpression, LOXL2 siRNA knockdown, Snail-FBP1 rescue epistasis, LOXL2 inhibitor (LOXL2-IN-1) treatment, HIF-1α/VEGF expression analysis","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant establishes enzymatic requirement, epistasis experiment places axis LOXL2→Snail→FBP1; single lab","pmids":["32323822"],"is_preprint":false},{"year":2024,"finding":"P4HA1 overexpression under hypoxia reduces intracellular α-ketoglutarate (α-KG) levels (by consuming α-KG during collagen hydroxylation), which reduces TET2 protein levels and TET2 recruitment to the FBP1 promoter, resulting in decreased FBP1 expression and enhanced glycolysis to promote endothelial angiogenesis.","method":"α-KG measurement, TET2 protein analysis, ChIP-PCR (TET2 at FBP1 promoter), P4HA1 overexpression/knockdown, FBP1 expression rescue, angiogenesis assays in vitro and HLI mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes TET2 at FBP1 promoter, metabolite-TET2 mechanism validated; single lab","pmids":["38238754"],"is_preprint":false},{"year":2018,"finding":"FBP1 (gluconeogenic enzyme) inhibits HIF-1α protein expression and reduces transcription of HIF-1α target genes (PDK1, LDHA, GLUT1, VEGF) in basal-like breast cancer cells under hypoxia. ChIP demonstrated FBP1 occupancy at hypoxia response elements (HREs) in the PDK1 promoter.","method":"FBP1 lentiviral overexpression, Western blot (HIF-1α protein), RT-qPCR (HIF-1α target genes), chromatin immunoprecipitation (FBP1 at HRE of PDK1), glycolysis and cell growth assays","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP shows FBP1 at HREs, functional HIF-1α suppression demonstrated; single lab, single study","pmids":["28485159"],"is_preprint":false},{"year":2023,"finding":"FOXP2 suppresses transcription of KDM5A (a histone demethylase), which blocks KDM5A-induced H3K4me3 demethylation at the FBP1 promoter, thereby increasing FBP1 expression and inhibiting the Warburg effect in HCC cells.","method":"ChIP (H3K4me3 at FBP1 promoter), FOXP2 and KDM5A gain/loss-of-function, FBP1 expression rescue, glycolysis assays, xenograft models","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes H3K4me3 regulation at FBP1 promoter, epistasis chain FOXP2→KDM5A→FBP1 validated; single lab","pmids":["37713600"],"is_preprint":false},{"year":2022,"finding":"Retinoic acid (RA) activates FBP1 transcription via retinoic acid receptor (RAR) binding to the FBP1 gene (ChIP-PCR validated), upregulating FBP1 to suppress glycolysis and inhibit angiogenesis in human embryonic stem cell-derived endothelial cells. Silencing FBP1 reverses RA-induced angiogenesis inhibition.","method":"ChIP-PCR (RAR at FBP1 promoter), FBP1 knockdown/pharmacological inhibition, RAR inhibitor (BMS493), RNA sequencing, angiogenesis assays (proliferation, migration, tube formation)","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR establishes direct RAR binding, functional angiogenesis rescue; single lab","pmids":["35672803"],"is_preprint":false},{"year":2020,"finding":"GATA4 interacts physically with FBP1 protein (identified by immunoprecipitation-mass spectrometry) and positively regulates FBP1 expression in dental pulp stem cells (DPSCs). GATA4 promotes gluconeogenesis via FBP1; loss of GATA4 decreases FBP1 expression, increases glucose consumption and lactate production.","method":"Co-immunoprecipitation-mass spectrometry (GATA4-FBP1 interaction), GATA4 knockdown/overexpression, FBP1 knockdown, glucose/lactate metabolic assays, in vivo lentiviral GATA4 overexpression in mouse root","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identifies physical interaction, functional metabolic validation; single lab","pmids":["31892855"],"is_preprint":false},{"year":2021,"finding":"In AML, Evi1 transcription factor directly interacts with the enhancer region of Fbp1 and upregulates its transcription. Fbp1 upregulation activates the pentose phosphate pathway in Evi1-driven leukemia, and pharmacological or shRNA-mediated Fbp1 inhibition selectively suppresses Evi1-driven leukemogenesis.","method":"ChIP (Evi1 at Fbp1 enhancer), transcriptomic and metabolomic profiling, Fbp1 shRNA knockdown, pharmacological Fbp1 inhibition, secondary transplantation leukemia mouse model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes enhancer binding, metabolomics confirms pathway activation, in vivo transplantation model; single lab","pmids":["34363719"],"is_preprint":false},{"year":1991,"finding":"In S. pombe, glucose repression of fbp1 transcription is mediated through the cAMP-PKA signaling pathway; git2/cyr1 (adenylate cyclase) is required for this repression, and exogenous cAMP restores repression in git mutants. The pathway is independent of ras1 and acts through activation of cAMP-dependent protein kinase.","method":"Genetic epistasis analysis with git mutants, fbp1-lacZ/fbp1-ura4 reporter fusions, exogenous cAMP supplementation, adenylate cyclase activity assays, intragenic complementation analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple pathway components, reporter fusions, cAMP rescue, replicated across multiple labs subsequently","pmids":["1849107"],"is_preprint":false},{"year":1994,"finding":"In S. pombe, gpa2 (git8) encodes a Gα-protein subunit that partially regulates adenylate cyclase (Cyr1/Git2) activity for glucose repression of fbp1 transcription. Git3 and git5 act in concert with or independently from gpa2 to regulate adenylate cyclase.","method":"Gene identity mapping (git8=gpa2), fbp1-lacZ reporter assays, genetic epistasis (git3/git5 combined with gpa2 deletions), high-copy suppression","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with reporter assays; single study, fission yeast ortholog","pmids":["8001792"],"is_preprint":false},{"year":2000,"finding":"In S. pombe, fbp1 transcription is antagonistically regulated at two upstream activation sites (UAS1, UAS2) by PKA and MAPK pathways. UAS1 binds the atf1-pcr1 heterodimeric activator; MAPK positively and PKA negatively regulate atf1 binding at UAS1. UAS2 is bound by activators and repressors regulated by both pathways but does not involve atf1.","method":"Deletion analysis defining UAS1 and UAS2, gel-shift/EMSA identifying atf1-pcr1 at UAS1, fbp1 promoter-reporter constructs, PKA and MAPK mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter dissection with mutagenesis, EMSA identifying activator complexes, validated with signaling mutants; rigorous mechanistic study","pmids":["10938120"],"is_preprint":false},{"year":2001,"finding":"In S. pombe, two redundant Tup1p-like corepressors (Tup11 and Tup12) repress fbp1 transcription downstream of PKA; double deletion causes ~100-fold increase in fbp1-lacZ expression. The CCAAT-binding factor subunit Php5 activates fbp1 transcription in parallel to atf1-pcr1.","method":"cDNA library screen, tup11/tup12 double deletion analysis, fbp1-lacZ reporter assays, genetic epistasis with atf1/spc1","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen and deletion analysis with quantitative reporter assays; single lab, S. pombe model","pmids":["11238405"],"is_preprint":false},{"year":2003,"finding":"In S. pombe, Tup11/Tup12 corepressors repress chromatin remodeling at two CRE-related regulatory elements in the fbp1+ promoter. Under derepressed conditions, chromatin is remodeled coordinately with transcriptional activation. Tup11/Tup12 deletion recapitulates the open chromatin state even under repressed conditions. Rst2 (a cAMP-PKA-controlled transcription factor) antagonizes Tup11/Tup12 chromatin repression.","method":"Chromatin immunoprecipitation (MNase sensitivity/nucleosome mapping), tup11/tup12 double deletion, rst2 deletion, chromatin structure analysis under repressed vs. derepressed conditions","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin structure directly measured by nuclease accessibility assays, multiple genetic backgrounds tested; single lab","pmids":["14573465"],"is_preprint":false},{"year":1985,"finding":"The S. cerevisiae FBP1 gene encodes fructose bisphosphatase; disruption by transplacement creates a hexose auxotroph. FBP1 mRNA (~1350 nt) is glucose-repressible. The cloned gene confers fructose bisphosphatase activity in E. coli sensitive to fructose 2,6-bisphosphate inhibition.","method":"Gene cloning by complementation, transplacement disruption, Northern blot, enzymatic activity assay in E. coli, antibody precipitation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic disruption with defined auxotrophic phenotype, enzymatic activity validated in heterologous system; foundational study","pmids":["3003364"],"is_preprint":false},{"year":1995,"finding":"The human FBP1 gene encodes fructose-1,6-bisphosphatase (EC 3.1.3.11), which catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. The gene contains seven exons spanning >31 kb and is localized to chromosome 9q22.2-q22.3 by FISH.","method":"Gene cloning and structural characterization, fluorescence in situ hybridization (FISH), mutational screening by DNA sequencing, exon-intron mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic function established by gene characterization, chromosomal localization by direct FISH; definitive molecular characterization","pmids":["7558035"],"is_preprint":false}],"current_model":"FBP1 (fructose-1,6-bisphosphatase 1) is a gluconeogenic enzyme that catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate; beyond this canonical metabolic role, it acts as a tumor suppressor through multiple non-enzymatic mechanisms: it is transcriptionally silenced by the Snail-G9a-Dnmt1 complex (via promoter methylation), by HDAC1/2 (via H3K27Ac reduction), and by C-MYC/FOXC1/ZEB1 binding to its promoter, while being activated by C/EBPα, HNF4α, and p53; at the protein level, FBP1 is ubiquitinated and degraded via MAGE-TRIM28, TRIM47, SKP2 (downstream of PTEN/AKT/CDK-mediated S271 phosphorylation), and UBR5 (via C/EBPα destabilization), and is stabilized by deubiquitinases USP22, USP44, and USP7; beyond metabolism, FBP1 physically interacts with BRD4-BD2 (in an acetylation-dependent manner), STAT3 (blocking its nuclear translocation), NICD1/FBXW7 (promoting Notch1 degradation), and DNMT1 (trapping PARP1 on chromatin), while in liver cancer FBP1 loss drives HMGB1-mediated hepatic stellate cell activation/senescence that promotes tumor progression."},"narrative":{"mechanistic_narrative":"FBP1 is a gluconeogenic enzyme that catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate [PMID:7558035], and which functions broadly as a metabolic brake on glycolysis whose loss reprograms cells toward the Warburg effect across diverse tissues [PMID:23453623, PMID:3003364]. In the liver, hepatic FBP1 is required for fructose tolerance—its deletion drives fructose-1-phosphate accumulation, steatosis, and injury [PMID:36964915]—and its loss promotes tumorigenesis through HMGB1 release that activates and senesces hepatic stellate cells [PMID:32367049], while in the MASH-to-HCC transition FBP1 acts as a p53-regulated enforcer of senescence whose degradation enables progression [PMID:39743585]. Beyond catalysis, FBP1 restrains glycolysis by suppressing HIF-1α and occupying hypoxia response elements at glycolytic gene promoters [PMID:28485159], and it executes several non-enzymatic tumor-suppressor functions: physically engaging STAT3 to block its nuclear translocation [PMID:34363022], binding the BRD4 BD2 bromodomain in a Tip60-acetylation-dependent manner to downregulate BRD4 target genes [PMID:32195024], scaffolding NICD1–FBXW7 to drive Notch1 degradation independently of its enzymatic activity [PMID:38349431], and translocating to the nucleus to interact with DNMT1 and trap PARP1 on chromatin [PMID:34854226]. FBP1 levels are controlled by an extensive regulatory network: transcriptional repression via the Snail–G9a–DNMT1 complex [PMID:23453623], HDAC1/2-mediated H3K27Ac loss [PMID:28262837], and repressors C-MYC, FOXC1, Ets1, and KDM5A [PMID:30171256, PMID:34363022, PMID:31444412, PMID:37713600], opposed by activators C/EBPα, HNF4α, retinoic-acid receptor, and FOXP2 [PMID:29566023, PMID:35672803, PMID:37713600]; and post-translationally by ubiquitin ligases MAGE-TRIM28, TRIM47, SKP2 (downstream of PTEN/AKT/CDK-driven S271 phosphorylation), and UBR5 versus the stabilizing deubiquitinases USP44 and USP7 [PMID:28394358, PMID:33529753, PMID:36237339, PMID:33122826, PMID:31497353, PMID:34854226]. Context-dependently, FBP1 is co-opted as a pro-tumor effector in Evi1-driven leukemia, where it feeds the pentose phosphate pathway [PMID:34363719], and impairs NK-cell antitumor function by inhibiting glycolysis [PMID:30033198].","teleology":[{"year":1985,"claim":"Established the molecular identity of the FBP1 gene product as fructose bisphosphatase and revealed glucose-repressible expression, defining the core gluconeogenic function.","evidence":"Gene cloning by complementation, transplacement disruption, and heterologous enzymatic assay in S. cerevisiae","pmids":["3003364"],"confidence":"High","gaps":["Yeast ortholog; human gene structure not yet defined","Regulatory transcription factors not identified"]},{"year":1991,"claim":"Mapped the upstream signaling that controls fbp1 transcription, showing glucose repression operates through the cAMP-PKA pathway.","evidence":"Genetic epistasis with git mutants, fbp1-reporter fusions, and cAMP rescue in S. pombe","pmids":["1849107"],"confidence":"High","gaps":["Downstream transcription factors at the promoter not yet defined","Yeast pathway; mammalian relevance unestablished"]},{"year":1995,"claim":"Defined the human FBP1 gene structure, enzymatic reaction, and chromosomal locus, anchoring the canonical metabolic function in humans.","evidence":"Gene cloning, exon-intron mapping, and FISH localization to 9q22","pmids":["7558035"],"confidence":"High","gaps":["No regulatory or non-enzymatic functions addressed","Disease relevance not yet established"]},{"year":2000,"claim":"Dissected the promoter logic of fbp1, showing antagonistic PKA/MAPK control through distinct upstream activation sites and the atf1-pcr1 activator complex.","evidence":"Promoter deletion, EMSA, and signaling-mutant reporter analysis in S. pombe","pmids":["10938120","8001792","11238405","14573465"],"confidence":"High","gaps":["Yeast transcriptional architecture may not map onto mammalian FBP1 regulation","Chromatin-level mechanism elaborated only in fission yeast"]},{"year":2011,"claim":"Revealed a non-degradative ubiquitination role, where USP22 deubiquitinates FBP1 to control its occupancy at the p21 promoter and thus proliferation.","evidence":"USP22 knockdown, ubiquitination assays, and ChIP at the p21 locus","pmids":["21779003"],"confidence":"High","gaps":["This FBP1 (FUSE-binding protein context) chromatin role not connected to metabolic FBP1 function","Mechanism of promoter occupancy unresolved"]},{"year":2013,"claim":"Established FBP1 as a metabolic tumor suppressor whose epigenetic silencing reprograms cells toward glycolysis and stemness, motivating the broad oncology framework.","evidence":"Promoter methylation/ChIP, metabolic flux assays, and β-catenin co-IP in basal-like breast cancer","pmids":["23453623"],"confidence":"High","gaps":["Whether tumor suppression requires enzymatic activity not separated here","Generality across tumor types not yet tested"]},{"year":2017,"claim":"Identified the first ubiquitin ligase axis and an enhancer-level epigenetic repressor controlling FBP1 protein and transcript levels in HCC.","evidence":"Co-IP, in vivo ubiquitination, and H3K27Ac ChIP with HDAC inhibition (MAGE-TRIM28; HDAC1/2)","pmids":["28394358","28262837"],"confidence":"High","gaps":["Degron/recognition motif on FBP1 not mapped","Crosstalk between transcriptional and post-translational control unaddressed"]},{"year":2018,"claim":"Broadened FBP1 biology beyond tumor cells (impairing NK antitumor function) and detailed its transcriptional activators and HIF-1α suppression.","evidence":"NK cell manipulation with glycolysis assays; promoter mutagenesis/EMSA (C/EBPα, HNF4α); FBP1 overexpression with HRE ChIP","pmids":["30033198","29566023","30171256","28485159"],"confidence":"High","gaps":["Mechanism of FBP1 occupancy at HREs unclear","Whether NK-intrinsic effect is enzymatic unresolved"]},{"year":2020,"claim":"Defined the non-cell-autonomous liver tumor-suppressor mechanism (HMGB1-driven stellate cell activation) and expanded the regulatory network of ligases, deubiquitinases, RNA-binding stabilizers, and non-enzymatic protein interactions.","evidence":"Conditional KO mice with HMGB1 inhibition; co-IP/ubiquitination (UBR5-C/EBPα); RIP (CELF6); FBP1-BRD4 domain mapping; FBP1-STAT3 co-IP; LOXL2/HSF2/GATA4 functional studies","pmids":["32367049","33122826","32601971","32195024","31497353","32323822","31497345","31892855"],"confidence":"High","gaps":["Non-enzymatic interactions largely from single labs without reciprocal validation","Structural basis of FBP1-BRD4 and FBP1-STAT3 binding unresolved"]},{"year":2021,"claim":"Established phosphorylation-coupled degradation (PTEN/AKT/CDK-S271/SKP2) and a nuclear FBP1-DNMT1-PARP1 axis, and revealed context-dependent pro-tumor co-option in Evi1 leukemia.","evidence":"S271 phospho-mutagenesis with ubiquitination assays; USP7/FBP1/DNMT1 co-IPs with chromatin PARP1 assays; Evi1 enhancer ChIP with metabolomics","pmids":["36237339","34854226","34363719","34363022","34298040","33529753"],"confidence":"Medium","gaps":["S271 kinase identity not pinned to a specific CDK","Pro- vs anti-tumor switch determinants not defined"]},{"year":2024,"claim":"Resolved enzymatic-independent Notch suppression and connected FBP1 loss to glycolysis-driven histone acetylation in non-cancer disease (psoriasis), plus FBXW7 stabilization controlling mTOR.","evidence":"FBP1-NICD1-FBXW7 complex co-IP with enzyme-dead mutant; 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standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"The Snail-G9a-Dnmt1 complex mediates promoter methylation and transcriptional repression of FBP1 in basal-like breast cancer. Loss of FBP1 induces glycolysis, increases glucose uptake, promotes tetrameric PKM2 formation, maintains ATP production under hypoxia, suppresses mitochondrial complex I activity and ROS production, and enhances β-catenin/TCF interaction to confer cancer stem cell-like properties.\",\n      \"method\": \"Promoter methylation analysis, ChIP, metabolic assays (glucose uptake, ATP, ROS, oxygen consumption), co-immunoprecipitation of β-catenin/TCF, loss-of-function and gain-of-function experiments in BLBC cells\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, metabolic flux, co-IP, functional rescue), replicated across multiple cell lines and in vivo\",\n      \"pmids\": [\"23453623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Aberrant FBP1 expression in NK cells inhibits glycolysis and impairs NK cell viability and antitumor function during lung cancer progression.\",\n      \"method\": \"FBP1 manipulation in primary NK cells, glycolysis assays (glucose uptake, lactate production, ECAR), functional cytotoxicity assays, in vivo Kras-driven lung cancer model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype (glycolysis inhibition, viability impairment), multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"30033198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatocyte-specific loss of FBP1 causes liver steatosis and promotes hepatic stellate cell (HSC) activation and senescence via HMGB1 release from FBP1-deficient hepatocytes. Blocking HMGB1 with inflachromene limits FBP1-dependent HSC activation and the subsequent senescence-associated secretory phenotype (SASP), establishing FBP1 as a metabolic tumor suppressor in liver cancer.\",\n      \"method\": \"Hepatocyte-specific Fbp1 conditional knockout mice, senolytic drug treatment (dasatinib/quercetin, ABT-263), HMGB1 inhibition with inflachromene, co-culture experiments, tumor progression assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic in vivo model, multiple pharmacological interventions, mechanistic HMGB1 release assay, replicated in human and murine tumors\",\n      \"pmids\": [\"32367049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAGE-A3/C2-TRIM28 ubiquitin ligase complexes bind directly to FBP1 and promote its ubiquitination and proteasomal degradation, thereby enhancing the Warburg effect and hepatocellular carcinoma growth.\",\n      \"method\": \"Co-immunoprecipitation (direct binding of TRIM28 to FBP1), in vivo ubiquitination assays, glucose consumption/lactate production assays, xenograft mouse models, bortezomib proteasome inhibition rescue\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated by Co-IP, ubiquitination confirmed in vivo, functional metabolic and tumor growth rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28394358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP22 deubiquitinates FBP1 (FUSE-binding protein 1); loss of USP22 increases FBP1 polyubiquitination without affecting its protein stability, but instead reduces FBP1 occupancy at the p21 gene promoter, thereby decreasing p21 expression and promoting cell proliferation.\",\n      \"method\": \"USP22 knockdown, ubiquitination assays, chromatin immunoprecipitation (ChIP) for FBP1 at p21 locus, p21 expression analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — deubiquitination assay combined with ChIP and functional gene expression readout, multiple orthogonal methods establishing a non-canonical (non-degradative) ubiquitination role\",\n      \"pmids\": [\"21779003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"E3 ubiquitin ligase UBR5 promotes FBP1 downregulation by directly binding to and ubiquitinating/degrading the transcription factor C/EBPα, which is required for FBP1 transcription, thereby activating aerobic glycolysis and pancreatic cancer growth.\",\n      \"method\": \"Co-immunoprecipitation (UBR5 binding to C/EBPα), ubiquitination assays, UBR5 knockdown/overexpression, FBP1 rescue experiments, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and ubiquitination demonstrated, mechanistic chain from UBR5→C/EBPα→FBP1 validated by rescue, multiple methods\",\n      \"pmids\": [\"33122826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM47 directly binds to and ubiquitinates FBP1, promoting its degradation and thereby accelerating aerobic glycolysis and pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation (TRIM47 direct binding to FBP1), ubiquitination assays, TRIM47 knockdown/overexpression, FBP1 overexpression rescue, in vivo xenograft assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and ubiquitination shown, FBP1 rescue validates axis, single lab\",\n      \"pmids\": [\"33529753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP44 binds to FBP1 and promotes its deubiquitination, stabilizing FBP1 protein levels and suppressing pancreatic cancer progression and gemcitabine resistance.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assays, USP44 knockdown/overexpression, FBP1 protein stability analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and deubiquitination shown by Co-IP and functional assays, single lab\",\n      \"pmids\": [\"31497353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP7 binds to and deubiquitinates FBP1, preventing its translocation to the nucleus. Nuclear FBP1 interacts with DNMT1 and traps PARP1 on chromatin, sensitizing pancreatic cancer cells to PARP inhibitors. USP7 inhibitors enhance PARP inhibitor antitumor effects in an FBP1-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (USP7-FBP1 and FBP1-DNMT1 interactions), deubiquitination assays, nuclear fractionation, chromatin-bound PARP1 assays, USP7 inhibitor functional assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and functional assays in single lab establishing USP7-FBP1-DNMT1 axis\",\n      \"pmids\": [\"34854226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTEN loss activates PI3K/AKT signaling, which promotes CDK-mediated phosphorylation of FBP1 at serine 271, enabling SKP2 E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation of FBP1, thus enhancing the Warburg effect and prostate cancer growth.\",\n      \"method\": \"Co-immunoprecipitation (SKP2-FBP1), in vivo ubiquitination assays, phospho-site mutagenesis (S271), PTEN-null cell lines and xenograft models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis of phospho-site, ubiquitination assay, in vivo validation; single lab\",\n      \"pmids\": [\"36237339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC1/HDAC2 repress FBP1 expression in hepatocellular carcinoma by reducing histone H3 lysine 27 acetylation (H3K27Ac) at the FBP1 enhancer. HDAC inhibitor treatment or HDAC1/2 knockdown restores FBP1 expression and suppresses HCC cell growth.\",\n      \"method\": \"ChIP for H3K27Ac at FBP1 enhancer, HDAC1/2 knockdown and inhibitor treatment, FBP1 expression and glycolysis assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay establishing epigenetic mechanism, knockdown validation, single lab\",\n      \"pmids\": [\"28262837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXC1 binds directly to the FBP1 gene promoter and negatively regulates its transcriptional activity, thereby promoting glycolysis and colorectal cancer proliferation.\",\n      \"method\": \"ChIP assay (FOXC1 binding to FBP1 promoter), luciferase reporter assay, FOXC1 knockdown/overexpression, glycolysis assays, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter demonstrate direct promoter binding, functional metabolic rescue, single lab\",\n      \"pmids\": [\"30171256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBP1 physically interacts with BRD4, binding to its BD2 bromodomain in an acetylation-dependent manner. Tip60 acetylates FBP1 at K110 and K113, and HDAC3 removes these marks; this acetylation is critical for FBP1-BRD4 binding in pancreatic cancer cells. FBP1-BRD4 interaction decreases expression of BRD4 target genes to inhibit pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation (FBP1-BRD4), domain mapping (BD2), acetylation-site mutagenesis (K110/K113), Tip60 and HDAC3 functional assays, downstream gene expression analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with domain mapping and acetylation mutagenesis, multiple Co-IPs; single lab\",\n      \"pmids\": [\"32195024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBP1 interacts with NICD1 (Notch1 intracellular domain) and the E3 ubiquitin ligase FBXW7 to facilitate ubiquitin-proteasome-dependent degradation of NICD1, inhibiting Notch signaling and NSCLC stemness. This function is independent of FBP1's metabolic enzymatic activity.\",\n      \"method\": \"Co-immunoprecipitation (FBP1-NICD1-FBXW7 complex), ubiquitination assays, enzymatic activity mutant of FBP1, CD133+ stem cell proportion analysis, tumorigenicity assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex Co-IP with enzymatic activity separation, functional stemness readout; single lab\",\n      \"pmids\": [\"38349431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBP1 physically interacts with STAT3 and suppresses nuclear translocation of STAT3, exerting non-enzymatic activity to impair STAT3 function in ovarian cancer cells. C-MYC binding to the FBP1 promoter inhibits FBP1 transcription (alongside DNA methylation).\",\n      \"method\": \"Co-immunoprecipitation (FBP1-STAT3), nuclear fractionation, ChIP (C-MYC at FBP1 promoter), FBP1 overexpression functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP for protein-protein interaction, ChIP for transcriptional repression, single lab\",\n      \"pmids\": [\"34363022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBP1 promotes FBP1 radiosensitivity in nasopharyngeal carcinoma by stabilizing FBXW7 protein (through suppressing FBXW7 auto-ubiquitination), which in turn promotes ubiquitination and degradation of mTOR, thereby suppressing glycolysis.\",\n      \"method\": \"Co-immunoprecipitation (FBXW7-FBP1 and FBXW7-mTOR), ubiquitination assays, FBP1 gain/loss-of-function, glycolysis assays, xenograft models\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays establish mechanistic chain FBP1→FBXW7→mTOR; single lab\",\n      \"pmids\": [\"34298040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ets1 transcription factor is overexpressed in irradiation-induced glioblastoma and acts as a transcriptional repressor of FBP1, leading to decreased FBP1 expression, elevated glycolysis, and increased GBM invasiveness after radiation.\",\n      \"method\": \"FBP1 expression analysis post-irradiation, Ets1 ChIP/promoter analysis, glycolysis assays (glucose uptake, ECAR), orthotopic xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional repressor identified by ChIP, functional metabolic and invasion phenotype validated in vivo; single lab\",\n      \"pmids\": [\"31444412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C/EBPα binds to two overlapping sites at nucleotide -228/-208 of the FBP1 promoter, and HNF4α binds to H4-SBM and DR3 sites at -566/-554 and -212/-198, respectively, to activate FBP1 transcription in hepatoma HepG2 cells. Mutation of these sites markedly reduces transcriptional activation.\",\n      \"method\": \"Luciferase reporter assays with promoter mutations, electrophoretic mobility shift assay (EMSA), siRNA knockdown of C/EBPα and HNF4α\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA and promoter mutagenesis define binding sites, functional reporter assays confirm transcriptional control; single lab\",\n      \"pmids\": [\"29566023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBP1 loss in keratinocytes facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 lysine 9 acetylation (H3K9Ac), leading to enhanced transcription of proliferation genes. This mechanism promotes keratinocyte proliferation while inhibiting differentiation and exacerbates psoriasis-like phenotypes.\",\n      \"method\": \"Fbp1 heterozygous mice (epidermis phenotyping), in vitro keratinocyte FBP1 loss-of-function, acetyl-CoA measurement, H3K9Ac ChIP, transcriptome sequencing, imiquimod psoriasis mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic-epigenetic link established by acetyl-CoA measurement and ChIP, in vivo genetic and pharmacological models; single lab\",\n      \"pmids\": [\"38834617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBP1 is a p53 transcriptional target elevated in senescent MASH hepatocytes. FBP1 is suppressed in HCC progenitor cells through promoter hypermethylation and proteasomal degradation driven by AKT and NRF2 activation. AKT and NRF2 accelerate both FBP1 and p53 degradation, reversing senescence and enabling proliferation and metabolic reprogramming needed for MASH-to-HCC progression.\",\n      \"method\": \"p53 ChIP (FBP1 as p53 target), AKT/NRF2 gain/loss-of-function, proteasomal degradation assays, promoter methylation analysis, mouse MASH-HCC models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP identifies FBP1 as p53 target, multiple genetic models in mice and human validation, mechanistic degradation assays; multiple orthogonal methods\",\n      \"pmids\": [\"39743585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatic but not intestinal FBP1 is required for fructose metabolism and tolerance. Liver-specific Fbp1 deletion in mice leads to fructose-1-phosphate accumulation (indicative of defective fructolysis, likely due to competitive inhibition by fructose-1,6-bisphosphate), hepatomegaly, and liver injury under high-fructose diet, while intestine-specific deletion has no effect.\",\n      \"method\": \"Inducible tissue-specific Fbp1 conditional knockout mice (liver vs. intestine), high-fructose diet challenge, metabolite (fructose-1-phosphate) measurement, liver histology and injury assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic in vivo tissue-specific KO with mechanistic metabolite accumulation measurement, organ-specific functional dissection\",\n      \"pmids\": [\"36964915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELF6 binds the 3'UTR of FBP1 mRNA and stabilizes it, increasing FBP1 protein expression and suppressing triple-negative breast cancer progression.\",\n      \"method\": \"Luciferase reporter assay (3'UTR binding), RNA immunoprecipitation (RIP), RNA pull-down, CELF6 overexpression/knockdown with FBP1 rescue\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein binding by RIP and pull-down confirmed, functional rescue validates axis; single lab\",\n      \"pmids\": [\"32601971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSF2 interacts with EHMT2 (G9a) to epigenetically silence FBP1 expression in hepatocellular carcinoma, thereby promoting aerobic glycolysis and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (HSF2-EHMT2), HSF2 knockdown/overexpression, glycolysis assays, FBP1 expression analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes HSF2-EHMT2 interaction, functional FBP1-glycolysis linkage shown; single lab\",\n      \"pmids\": [\"31497345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LOXL2 intracellular enzymatic activity (not extracellular) upregulates Snail expression, which represses FBP1, thereby enhancing glycolysis and HIF-1α/VEGF signaling in hepatocellular carcinoma cells. The catalytically inactive LOXL2(Y689F) mutant does not affect Snail or FBP1.\",\n      \"method\": \"LOXL2 wild-type vs. catalytic mutant (Y689F) overexpression, LOXL2 siRNA knockdown, Snail-FBP1 rescue epistasis, LOXL2 inhibitor (LOXL2-IN-1) treatment, HIF-1α/VEGF expression analysis\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant establishes enzymatic requirement, epistasis experiment places axis LOXL2→Snail→FBP1; single lab\",\n      \"pmids\": [\"32323822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P4HA1 overexpression under hypoxia reduces intracellular α-ketoglutarate (α-KG) levels (by consuming α-KG during collagen hydroxylation), which reduces TET2 protein levels and TET2 recruitment to the FBP1 promoter, resulting in decreased FBP1 expression and enhanced glycolysis to promote endothelial angiogenesis.\",\n      \"method\": \"α-KG measurement, TET2 protein analysis, ChIP-PCR (TET2 at FBP1 promoter), P4HA1 overexpression/knockdown, FBP1 expression rescue, angiogenesis assays in vitro and HLI mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes TET2 at FBP1 promoter, metabolite-TET2 mechanism validated; single lab\",\n      \"pmids\": [\"38238754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBP1 (gluconeogenic enzyme) inhibits HIF-1α protein expression and reduces transcription of HIF-1α target genes (PDK1, LDHA, GLUT1, VEGF) in basal-like breast cancer cells under hypoxia. ChIP demonstrated FBP1 occupancy at hypoxia response elements (HREs) in the PDK1 promoter.\",\n      \"method\": \"FBP1 lentiviral overexpression, Western blot (HIF-1α protein), RT-qPCR (HIF-1α target genes), chromatin immunoprecipitation (FBP1 at HRE of PDK1), glycolysis and cell growth assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP shows FBP1 at HREs, functional HIF-1α suppression demonstrated; single lab, single study\",\n      \"pmids\": [\"28485159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXP2 suppresses transcription of KDM5A (a histone demethylase), which blocks KDM5A-induced H3K4me3 demethylation at the FBP1 promoter, thereby increasing FBP1 expression and inhibiting the Warburg effect in HCC cells.\",\n      \"method\": \"ChIP (H3K4me3 at FBP1 promoter), FOXP2 and KDM5A gain/loss-of-function, FBP1 expression rescue, glycolysis assays, xenograft models\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes H3K4me3 regulation at FBP1 promoter, epistasis chain FOXP2→KDM5A→FBP1 validated; single lab\",\n      \"pmids\": [\"37713600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Retinoic acid (RA) activates FBP1 transcription via retinoic acid receptor (RAR) binding to the FBP1 gene (ChIP-PCR validated), upregulating FBP1 to suppress glycolysis and inhibit angiogenesis in human embryonic stem cell-derived endothelial cells. Silencing FBP1 reverses RA-induced angiogenesis inhibition.\",\n      \"method\": \"ChIP-PCR (RAR at FBP1 promoter), FBP1 knockdown/pharmacological inhibition, RAR inhibitor (BMS493), RNA sequencing, angiogenesis assays (proliferation, migration, tube formation)\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR establishes direct RAR binding, functional angiogenesis rescue; single lab\",\n      \"pmids\": [\"35672803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GATA4 interacts physically with FBP1 protein (identified by immunoprecipitation-mass spectrometry) and positively regulates FBP1 expression in dental pulp stem cells (DPSCs). GATA4 promotes gluconeogenesis via FBP1; loss of GATA4 decreases FBP1 expression, increases glucose consumption and lactate production.\",\n      \"method\": \"Co-immunoprecipitation-mass spectrometry (GATA4-FBP1 interaction), GATA4 knockdown/overexpression, FBP1 knockdown, glucose/lactate metabolic assays, in vivo lentiviral GATA4 overexpression in mouse root\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identifies physical interaction, functional metabolic validation; single lab\",\n      \"pmids\": [\"31892855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In AML, Evi1 transcription factor directly interacts with the enhancer region of Fbp1 and upregulates its transcription. Fbp1 upregulation activates the pentose phosphate pathway in Evi1-driven leukemia, and pharmacological or shRNA-mediated Fbp1 inhibition selectively suppresses Evi1-driven leukemogenesis.\",\n      \"method\": \"ChIP (Evi1 at Fbp1 enhancer), transcriptomic and metabolomic profiling, Fbp1 shRNA knockdown, pharmacological Fbp1 inhibition, secondary transplantation leukemia mouse model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes enhancer binding, metabolomics confirms pathway activation, in vivo transplantation model; single lab\",\n      \"pmids\": [\"34363719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"In S. pombe, glucose repression of fbp1 transcription is mediated through the cAMP-PKA signaling pathway; git2/cyr1 (adenylate cyclase) is required for this repression, and exogenous cAMP restores repression in git mutants. The pathway is independent of ras1 and acts through activation of cAMP-dependent protein kinase.\",\n      \"method\": \"Genetic epistasis analysis with git mutants, fbp1-lacZ/fbp1-ura4 reporter fusions, exogenous cAMP supplementation, adenylate cyclase activity assays, intragenic complementation analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple pathway components, reporter fusions, cAMP rescue, replicated across multiple labs subsequently\",\n      \"pmids\": [\"1849107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In S. pombe, gpa2 (git8) encodes a Gα-protein subunit that partially regulates adenylate cyclase (Cyr1/Git2) activity for glucose repression of fbp1 transcription. Git3 and git5 act in concert with or independently from gpa2 to regulate adenylate cyclase.\",\n      \"method\": \"Gene identity mapping (git8=gpa2), fbp1-lacZ reporter assays, genetic epistasis (git3/git5 combined with gpa2 deletions), high-copy suppression\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with reporter assays; single study, fission yeast ortholog\",\n      \"pmids\": [\"8001792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In S. pombe, fbp1 transcription is antagonistically regulated at two upstream activation sites (UAS1, UAS2) by PKA and MAPK pathways. UAS1 binds the atf1-pcr1 heterodimeric activator; MAPK positively and PKA negatively regulate atf1 binding at UAS1. UAS2 is bound by activators and repressors regulated by both pathways but does not involve atf1.\",\n      \"method\": \"Deletion analysis defining UAS1 and UAS2, gel-shift/EMSA identifying atf1-pcr1 at UAS1, fbp1 promoter-reporter constructs, PKA and MAPK mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter dissection with mutagenesis, EMSA identifying activator complexes, validated with signaling mutants; rigorous mechanistic study\",\n      \"pmids\": [\"10938120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In S. pombe, two redundant Tup1p-like corepressors (Tup11 and Tup12) repress fbp1 transcription downstream of PKA; double deletion causes ~100-fold increase in fbp1-lacZ expression. The CCAAT-binding factor subunit Php5 activates fbp1 transcription in parallel to atf1-pcr1.\",\n      \"method\": \"cDNA library screen, tup11/tup12 double deletion analysis, fbp1-lacZ reporter assays, genetic epistasis with atf1/spc1\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen and deletion analysis with quantitative reporter assays; single lab, S. pombe model\",\n      \"pmids\": [\"11238405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In S. pombe, Tup11/Tup12 corepressors repress chromatin remodeling at two CRE-related regulatory elements in the fbp1+ promoter. Under derepressed conditions, chromatin is remodeled coordinately with transcriptional activation. Tup11/Tup12 deletion recapitulates the open chromatin state even under repressed conditions. Rst2 (a cAMP-PKA-controlled transcription factor) antagonizes Tup11/Tup12 chromatin repression.\",\n      \"method\": \"Chromatin immunoprecipitation (MNase sensitivity/nucleosome mapping), tup11/tup12 double deletion, rst2 deletion, chromatin structure analysis under repressed vs. derepressed conditions\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin structure directly measured by nuclease accessibility assays, multiple genetic backgrounds tested; single lab\",\n      \"pmids\": [\"14573465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"The S. cerevisiae FBP1 gene encodes fructose bisphosphatase; disruption by transplacement creates a hexose auxotroph. FBP1 mRNA (~1350 nt) is glucose-repressible. The cloned gene confers fructose bisphosphatase activity in E. coli sensitive to fructose 2,6-bisphosphate inhibition.\",\n      \"method\": \"Gene cloning by complementation, transplacement disruption, Northern blot, enzymatic activity assay in E. coli, antibody precipitation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic disruption with defined auxotrophic phenotype, enzymatic activity validated in heterologous system; foundational study\",\n      \"pmids\": [\"3003364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human FBP1 gene encodes fructose-1,6-bisphosphatase (EC 3.1.3.11), which catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. The gene contains seven exons spanning >31 kb and is localized to chromosome 9q22.2-q22.3 by FISH.\",\n      \"method\": \"Gene cloning and structural characterization, fluorescence in situ hybridization (FISH), mutational screening by DNA sequencing, exon-intron mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic function established by gene characterization, chromosomal localization by direct FISH; definitive molecular characterization\",\n      \"pmids\": [\"7558035\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBP1 (fructose-1,6-bisphosphatase 1) is a gluconeogenic enzyme that catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate; beyond this canonical metabolic role, it acts as a tumor suppressor through multiple non-enzymatic mechanisms: it is transcriptionally silenced by the Snail-G9a-Dnmt1 complex (via promoter methylation), by HDAC1/2 (via H3K27Ac reduction), and by C-MYC/FOXC1/ZEB1 binding to its promoter, while being activated by C/EBPα, HNF4α, and p53; at the protein level, FBP1 is ubiquitinated and degraded via MAGE-TRIM28, TRIM47, SKP2 (downstream of PTEN/AKT/CDK-mediated S271 phosphorylation), and UBR5 (via C/EBPα destabilization), and is stabilized by deubiquitinases USP22, USP44, and USP7; beyond metabolism, FBP1 physically interacts with BRD4-BD2 (in an acetylation-dependent manner), STAT3 (blocking its nuclear translocation), NICD1/FBXW7 (promoting Notch1 degradation), and DNMT1 (trapping PARP1 on chromatin), while in liver cancer FBP1 loss drives HMGB1-mediated hepatic stellate cell activation/senescence that promotes tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBP1 is a gluconeogenic enzyme that catalyzes hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate [#36], and which functions broadly as a metabolic brake on glycolysis whose loss reprograms cells toward the Warburg effect across diverse tissues [#0, #35]. In the liver, hepatic FBP1 is required for fructose tolerance—its deletion drives fructose-1-phosphate accumulation, steatosis, and injury [#20]—and its loss promotes tumorigenesis through HMGB1 release that activates and senesces hepatic stellate cells [#2], while in the MASH-to-HCC transition FBP1 acts as a p53-regulated enforcer of senescence whose degradation enables progression [#19]. Beyond catalysis, FBP1 restrains glycolysis by suppressing HIF-1α and occupying hypoxia response elements at glycolytic gene promoters [#25], and it executes several non-enzymatic tumor-suppressor functions: physically engaging STAT3 to block its nuclear translocation [#14], binding the BRD4 BD2 bromodomain in a Tip60-acetylation-dependent manner to downregulate BRD4 target genes [#12], scaffolding NICD1–FBXW7 to drive Notch1 degradation independently of its enzymatic activity [#13], and translocating to the nucleus to interact with DNMT1 and trap PARP1 on chromatin [#8]. FBP1 levels are controlled by an extensive regulatory network: transcriptional repression via the Snail–G9a–DNMT1 complex [#0], HDAC1/2-mediated H3K27Ac loss [#10], and repressors C-MYC, FOXC1, Ets1, and KDM5A [#11, #14, #16, #26], opposed by activators C/EBPα, HNF4α, retinoic-acid receptor, and FOXP2 [#17, #27, #26]; and post-translationally by ubiquitin ligases MAGE-TRIM28, TRIM47, SKP2 (downstream of PTEN/AKT/CDK-driven S271 phosphorylation), and UBR5 versus the stabilizing deubiquitinases USP44 and USP7 [#3, #6, #9, #5, #7, #8]. Context-dependently, FBP1 is co-opted as a pro-tumor effector in Evi1-driven leukemia, where it feeds the pentose phosphate pathway [#29], and impairs NK-cell antitumor function by inhibiting glycolysis [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Established the molecular identity of the FBP1 gene product as fructose bisphosphatase and revealed glucose-repressible expression, defining the core gluconeogenic function.\",\n      \"evidence\": \"Gene cloning by complementation, transplacement disruption, and heterologous enzymatic assay in S. cerevisiae\",\n      \"pmids\": [\"3003364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast ortholog; human gene structure not yet defined\", \"Regulatory transcription factors not identified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Mapped the upstream signaling that controls fbp1 transcription, showing glucose repression operates through the cAMP-PKA pathway.\",\n      \"evidence\": \"Genetic epistasis with git mutants, fbp1-reporter fusions, and cAMP rescue in S. pombe\",\n      \"pmids\": [\"1849107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcription factors at the promoter not yet defined\", \"Yeast pathway; mammalian relevance unestablished\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the human FBP1 gene structure, enzymatic reaction, and chromosomal locus, anchoring the canonical metabolic function in humans.\",\n      \"evidence\": \"Gene cloning, exon-intron mapping, and FISH localization to 9q22\",\n      \"pmids\": [\"7558035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No regulatory or non-enzymatic functions addressed\", \"Disease relevance not yet established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Dissected the promoter logic of fbp1, showing antagonistic PKA/MAPK control through distinct upstream activation sites and the atf1-pcr1 activator complex.\",\n      \"evidence\": \"Promoter deletion, EMSA, and signaling-mutant reporter analysis in S. pombe\",\n      \"pmids\": [\"10938120\", \"8001792\", \"11238405\", \"14573465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast transcriptional architecture may not map onto mammalian FBP1 regulation\", \"Chromatin-level mechanism elaborated only in fission yeast\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-degradative ubiquitination role, where USP22 deubiquitinates FBP1 to control its occupancy at the p21 promoter and thus proliferation.\",\n      \"evidence\": \"USP22 knockdown, ubiquitination assays, and ChIP at the p21 locus\",\n      \"pmids\": [\"21779003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"This FBP1 (FUSE-binding protein context) chromatin role not connected to metabolic FBP1 function\", \"Mechanism of promoter occupancy unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established FBP1 as a metabolic tumor suppressor whose epigenetic silencing reprograms cells toward glycolysis and stemness, motivating the broad oncology framework.\",\n      \"evidence\": \"Promoter methylation/ChIP, metabolic flux assays, and β-catenin co-IP in basal-like breast cancer\",\n      \"pmids\": [\"23453623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tumor suppression requires enzymatic activity not separated here\", \"Generality across tumor types not yet tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the first ubiquitin ligase axis and an enhancer-level epigenetic repressor controlling FBP1 protein and transcript levels in HCC.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, and H3K27Ac ChIP with HDAC inhibition (MAGE-TRIM28; HDAC1/2)\",\n      \"pmids\": [\"28394358\", \"28262837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron/recognition motif on FBP1 not mapped\", \"Crosstalk between transcriptional and post-translational control unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened FBP1 biology beyond tumor cells (impairing NK antitumor function) and detailed its transcriptional activators and HIF-1α suppression.\",\n      \"evidence\": \"NK cell manipulation with glycolysis assays; promoter mutagenesis/EMSA (C/EBPα, HNF4α); FBP1 overexpression with HRE ChIP\",\n      \"pmids\": [\"30033198\", \"29566023\", \"30171256\", \"28485159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of FBP1 occupancy at HREs unclear\", \"Whether NK-intrinsic effect is enzymatic unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the non-cell-autonomous liver tumor-suppressor mechanism (HMGB1-driven stellate cell activation) and expanded the regulatory network of ligases, deubiquitinases, RNA-binding stabilizers, and non-enzymatic protein interactions.\",\n      \"evidence\": \"Conditional KO mice with HMGB1 inhibition; co-IP/ubiquitination (UBR5-C/EBPα); RIP (CELF6); FBP1-BRD4 domain mapping; FBP1-STAT3 co-IP; LOXL2/HSF2/GATA4 functional studies\",\n      \"pmids\": [\"32367049\", \"33122826\", \"32601971\", \"32195024\", \"31497353\", \"32323822\", \"31497345\", \"31892855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-enzymatic interactions largely from single labs without reciprocal validation\", \"Structural basis of FBP1-BRD4 and FBP1-STAT3 binding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established phosphorylation-coupled degradation (PTEN/AKT/CDK-S271/SKP2) and a nuclear FBP1-DNMT1-PARP1 axis, and revealed context-dependent pro-tumor co-option in Evi1 leukemia.\",\n      \"evidence\": \"S271 phospho-mutagenesis with ubiquitination assays; USP7/FBP1/DNMT1 co-IPs with chromatin PARP1 assays; Evi1 enhancer ChIP with metabolomics\",\n      \"pmids\": [\"36237339\", \"34854226\", \"34363719\", \"34363022\", \"34298040\", \"33529753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"S271 kinase identity not pinned to a specific CDK\", \"Pro- vs anti-tumor switch determinants not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved enzymatic-independent Notch suppression and connected FBP1 loss to glycolysis-driven histone acetylation in non-cancer disease (psoriasis), plus FBXW7 stabilization controlling mTOR.\",\n      \"evidence\": \"FBP1-NICD1-FBXW7 complex co-IP with enzyme-dead mutant; acetyl-CoA/H3K9Ac ChIP in keratinocytes; FBXW7-mTOR ubiquitination assays\",\n      \"pmids\": [\"38349431\", \"38834617\", \"34298040\", \"38238754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic vs scaffold contributions not fully separated across contexts\", \"Single-lab validation for most interaction claims\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned FBP1 within a p53-dependent senescence program that gatekeeps MASH-to-HCC progression, integrating transcriptional and degradative control.\",\n      \"evidence\": \"p53 ChIP, AKT/NRF2 gain/loss, proteasomal degradation and methylation assays in mouse MASH-HCC models\",\n      \"pmids\": [\"39743585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether senescence enforcement requires FBP1 enzymatic activity not resolved\", \"Direct molecular link between FBP1 and p53 stability not fully mechanistic\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which FBP1 functions require its catalytic activity versus non-enzymatic scaffolding, and how the dense regulatory network is integrated to set FBP1 levels in a given tissue or tumor context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model distinguishing enzymatic and protein-interaction surfaces\", \"Determinants of pro-tumor vs tumor-suppressor behavior undefined\", \"Reciprocal/independent validation lacking for many single-lab interaction claims\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [36, 35]},\n      {\"term_id\": \"GO:0016791\", \"supporting_discovery_ids\": [36]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [36, 35]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4, 8, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [36, 35, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BRD4\", \"STAT3\", \"DNMT1\", \"FBXW7\", \"TRIM28\", \"USP7\", \"SKP2\", \"GATA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}