Affinage

PFKFB4

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 · UniProt Q16877

Length
469 aa
Mass
54.0 kDa
Annotated
2026-06-10
74 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PFKFB4 is a bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase whose recombinant kinase activity exceeds its phosphatase activity ~4.3-fold, generating fructose-2,6-bisphosphate to allosterically activate PFK-1 and drive glycolytic flux, glucose uptake, and ATP production (PMID:25115398). Beyond this metabolic role, PFKFB4 acts as a protein kinase: it directly phosphorylates the steroid receptor coactivator SRC-3 at Ser857 to enhance its interaction with ATF4 and upregulate transketolase, redirecting glucose into the pentose phosphate pathway for purine synthesis (PMID:29615789), and phosphorylates SRC-2 at Ser487 to reprogram transcription via CARM1 in lung adenocarcinoma (PMID:33593309). Additional substrates and partners place PFKFB4 at multiple non-glycolytic nodes — it phosphorylates HSPB1 to suppress ferroptosis (PMID:41577048), interacts with ICMT to control RAS plasma-membrane localization and AKT signaling (PMID:35914811), associates with the E3 ligase FBXO28 to modulate HIF-1α ubiquitination and stability (PMID:36115843), and translocates to the nucleus under hypoxia to non-canonically activate HIF-1α transcription (PMID:36476868). During Xenopus development PFKFB4 governs dorsal ectoderm patterning and neural crest specification/migration through AKT signaling independently of glycolysis (PMID:25601028, PMID:29038306). PFKFB4 expression is induced by HIF-1α under hypoxia (PMID:27181362) and by numerous transcription factors and coactivators, and its protein level is set post-translationally by PIM2-mediated stabilizing phosphorylation at Thr140 (PMID:36109523) and by E3-ligase-mediated ubiquitination (CHIP at K305, FBXL7) (PMID:40684802, PMID:37179372). Its enzymatic direction is context-dependent: in hepatocellular carcinoma PFKFB4 acts predominantly as a phosphatase, with ablation causing accumulation of glycolytic and PPP metabolites (PMID:36806581).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Before its enzymatic and signaling roles were dissected, the basal transcriptional control of PFKFB4 needed mapping to understand how the gene is switched on.

    Evidence 5'-deletion promoter-luciferase reporter assays in germ-cell-derived lines

    PMID:15642344

    Open questions at the time
    • Did not identify the protein products binding the GC-rich/ETF elements
    • Hypoxia responsiveness defined only via CoCl2 chemical mimic
  2. 2014 High

    The central biochemical question — which of PFKFB4's two opposing activities dominates — was resolved by direct enzymology, establishing it as a predominantly kinase-driven producer of F2,6BP that fuels glycolysis.

    Evidence Recombinant enzyme kinase/phosphatase assays with siRNA, genomic deletion, overexpression, and in vivo inhibitor F2,6BP measurements

    PMID:25115398

    Open questions at the time
    • Activity ratio measured for a single isoform under defined conditions
    • Did not address context-dependent shifts toward phosphatase activity
  3. 2015 High

    Whether PFKFB4 has functions beyond metabolism was tested in vivo, showing it directs ectoderm patterning through AKT signaling independent of glycolytic output.

    Evidence Xenopus morpholino depletion with AKT-restoration rescue and epistasis

    PMID:25601028

    Open questions at the time
    • Molecular link between PFKFB4 and AKT not biochemically defined
    • Whether this generalizes beyond embryonic ectoderm unaddressed
  4. 2017 High

    Extending the developmental role, PFKFB4 was shown to control neural crest specification (AKT-dependent) and migration (AKT- and glycolysis-dependent), separating its two functional modes.

    Evidence Time-controlled/hypomorphic Xenopus depletion with AKT-pathway epistasis and neural crest gene readouts

    PMID:29038306

    Open questions at the time
    • Direct PFKFB4 effector at the molecular level not identified
    • Mechanism distinguishing specification vs migration requirements unclear
  5. 2018 High

    The discovery that PFKFB4 is a protein kinase reframed it as a signaling enzyme: it phosphorylates SRC-3 at Ser857 to remodel transcription toward the PPP for nucleotide synthesis.

    Evidence Kinome-wide RNAi screen, in vitro kinase assay, Ser857Ala rescue, Co-IP, promoter-binding, orthotopic tumor models

    PMID:29615789

    Open questions at the time
    • Structural basis for substrate recognition not defined
    • Whether kinase and metabolic activities use the same catalytic mechanism unresolved
  6. 2021 Medium

    The protein-kinase repertoire was broadened to a second coactivator substrate, SRC-2 at Ser487, linking PFKFB4 to CARM1-driven transcriptional programs in lung adenocarcinoma.

    Evidence Co-IP, phospho-SRC-2 Western blot, transcriptome sequencing, invasion assays

    PMID:33593309

    Open questions at the time
    • Direct in vitro kinase assay on SRC-2 not shown
    • Site-specific mutant rescue not reported
  7. 2022 Medium

    Multiple interactome studies positioned PFKFB4 as a hub controlling oncogenic signaling and protein stability beyond its catalytic substrates.

    Evidence MS-based interactome with FBXO28/HIF-1α (GSCs), Co-IP with ICMT/RAS (melanoma), and PIM2-mediated Thr140 phosphorylation (endometriosis)

    PMID:35914811 PMID:36109523 PMID:36115843

    Open questions at the time
    • Direct vs indirect nature of HIF-1α regulation not fully separated
    • ICMT and FBXO28 interactions validated in single contexts
  8. 2022 Medium

    Hypoxia-driven nuclear translocation revealed a moonlighting function in which PFKFB4 non-canonically activates HIF-1α transcription, adding a feed-forward loop to its hypoxia biology.

    Evidence Photoacoustic imaging, metabolomics, genetic ablation, and nuclear-localization immunofluorescence in mouse breast cancer

    PMID:36476868

    Open questions at the time
    • Mechanism of nuclear import not defined
    • Whether nuclear function requires catalytic activity unclear
  9. 2023 Medium

    The assumption of constitutive kinase dominance was qualified by evidence that PFKFB4 can act predominantly as a phosphatase in hepatocellular carcinoma, establishing context-dependence of its enzymatic direction.

    Evidence CRISPR/Cas9 knockout with targeted metabolomics and RNA-seq in HCC models

    PMID:36806581

    Open questions at the time
    • Molecular switch determining kinase vs phosphatase bias not identified
    • Direct enzymatic-direction measurement on the tumor isoform not shown
  10. 2023 Medium

    Layered post-transcriptional and post-translational control was mapped, showing PFKFB4 abundance is set by E3-ligase-mediated degradation and by mRNA-stabilizing RNA-binding machinery.

    Evidence TAP/MS and ubiquitination assays (FBXL7/EZH2/HIF-1α) and Co-IP/mRNA export-stability assays (THOC3/YBX1, m5C)

    PMID:37179372 PMID:37500615

    Open questions at the time
    • Relative contribution of transcriptional vs degradative control in vivo unquantified
    • Cross-talk between the regulatory layers not integrated
  11. 2025 High

    Substrate and isoform studies extended PFKFB4's signaling outputs to ferroptosis suppression and AKT activation, the latter encoded by a splice variant rather than the full-length enzyme.

    Evidence Co-IP/in vitro kinase assay on HSPB1 (gastric cancer) and immunoprecipitation/kinase assay showing PFKFB4-ΔEx6 binds and activates AKT (HCC)

    PMID:41281445 PMID:41577048

    Open questions at the time
    • Whether HSPB1 and AKT effects share a common catalytic mode unknown
    • Tissue distribution and prevalence of the ΔEx6 variant not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • What structurally and mechanistically determines PFKFB4's switch between metabolic kinase, phosphatase, and protein-kinase modes — and how a single enzyme selects among its many substrates and partners — remains unresolved.
  • No structural model linking catalytic site to protein-substrate phosphorylation
  • Determinants of context-dependent kinase-vs-phosphatase bias unknown
  • Substrate-selection rules across SRC-3, SRC-2, HSPB1, and AKT not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2 GO:0016853 isomerase activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CHIPFBXO28GSK3BHSPB1ICMTPIM2SRC-2SRC-3/NCOA3

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 PFKFB4 directly phosphorylates SRC-3 (steroid receptor coactivator-3) at serine 857, enhancing its transcriptional activity. This phosphorylation increases SRC-3 interaction with transcription factor ATF4, stabilizing recruitment of SRC-3 and ATF4 to target gene promoters, thereby upregulating transketolase expression and driving glucose flux toward the pentose phosphate pathway for purine synthesis. Kinome-wide RNAi screen, in vitro kinase assay, phospho-specific antibodies, Co-IP, promoter-binding assays, Ser857Ala phosphorylation-deficient mutant rescue experiments, mouse orthotopic tumor models Nature High 29615789
2014 Recombinant human PFKFB4 kinase activity is 4.3-fold greater than its phosphatase activity. PFKFB4 kinase activity synthesizes fructose-2,6-bisphosphate (F2,6BP), which allosterically activates PFK-1, increasing glycolytic flux. siRNA and genomic deletion of PFKFB4 decrease F2,6BP levels, while overexpression increases them, and selective PFKFB4 inhibition in vivo reduces F2,6BP, glucose uptake, and ATP. Recombinant enzyme kinase/phosphatase activity assay, siRNA knockdown, genomic deletion, F2,6BP measurement, in vivo inhibitor studies Oncotarget High 25115398
2015 PFKFB4 controls dorsal ectoderm patterning in Xenopus embryos via AKT signaling independently of glycolysis. Restoring AKT signaling rescues loss-of-PFKFB4 phenotypes in vivo, whereas glycolysis is not essential at this developmental stage. Xenopus embryo loss-of-function (morpholino depletion), rescue experiments with AKT signaling restoration, in vivo epistasis Nature Communications High 25601028
2017 PFKFB4 controls AKT signaling during neural crest specification and migration in Xenopus. AKT signaling mediates PFKFB4 function in late neural crest specification, while both AKT signaling and glycolysis regulate neural crest migration. PFKFB4-depleted embryos fail to activate N-cadherin and late neural crest specifiers and exhibit severe migration defects. Time-controlled and hypomorphic PFKFB4 depletion in Xenopus, epistasis with AKT pathway manipulation, in vivo neural crest gene expression assays Development High 29038306
2015 Structure-based virtual screening identified 5MPN (5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate) as a first-in-class selective inhibitor of PFKFB4 that suppresses glycolysis and cancer cell proliferation in vitro and reduces tumor glucose metabolism and growth in vivo upon oral administration. Structure-based virtual computational screening, in vitro glycolysis and proliferation assays, in vivo oral bioavailability and tumor growth assays Oncotarget Medium 26221874
2017 Etk (BMX tyrosine kinase) physically interacts with PFKFB4 and acts upstream of it to promote chemoresistance through regulation of autophagy in small-cell lung cancer cells. Co-immunoprecipitation, GST pull-down, microarray analysis, gain/loss-of-function assays, in vivo PDX model Clinical Cancer Research Medium 29208667
2022 PFKFB4 interacts with FBXO28 (a ubiquitin E3 ligase) and regulates HIF-1α protein levels by modulating its ubiquitylation and subsequent proteasomal degradation in glioblastoma stem-like cells. Mass spectrometry of immunoprecipitated PFKFB4, Co-IP, gene expression profiling in PFKFB4-silenced GSCs, Western blot for HIF protein levels, orthotopic mouse model Oncogenesis Medium 36115843
2022 PFKFB4 interacts with ICMT (a posttranslational modifier of RAS), promotes ICMT/RAS interaction, controls RAS localization at the plasma membrane, activates AKT signaling, and enhances melanoma cell migration independently of glycolysis. Co-IP, RAS localization assays, AKT signaling readouts, cell migration assays, gain/loss-of-function experiments Life Science Alliance Medium 35914811
2022 PIM2 kinase phosphorylates PFKFB4 at threonine 140 (Thr140), stabilizing PFKFB4 protein through the ubiquitin-proteasome pathway and promoting glycolysis and cell growth in endometriosis. Co-immunoprecipitation, in vitro kinase assay, ubiquitin-proteasome pathway analysis, site-directed mutagenesis (Thr140), functional glycolysis assays, in vivo endometriosis model Cell Death & Disease Medium 36109523
2021 PFKFB4 phosphorylates SRC-2 at Ser487, altering its transcriptional activity, and PFKFB4-SRC-2 interaction promotes lung adenocarcinoma proliferation, migration, and invasion via upregulation of CARM1 expression. Co-immunoprecipitation, Western blot for phospho-SRC-2, transcriptome sequencing, cell proliferation and invasion assays BMC Pulmonary Medicine Medium 33593309
2021 In clear-cell renal cell carcinoma, PFKFB4 overexpression is associated with enriched pentose phosphate pathway metabolites; phosphoproteomics and immunoprecipitation showed PFKFB4 also phosphorylates NCOA3, which interacts with FBP1 to form a regulatory loop counteracting overactive PPP flux. Metabolomics, phosphoproteomics, immunoprecipitation, CRISPR/Cas9 knockout Journal of Experimental & Clinical Cancer Research Medium 34593007
2023 In hepatocellular carcinoma, PFKFB4 functions predominantly as a phosphatase (reducing F2,6BP), not a kinase, as shown by CRISPR/Cas9 knockout and targeted metabolomic profiling demonstrating accumulation of downstream glycolysis and PPP metabolites upon PFKFB4 ablation. CRISPR/Cas9-mediated PFKFB4 knockout, targeted metabolomics, RNA sequencing, in vivo HCC models Cellular and Molecular Gastroenterology and Hepatology Medium 36806581
2021 PFKFB4 promotes breast cancer metastasis by activating HAS2 expression and hyaluronan (HA) production through p38 signaling activation. PFKFB4 knockdown suppresses HAS2 upregulation and HA production. Gain/loss-of-function assays, ELISA for HA production, qRT-PCR and Western blot for HAS2, in vivo orthotopic xenograft and experimental metastasis models, pharmacological p38 inhibition Cellular Physiology and Biochemistry Medium 30415245
2016 HIF-1α transcriptionally activates PFKFB4 expression in bladder cancer cells under hypoxia by binding to a specific hypoxia-responsive element (HRE-D) in the PFKFB4 promoter. Luciferase reporter assay with HRE deletion constructs, dual-immunofluorescence co-localization, promoter analysis Biochemical and Biophysical Research Communications Medium 27181362
2012 FGF-2 secreted by Sertoli cells, acting through the MEK/ERK/CREB pathway, induces PFKFB4 expression in spermatogenic cells. A putative CRE-binding sequence at -1,463 relative to the PFKFB4 transcription start site is required for this regulation, and CREB binds to this site as shown by pulldown assays. Conditioned medium experiments, MEK inhibitors, FGF-2 neutralizing antibodies, luciferase reporter assays with PFKFB4 promoter constructs, CREB pulldown assays American Journal of Physiology - Endocrinology and Metabolism Medium 22811469
2016 PPARγ phosphorylated at Ser84 by MEK/ERK transcriptionally activates PFKFB4 expression by binding directly to its promoter in hepatocellular carcinoma cells, and PFKFB4 knockdown abolishes PPARγ phosphorylation-driven glycolysis and proliferation. ChIP assay, RNA microarray, siRNA knockdown of PFKFB4, HCC mouse model Oncotarget Medium 27769068
2020 The epigenetic regulator MLL promotes PFKFB4 expression at the transcriptional level through the E2F6 binding site in the PFKFB4 promoter in acute monocytic leukemia cells. TCGA expression analysis, siRNA knockdown, PFKFB4 inhibitor treatment, promoter binding site analysis Biochemical and Biophysical Research Communications Low 32299611
2022 PFKFB4 promotes angiogenesis by upregulating IL-6 expression via NF-κB signaling in breast cancer cells; PFKFB4-induced lactate secretion contributes to NF-κB activation, and IL-6 then elicits angiogenesis via STAT5A/P-STAT5 in HUVECs. HUVEC tube formation assay, orthotopic mouse model, qPCR, Western blot, ELISA, immunofluorescence, gene editing with siRNA and PFKFB4 inhibitor 5MPN Journal of Cancer Medium 34976184
2022 Hypoxic induction triggers nuclear translocation of PFKFB4, where it non-canonically activates HIF-1α transcription; breast cancer patients with increased nuclear PFKFB4 correlate with poor prognosis. Photoacoustic imaging, metabolomics, genetic ablation of PFKFB4 in mouse breast cancer models, immunofluorescence for nuclear PFKFB4 localization Cell Reports Medium 36476868
2018 CD44 intracellular domain (CD44ICD) interacts with CREB and binds the PFKFB4 promoter to regulate PFKFB4 transcription and expression, promoting breast cancer stemness via PFKFB4-mediated glycolysis. Chromatin immunoprecipitation, luciferase reporter assay, gain/loss-of-function, glycolysis assays, xenograft model with PFKFB4 inhibitor 5MPN Theranostics Medium 30613295
2021 E2F2 transcription factor elevates PFKFB4 expression by directly binding to its promoter (confirmed by ChIP and luciferase assays), activating the PI3K/AKT pathway to promote glioma malignancy; PFKFB4 knockdown mitigates E2F2-driven glioma metastasis and glycolysis. ChIP assay, luciferase reporter assay, siRNA knockdown, PI3K/AKT signaling measurement, in vivo glioma growth and metastasis assays Life Sciences Medium 33774025
2023 FBXL7 E3 ubiquitin ligase ubiquitinates and degrades PFKFB4 protein, suppressing glucose metabolism. Hypoxia-induced HIF-1α upregulates EZH2, which inhibits FBXL7 transcription, thereby stabilizing PFKFB4 protein to promote glycolysis and NSCLC malignancy. Tandem affinity purification/mass spectrometry (TAP/MS), ubiquitination assays, in vitro/in vivo functional assays, EZH2 knockdown with rescue Cell Death & Disease Medium 37179372
2023 THOC3 forms a complex with YBX1 to promote PFKFB4 transcription and also exports PFKFB4 mRNA to the cytoplasm, while YBX1 stabilizes PFKFB4 mRNA by recognizing m5C sites in its 3'UTR. Co-IP for complex identification, RNA export assays, mRNA stability assays, siRNA knockdown, glycolysis assays Cell Death & Disease Medium 37500615
2025 PTBP1 lactylation at K436 inhibits its proteasomal degradation by reducing interaction with TRIM21, and lactylated PTBP1 enhances RNA-binding capacity to stabilize PFKFB4 mRNA, increasing glycolysis and maintaining glioma stem cells. SIRT1 induces PTBP1 delactylation, reversing this effect. Lactylation proteomics, Co-IP with TRIM21, RNA-binding assays, PFKFB4 mRNA stability assays, SIRT1 manipulation, in vivo glioma models Cancer Research Medium 39570804
2021 GSK3β is identified as a downstream target and interacting protein of PFKFB4 in pancreatic cancer. Bruceine A binds directly to PFKFB4, inhibiting its activity; this suppresses glycolysis and dysregulates GSK3β, leading to cell cycle arrest and apoptosis. Human proteome microarray, fluorescence binding assay, microscale thermophoresis, Co-IP for PFKFB4-GSK3β interaction, glycolysis assays Pharmacological Research Medium 33992797
2025 PFKFB4 directly phosphorylates HSPB1 (Heat Shock Protein Beta-1) in gastric cancer cells, suppressing ferroptosis. Pharmacological inhibition of PFKFB4 with 5MPN potentiates ferroptotic cell death and suppresses tumor growth. Co-IP demonstrating PFKFB4-HSPB1 interaction, in vitro kinase assay, ferroptosis assays, in vivo xenograft with 5MPN Biochemical Pharmacology Medium 41577048
2025 A non-canonical splice variant of PFKFB4 (PFKFB4-ΔEx6, with in-frame deletion of 19 amino acids from exon 6 skipping) directly activates AKT through binding to its kinase domain, whereas canonical PFKFB4-FL does not bind or activate AKT in this manner. This variant promotes HCC cell proliferation, migration, and tumorigenicity via PI3K/AKT/mTOR pathway activation. Human Phospho-Kinase Array, protein immunoprecipitation, in vitro kinase assay, xenograft models JHEP Reports High 41281445
2025 USP5 deubiquitinase stabilizes STAT2 protein by reducing its ubiquitination, and stabilized STAT2 activates PFKFB4 transcription (confirmed by dual-luciferase reporter, ChIP, and Co-IP), driving glycolysis and lactate-mediated M2-like macrophage polarization in multiple myeloma. Dual-luciferase reporter assay, ChIP, Co-IP, ubiquitination assay, flow cytometry for macrophage polarization, xenograft model Cancer Immunology, Immunotherapy Medium 40274624
2025 CHIP E3 ubiquitin ligase directly binds PFKFB4 and ubiquitinates it at lysine 305 (K305), promoting its proteasomal degradation and suppressing glycolytic activity and invasive/migratory capacity of endometriotic cells. Co-IP, ubiquitination assay, site-directed mutagenesis (K305), siRNA knockdown, glycolysis assays, in vitro and in vivo endometriosis models Biology of Reproduction Medium 40684802
2024 FBL (fibrillarin) interacts with transcription factor KHSRP and together they co-occupy PFKFB4 enhancer and promoter elements to transcriptionally activate PFKFB4 expression and reprogram glucose metabolism in liver cancer. ChIP assay, Co-IP for FBL-KHSRP interaction, in vitro and in vivo proliferation assays Cancer Letters Medium 39182558
2026 RBM15 m6A writer increases m6A modification and stability of PFKFB4 mRNA through an IGF2BP3-dependent mechanism in bladder cancer, promoting glycolysis and suppressing anti-tumor CD8+ T cell function. RIP-qPCR, MeRIP-qPCR, RNA stability tests, luciferase reporter assay, proteomic profiling, rescue experiments, in vivo LNP-siRNA knockdown International Journal of Biological Macromolecules Medium 41579989
2026 PFKFB4 interacts with GSK3β in decidual cells; PFKFB4 knockdown inhibits the GSK3β/β-catenin pathway, suppressing LDHA expression, reducing glycolysis, and impairing decidualization. Co-immunoprecipitation, siRNA knockdown, glycolysis assays, decidualization model Cellular Signalling Low 42235627
2005 The minimal promoter of the PFKFB4 gene (within the first -141 nucleotides) contains GC-rich and ETF sequences essential for basal expression. The gene is activated by serum and chemical hypoxia (CoCl2) and repressed by beta-estradiol, as determined by transient transfection assays with 5'-deletion promoter constructs. 5'-deletion promoter-luciferase reporter transfection assays in GC-1spg and TM-4 cells FEBS Letters Medium 15642344
2016 In fibrous dysplasia (FD) cells carrying GNAS(R201H) mutation, augmented glycolysis dependent on PFKFB4 activates pro-fibrotic TGFβ signaling. Depletion of PFKFB4 or inhibition of glycolysis blocks fibrosis progression in FD model cells. iPSC-derived isogenic FD model, PFKFB4 siRNA depletion, glycolysis inhibition, TGFβ signaling readouts, 2D and 3D MSC culture models Biomaterials Medium 27614159
2025 PFKFB4 suppresses phosphorylated AMPK (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates SREBP1 levels to upregulate de novo lipid synthesis in HBV-associated hepatocellular carcinoma. Functional assays, Western blot for p-AMPK and SREBP1, glycolysis measurements, PFKFB4 knockdown/overexpression Cancer Letters Low 40339954

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 208 29615789
2021 Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers 120 33671514
2011 RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene 118 22056879
2018 CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism. Theranostics 84 30613295
2014 Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth. Oncotarget 74 25115398
2017 Etk Interaction with PFKFB4 Modulates Chemoresistance of Small-cell Lung Cancer by Regulating Autophagy. Clinical cancer research : an official journal of the American Association for Cancer Research 66 29208667
2025 PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis. Cancer research 58 39570804
2017 CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget 56 29029419
2016 HIF-1α activates hypoxia-induced PFKFB4 expression in human bladder cancer cells. Biochemical and biophysical research communications 52 27181362
2023 THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification. Cell death & disease 49 37500615
2022 Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis. Cell death & disease 44 36109523
2021 Carbonic Anhydrase IX Promotes Human Cervical Cancer Cell Motility by Regulating PFKFB4 Expression. Cancers 40 33803236
2015 Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor. Oncotarget 40 26221874
2021 Bruceine A induces cell growth inhibition and apoptosis through PFKFB4/GSK3β signaling in pancreatic cancer. Pharmacological research 36 33992797
2021 E2F2 drives glioma progression via PI3K/AKT in a PFKFB4-dependent manner. Life sciences 35 33774025
2021 PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance. Journal of experimental & clinical cancer research : CR 34 34593007
2016 Phosphorylation of PPARγ at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4. Oncotarget 34 27769068
2015 PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis. Nature communications 33 25601028
2017 PFKFB4 control of AKT signaling is essential for premigratory and migratory neural crest formation. Development (Cambridge, England) 28 29038306
2023 PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner. Cellular and molecular gastroenterology and hepatology 27 36806581
2018 PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 30415245
2021 Long Non-Coding RNA LINC01572 Promotes Hepatocellular Carcinoma Progression via Sponging miR-195-5p to Enhance PFKFB4-Mediated Glycolysis and PI3K/AKT Activation. Frontiers in cell and developmental biology 24 34970545
2017 Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells. Oncotarget 24 28152500
2021 Long noncoding RNA FIRRE contributes to the proliferation and glycolysis of hepatocellular carcinoma cells by enhancing PFKFB4 expression. Journal of Cancer 23 34093813
2020 PFKFB4 negatively regulated the expression of histone acetyltransferase GCN5 to mediate the tumorigenesis of thyroid cancer. Development, growth & differentiation 23 31912488
2022 Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence. Cell reports 21 36476868
2021 PFKFB4 promotes lung adenocarcinoma progression via phosphorylating and activating transcriptional coactivator SRC-2. BMC pulmonary medicine 21 33593309
2012 Sertoli-secreted FGF-2 induces PFKFB4 isozyme expression in mouse spermatogenic cells by activation of the MEK/ERK/CREB pathway. American journal of physiology. Endocrinology and metabolism 21 22811469
2023 Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis. Cell death & disease 19 37179372
2022 KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development. BMC cancer 16 35590288
2023 Reprogramming of glucose metabolism via PFKFB4 is critical in FGF16-driven invasion of breast cancer cells. Bioscience reports 15 37222403
2022 PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer. Journal of Cancer 15 34976184
2022 PFKFB4 facilitates palbociclib resistance in oestrogen receptor-positive breast cancer by enhancing stemness. Cell proliferation 15 36127291
2020 The metabolic role of PFKFB4 in androgen-independent growth in vitro and PFKFB4 expression in human prostate cancer tissue. BMC urology 14 32487245
2025 Targeting PFKFB4 Biomimetic Codelivery System Synergistically Enhances Ferroptosis to Suppress Small Cell Lung Cancer and Augments the Efficacy of Anti-PD-L1 Immunotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 40213972
2022 Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions. Biomarker research 13 35578370
2022 PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma. Oncogenesis 13 36115843
2019 The influence of PFK-II overexpression on neuroblastoma patients' survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4. Cancer cell international 13 31754349
2018 Analysis of Malignant Melanoma Cell Lines Exposed to Hypoxia Reveals the Importance of PFKFB4 Overexpression for Disease Progression. Anticancer research 13 30504385
2025 Targeting the proliferation of glioblastoma cells and enhancement of doxorubicin and temozolomide cytotoxicity through inhibition of PFKFB4 and HMOX1 genes with siRNAs. Scientific reports 12 40739397
2022 PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma. Life science alliance 11 35914811
2005 Specific expression of pfkfb4 gene in spermatogonia germ cells and analysis of its 5'-flanking region. FEBS letters 11 15642344
2016 Pro-fibrotic effects of PFKFB4-mediated glycolytic reprogramming in fibrous dysplasia. Biomaterials 10 27614159
2024 Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer. Cancer letters 9 39182558
2022 Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 9 35659173
2022 β-elemene Isopropanolamine Derivative LXX-8250 Induces Apoptosis Through Impairing Autophagic Flux via PFKFB4 Repression in Melanoma Cells. Frontiers in pharmacology 8 36034839
2020 PFKFB4 is critical for the survival of acute monocytic leukemia cells. Biochemical and biophysical research communications 8 32299611
2025 Kaempferol Induces DNA Damage in Colorectal Cancer Cells by Regulating the MiR-195/miR-497-PFKFB4-Mediated Nonoxidative Pentose Phosphate Pathway. Journal of agricultural and food chemistry 7 40091822
2025 Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma. Cancer letters 7 40339954
2024 Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma. Biomolecules 7 39595571
2023 Differential roles of highly expressed PFKFB4 in colon adenocarcinoma patients. Scientific reports 7 37770581
2025 PFKFB4 promotes endometrial cancer by regulating glycolysis through SRC‑3 phosphorylation. Oncology reports 6 40116122
2022 PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells. Bioorganic & medicinal chemistry letters 6 35926796
2025 USP5 motivates immunosuppressive microenvironment in multiple myeloma by activating STAT2-PFKFB4-mediated glycolysis. Cancer immunology, immunotherapy : CII 5 40274624
2024 Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids. Biotechnology journal 4 39295558
2025 Emd-D inhibited ovarian cancer progression via PFKFB4-dependent glycolysis and apoptosis. Chinese journal of natural medicines 3 40274346
2024 MiR-3195 inhibits non-small cell lung cancer malignant behaviors along with cisplatin resistance through targeting PFKFB4. Cellular and molecular biology (Noisy-le-Grand, France) 3 39097893
2025 Sulforaphane-cysteine inhibits α-tubulin/PD-L1/PFKFB4 axis leading to apoptosis in human glioblastoma. Medical oncology (Northwood, London, England) 2 40659958
2026 Proteomic Identification of PFKFB3 and PFKFB4 Associated with Coenzyme Metabolism and Redox Imbalance in Dairy Cows with Clinical Mastitis. Antioxidants (Basel, Switzerland) 1 41750620
2025 Targeting phosphofructokinase 2 the isoform PFKFB4 suppresses glioblastoma proliferation and malignancy. Genes & genomics 1 41118116
2025 Bruceine A abrogates pancreatic cancer metastasis by suppressing PFKFB4-glycolysis-EMT axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 41411889
2022 Recessive Dystrophic Epidermolysis bullosa due to Hemizygous 40 kb Deletion of COL7A1 and the Proximate PFKFB4 Gene Focusing on the Mutation c.425A>G Mimicking Homozygous Status. Diagnostics (Basel, Switzerland) 1 36292148
2026 PFKFB4-Mediated HSPB1 phosphorylation suppresses ferroptosis to Promote gastric cancer progression. Biochemical pharmacology 0 41577048
2026 RBM15/IGF2BP3 promotes immune escape in bladder cancer by enhancing m6A modification of PFKFB4. International journal of biological macromolecules 0 41579989
2026 PFKFB4 promotes M2 polarization of tumor-associated macrophages through aerobic glycolysis-mediated modification of histone H3K18 lactylation in hepatocellular carcinoma. Cancer & metabolism 0 41987314
2026 Integrated analyses reveal a potential role for PFKFB4 in M2 macrophage polarization and hepatocellular carcinoma progression. Cancer cell international 0 42098724
2026 PFKFB4 downregulation impairs decidualization via disturbing the glycolysis and GSK3β/β-catenin pathway and contributes to preeclampsia. Cellular signalling 0 42235627
2025 siRNA Knocking Down in HepG2 Cells Identifies PFKFB4 and HNF4α as Key Genes Important for Cancer Cell Survival. Current gene therapy 0 39835559
2025 Correction: Desterke et al. Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma. Biomolecules 2024, 14, 1394. Biomolecules 0 40563546
2025 Ubiquitination of PFKFB4 by CHIP regulates glycolysis and progression in endometriosis†. Biology of reproduction 0 40684802
2025 Structure-guided discovery of nitrobenzo-2-oxa-1,3-diazole (NBD) scaffold-based PFKFB4 inhibitors for cancer therapy. European journal of medicinal chemistry 0 40925147
2025 Non-canonical splice variant of PFKFB4 in hepatocellular carcinoma activates AKT through direct interaction. JHEP reports : innovation in hepatology 0 41281445
2025 5MPN effectively targets PFKFB4 and inhibits the glucose metabolism process and invasion of glioblastoma. Translational cancer research 0 41510091
2024 Multi-omics analysis reveals that Cas13d contributes to PI3K-AKT signaling and facilitates cell proliferation via PFKFB4 upregulation. Gene 0 38992762

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