Affinage

HK2

Hexokinase-2 · UniProt P52789

Length
917 aa
Mass
102.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HK2 (hexokinase II) catalyzes the phosphorylation of glucose to glucose-6-phosphate as the first committed step of glycolysis, and functions as a signaling hub whose subcellular localization—particularly its binding to VDAC1 on the mitochondrial outer membrane—governs cell fate decisions including apoptosis, autophagy, and inflammasome activation (PMID:31669347, PMID:22233811, PMID:40500776). HK2 transcription is controlled by a convergence of metabolic and stress-responsive transcription factors including HIF-1α, PPARγ, c-MYC, STAT1, KLF14, and YAP/NF-κB, and is further tuned by AMPK, calcium/calcineurin signaling, and epigenetic mechanisms such as promoter CpG methylation and histone lactylation (PMID:22334075, PMID:12388122, PMID:27260001, PMID:39217289). HK2 mRNA stability is enhanced by NAT10-mediated ac4C and METTL3-mediated m6A modifications, while HK2 protein turnover is regulated by chaperone-mediated autophagy and ubiquitin-proteasome degradation modulated by deubiquitinases CSN5 and OTUD1, with OTUD1-mediated removal of K63-linked ubiquitin chains triggering mitochondrial dissociation and NLRP3 inflammasome activation (PMID:39990211, PMID:36403721, PMID:26323688, PMID:31991125, PMID:40500776). STING directly inhibits HK2 enzymatic activity to restrict aerobic glycolysis independently of innate immune signaling, and mitochondrial HK2 binding—mediated through its N-terminal domain and regulated by AKT/GSK-3β phosphorylation of VDAC1—is required for pro-survival and pro-invasive cellular phenotypes (PMID:37443289, PMID:37529037, PMID:30528266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Establishing that HK2 transcription is metabolically regulated beyond substrate availability, AMPK activation was shown to directly upregulate HKII gene expression in skeletal muscle, linking energy-sensing signaling to glycolytic enzyme induction.

    Evidence In vivo single-leg AICAR arterial infusion in rat skeletal muscle with transcription assays

    PMID:12388122

    Open questions at the time
    • Direct promoter-binding mechanism of AMPK-mediated transcription not defined
    • Whether AMPK acts through intermediate transcription factors was not resolved
  2. 2007 Medium

    Calcium signaling via calcineurin and CaMK pathways was identified as an additional transcriptional regulator of HKII in muscle, broadening the signaling inputs controlling glycolytic gene expression beyond AMPK.

    Evidence Ionomycin stimulation with cyclosporin A and KN-62 inhibitors in primary rat skeletal muscle cells and ex vivo muscle

    PMID:17516843

    Open questions at the time
    • Identity of transcription factor(s) downstream of calcineurin/CaMK that bind the HK2 promoter not determined
    • Relevance outside skeletal muscle not tested
  3. 2009 High

    Dynamic redistribution of HKII between cytosolic and mitochondrial compartments during ischemia-reperfusion established that HK2 localization is acutely regulated and functionally linked to cardiac protection.

    Evidence Subcellular fractionation with enzyme activity assays in Langendorff-perfused rat hearts at multiple time points

    PMID:19228992

    Open questions at the time
    • Molecular signals driving translocation during ischemic preconditioning not identified
    • Whether redistribution directly mediates cardioprotection or is correlative was not resolved
  4. 2012 High

    Two key discoveries defined the molecular logic of HK2's mitochondrial interactions: PPARγ was shown to directly bind the HK2 promoter under Akt2 control, and PEA15 was identified as a direct mitochondrial partner of HK2 that converts it from a pro-apoptotic to an anti-apoptotic effector depending on glucose availability.

    Evidence ChIP for PPARγ at HK2 promoter in PTEN-null mouse liver; reciprocal Co-IP of HK2-PEA15 with hypoxia/glucose deprivation phenotypic assays

    PMID:22233811 PMID:22334075

    Open questions at the time
    • Structural basis of HK2-PEA15 interaction unknown
    • How PEA15 binding alters HK2 conformation or enzymatic output not determined
  5. 2015 High

    HK2 was found to serve as a molecular switch from glycolysis to autophagy under glucose deprivation in cardiomyocytes, and separately was identified as a substrate of chaperone-mediated autophagy (CMA), establishing dual roles for HK2 in both initiating and being degraded by autophagy pathways.

    Evidence Loss/gain-of-function in cardiomyocytes; CMA substrate validation via proteomics with FLT3 inhibition in leukemia cells

    PMID:26075878 PMID:26323688

    Open questions at the time
    • CMA recognition motif on HK2 not mapped
    • Whether autophagy-promoting and CMA-degradation functions are mutually exclusive or temporally coordinated unknown
  6. 2016 Medium

    Epigenetic regulation of HK2 was characterized: CpG methylation status of the HK2 promoter controls HIF-1α access to a hypoxia response element, providing a mechanism for tissue-specific and cancer-specific HK2 expression.

    Evidence HumanMethylation450 array with HIF-1α ChIP at -234/-230 HRE in HCC tissues

    PMID:27260001

    Open questions at the time
    • Whether DNA methyltransferases are specifically recruited to the HK2 promoter not identified
    • Functional consequences of N-shore vs CGI methylation not fully dissected
  7. 2017 Medium

    A TNFα-IKK-YAP/p65 signaling axis was shown to converge on the HK2 promoter, linking inflammatory NF-κB signaling directly to glycolytic gene activation in cancer cells.

    Evidence ChIP showing YAP-p65 complex at HK2 promoter, Co-IP, IKK inhibitors in breast cancer cells

    PMID:28945218

    Open questions at the time
    • Whether YAP-p65 co-binding is a general glycolytic gene regulatory mechanism or HK2-specific unknown
    • Epigenomic context of this binding not explored
  8. 2018 Medium

    The AKT/GSK-3β axis was mechanistically linked to HK2-VDAC1 interaction: GSK-3β-mediated VDAC1 phosphorylation disrupts HK2 mitochondrial binding, explaining how upstream oncogenic signaling (including KRAS) controls HK2 localization and apoptotic sensitivity.

    Evidence Co-IP of HK2-VDAC1 with AKT/GSK-3β pathway analysis in prostate and breast cancer cells, xenograft models; KRAS-HK2 epistasis via shRNA in lung cancer

    PMID:26884725 PMID:30528266

    Open questions at the time
    • Specific VDAC1 phosphorylation site(s) mediating HK2 release not mapped in these studies
    • Whether HK2 enzymatic activity changes upon mitochondrial dissociation not measured
  9. 2020 Medium

    Post-translational stabilization of HK2 protein was attributed to the deubiquitinase CSN5, which attenuates ubiquitin-proteasomal degradation, and negative transcriptional regulation by FOXE1 was established, refining the picture of multi-layered HK2 control.

    Evidence CSN5 Co-IP/ubiquitination assays in HCC; FOXE1 ChIP at HK2 promoter in CRC cells with xenograft validation

    PMID:31918722 PMID:31991125

    Open questions at the time
    • E3 ligase counterpart to CSN5 for HK2 ubiquitination not identified
    • Whether FOXE1 repression is context-dependent (e.g., hypoxia) not tested
  10. 2021 Medium

    HK2's mitochondrial regulation was further resolved: Drp1 recruits LRRK2 whose kinase inactivation leads to HK2 Thr-473 dephosphorylation and mitochondrial dissociation with excessive mPTP opening, while c-MYC stabilization by OTUB1 was shown to transcriptionally drive HK2 in breast cancer.

    Evidence Co-IP/phosphorylation mapping of HK2-T473 with Drp1/LRRK2; OTUB1-MYC deubiquitination at K323 with KO mice and tumor models

    PMID:34741026 PMID:35296795

    Open questions at the time
    • Kinase responsible for HK2-T473 phosphorylation under normal conditions not identified
    • Whether OTUB1-MYC-HK2 axis operates in non-breast cancer contexts unknown
  11. 2022 Medium

    A wave of discoveries revealed extensive transcriptional and post-transcriptional control of HK2: multiple new transcription factors (KLF14, ZNF281, ATF4/HIF-1α, PPARγ/PER1) were shown to bind the HK2 promoter, while METTL3-mediated m6A modification and UPF1-mediated mRNA stabilization were identified as RNA-level regulators, and histone lactylation at the HK2 promoter established a glycolysis-epigenetic positive feedback loop.

    Evidence KLF14-KO mice/sepsis models; ZNF281 ChIP with binding motif; m6A assays with METTL3; mRNA stability assays with UPF1; H3K18 lactylation ChIP at HK2 promoter

    PMID:34983946 PMID:35255118 PMID:35863742 PMID:36403721 PMID:36514923

    Open questions at the time
    • Hierarchy among multiple transcription factors at the HK2 promoter under any single condition not established
    • Whether lactylation feedback loop operates in non-renal tissues unknown
    • Interplay between m6A and ac4C modifications on HK2 mRNA not tested
  12. 2023 High

    STING was discovered to directly inhibit HK2 enzymatic activity independently of innate immune signaling, and the N-terminal mitochondrial binding domain of HK2 was shown to be required for invasive cellular phenotypes in rheumatoid arthritis synoviocytes, establishing that both catalytic and scaffolding functions of mitochondrial HK2 have distinct biological outputs.

    Evidence In vitro HK activity assays with STING, genetic KO, in vivo tumor models; FL-HK2 vs HK2ΔN adenoviral expression with migration/invasion assays and in vivo knee injection

    PMID:37443289 PMID:37529037

    Open questions at the time
    • STING-HK2 binding interface not structurally resolved
    • Whether STING inhibition of HK2 occurs in non-tumor physiological contexts not determined
  13. 2023 High

    Cell-type-specific genetic ablation revealed that HK2 in dorsal root ganglion macrophages—rather than spinal microglia—is the primary driver of neuropathic pain, establishing a non-cancer immunometabolic role for HK2 in pain signaling.

    Evidence HK2-tdTomato reporter mice, conditional Hk2 KO in microglia vs myeloid cells, nerve injury behavioral assays

    PMID:37909251

    Open questions at the time
    • Downstream metabolic products of HK2 responsible for pain signaling not identified
    • Whether HK2 in DRG macrophages acts through glycolysis or a non-canonical mechanism not resolved
  14. 2024 Medium

    AKT-mediated phosphorylation was shown to drive HK2 nuclear translocation where it promotes PD-L1 transcription by binding HIF-1α, revealing a moonlighting transcriptional co-activator function for HK2 beyond its metabolic role.

    Evidence Nuclear fractionation, phospho-HK2 Western blot, HK2-HIF-1α Co-IP in gastric cancer with IL-8 conditioned medium

    PMID:37300724

    Open questions at the time
    • HK2 phosphorylation site(s) driving nuclear import not mapped
    • Whether nuclear HK2 retains kinase activity not tested
    • Generality of nuclear HK2 function across cell types unknown
  15. 2025 High

    OTUD1 was identified as a deubiquitinase that directly binds HK2's C-terminal domain and selectively removes K63-linked polyubiquitin chains, triggering mitochondrial dissociation and NLRP3 inflammasome activation, while NAT10-mediated ac4C modification of HK2 mRNA was shown to stabilize it and promote glycolysis.

    Evidence Co-IP, domain mapping, K63-Ub cleavage assays, OTUD1-KO mice for NLRP3 activation; acRIP-seq, conditional KO mice, organoids for ac4C modification

    PMID:39990211 PMID:40500776

    Open questions at the time
    • Whether K63-ubiquitination is the signal that retains HK2 on mitochondria not confirmed
    • Interplay between OTUD1-mediated K63 deubiquitination and CSN5-mediated K48 deubiquitination not explored
    • Relative contributions of ac4C vs m6A to HK2 mRNA stability not compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the structural basis of the HK2-VDAC1 interaction and how post-translational modifications alter it; the hierarchy and combinatorial logic among the many transcription factors and RNA modifications controlling HK2 expression in any single cellular context; and whether nuclear HK2 functions as a bona fide transcriptional co-activator broadly or only in specific signaling contexts.
  • No high-resolution structure of HK2-VDAC1 complex
  • Integrated model of HK2 regulation across transcription, mRNA stability, protein stability, and localization not established
  • Moonlighting nuclear function of HK2 lacks independent replication

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 7 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CSN5DRP1HIF1ALRRK2OTUD1PEA15STINGVDAC1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 HK2 facilitates autophagy in response to glucose deprivation, functioning as a molecular switch from glycolysis to autophagy to ensure cellular energy homeostasis under starvation conditions in cardiomyocytes. Loss-of-function/gain-of-function in cardiomyocytes with glucose deprivation assays Autophagy Medium 26075878
2015 HK2 is a substrate of chaperone-mediated autophagy (CMA); its degradation by CMA is regulated by glucose availability and is triggered by perturbation of FLT3 receptor tyrosine kinase signaling in cancer cells. Proteome analysis, CMA substrate validation, FLT3 inhibition in leukemia cell lines The Journal of cell biology High 26323688
2012 Mitochondrial HKII interacts directly with PEA15 (phosphoprotein enriched in astrocytes) to form a molecular switch governing cell fate: together they inhibit apoptosis after hypoxia, while HKII promotes apoptosis in the absence of PEA15 under glucose deprivation. Co-immunoprecipitation, direct molecular interaction assays, hypoxia/glucose deprivation cell models, loss-of-function Proceedings of the National Academy of Sciences of the United States of America High 22233811
2023 STING directly targets HK2 to block its hexokinase enzymatic activity, thereby restricting aerobic glycolysis independent of STING's innate immune signaling function. In vitro hexokinase activity assays, genetic KO/KD, in vivo tumor models Nature cell biology High 37443289
2012 PPARγ transcription factor binds directly to the HK2 promoter to activate its transcription in PTEN-null fatty liver, under control of Akt2 kinase. Chromatin immunoprecipitation (ChIP), promoter reporter assays, in vivo mouse models with PTEN deletion Nature communications High 22334075
2002 AMPK activation by AICAR transcriptionally upregulates the HKII gene in skeletal muscle, demonstrated by single-leg arterial infusion showing muscle-specific induction without systemic effects. In vivo AICAR infusion in rat skeletal muscle, transcription assays, AMPK activation measurement American journal of physiology. Endocrinology and metabolism High 12388122
2009 Ischemic preconditioning causes subcellular redistribution of HKII (but not HKI) between cytosolic and mitochondrial compartments during cardiac ischemia-reperfusion, with decreased cytosolic HKII during ischemia and increased mitochondrial HKII during reperfusion. Subcellular fractionation of Langendorff-perfused rat hearts, HK activity assays, Western blotting at multiple time points Journal of applied physiology High 19228992
2019 HK2 binds to VDAC (voltage-dependent anion channel) on the mitochondrial outer membrane; this interaction is disrupted by GSK-3β-mediated phosphorylation of VDAC, leading to HKII dissociation, glycolytic inhibition, and mitochondrial-mediated apoptosis. Co-immunoprecipitation, Western blot, GSK-3β/AKT pathway inhibitors, breast cancer cell lines and in vivo xenograft Free radical biology & medicine Medium 31669347
2018 Zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by promoting phosphorylation of VDAC1, mediated through AKT inhibition and GSK3β activation. Co-immunoprecipitation, Western blot, AKT/GSK3β pathway analysis, xenograft tumor model Experimental cell research Medium 30528266
2021 After mitochondrial translocation, Drp1 recruits LRRK2 whose kinase activity is inhibited; this leads to inactivation of HK2 at Thr-473, causing HK2 dissociation from the mitochondrial membrane and excessive mPTP opening after hypoxia. Co-immunoprecipitation, colocalization assays, interaction assays, HK2 phosphorylation site mapping Cell death & disease Medium 34741026
2022 KLF14 transcription factor inhibits HK2 transcription to decrease glycolysis and inflammatory cytokine secretion in macrophages during sepsis. KLF14 knockout mice, LPS/sepsis models, transcriptional reporter assays, macrophage glycolysis assays Cellular & molecular immunology Medium 34983946
2022 OTUB1 deubiquitinase directly deubiquitinates MYC at K323, stabilizing MYC protein which then transcriptionally activates HK2 expression, promoting aerobic glycolysis and breast tumorigenesis. Co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K323), OTUB1-KO mice, in vivo tumor models Cell death and differentiation High 35296795
2020 CSN5 stabilizes HK2 protein by attenuating ubiquitin-proteasome-mediated degradation through its deubiquitinase activity, thereby promoting glycolysis and HCC metastasis. Co-immunoprecipitation, ubiquitination assays, CSN5 knockdown/curcumin inhibition, in vitro and in vivo HCC models Experimental cell research Medium 31991125
2016 HK2 expression is regulated by CpG methylation of its promoter: hypomethylation of the CGI N-shore enhances HK2 expression, while hypermethylation of the CGI suppresses HK2 by blocking HIF-1α interaction with a hypoxia response element (HRE) at -234/-230 of the HK2 promoter. HumanMethylation450 BeadChip array, methylation-specific analysis, HIF-1α ChIP, HCC tissue analysis Oncotarget Medium 27260001
2017 TNFα triggers IKK-mediated YAP phosphorylation and activation; activated YAP forms a complex with p65 (NF-κB) which synergistically binds the HK2 promoter (demonstrated by ChIP) to drive HK2 transcription and cancer cell migration. ChIP assay, Co-immunoprecipitation, IKK inhibitors, YAP/p65 overexpression/knockdown in breast cancer cells Oncogenesis Medium 28945218
2022 ATF4 binds to the HK2 promoter and interacts with HIF-1α to stabilize it via modulation of ubiquitination, activating the ATF4-HIF-1α-HK2-glycolysis axis in macrophages during sepsis. Promoter binding assays, co-immunoprecipitation, ubiquitination assays, macrophage KD/KO models Clinical immunology Medium 37481013
2020 FOXE1 transcription factor directly binds the HK2 promoter and negatively regulates its transcription, suppressing aerobic glycolysis and cell proliferation in colorectal cancer. ChIP assay, promoter reporter assay, gain/loss-of-function in CRC cell lines and xenografts Cell communication and signaling Medium 31918722
2022 ZNF281 transcriptionally represses HK2 by directly binding to the 5'-GGCGGCGGGCGG-3' motif within the HK2 promoter, reducing HK2-mediated stabilization of PINK1/Parkin signaling and promoting mitophagy impairment and hepatocyte senescence in alcoholic liver disease. ChIP assay, promoter motif analysis, siRNA knockdown, mitophagy/mitochondrial function assays Cell proliferation Medium 36514923
2022 UBR7 E3 ligase monoubiquitinates histone H2B at K120 (H2BK120ub) at the Keap1 promoter to upregulate Keap1, which suppresses downstream Nrf2/Bach1/HK2 signaling and glycolysis in HCC. RNAi screening, ChIP (H2BK120ub at Keap1 promoter), epistasis experiments, in vitro/in vivo HCC models Journal of experimental & clinical cancer research Medium 36419136
2022 In trastuzumab-resistant gastric cancer, HK2 circadian oscillation is regulated by a transcriptional complex of PPARγ and the core clock gene PER1; disruption of PER1 abrogates this circadian glycolytic pattern and reverses drug resistance. In vitro/in vivo silencing of PER1, circadian time-point assays, transcriptional complex analysis Cancer research Medium 35255118
2021 The PI3K-Akt-mTOR pathway mediates pericyte-myofibroblast transition (PMT) by upregulating HKII expression and glycolysis; HKII overexpression rescues PMT inhibited by PI3K/mTOR blockade, placing HKII downstream of this pathway. Genetic epistasis (HKII plasmid rescue), PI3K/mTOR inhibitors (LY294002, rapamycin), pericyte isolation, metabolomics Journal of translational medicine Medium 37179292
2023 GCMSC-derived IL-8 promotes AKT-mediated phosphorylation of HK2, causing its nuclear localization; phosphorylated nuclear HK2 promotes PD-L1 transcription by binding to HIF-1α. Western blot for phospho-HK2, nuclear fractionation, co-immunoprecipitation of HK2/HIF-1α, conditional medium experiments Gastric cancer Medium 37300724
2025 OTUD1 deubiquitinase directly binds the C-terminal domain of HK2 via its Ala-rich domain and selectively cleaves K63-linked polyubiquitin chains on HK2, promoting dissociation of HK2 from mitochondria and activation of the NLRP3 inflammasome, driving microglia pyroptosis in sepsis-associated encephalopathy. Co-immunoprecipitation, molecular docking, 3D confocal microscopy, K63-ubiquitin chain cleavage assays, OTUD1 KO mice Journal of neuroinflammation High 40500776
2024 After renal ischemia-reperfusion injury, HK2-mediated glycolysis drives H3K18 lactylation, which in turn is enriched at the HK2 promoter and upregulates HK2 expression in a positive feedback loop. ChIP for H3K18 lactylation at HK2 promoter, HK2 knockdown, Seahorse glycolysis assay, in vivo IRI model Molecular medicine Medium 39217289
2025 NAT10 acetyltransferase stimulates ac4C modification at the junction of the CDS and 3'UTR of HK2 mRNA, enhancing HK2 mRNA stability and activating glycolysis in gastric cancer; glucose deprivation triggers NAT10 degradation via autophagy-lysosome pathway, reducing ac4C modification. Dot blotting, high-throughput sequencing (acRIP-seq), co-immunoprecipitation, GC xenografts, organoids, conditional KO mice Theranostics High 39990211
2022 Glutamate from nerve cells activates NMDAR on pancreatic ductal adenocarcinoma cells causing calcium influx, which activates CaMKII/ERK-MAPK pathway and promotes METTL3 transcription; METTL3 then upregulates HK2 through m6A modification of HK2 mRNA, enhancing glycolysis and perineural invasion. NMDAR inhibition, calcium imaging, METTL3 manipulation, m6A methylation assays, in vivo perineural invasion models Pharmacological research Medium 36403721
2022 HPV oncogenes E6E7 activate GSK3β transcription; GSK3β promotes ubiquitination-proteasomal degradation of FTO; reduced FTO allows HK2 pre-mRNA maturation and increased cytoplasmic HK2 mRNA translation, enhancing glycolysis in cervical cancer. Exogenous E6E7/FTO expression, RT-qPCR for pre-mRNA vs mature mRNA, nuclear/cytoplasmic fractionation, ubiquitination assays Archives of biochemistry and biophysics Medium 36075458
2023 HK2 in dorsal root ganglion macrophages (rather than spinal microglia) is the primary contributor to neuropathic pain; selective ablation of Hk2 in myeloid cells (microglia + DRG macrophages) alleviates mechanical pain and attenuates inflammatory responses, while microglia-specific Hk2 deletion has minimal analgesic effect. HK2-tdTomato reporter mice, conditional Hk2 KO in microglia vs myeloid cells, nerve injury models, flow cytometry, behavioral assays Glia High 37909251
2024 HK2 suppression in microglia after intracerebral hemorrhage impairs mitochondrial membrane potential, driving inflammatory responses; HK2 downregulation is mechanistically linked to decreased GLUT1-mediated glucose-6-phosphate production and subsequent mitochondrial dysfunction, which can be rescued by MitoROS scavengers. FDG-PET, FACS-isolated microglia metabolomics, 13C-glucose isotope tracing, mitochondrial membrane potential measurement, HK2 inhibitors in vivo Journal of advanced research Medium 39142439
2023 Mitochondria-bound HK2 (via its N-terminal mitochondrial binding motif) promotes the invasive and migratory phenotype of rheumatoid arthritis fibroblast-like synoviocytes; overexpression of HK2 lacking the mitochondrial binding domain (HK2ΔN) reverses this invasive phenotype, and in vivo injection of FL-HK2 induces synovial hypertrophy while HK2ΔN does not. Adenoviral expression of FL-HK2 vs. HK2ΔN, confocal microscopy for localization, migration/invasion assays, in vivo knee injection, scRNA-seq Frontiers in immunology High 37529037
2022 Kaempferol inhibits aerobic glycolysis in melanoma by blocking the binding of HK2 to VDAC1 on mitochondria through the AKT/GSK-3β signaling pathway, without significantly altering total HK2 protein expression. Co-immunoprecipitation of HK2/VDAC1, ECAR measurement, glucose consumption, in vivo lung metastasis assay European journal of pharmacology Medium 36007607
2022 Bmi1 upregulates UPF1 expression which enhances HK2 mRNA stability, increasing HK2 protein levels and aerobic glycolysis under hyperglycemic conditions in pancreatic cancer; this pathway suppresses antitumor immunity. Gain/loss-of-function, mRNA stability assays, immune-competent and immunodeficient mouse models, flow cytometry Cellular and molecular gastroenterology and hepatology Medium 35863742
2024 Foxp1 in endothelial cells directly transcriptionally suppresses Hif1α, which in turn drives Hk2 expression; deletion of EC-Foxp1 increases tumor and developmental angiogenesis through the Foxp1-Hif1α-Hk2 glycolytic axis. EC-Foxp1 KO mice, ChIP/transcriptional analysis, EC-Hif1α KO epistasis, RGD-nanoparticle siRNA delivery, retinal/tumor angiogenesis assays Redox biology Medium 39083899
2007 Calcium signaling via calcineurin and CaMK pathways regulates HKII mRNA expression in skeletal muscle; ionomycin-induced calcium elevation increases HKII mRNA ~2-fold, and this effect is inhibited by calcineurin inhibitor cyclosporin A and CaMK inhibitor KN-62. Primary rat skeletal muscle cell culture, ionomycin/caffeine stimulation, cyclosporin A/KN-62 inhibition, electrical stimulation of isolated EDL muscle Biological chemistry Medium 17516843
2024 CCT6A chaperonin interacts with STAT1 protein, protecting it from ubiquitin-mediated degradation; stabilized STAT1 then transcriptionally activates HK2 to promote aerobic glycolysis in lung adenocarcinoma. Co-immunoprecipitation, ChIP assay, transcriptomic sequencing, mass spectrometry, CCT6A knockdown with phenotypic readouts Journal of translational medicine Medium 38750462
2022 WNT5A physically interacts with HK2 (demonstrated by co-immunoprecipitation), and cancer-associated fibroblast-derived WNT5A promotes HK2 expression to enhance gastric cancer glycolysis, proliferation, and stemness. Co-immunoprecipitation, CAF conditioned medium experiments, xenograft model, WNT5A/HK2 knockdown World journal of surgical oncology Low 39054546
2021 Leptin promotes dendritic cell activation by enhancing glycolysis through a STAT3-HK2 pathway; STAT3 inhibition blocks leptin-induced HK2 upregulation, and glycolysis inhibitor 2-DG blocks leptin-induced DC activation. STAT3 inhibitor (NSC74859), 2-DG, glucose/lactate assays, cytokine measurement, PBMC co-culture Immunology letters Medium 34480980
2018 HK2 is required for KRAS-driven lung cancer cell growth; Kras knockdown downregulates HK2, and HK2 knockdown inhibits human and mouse lung cancer growth in vitro and in vivo. shRNA knockdown, lentivirus infection, xenograft models, flow cytometry for apoptosis Cancer cell international Medium 26884725

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer. Molecular cancer 300 30825877
1998 Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Critical reviews in clinical laboratory sciences 267 9759557
2020 Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2. Cell death & disease 257 32094325
2015 HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection. Autophagy 228 26075878
2019 Unlocking the Potential of HK2 in Cancer Metabolism and Therapeutics. Current medicinal chemistry 168 30543165
2017 Long non-coding RNA PVT1 promotes glycolysis and tumor progression by regulating miR-497/HK2 axis in osteosarcoma. Biochemical and biophysical research communications 138 28602700
2012 PPARγ contributes to PKM2 and HK2 expression in fatty liver. Nature communications 132 22334075
2023 STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2. Nature cell biology 116 37443289
2015 Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. The Journal of cell biology 109 26323688
2021 Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells. Cells 96 34200774
2022 The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis. Cellular & molecular immunology 93 34983946
2016 Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer cell international 88 26884725
2002 AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 84 12388122
2022 Disrupting Circadian Rhythm via the PER1-HK2 Axis Reverses Trastuzumab Resistance in Gastric Cancer. Cancer research 80 35255118
2022 Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis. Cell death and differentiation 80 35296795
2017 MicroRNA-124 suppresses proliferation and glycolysis in non-small cell lung cancer cells by targeting AKT-GLUT1/HKII. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 80 28488541
2017 TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration. Oncogenesis 72 28945218
2022 Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling. Journal of experimental & clinical cancer research : CR 70 36411480
2022 UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. Journal of experimental & clinical cancer research : CR 68 36419136
2018 Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 68 30322879
2022 HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways. Cell communication and signaling : CCS 65 36042519
2016 MicroRNA-98 Suppress Warburg Effect by Targeting HK2 in Colon Cancer Cells. Digestive diseases and sciences 63 28025745
2021 Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2. Cell death & disease 62 34741026
2012 Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. Proceedings of the National Academy of Sciences of the United States of America 61 22233811
2017 The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma. Scientific reports 55 28596599
2009 Ischemic preconditioning affects hexokinase activity and HKII in different subcellular compartments throughout cardiac ischemia-reperfusion. Journal of applied physiology (Bethesda, Md. : 1985) 51 19228992
2022 Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification. Pharmacological research 49 36403721
2019 An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1-HK2+ Multiple Myeloma. Cancer research 49 30885978
2023 ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis. Clinical immunology (Orlando, Fla.) 47 37481013
2017 Roles of claudin-2, ZO-1 and occludin in leaky HK-2 cells. PloS one 46 29252987
2024 Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 45 38889331
2019 Flavonoid GL-V9 induces apoptosis and inhibits glycolysis of breast cancer via disrupting GSK-3β-modulated mitochondrial binding of HKII. Free radical biology & medicine 45 31669347
2021 MIR210HG regulates glycolysis, cell proliferation, and metastasis of pancreatic cancer cells through miR-125b-5p/HK2/PKM2 axis. RNA biology 44 34110962
2015 Epigallocatechin gallate inhibits human tongue carcinoma cells via HK2‑mediated glycolysis. Oncology reports 44 25591943
2023 Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 40 37300724
2019 The Roles of HK2 on Tumorigenesis of Cervical Cancer. Technology in cancer research & treatment 40 31530094
2020 CSN5 upregulates glycolysis to promote hepatocellular carcinoma metastasis via stabilizing the HK2 protein. Experimental cell research 39 31991125
2019 Novel xanthine oxidase-based cell model using HK-2 cell for screening antihyperuricemic functional compounds. Free radical biology & medicine 38 30980888
2005 Relative concentrations of hK2/PSA mRNA in benign and malignant prostatic tissue. The Prostate 37 15599939
2023 The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII. Journal of translational medicine 36 37179292
2020 TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2. Gene 35 32165307
2016 Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget 35 27260001
2003 TGF-beta1-mediated inhibition of HK-2 cell migration. Journal of the American Society of Nephrology : JASN 34 12595498
2022 Hyperglycemia Enhances Immunosuppression and Aerobic Glycolysis of Pancreatic Cancer Through Upregulating Bmi1-UPF1-HK2 Pathway. Cellular and molecular gastroenterology and hepatology 33 35863742
2022 A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors. Scientific reports 33 36335239
2019 PLOD2 promotes aerobic glycolysis and cell progression in colorectal cancer by upregulating HK2. Biochemistry and cell biology = Biochimie et biologie cellulaire 32 31742425
2018 Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1. Experimental cell research 30 30528266
2007 Calcium signalling in the regulation of PGC-1alpha, PDK4 and HKII mRNA expression. Biological chemistry 29 17516843
2022 ZNF281 drives hepatocyte senescence in alcoholic liver disease by reducing HK2-stabilized PINK1/Parkin-mediated mitophagy. Cell proliferation 28 36514923
2021 NR2F1-AS1/miR-140/HK2 Axis Regulates Hypoxia-Induced Glycolysis and Migration in Hepatocellular Carcinoma. Cancer management and research 28 33488124
2020 FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer. Cell communication and signaling : CCS 28 31918722
2020 FoxA2 inhibits the proliferation of hepatic progenitor cells by reducing PI3K/Akt/HK2-mediated glycolysis. Journal of cellular physiology 28 32495363
2020 LncRNA ZFAS1/miR-1271-5p/HK2 Promotes Glioma Development Through Regulating Proliferation, Migration, Invasion and Apoptosis. Neurochemical research 28 32964288
2020 Circular RNA circMDM2 accelerates the glycolysis of oral squamous cell carcinoma by targeting miR-532-3p/HK2. Journal of cellular and molecular medicine 27 32410389
2024 CCT6A facilitates lung adenocarcinoma progression and glycolysis via STAT1/HK2 axis. Journal of translational medicine 26 38750462
2022 Kaempferol impairs aerobic glycolysis against melanoma metastasis via inhibiting the mitochondrial binding of HK2 and VDAC1. European journal of pharmacology 26 36007607
2022 Arsenic exposure elevated ROS promotes energy metabolic reprogramming with enhanced AKT-dependent HK2 expression. The Science of the total environment 24 35525345
2022 Exosome-delivered circular RNA DLGAP4 induces chemoresistance via miR-143-HK2 axis in neuroblastoma. Cancer biomarkers : section A of Disease markers 23 35068445
2020 Hsa_circ_0069094 accelerates cell malignancy and glycolysis through regulating the miR-591/HK2 axis in breast cancer. Cellular signalling 22 33309838
2015 Involvement of PPARγ in emodin-induced HK-2 cell apoptosis. Toxicology in vitro : an international journal published in association with BIBRA 22 25448808
2024 Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction. Journal of advanced research 21 39142439
2023 CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress. Allergologia et immunopathologia 21 36916093
2021 Methylation-associated silencing of miR-9-1 promotes nasopharyngeal carcinoma progression and glycolysis via HK2. Cancer science 21 34382305
2022 E6E7 regulates the HK2 expression in cervical cancer via GSK3β/FTO signal. Archives of biochemistry and biophysics 20 36075458
2020 FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway. Experimental cell research 20 33253711
2019 Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics. Theranostics 20 31149033
2018 Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice. Animal models and experimental medicine 20 30891546
2022 CDK6 increases glycolysis and suppresses autophagy by mTORC1-HK2 pathway activation in cervical cancer cells. Cell cycle (Georgetown, Tex.) 19 35167417
2022 miR-532-3p suppresses proliferation and invasion of ovarian cancer cells via GPNMB/HIF-1α/HK2 axis. Pathology, research and practice 19 35914373
2021 ROCK2 Promotes Osteosarcoma Growth and Glycolysis by Up-Regulating HKII via Phospho-PI3K/AKT Signalling. Cancer management and research 19 33500659
2021 Leptin promotes glycolytic metabolism to induce dendritic cells activation via STAT3-HK2 pathway. Immunology letters 18 34480980
2020 Regulation on Calcium Oxalate Crystallization and Protection on HK-2 Cells of Tea Polysaccharides with Different Molecular Weights. Oxidative medicine and cellular longevity 18 32454940
2024 AST-120 alleviates renal ischemia-reperfusion injury by inhibiting HK2-mediated glycolysis. Molecular medicine (Cambridge, Mass.) 17 39217289
2018 Effect of HK2, PKM2 and LDHA on Cetuximab efficacy in metastatic colorectal cancer. Oncology letters 17 29552193
2023 Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes. Frontiers in immunology 16 37529037
2021 ZMYND8 promotes the growth and metastasis of hepatocellular carcinoma by promoting HK2-mediated glycolysis. Pathology, research and practice 16 33517164
2021 Expression and Clinical Significance of HKII and HIF-1α in Grade Groups of Prostate Cancer. Frontiers in genetics 16 34220956
2022 Angelica sinensis Polysaccharide and Astragalus membranaceus Polysaccharide Accelerate Liver Regeneration by Enhanced Glycolysis via Activation of JAK2/STAT3/HK2 Pathway. Molecules (Basel, Switzerland) 15 36431990
2019 Fubp1 supports the lactate-Akt-mTOR axis through the upregulation of Hk1 and Hk2. Biochemical and biophysical research communications 15 30871777
2021 Long Noncoding RNA LINC01410 Suppresses Tumorigenesis and Enhances Radiosensitivity in Neuroblastoma Cells Through Regulating miR-545-3p/HK2 Axis. OncoTargets and therapy 14 34040388
2021 Renal Ischemia/Reperfusion Early Induces Myostatin and PCSK9 Expression in Rat Kidneys and HK-2 Cells. International journal of molecular sciences 14 34576046
2020 MiR-3662 suppresses cell growth, invasion and glucose metabolism by targeting HK2 in hepatocellular carcinoma cells. Neoplasma 14 32726127
2025 The Role of HK2 in Tumorigenesis and Development: Potential for Targeted Therapy with Natural Products. International journal of medical sciences 13 39991762
2023 HK2 in microglia and macrophages contribute to the development of neuropathic pain. Glia 13 37909251
2022 Sevoflurane ameliorates LPS-induced inflammatory injury of HK-2 cells through Sirtuin1/NF-κB pathway. Allergologia et immunopathologia 13 35789410
2021 Hsa_circ_0001806 promotes glycolysis and cell progression in hepatocellular carcinoma through miR-125b/HK2. Journal of clinical laboratory analysis 13 34664737
2024 Therapeutic efficacy of ECs Foxp1 targeting Hif1α-Hk2 glycolysis signal to restrict angiogenesis. Redox biology 12 39083899
2022 BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming. Translational lung cancer research 12 35958341
2019 Activation of TRPC6 channels contributes to (+)-conocarpan-induced apoptotic cell death in HK-2 cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 12 31054997
2019 Niban protein regulates apoptosis in HK-2 cells via caspase-dependent pathway. Renal failure 12 31163002
2019 ATAD2 expression increases [18F]Fluorodeoxyglucose uptake value in lung adenocarcinoma via AKT-GLUT1/HK2 pathway. BMB reports 12 31186081
2017 Enhanced anticancer effect of fabricated gallic acid/CdS on the rGO nanosheets on human glomerular mesangial (IP15) and epithelial proximal (HK2) kidney cell lines - Cytotoxicity investigations. Journal of photochemistry and photobiology. B, Biology 12 29161651
1996 Prostate-specific human kallikrein (hK2) as a novel marker for prostate cancer. The Prostate. Supplement 12 8950360
2025 Glucose homeostasis controls N-acetyltransferase 10-mediated ac4C modification of HK2 to drive gastric tumorigenesis. Theranostics 11 39990211
2024 Cancer-associated fibroblast-derived WNT5A promotes cell proliferation, metastasis, stemness and glycolysis in gastric cancer via regulating HK2. World journal of surgical oncology 11 39054546
2023 Advances in the Study of Hexokinase 2 (HK2) Inhibitors. Anti-cancer agents in medicinal chemistry 11 36278443
2023 Sanghuangporus vaninii ethanol extract alleviates hyperuricemic renal injury by regulating the uric acid transporters and inhibiting HK-2 apoptosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 11 37279627
2022 Thrombospondin 1 Promotes Endoplasmic Reticulum Stress and Apoptosis in HK-2 Cells by Upregulating ATF6-CHOP. Current medical science 11 35192143
2021 hsa-miR-9-5p Down-Regulates HK2 and Confers Radiosensitivity to Nasopharyngeal Carcinoma. Technology in cancer research & treatment 11 33627057
2025 OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis. Journal of neuroinflammation 10 40500776