Affinage

HK2

Hexokinase-2 · UniProt P52789

Length
917 aa
Mass
102.4 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HK2 catalyzes the committed, glucose-6-phosphate-generating step of glycolysis and serves as a metabolic hub whose subcellular localization, abundance, and even non-enzymatic activities couple glucose availability to cell fate (PMID:22233811, PMID:19228992). A defining feature is its N-terminal binding to mitochondria via VDAC: this association is dynamically controlled by Akt/GSK3β signaling, where GSK3β-mediated VDAC phosphorylation drives HK2 dissociation, glycolytic inhibition, and mitochondrial apoptosis (PMID:31669347, PMID:30528266). At the mitochondrion HK2 forms a molecular switch that determines survival versus death—partnering with PEA15 to suppress apoptosis after hypoxia while triggering apoptosis under glucose deprivation (PMID:22233811)—and its enzymatic activity is potentiated by hypoxia-driven recruitment of TIGAR, which limits mitochondrial ROS (PMID:23185017). HK2 dissociation from mitochondria, induced by Drp1/CaMKII signaling or by OTUD1-mediated K63 deubiquitination, disrupts the mitochondrial permeability transition pore and activates the NLRP3 inflammasome and pyroptosis (PMID:34741026, PMID:40500776, PMID:37506502). HK2 protein abundance is tightly set by competing degradation routes, including chaperone-mediated autophagy responsive to glucose levels (PMID:26323688), CSN5/OTUD1 deubiquitination (PMID:31991125, PMID:40500776), and TRIM36/UBR7-linked ubiquitin-proteasome turnover (PMID:36799474, PMID:36419136). HK2 transcription integrates an extensive regulatory network spanning nutritional and stress signaling (SREBP-1, AMPK, PPARγ, calcium/calcineurin-CaMK, ATF4/HIF-1α) and repressive factors (KLF14, FOXE1, ZNF281, Foxp1) (PMID:15627654, PMID:12388122, PMID:22334075, PMID:17516843, PMID:37481013, PMID:34983946, PMID:31918722, PMID:36514923, PMID:39083899), and its mRNA is further controlled by epitranscriptomic marks (m6A via METTL3, ac4C via NAT10) and nuclear pre-mRNA retention (PMID:36403721, PMID:39990211, PMID:36075458). Beyond catalysis, HK2 has non-canonical functions: it acts as a protein kinase phosphorylating IκBα at Thr291 to activate NF-κB and induce PD-L1 (PMID:37377974), translocates to the nucleus where, phosphorylated by AKT, it binds HIF-1α to drive PD-L1 transcription (PMID:37300724), and functions as a switch from glycolysis to autophagy under substrate deprivation (PMID:26075878). STING directly inhibits HK2 enzymatic activity to restrict aerobic glycolysis and promote antitumor immunity, independent of innate immune signaling (PMID:37443289).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    Established that HK2 transcription is directly wired to nutritional state, defining the lipogenic transcription factor SREBP-1 as a direct activator of the HK2 promoter in metabolic tissues.

    Evidence In vivo ChIP and fasting/refeeding expression analysis in rat liver, adipose, and muscle

    PMID:15627654

    Open questions at the time
    • Does not address protein-level or localization regulation
    • Co-regulation with other nutrient-responsive factors not resolved
  2. 2009 Medium

    Showed that HK2, uniquely among hexokinases, redistributes between cytosol and mitochondria during ischemic preconditioning, framing subcellular localization as a regulated functional variable.

    Evidence Subcellular fractionation and hexokinase activity assays in Langendorff-perfused rat hearts

    PMID:19228992

    Open questions at the time
    • Molecular trigger of redistribution not identified
    • Consequences for cell survival not directly tested here
  3. 2012 High

    Defined mitochondrial HK2 as a glucose-sensing molecular switch governing cell fate and showed hypoxic recruitment of TIGAR potentiates its activity to limit ROS.

    Evidence Co-IP, subcellular fractionation, ROS and cell death assays under hypoxia and glucose deprivation

    PMID:22233811 PMID:23185017

    Open questions at the time
    • Structural basis of the HK2-PEA15 and HK2-TIGAR interactions unresolved
    • Quantitative thresholds for switch behavior undefined
  4. 2002 Medium

    Identified AMPK and calcium/calcineurin-CaMK signaling as upstream transcriptional regulators linking metabolic and contractile signals to HKII expression in muscle.

    Evidence AICAR infusion in rats and pharmacological calcineurin/CaMK inhibition in skeletal muscle

    PMID:12388122 PMID:17516843

    Open questions at the time
    • Direct promoter-binding effectors downstream of these kinases not mapped
    • Generalizability beyond muscle untested
  5. 2015 High

    Resolved how HK2 abundance is coupled to glucose supply, identifying it as a glucose-regulated chaperone-mediated autophagy substrate whose excessive degradation causes metabolic catastrophe.

    Evidence CMA-substrate proteomics, lysosomal fractionation, and genetic/pharmacological CMA manipulation

    PMID:26075878 PMID:26323688

    Open questions at the time
    • Interplay between CMA and proteasomal turnover not quantified
    • Autophagy-switch mechanism in cardiomyocytes mechanistically thin
  6. 2019 Medium

    Mechanistically linked Akt/GSK3β signaling to HK2 mitochondrial release, showing GSK3β-driven VDAC phosphorylation dissociates HK2 to trigger apoptosis.

    Evidence HK2-VDAC Co-IP, phospho-VDAC blots, glycolysis and apoptosis assays with GSK3β activator/AKT inhibitor; p53/zinc context in prostate cancer

    PMID:30528266 PMID:31669347

    Open questions at the time
    • VDAC phosphosite specificity not fully mapped
    • Single-lab pharmacological models
  7. 2017 Medium

    Expanded the HK2 transcriptional network by showing oncogenic YAP/TEAD-p65 cooperation drives HK2 expression to promote migration, and subsequent studies added repressors and additional activators.

    Evidence Co-IP, ChIP at HK2 promoter, and reporter/migration assays; later ChIP studies of FOXE1, KLF14, ZNF281, Foxp1, PPARγ/PER1, ATF4/HIF-1α, CCT6A/STAT1

    PMID:22233811 PMID:22334075 PMID:28945218 PMID:31918722 PMID:34983946 PMID:35255118 PMID:36514923 PMID:37481013 PMID:38750462 PMID:39083899

    Open questions at the time
    • Hierarchy and combinatorial logic among these factors unresolved
    • Most defined in single cancer/inflammation contexts
  8. 2022 Medium

    Established a layer of post-transcriptional and epitranscriptomic control of HK2, with m6A (METTL3), ac4C (NAT10), and nuclear pre-mRNA retention (FTO) tuning HK2 mRNA fate.

    Evidence m6A/ac4C sequencing, nuclear/cytoplasmic fractionation, and ubiquitination assays across cancer models

    PMID:36075458 PMID:36403721 PMID:39990211

    Open questions at the time
    • Relative contribution of each RNA modification not compared
    • Reader proteins for HK2 mRNA marks not all identified
  9. 2022 Medium

    Revealed non-canonical HK2 functions beyond glycolysis: a protein-kinase activity phosphorylating IκBα at Thr291 and nuclear HK2 binding HIF-1α, both converging on NF-κB/HIF-driven PD-L1 to enable immune evasion.

    Evidence Site-directed mutagenesis, phosphorylation and Co-IP assays, PD-L1 reporters, and tumor specimen analysis

    PMID:37300724 PMID:37377974

    Open questions at the time
    • Structural basis of HK2 protein-kinase activity undefined
    • Substrate repertoire beyond IκBα unknown
  10. 2023 Medium

    Defined competing ubiquitin codes governing HK2 stability and localization—K48 ubiquitination (TRIM36, UBR7-Keap1 axis) drives degradation while CSN5 and K63-specific OTUD1 deubiquitination control abundance and mitochondrial residence.

    Evidence Linkage-specific ubiquitination assays, Co-IP, domain mapping, and in vivo KO models

    PMID:31991125 PMID:36419136 PMID:36799474 PMID:40500776

    Open questions at the time
    • Coordination among these E3s/DUBs not integrated
    • Cell-type specificity of each enzyme pair unclear
  11. 2023 High

    Identified STING as a direct enzymatic inhibitor of HK2, decoupling glycolytic restriction from innate immune signaling and connecting HK2 activity to antitumor immunity.

    Evidence In vitro hexokinase activity assays, STING manipulation, in vivo tumor models, and human CRC correlation

    PMID:37443289

    Open questions at the time
    • Structural mode of STING-HK2 inhibition undefined
    • Stoichiometry and reversibility not established
  12. 2024 Medium

    Connected HK2-driven glycolysis to chromatin via lactate, showing HK2-generated lactate promotes H3K18 lactylation that feeds back to activate the HK2 promoter, forming a self-amplifying loop.

    Evidence HK2 knockout mice, Seahorse analysis, and ChIP for H3K18 lactylation at the HK2 promoter in renal ischemia-reperfusion

    PMID:39217289

    Open questions at the time
    • Single disease context
    • Direct vs indirect lactylation effects on transcription not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HK2's canonical glycolytic, moonlighting protein-kinase, nuclear transcriptional, and mitochondrial death-switch functions are spatially and temporally coordinated within a single cell remains unresolved.
  • No structural model linking localization to non-canonical activities
  • Quantitative partitioning of HK2 pools (cytosolic/mitochondrial/nuclear) undefined
  • Causal hierarchy among the regulatory layers not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 7 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2
Partners
CSN5HIF-1ΑOTUD1PEA15STINGTIGARTRIM36VDAC1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Under hypoxia, TIGAR protein relocalizes to mitochondria and forms a direct complex with HK2, resulting in an increase in HK2 hexokinase activity. Mitochondrial localization of TIGAR depends on mitochondrial HK2 and HIF1α activity. TIGAR's fructose-2,6-bisphosphatase activity is independent of HK2 binding, but both activities contribute to limiting mitochondrial ROS and protecting from cell death. Co-immunoprecipitation, subcellular fractionation, mitochondrial localization assays, ROS measurement, cell death assays in hypoxic cells Proceedings of the National Academy of Sciences of the United States of America High 23185017
2012 Mitochondrial HK2 interacts directly with PEA15 (phosphoprotein enriched in astrocytes) to form a molecular switch governing cell fate: HK2 + PEA15 inhibits apoptosis after hypoxia, whereas HK2 without PEA15 under glucose deprivation accelerates apoptosis. HK2 thus functions both as a cytoprotective molecule and as a glucose availability sensor that triggers apoptosis under metabolic stress. Co-immunoprecipitation, genetic overexpression/knockdown, cell death assays under hypoxia and glucose deprivation Proceedings of the National Academy of Sciences of the United States of America High 22233811
2015 HK2 is degraded by chaperone-mediated autophagy (CMA) and is a bona fide CMA substrate. HK2 degradation by CMA is regulated by glucose availability (reduced glucose increases CMA-mediated HK2 degradation). Excessive CMA activation, triggered by perturbation of FLT3 signaling, leads to HK2 degradation, metabolic catastrophe, and cancer cell death. Proteome analysis identifying CMA substrates, lysosomal fraction assays, genetic manipulation of CMA pathway components, glucose availability modulation The Journal of cell biology High 26323688
2015 HK2 facilitates autophagy in response to glucose deprivation (substrate deprivation) to protect cardiomyocytes, functioning as a molecular switch from glycolysis to autophagy to ensure cellular energy homeostasis under starvation conditions. Glucose deprivation experiments in cardiomyocytes, autophagy flux assays, HK2 overexpression/knockdown with cellular survival readouts Autophagy Medium 26075878
2023 STING directly targets HK2 to block its hexokinase enzymatic activity, thereby restricting aerobic glycolysis independent of STING's innate immune signaling function. STING inhibition of HK2 promotes antitumor immunity in vivo. In vitro hexokinase activity assays, genetic manipulation of STING expression, in vivo tumor models, correlative analysis in human colorectal carcinoma samples Nature cell biology High 37443289
2021 After mitochondrial translocation under hypoxia, Drp1 promotes excessive mPTP opening through a pathway involving HK2: LRRK2 is recruited and its kinase activity is inhibited by mitochondrial Drp1, causing HK2 inactivation at Thr-473 and its dissociation from the mitochondrial membrane, which disrupts mPTP structure and causes mPTP overopening. Colocalization assays, co-immunoprecipitation, phosphorylation site identification (Thr-473), mitochondrial fractionation, mPTP opening assays in hypoxic cells Cell death & disease Medium 34741026
2019 GSK-3β-mediated phosphorylation of mitochondrial VDAC induces dissociation of HK2 from VDAC/mitochondria, leading to glycolytic inhibition and mitochondrial-mediated apoptosis. The flavonoid GL-V9 triggers this mechanism by activating GSK-3β and inhibiting AKT. Co-immunoprecipitation of HK2-VDAC complex, Western blot for phospho-VDAC, glycolysis assays, apoptosis assays, 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, leading to HK2 mitochondrial dissociation. Subcellular fractionation, Western blot for phospho-VDAC1, co-immunoprecipitation, Akt inhibition and GSK3β activation assays, xenograft model Experimental cell research Medium 30528266
2009 Ischemic preconditioning (IPC) causes cellular redistribution of HKII (but not HKI): decreased cytosolic HKII during ischemia and increased mitochondrial HKII activity before ischemia and during reperfusion. IPC-mediated decreased cytosolic HK activity during ischemia is explained by decreased HKII protein content in the cytosolic fraction. Subcellular fractionation (mitochondrial, cytosolic, microsomal fractions), hexokinase activity assays, Western blot for HKII protein content in isolated Langendorff-perfused rat hearts Journal of applied physiology Medium 19228992
2017 TNFα triggers IKK-mediated YAP phosphorylation and activation in breast cancer cells. YAP and p65 interact physically, and the YAP/TEAD and p65 complex synergistically regulates HK2 transcription to promote TNFα-induced cell migration. Co-immunoprecipitation of YAP and p65, chromatin immunoprecipitation (ChIP) showing YAP/TEAD and p65 binding to HK2 promoter, migration assays, reporter assays Oncogenesis Medium 28945218
2022 KLF14 transcriptionally inhibits HK2 expression in macrophages. KLF14 deletion leads to increased glycolysis (via HK2 upregulation) and increased inflammatory cytokine secretion. Pharmacological KLF14 activation reduces HK2 expression, decreases glycolysis, and confers protection against sepsis. KLF14 knockout mice, siRNA knockdown, promoter assays, cytokine measurement, glycolysis assays, in vivo endotoxemia/sepsis models Cellular & molecular immunology Medium 34983946
2005 SREBP-1 binds to the HK2 (HKII) promoter in vivo in liver, adipose tissue, and skeletal muscle (demonstrated by chromatin immunoprecipitation), and regulates HKII expression in response to nutritional status (fasting/refeeding). SREBP-1 thus plays a major role in nutritional regulation of glucose metabolism via HKII. Chromatin immunoprecipitation (ChIP) in rat tissues, mRNA and protein expression analysis during fasting/refeeding Journal of lipid research Medium 15627654
2012 PPARγ transcription factor binds directly to the HK2 (hexokinase 2) promoter to activate HK2 transcription in PTEN-null fatty liver. HK2 expression, along with PKM2, is under control of Akt2 kinase through PPARγ in this context. Chromatin immunoprecipitation (ChIP) demonstrating PPARγ binding to HK2 promoter, genetic models (PTEN-null liver, Akt2 knockout), transcriptional reporter assays Nature communications Medium 22334075
2002 AMPK signaling activates transcription of the HKII gene in rat skeletal muscle. Single-leg AICAR infusion (activating AMPK-α2) induced a dose-dependent 2–4-fold increase in HKII transcription specifically in muscle of the infused leg, establishing AMPK as a transcriptional regulator of HKII. Single-leg arterial infusion of AICAR in conscious rats, AMPK activity assays, HKII mRNA quantification in red and white skeletal muscle American journal of physiology. Endocrinology and metabolism Medium 12388122
2007 Calcium signaling via calcineurin and CaMK pathways regulates HKII mRNA expression in skeletal muscle. Ionomycin treatment increased HKII mRNA ~2-fold; cyclosporin A (calcineurin inhibitor) and KN-62 (CaMK inhibitor) reduced ionomycin-induced HKII transcription, establishing calcineurin and CaMK as upstream regulators of HKII. Pharmacological inhibition (cyclosporin A, KN-62), ionomycin stimulation, electrical stimulation of isolated muscle, mRNA quantification in primary rat skeletal muscle cells and EDL muscle Biological chemistry Medium 17516843
2022 HK2 acts as a protein kinase (non-canonical activity) and phosphorylates IκBα at Thr291 under high glucose conditions in breast cancer cells, leading to rapid IκBα degradation, NF-κB activation, and transcriptional upregulation of PD-L1, thereby promoting immune evasion. Phosphorylation assays, mutagenesis of IκBα Thr291, Co-IP, NF-κB reporter assays, PD-L1 expression analysis, immunohistochemistry in human breast cancer specimens Frontiers in immunology Medium 37377974
2020 CSN5 (COP9 signalosome subunit 5) stabilizes HK2 protein through its deubiquitinase function, attenuating ubiquitin-proteasome-mediated HK2 degradation. CSN5 knockdown decreases HK2 protein level and glycolytic flux; re-expression of HK2 rescues glycolysis. Curcumin inhibition of CSN5 kinase activity decreases HK2 expression. Co-immunoprecipitation, ubiquitination assays, glycolysis flux measurements, HK2 rescue experiments, in vivo tumor models Experimental cell research Medium 31991125
2023 TRIM36 E3 ubiquitin ligase directly binds HK2 and promotes its degradation via K48-linked ubiquitination. TRIM36-mediated HK2 ubiquitination reduces HK2 protein, suppresses glycolysis, decreases GPx4 expression, and activates ferroptosis to inhibit neuroendocrine differentiation in prostate cancer. Co-immunoprecipitation, ubiquitination assays specifying K48-linkage, proteomic analysis, ferroptosis assays, HK2 knockdown/overexpression Cancer science Medium 36799474
2025 OTUD1 deubiquitinase directly binds to the C-terminal domain of HK2 via its Ala-rich domain and selectively cleaves K63-linked polyubiquitin chains on HK2, promoting HK2 dissociation from mitochondria. Mitochondrial HK2 dissociation activates the NLRP3 inflammasome and pyroptosis in microglia, causing neuroinflammation in sepsis-associated encephalopathy. Molecular docking, co-immunoprecipitation, 3D confocal microscopy, OTUD1 knockout mice, primary microglia experiments, behavioral tests, Western blot for K63-ubiquitin linkage Journal of neuroinflammation Medium 40500776
2022 HK2 undergoes circadian oscillation in trastuzumab-resistant gastric cancer cells, regulated by a transcriptional complex composed of PPARγ and the core clock gene PER1. Higher HK2-dependent glycolysis at ZT6 and lower at ZT18 is controlled by the BMAL1-CLOCK-PER1-HK2 axis. Silencing PER1 disrupts HK2 circadian rhythm and reverses trastuzumab resistance. In vivo and in vitro circadian glycolysis assays, PER1 silencing, ChIP for transcriptional complex at HK2 promoter, trastuzumab resistance models Cancer research Medium 35255118
2022 UBR7 E3 ligase monoubiquitinates histone H2B at K120 (H2BK120ub), which regulates Keap1 promoter binding, thereby controlling Keap1 expression and downstream Nrf2/Bach1/HK2 signaling. UBR7 loss de-represses HK2 expression to promote aerobic glycolysis and HCC tumorigenesis. RNAi screening, ChIP showing H2BK120ub at Keap1 promoter, Western blot, glycolysis assays, in vivo tumor models Journal of experimental & clinical cancer research Medium 36419136
2020 FOXE1 transcription factor directly binds to the HK2 promoter and negatively regulates HK2 transcription, thereby suppressing aerobic glycolysis in colorectal cancer cells. ChIP assay demonstrating FOXE1 binding to HK2 promoter, luciferase reporter assays, gene knockdown/overexpression, glycolysis assays Cell communication and signaling Medium 31918722
2024 CCT6A interacts with STAT1 protein via co-immunoprecipitation, forming a complex that enhances STAT1 stability by protecting it from ubiquitin-mediated degradation. Stabilized STAT1 then facilitates transcription of HK2, stimulating aerobic glycolysis in lung adenocarcinoma. Co-immunoprecipitation, ChIP assay, transcriptomic sequencing, LC-MS/MS, gene silencing with phenotypic readouts Journal of translational medicine Medium 38750462
2023 ATF4 directly binds to the HK2 promoter region and interacts with HIF-1α, stabilizing HIF-1α through ubiquitination modification in response to LPS. The ATF4-HIF-1α-HK2-glycolysis axis activates pro-inflammatory macrophage response via mTOR. Promoter binding assays, co-immunoprecipitation of ATF4-HIF-1α, ubiquitination assays, glycolysis measurements, cytokine assays, Atf4 knockdown/overexpression Clinical immunology Medium 37481013
2022 Glutamate from nerve cells activates NMDAR on pancreatic cancer cells, causing Ca2+ influx and CaMKII/ERK-MAPK pathway activation, which promotes METTL3 transcription. METTL3 then upregulates HK2 expression through N6-methyladenosine (m6A) modification of HK2 mRNA, enhancing glycolysis and perineural invasion. Ca2+ influx assays, pathway inhibition, METTL3 knockdown/overexpression, m6A sequencing/modification assays, HK2 expression analysis, in vivo sciatic nerve invasion model Pharmacological research Medium 36403721
2025 NAT10 RNA acetyltransferase stimulates ac4C modification at the junction of the CDS and 3'UTR of HK2 mRNA, enhancing HK2 mRNA stability and protein expression to activate glycolysis and drive gastric tumorigenesis. Glucose deprivation activates autophagy-lysosome degradation of NAT10, reducing ac4C modification of HK2. Dot blotting, immunofluorescence, co-immunoprecipitation, high-throughput sequencing (ac4C-seq), conditional knockout mouse model, organoids, GC xenografts, PET/CT imaging Theranostics High 39990211
2022 E6E7 HPV oncogenes activate GSK3β transcription in cervical cancer cells; GSK3β promotes ubiquitination-proteasomal degradation of FTO; reduced FTO retains HK2 pre-mRNA in the nucleus, preventing maturation to cytoplasmic HK2 mRNA, thereby upregulating HK2 protein expression. qRT-PCR for pre-mRNA vs. mature mRNA, Western blot, nuclear/cytoplasmic fractionation, overexpression of E6E7 and FTO, ubiquitination assays Archives of biochemistry and biophysics Medium 36075458
2023 HK2 translocates to the nucleus in gastric cancer cells under GCMSC-derived IL-8 stimulation via AKT-mediated phosphorylation. Phosphorylated nuclear HK2 promotes PD-L1 transcription by binding to HIF-1α. Subcellular fractionation, Western blot, co-immunoprecipitation of HK2 and HIF-1α, AKT inhibition experiments, PD-L1 reporter assays Gastric cancer Medium 37300724
2022 ZNF281 directly binds to the 5'-GGCGGCGGGCGG-3' motif within the HK2 promoter and transcriptionally represses HK2 expression, reducing HK2-PINK1/Parkin signaling-mediated mitophagy and promoting hepatocyte senescence in alcoholic liver disease. ChIP assay, promoter binding assays identifying specific binding motif, siRNA knockdown, adeno-associated virus ZNF281 shRNA in vivo, mitophagy assays Cell proliferation Medium 36514923
2024 In renal ischemia-reperfusion injury, HK2-mediated glycolysis generates lactate that promotes H3K18 lactylation, which in turn is enriched at the HK2 promoter (ChIP) and upregulates HK2 expression, forming a positive feedback loop. AST-120 breaks this loop by suppressing HK2. HK2 knockout mice, Seahorse analysis, chromatin immunoprecipitation for H3K18 lactylation at HK2 promoter, Western blotting, H/R cell model Molecular medicine Medium 39217289
2024 In endothelial cells, Foxp1 transcriptionally represses Hif1α, which in turn represses Hk2 transcription. Foxp1 deletion in ECs increases Hif1α→Hk2 expression, hyperglycolysis, and tumor angiogenesis. Genetic deletion of EC-Hif1α or siRNA knockdown of Hif1α/Hk2 delivered via RGD-peptide nanoparticles reduces tumor EC hyperglycolysis and restricts angiogenesis. EC-specific Foxp1/Hif1α knockout mice, nanoparticle-mediated siRNA delivery, angiogenesis assays, retinal and tumor vascularization studies, TCGA analysis Redox biology Medium 39083899
2018 Dhcr24 overexpression activates the PI3K/Akt/HKII pathway in cardiomyocytes, leading to reduced Bax translocation and inhibition of mitochondrial-dependent apoptosis. Knockdown of Dhcr24 reduces PI3K/Akt/HKII pathway activation. HKII inhibition partially reverses the anti-apoptotic effect of Dhcr24 in H9c2 cells. Transgenic overexpression, Dhcr24 knockdown, Western blot, TUNEL assay, HKII inhibitor (2-DG) in H9c2 cells, PI3K inhibitor Animal models and experimental medicine Medium 30891546
2023 Mitochondria-bound HK2 (requiring intact N-terminal mitochondrial binding motif) regulates the invasive and migratory phenotype of RA fibroblast-like synoviocytes (FLS). Overexpression of full-length HK2 promotes FLS invasion/migration after PDGF stimulation; HK2 lacking its mitochondrial binding motif (HK2ΔN) reverses this. Tofacitinib but not methotrexate promotes HK2 dissociation from mitochondria. Adenoviral overexpression of FL-HK2 vs. HK2ΔN, confocal microscopy for localization, migration/invasion assays, in vivo arthritis model, scRNA-seq data analysis Frontiers in immunology Medium 37529037
2024 TRPV4 calcium channel activation induces Drp1 mitochondrial translocation via Ca2+-CaMKII signaling, which subsequently causes HK2 dissociation from the mitochondrial membrane, leading to mPTP overopening, mitochondrial dysfunction, and chondrocyte pyroptosis in osteoarthritis. Ca2+ measurement, CaMKII signaling assays, Drp1 translocation assays, HK2 mitochondrial fractionation, mPTP opening assays, TRPV4 inhibitor in ACLT mouse model International immunopharmacology Medium 37506502

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2015 HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection. Autophagy 234 26075878
2012 Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proceedings of the National Academy of Sciences of the United States of America 197 23185017
2019 Unlocking the Potential of HK2 in Cancer Metabolism and Therapeutics. Current medicinal chemistry 170 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 125 37443289
2015 Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. The Journal of cell biology 110 26323688
2022 The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis. Cellular & molecular immunology 105 34983946
2005 Regulation of SREBP-1 expression and transcriptional action on HKII and FAS genes during fasting and refeeding in rat tissues. Journal of lipid research 100 15627654
2021 Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells. Cells 99 34200774
2016 Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer cell international 93 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 83 35255118
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
2022 Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4). Bioengineered 75 35226829
2022 UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. Journal of experimental & clinical cancer research : CR 72 36419136
2017 TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration. Oncogenesis 72 28945218
2022 HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways. Cell communication and signaling : CCS 70 36042519
2018 Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 70 30322879
2021 Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2. Cell death & disease 65 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 62 22233811
2017 The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma. Scientific reports 56 28596599
2024 Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 55 38889331
2023 ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis. Clinical immunology (Orlando, Fla.) 55 37481013
2022 Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification. Pharmacological research 55 36403721
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
2019 An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1-HK2+ Multiple Myeloma. Cancer research 49 30885978
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 47 31669347
2023 TRPV4-mediated mitochondrial dysfunction induces pyroptosis and cartilage degradation in osteoarthritis via the Drp1-HK2 axis. International immunopharmacology 45 37506502
2023 Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion. Frontiers in immunology 44 37377974
2021 MIR210HG regulates glycolysis, cell proliferation, and metastasis of pancreatic cancer cells through miR-125b-5p/HK2/PKM2 axis. RNA biology 44 34110962
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 41 37300724
2023 The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII. Journal of translational medicine 40 37179292
2019 Novel xanthine oxidase-based cell model using HK-2 cell for screening antihyperuricemic functional compounds. Free radical biology & medicine 40 30980888
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
2022 Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway. Bioengineered 38 35719058
2022 Hyperglycemia Enhances Immunosuppression and Aerobic Glycolysis of Pancreatic Cancer Through Upregulating Bmi1-UPF1-HK2 Pathway. Cellular and molecular gastroenterology and hepatology 36 35863742
2022 A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors. Scientific reports 36 36335239
2016 Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget 36 27260001
2019 PLOD2 promotes aerobic glycolysis and cell progression in colorectal cancer by upregulating HK2. Biochemistry and cell biology = Biochimie et biologie cellulaire 34 31742425
2003 TGF-beta1-mediated inhibition of HK-2 cell migration. Journal of the American Society of Nephrology : JASN 34 12595498
2023 Trigred motif 36 regulates neuroendocrine differentiation of prostate cancer via HK2 ubiquitination and GPx4 deficiency. Cancer science 32 36799474
2021 CPNE1 Enhances Colorectal Cancer Cell Growth, Glycolysis, and Drug Resistance Through Regulating the AKT-GLUT1/HK2 Pathway. OncoTargets and therapy 32 33536762
2018 Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1. Experimental cell research 30 30528266
2024 CCT6A facilitates lung adenocarcinoma progression and glycolysis via STAT1/HK2 axis. Journal of translational medicine 29 38750462
2022 Expression of HK2, PKM2, and PFKM Is Associated with Metastasis and Late Disease Onset in Breast Cancer Patients. Genes 29 35328104
2020 FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer. Cell communication and signaling : CCS 29 31918722
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 CircPRKCI relieves lipopolysaccharide-induced HK2 cell injury by upregulating the expression of miR-545 target gene ZEB2. BioFactors (Oxford, England) 28 32104945
2020 Circular RNA circMDM2 accelerates the glycolysis of oral squamous cell carcinoma by targeting miR-532-3p/HK2. Journal of cellular and molecular medicine 28 32410389
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
2015 XBP1 silencing decreases glioma cell viability and glycolysis possibly by inhibiting HK2 expression. Journal of neuro-oncology 28 26680227
2024 AST-120 alleviates renal ischemia-reperfusion injury by inhibiting HK2-mediated glycolysis. Molecular medicine (Cambridge, Mass.) 25 39217289
2024 Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction. Journal of advanced research 24 39142439
2022 Exosome-delivered circular RNA DLGAP4 induces chemoresistance via miR-143-HK2 axis in neuroblastoma. Cancer biomarkers : section A of Disease markers 24 35068445
2021 Methylation-associated silencing of miR-9-1 promotes nasopharyngeal carcinoma progression and glycolysis via HK2. Cancer science 23 34382305
2021 AKT1/HK2 Axis-mediated Glucose Metabolism: A Novel Therapeutic Target of Sulforaphane in Bladder Cancer. Molecular nutrition & food research 23 34791822
2023 ASPP2 suppresses tumour growth and stemness characteristics in HCC by inhibiting Warburg effect via WNT/β-catenin/HK2 axis. Journal of cellular and molecular medicine 22 36752127
2020 Hsa_circ_0069094 accelerates cell malignancy and glycolysis through regulating the miR-591/HK2 axis in breast cancer. Cellular signalling 22 33309838
2020 FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway. Experimental cell research 21 33253711
2022 CDK6 increases glycolysis and suppresses autophagy by mTORC1-HK2 pathway activation in cervical cancer cells. Cell cycle (Georgetown, Tex.) 20 35167417
2022 miR-532-3p suppresses proliferation and invasion of ovarian cancer cells via GPNMB/HIF-1α/HK2 axis. Pathology, research and practice 20 35914373
2022 E6E7 regulates the HK2 expression in cervical cancer via GSK3β/FTO signal. Archives of biochemistry and biophysics 20 36075458
2020 Circular RNA circFAT1(e2) Promotes Osteosarcoma Progression and Metastasis by Sponging miR-181b and Regulating HK2 Expression. BioMed research international 20 32733938
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 Exosomes derived from calcium oxalate-treated macrophages promote apoptosis of HK-2 cells by promoting autophagy. Bioengineered 19 35037827
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
2025 OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis. Journal of neuroinflammation 17 40500776
2023 HK2 in microglia and macrophages contribute to the development of neuropathic pain. Glia 17 37909251
2021 Expression and Clinical Significance of HKII and HIF-1α in Grade Groups of Prostate Cancer. Frontiers in genetics 17 34220956
2023 Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes. Frontiers in immunology 16 37529037
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
2025 The Role of HK2 in Tumorigenesis and Development: Potential for Targeted Therapy with Natural Products. International journal of medical sciences 14 39991762
2024 Therapeutic efficacy of ECs Foxp1 targeting Hif1α-Hk2 glycolysis signal to restrict angiogenesis. Redox biology 14 39083899
2023 ErbB2-upregulated HK1 and HK2 promote breast cancer cell proliferation, migration and invasion. Medical oncology (Northwood, London, England) 14 37079118
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
2021 Hsa_circ_0001806 promotes glycolysis and cell progression in hepatocellular carcinoma through miR-125b/HK2. Journal of clinical laboratory analysis 13 34664737
2025 Glucose homeostasis controls N-acetyltransferase 10-mediated ac4C modification of HK2 to drive gastric tumorigenesis. Theranostics 12 39990211
2023 Advances in the Study of Hexokinase 2 (HK2) Inhibitors. Anti-cancer agents in medicinal chemistry 12 36278443
2023 Effect of transferrin glycation induced by high glucose on HK-2 cells in vitro. Frontiers in endocrinology 12 36778593
2022 BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming. Translational lung cancer research 12 35958341
2020 CaMKII as a key regulator of contrast-induced nephropathy through mPTP opening in HK-2 cells. Cellular signalling 12 32791339
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
1996 Prostate-specific human kallikrein (hK2) as a novel marker for prostate cancer. The Prostate. Supplement 12 8950360
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
2024 FKBP4 promotes glycolysis and hepatocellular carcinoma progression via p53/HK2 axis. Scientific reports 11 39505995
2021 hsa-miR-9-5p Down-Regulates HK2 and Confers Radiosensitivity to Nasopharyngeal Carcinoma. Technology in cancer research & treatment 11 33627057
2014 ATF3 attenuates cyclosporin A-induced nephrotoxicity by downregulating CHOP in HK-2 cells. Biochemical and biophysical research communications 11 24768635
2024 Hydroxysafflor yellow A induced ferroptosis of Osteosarcoma cancer cells by HIF-1α/HK2 and SLC7A11 pathway. Oncology research 10 38686047
2020 Gomisin J inhibits the glioma progression by inducing apoptosis and reducing HKII-regulated glycolysis. Biochemical and biophysical research communications 10 32560813

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