Affinage

PFKFB4

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

Length
469 aa
Mass
54.0 kDa
Annotated
2026-04-28
71 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PFKFB4 is a bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase that integrates glycolytic control with non-metabolic signaling through its dual capacity as a metabolic enzyme and an atypical protein kinase. Its kinase activity predominates (~4-fold over phosphatase activity), synthesizing fructose-2,6-bisphosphate to allosterically activate PFK-1 and drive glycolytic flux, though in specific genetic contexts such as TP53-mutant hepatocellular carcinoma the phosphatase activity dominates (PMID:25115398, PMID:36806581). Beyond canonical metabolic function, PFKFB4 acts as an atypical protein kinase that phosphorylates nuclear transcriptional coactivators SRC-3 (at Ser857) and SRC-2 (at Ser487), redirecting glucose flux toward the pentose phosphate pathway and purine synthesis via ATF4-dependent transcription, and also phosphorylates HSPB1 to suppress ferroptosis (PMID:29615789, PMID:33593309, PMID:41577048). PFKFB4 additionally engages non-glycolytic signaling by interacting with ICMT to control RAS membrane localization and AKT activation, by translocating to the nucleus under hypoxia to activate HIF-1α transcription in a feed-forward loop with its own HIF-1α-driven expression, and by directly binding AKT through a splice variant (PFKFB4-ΔEx6) to activate AKT/mTOR signaling (PMID:35914811, PMID:36476868, PMID:41281445, PMID:25601028).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2012 Medium

    Identifying how PFKFB4 transcription is controlled established the FGF-2/MEK/ERK/CREB axis as an upstream activating pathway, with a functional CRE site at −1,463 in the promoter, linking extracellular growth factor signaling to glycolytic gene regulation in spermatogenic cells.

    Evidence Conditioned medium, MAPK inhibitor panel, promoter deletion/luciferase assays, and CREB pulldown in mouse spermatogenic cells

    PMID:22811469

    Open questions at the time
    • Whether CREB-dependent activation operates in somatic/cancer cell contexts
    • No chromatin-level mechanism described
  2. 2014 High

    Resolving the long-debated kinase-versus-phosphatase balance for human PFKFB4 demonstrated that recombinant PFKFB4 functions primarily as a kinase (4.3-fold kinase > phosphatase), synthesizing F2,6BP to activate PFK-1 and glycolytic flux — establishing the canonical enzymatic function.

    Evidence In vitro enzymatic assay with recombinant protein, siRNA knockdown, genomic deletion, and F2,6BP/glucose/ATP measurement in cancer cells

    PMID:25115398

    Open questions at the time
    • Whether kinase/phosphatase ratio varies across tissues or genetic backgrounds
    • No structural basis for the kinase-dominant activity
  3. 2015 High

    Discovery of a glycolysis-independent developmental role established that PFKFB4 controls dorsal ectoderm patterning via AKT signaling in Xenopus embryos, revealing that PFKFB4 has non-metabolic functions that cannot be explained by F2,6BP synthesis alone.

    Evidence Morpholino depletion in Xenopus embryos with epistasis rescue by constitutively active AKT; glycolysis inhibitors failed to phenocopy

    PMID:25601028

    Open questions at the time
    • Molecular mechanism linking PFKFB4 to AKT activation unknown at this point
    • Whether the non-glycolytic function is conserved in mammals
  4. 2015 High

    Development of a first-in-class selective PFKFB4 kinase inhibitor (5MPN) provided pharmacological proof that PFKFB4 kinase activity drives F2,6BP production and tumor growth, and delivered a chemical tool for functional studies.

    Evidence Structure-based virtual screening, in vitro enzyme inhibition, and oral xenograft efficacy in mice

    PMID:26221874

    Open questions at the time
    • Selectivity over other PFKFB family members not fully resolved
    • No co-crystal structure reported
  5. 2016 Medium

    Identification of HIF-1α binding to a specific HRE (HRE-D) in the PFKFB4 promoter, and separately of phospho-PPARγ-driven PFKFB4 transcription, established that multiple hypoxia and oncogenic transcription factors directly induce PFKFB4 expression, explaining its upregulation across diverse cancers.

    Evidence Promoter deletion/luciferase and ChIP in bladder cancer (HIF-1α); ChIP and knockdown rescue in HCC (PPARγ)

    PMID:27181362 PMID:27769068

    Open questions at the time
    • How multiple transcription factors coordinate at the PFKFB4 promoter
    • Relative contribution of each factor in different tumor types unknown
  6. 2017 High

    Demonstrating that PFKFB4 is essential for neural crest specification and migration through AKT signaling extended the non-glycolytic paradigm to a specific developmental cell type, while showing that glycolysis is separately required for NC migration.

    Evidence Time-controlled and hypomorph depletions with AKT rescue and glycolysis inhibition in Xenopus NC cells

    PMID:29038306

    Open questions at the time
    • Direct PFKFB4-AKT biochemical interaction not demonstrated in this system
    • Mammalian NC relevance untested
  7. 2017 Medium

    Identification of Etk/BMX tyrosine kinase as a direct PFKFB4-binding partner linked PFKFB4 to chemoresistance via autophagy regulation in small-cell lung cancer, broadening its signaling network beyond AKT.

    Evidence Reciprocal co-IP, GST pulldown, microarray, PDX model in SCLC

    PMID:29208667

    Open questions at the time
    • Whether Etk phosphorylates PFKFB4 and at which site is unknown
    • Autophagy mechanism downstream of PFKFB4 not dissected
  8. 2018 High

    The pivotal discovery that PFKFB4 acts as an atypical protein kinase phosphorylating SRC-3 at Ser857 revealed a fundamentally new non-metabolic function: PFKFB4-mediated SRC-3 phosphorylation promotes SRC-3–ATF4 interaction, driving pentose phosphate pathway gene transcription and purine synthesis, thus redirecting glucose carbon beyond glycolysis.

    Evidence Kinome-wide RNAi screen, in vitro kinase assay, Ser857Ala mutagenesis, Co-IP, ChIP, orthotopic xenograft in breast cancer

    PMID:29615789

    Open questions at the time
    • Structural basis for PFKFB4's protein kinase activity versus its metabolic kinase activity unknown
    • Whether PFKFB4 protein kinase activity uses the same active site as F6P phosphorylation
  9. 2021 Medium

    Extension of the atypical kinase paradigm showed PFKFB4 phosphorylates SRC-2 at Ser487 (upregulating CARM1 transcription) and that phospho-SRC-3 interacts with FBP1 to form a regulatory feedback loop controlling pentose phosphate pathway flux in ccRCC, demonstrating substrate diversification.

    Evidence Co-IP and phosphorylation analysis with transcriptome sequencing (SRC-2, lung adenocarcinoma); phosphoproteomics and metabolomics with CRISPR KO (SRC-3/FBP1, ccRCC)

    PMID:33593309 PMID:34593007

    Open questions at the time
    • In vitro kinase assay for SRC-2 not explicitly shown
    • Whether SRC-2 and SRC-3 phosphorylation occur simultaneously in the same cells
  10. 2021 Medium

    Demonstration that PFKFB4 phosphatase activity predominates in TP53-mutant HCC — opposite to the canonical kinase-dominant model — revealed that the kinase/phosphatase balance is genetically context-dependent, with TP53 status switching PFKFB4's functional output.

    Evidence CRISPR/Cas9 knockout with targeted metabolomics and RNA-seq in TP53-mutant HCC

    PMID:36806581

    Open questions at the time
    • Molecular mechanism by which p53 loss shifts kinase/phosphatase ratio unknown
    • Whether this applies to other p53-mutant cancer types
  11. 2022 Medium

    Three concurrent discoveries expanded PFKFB4's non-metabolic signaling network: (1) PFKFB4 interacts with FBXO28 to regulate HIF-1α ubiquitination and stability, (2) PFKFB4 interacts with ICMT to promote RAS membrane localization and AKT activation independently of glycolysis, and (3) PIM2 phosphorylates PFKFB4 at Thr140 to stabilize it against proteasomal degradation — collectively revealing PFKFB4 as a signaling hub regulated by and regulating multiple oncogenic pathways.

    Evidence MS-identified FBXO28 interaction and HIF-1α ubiquitination (glioblastoma); Co-IP of ICMT with RAS localization imaging (melanoma); Co-IP and phosphorylation/ubiquitin assays for PIM2-Thr140 (endometriosis)

    PMID:35914811 PMID:36109523 PMID:36115843

    Open questions at the time
    • Whether PFKFB4 enzymatic activity is required for its interaction with FBXO28 or ICMT
    • Direct structural characterization of PFKFB4-ICMT or PFKFB4-FBXO28 complexes lacking
    • PIM2-Thr140 regulation not validated in cancer contexts
  12. 2022 Medium

    Discovery that hypoxia triggers PFKFB4 nuclear translocation where it non-canonically activates HIF-1α transcription established a feed-forward loop between HIF-1α (which transcribes PFKFB4) and nuclear PFKFB4 (which activates HIF-1α), linking metabolic enzyme subcellular redistribution to transcriptional rewiring.

    Evidence Nuclear fractionation, immunofluorescence, metabolomics, genetic ablation in breast cancer mouse models

    PMID:36476868

    Open questions at the time
    • Nuclear translocation signal or mechanism not identified
    • Whether nuclear PFKFB4 directly binds the HIF-1α promoter or acts through an intermediary
  13. 2023 Medium

    Identification of FBXL7 as an E3 ligase that ubiquitinates and degrades PFKFB4, repressed by HIF-1α→EZH2 signaling, completed a regulatory circuit: HIF-1α stabilizes PFKFB4 both transcriptionally and post-translationally, while PFKFB4 in turn activates HIF-1α.

    Evidence TAP/MS substrate identification, ubiquitination assays, ChIP for EZH2-mediated FBXL7 repression in NSCLC

    PMID:37179372

    Open questions at the time
    • Ubiquitination site(s) on PFKFB4 targeted by FBXL7 not mapped
    • Whether CHIP and FBXL7 target the same or different PFKFB4 pools
  14. 2025 Medium

    Identification of CHIP-mediated ubiquitination of PFKFB4 at K305, a splice variant (PFKFB4-ΔEx6) that directly binds and activates AKT, and PFKFB4 phosphorylation of HSPB1 to suppress ferroptosis broadened the post-translational regulatory landscape and substrate repertoire of PFKFB4.

    Evidence Co-IP and K305 mutagenesis for CHIP (endometriosis); IP and kinase assay for AKT-binding splice variant (HCC); Co-IP and ferroptosis assays for HSPB1 (gastric cancer)

    PMID:40684802 PMID:41281445 PMID:41577048

    Open questions at the time
    • HSPB1 phosphorylation site not mapped
    • How the ΔEx6 deletion alters PFKFB4 structure to enable AKT binding is unknown
    • Whether K305 ubiquitination by CHIP competes with FBXL7 activity

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis for PFKFB4's dual metabolic and protein kinase activities (whether the same active site catalyzes both), the signals governing nuclear translocation, how genetic context (e.g. TP53 status) switches kinase/phosphatase dominance, and whether the non-glycolytic developmental functions observed in Xenopus are conserved in mammalian development.
  • No crystal structure of PFKFB4 in complex with a protein substrate
  • Nuclear localization signal not mapped
  • Kinase/phosphatase switch mechanism undefined
  • Mammalian developmental phenotypes untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
BMXCHIPFBXL7FBXO28ICMTPIM2SRC-2SRC-3

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 PFKFB4 phosphorylates the transcriptional coactivator SRC-3 at serine 857, enhancing SRC-3 transcriptional activity. Phospho-Ser857 SRC-3 increases its interaction with transcription factor ATF4, stabilizing recruitment of SRC-3 and ATF4 to target gene promoters. This drives glucose flux toward the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating transketolase, AMPD1, and XDH. Kinome-wide RNAi screen, in vitro kinase assay, phosphorylation-deficient mutant (Ser857Ala), Co-IP, ChIP, orthotopic xenograft mouse model Nature High 29615789
2014 Recombinant human PFKFB4 exhibits kinase activity 4.3-fold greater than its phosphatase activity, functioning primarily to synthesize fructose-2,6-bisphosphate (F2,6BP), which allosterically activates PFK-1 to increase glycolytic flux. siRNA and genomic deletion of PFKFB4 decrease F2,6BP levels, while overexpression increases them. In vitro enzymatic assay with recombinant human PFKFB4, siRNA knockdown, genomic deletion, metabolite measurement (F2,6BP, glucose uptake, ATP) Oncotarget High 25115398
2015 A first-in-class PFKFB4 inhibitor (5MPN), identified by structure-based virtual screening, selectively inhibits PFKFB4 kinase activity, suppresses intracellular F2,6BP synthesis, reduces glycolysis, and inhibits tumor growth in mice upon oral administration. Structure-based virtual computational screening, in vitro enzyme inhibition assay, cell proliferation assays, in vivo xenograft mouse model Oncotarget High 26221874
2015 In Xenopus (frog) embryos, PFKFB4 controls dorsal ectoderm patterning and progenitor differentiation via a non-glycolytic function mediated by AKT signaling. Restoring AKT signaling rescues the PFKFB4 loss-of-function phenotype, while glycolysis inhibition does not recapitulate the patterning defects. Loss-of-function morpholino depletion in Xenopus embryos, epistasis rescue with constitutively active AKT, glycolysis inhibitors as controls Nature Communications High 25601028
2017 PFKFB4 is essential for neural crest (NC) specification and migration in Xenopus embryos. PFKFB4 controls AKT signaling during late NC specification, while both AKT signaling and glycolysis regulate NC migration. NC gene regulatory network drives pfkfb4 upregulation during NC specification. Time-controlled and hypomorph depletions in vivo (Xenopus), AKT signaling rescue, glycolysis inhibition experiments Development High 29038306
2017 Etk (BMX) tyrosine kinase directly interacts with PFKFB4 (identified by co-IP and GST pulldown), and PFKFB4 is a downstream target of Etk that promotes chemoresistance in small-cell lung cancer through regulation of autophagy. Co-immunoprecipitation, GST pulldown, microarray analysis, gain/loss-of-function in vitro and in vivo, PDX model Clinical Cancer Research Medium 29208667
2022 PIM2 kinase phosphorylates PFKFB4 at threonine 140 (Thr140), enhancing PFKFB4 protein stability via the ubiquitin-proteasome pathway and promoting glycolysis and cell growth in endometriosis. PIM2 was identified as a binding partner of PFKFB4. Co-IP, biochemical phosphorylation assays, ubiquitin-proteasome pathway analysis, in vivo endometriosis model Cell Death & Disease Medium 36109523
2022 PFKFB4 interacts with the E3 ubiquitin ligase FBXO28, and this interaction regulates ubiquitylation and proteasomal degradation of HIF-1α in glioblastoma. PFKFB4 silencing dramatically reduces HIF protein levels and hypoxia-related gene expression. Mass spectrometric analysis of immunoprecipitated PFKFB4 (identifying FBXO28), Western blot, gene expression profiling, orthotopic patient-derived 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 imaging, AKT signaling assays, migration assays with PFKFB4 loss-of-function Life Science Alliance Medium 35914811
2021 PFKFB4 phosphorylates NCOA3 (SRC-3/AIB1) in clear-cell renal cell carcinoma, and this phosphorylated NCOA3 interacts with FBP1 to counteract overactive pentose phosphate pathway flux, forming a regulatory loop. PFKFB4 also promotes the pentose phosphate pathway in ccRCC. Phosphoproteomics, immunoprecipitation, metabolomics, CRISPR/Cas9 knockout Journal of Experimental & Clinical Cancer Research Medium 34593007
2021 PFKFB4 promotes lung adenocarcinoma progression by phosphorylating SRC-2 (steroid receptor coactivator-2) at Ser487, altering its transcriptional activity, which transcriptionally upregulates CARM1. Co-immunoprecipitation, Western blot for phosphorylation, PFKFB4 knockdown, transcriptome sequencing BMC Pulmonary Medicine Medium 33593309
2022 PFKFB4 promotes breast cancer metastasis via induction of HAS2 expression and hyaluronan (HA) production in a p38 signaling-dependent manner. PFKFB4 loss-of-function reduces HAS2 mRNA/protein and HA secretion. Gain- and loss-of-function assays, ELISA, immunofluorescence, orthotopic xenograft, experimental metastasis model Cellular Physiology and Biochemistry Medium 30415245
2022 Hypoxic induction of PFKFB4 triggers its nuclear translocation, where it non-canonically activates HIF-1α transcription, creating a feed-forward loop. Breast cancer patients with increased nuclear PFKFB4 correlate with poor prognosis. Photoacoustic imaging, metabolomics, genetic ablation in mouse models, nuclear fractionation/immunofluorescence localization, gene expression analysis Cell Reports Medium 36476868
2023 FBXL7 (an E3 ubiquitin ligase) ubiquitinates and degrades PFKFB4 protein, suppressing glucose metabolism. Hypoxia-induced HIF-1α upregulates EZH2, which represses FBXL7 transcription, thereby stabilizing PFKFB4 and promoting glycolysis in NSCLC. PFKFB4 was identified as an FBXL7 substrate by tandem affinity purification/mass spectrometry. Tandem affinity purification coupled with mass spectrometry (TAP/MS), ubiquitination assay, ChIP, loss-of-function, rescue experiments Cell Death & Disease Medium 37179372
2023 THOC3 forms a complex with YBX1 to promote PFKFB4 transcription and is responsible for exporting PFKFB4 mRNA to the cytoplasm; YBX1 ensures stability of PFKFB4 mRNA by recognizing m5C sites in its 3'UTR. Co-IP, mRNA export assays, YBX1-m5C binding analysis, knockdown functional assays Cell Death & Disease Medium 37500615
2016 HIF-1α directly transactivates PFKFB4 expression in bladder cancer under hypoxia by binding to a specific hypoxia-responsive element (HRE-D) in the PFKFB4 promoter, as identified by deletion constructs and double-immunofluorescence co-localization. Promoter deletion/luciferase assays, ChIP, double-immunofluorescence co-localization, hypoxia exposure Biochemical and Biophysical Research Communications Medium 27181362
2016 Phosphorylation of PPARγ at Ser84 (by MEK/ERK) drives PFKFB4 expression by directly modulating its promoter transcriptional activity, as shown by ChIP. PFKFB4 is required for the PPARγ phosphorylation-mediated stimulation of glycolysis and proliferation in hepatocellular carcinoma. RNA microarray, ChIP assay, PFKFB4 knockdown rescue experiments, HCC mouse model Oncotarget Medium 27769068
2012 Sertoli cell-secreted FGF-2 induces PFKFB4 expression in mouse spermatogenic cells via the MEK/ERK/CREB pathway. A CRE-binding sequence at -1,463 relative to the transcription start site is required for PFKFB4 gene activation. CREB transcription factor binding to this site was confirmed by pulldown assays. Conditioned medium experiments, MAPK inhibitor panel, luciferase analysis of promoter deletion constructs, CREB pulldown assay, anti-FGF-2 neutralizing antibodies American Journal of Physiology – Endocrinology and Metabolism Medium 22811469
2021 In hepatocellular carcinoma with TP53 loss-of-function mutations, PFKFB4 functions predominantly as a phosphatase (not kinase); its ablation causes accumulation of metabolites in downstream glycolysis and the pentose phosphate pathway, and also induces hypoxia-responsive genes in glycolysis and ROS detoxification. CRISPR/Cas9 knockout, targeted metabolomic profiling, RNA sequencing, in vivo HCC model Cellular and Molecular Gastroenterology and Hepatology Medium 36806581
2025 The E3 ubiquitin ligase CHIP directly binds and ubiquitinates PFKFB4 at lysine 305 (K305), promoting its proteasomal degradation and suppressing glycolysis and invasiveness in endometriosis cells. Co-IP, ubiquitination assay, site-directed mutagenesis (K305), in vitro and in vivo endometriosis models Biology of Reproduction Medium 40684802
2025 A non-canonical splice variant of PFKFB4 (PFKFB4-ΔEx6, skipping exon 6, resulting in a 19-amino acid in-frame deletion) directly binds the kinase domain of AKT and activates AKT/mTOR signaling in hepatocellular carcinoma, promoting HCC proliferation and tumorigenicity more potently than canonical PFKFB4. Protein immunoprecipitation, in vitro kinase assay, Human Phospho-Kinase Array profiling, HCC cell line and xenograft models JHEP Reports Medium 41281445
2021 MLL (a histone methyltransferase/epigenetic regulator) promotes PFKFB4 expression at the transcriptional level through the putative E2F6 binding site in the pfkfb4 gene promoter in acute monocytic leukemia cells. ChIP, promoter analysis, PFKFB4 knockdown/inhibitor functional assays Biochemical and Biophysical Research Communications Low 32299611
2016 PFKFB4-mediated glycolytic reprogramming activates pro-fibrotic TGFβ signaling in fibrous dysplasia. Depletion of PFKFB4 blocks fibrosis progression in GNAS(R201H)-mutated iPSC-derived mesenchymal stem cells. iPSC-derived FD disease models (2D and 3D), PFKFB4 depletion, glycolysis and TGFβ signaling inhibition experiments Biomaterials Low 27614159
2021 E2F2 transcriptionally activates PFKFB4 by directly binding to its promoter (shown by ChIP and luciferase assays), and PFKFB4 activates the PI3K/AKT pathway to promote glioma glycolysis and metastasis. ChIP, luciferase reporter assays, PFKFB4 knockdown rescue, PI3K/AKT pathway analysis Life Sciences Low 33774025
2025 PFKFB4 directly interacts with and phosphorylates HSPB1 (Heat Shock Protein Beta-1), suppressing ferroptosis and promoting gastric cancer progression. Pharmacological inhibition of PFKFB4 with 5MPN sensitizes gastric cancer cells to ferroptotic death. Co-IP, in vitro kinase assay (implied by 'direct interaction with and phosphorylation of HSPB1'), ferroptosis assays, 5MPN inhibitor treatment in vivo Biochemical Pharmacology Low 41577048
2021 CD44ICD (the cleaved intracellular domain of CD44) interacts with CREB and binds to the PFKFB4 promoter, thereby regulating PFKFB4 transcription and expression, which in turn facilitates glycolysis and promotes breast cancer stemness. ChIP (CD44ICD-CREB-PFKFB4 promoter binding), gain/loss-of-function, glycolysis assays, stemness assays, xenograft model Theranostics Low 30613295
2025 In zebrafish larval xenografts, PFKFB4 depletion reduces invasion in MeWo melanoma cells (associated with reduced SNAIL2 expression) without affecting tumor growth, while in A375P cells it decreases tumor growth without affecting invasion—demonstrating context-dependent roles of PFKFB4 in melanoma progression. Zebrafish larval xenograft model, PFKFB4 depletion, SNAIL2 expression analysis, rescue experiments bioRxiv (preprint)preprint Low bio_10.1101_2025.09.06.674616
2025 PTBP1 lactylation (at K436) inhibits PTBP1 proteasomal degradation by attenuating its interaction with TRIM21, and lactylated PTBP1 enhances RNA-binding capacity and facilitates PFKFB4 mRNA stabilization, further increasing glycolysis in glioma stem cells. SIRT1 induces PTBP1 delactylation. Lactylation proteomics, co-IP, RNA-binding assays, PFKFB4 mRNA stability assays, PTBP1 K436 site-specific mutagenesis Cancer Research Medium 39570804
2025 PFKFB4 suppresses phosphorylated AMPK (p-AMPK) activity through enhanced aerobic glycolysis, which in turn stimulates SREBP1 expression, driving de novo lipid synthesis and promoting HCC proliferation. Functional assays (glycolysis and lipid synthesis), PFKFB4 knockdown/overexpression, AMPK and SREBP1 signaling pathway analysis Cancer Letters Low 40339954

Source papers

Stage 0 corpus · 71 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 205 29615789
2011 RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival. Oncogene 118 22056879
2021 Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers 116 33671514
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 73 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 65 29208667
2017 CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget 56 29029419
2025 PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis. Cancer research 53 39570804
2016 HIF-1α activates hypoxia-induced PFKFB4 expression in human bladder cancer cells. Biochemical and biophysical research communications 51 27181362
2023 THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification. Cell death & disease 42 37500615
2022 Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis. Cell death & disease 41 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 35 33992797
2021 E2F2 drives glioma progression via PI3K/AKT in a PFKFB4-dependent manner. Life sciences 34 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 33 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
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
2023 PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner. Cellular and molecular gastroenterology and hepatology 24 36806581
2017 Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells. Oncotarget 24 28152500
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 23 34970545
2020 PFKFB4 negatively regulated the expression of histone acetyltransferase GCN5 to mediate the tumorigenesis of thyroid cancer. Development, growth & differentiation 23 31912488
2021 Long noncoding RNA FIRRE contributes to the proliferation and glycolysis of hepatocellular carcinoma cells by enhancing PFKFB4 expression. Journal of Cancer 22 34093813
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 17 37179372
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 KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development. BMC cancer 15 35590288
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
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 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) 12 40213972
2022 PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma. Oncogenesis 12 36115843
2022 Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions. Biomarker research 11 35578370
2005 Specific expression of pfkfb4 gene in spermatogonia germ cells and analysis of its 5'-flanking region. FEBS letters 11 15642344
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 10 40739397
2022 PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma. Life science alliance 10 35914811
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
2016 Pro-fibrotic effects of PFKFB4-mediated glycolytic reprogramming in fibrous dysplasia. Biomaterials 9 27614159
2024 Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer. Cancer letters 8 39182558
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 Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma. Cancer letters 7 40339954
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
2024 Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma. Biomolecules 5 39595571
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 4 40091822
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
2025 USP5 motivates immunosuppressive microenvironment in multiple myeloma by activating STAT2-PFKFB4-mediated glycolysis. Cancer immunology, immunotherapy : CII 3 40274624
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
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 Proteomic Identification of PFKFB3 and PFKFB4 Associated with Coenzyme Metabolism and Redox Imbalance in Dairy Cows with Clinical Mastitis. Antioxidants (Basel, Switzerland) 0 41750620
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 Targeting phosphofructokinase 2 the isoform PFKFB4 suppresses glioblastoma proliferation and malignancy. Genes & genomics 0 41118116
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