Affinage

HKDC1

Hexokinase HKDC1 · UniProt Q2TB90

Length
917 aa
Mass
102.5 kDa
Annotated
2026-06-10
52 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HKDC1 is a fifth hexokinase that phosphorylates glucose and contributes to whole-body glucose homeostasis, with genetic loss in mice impairing glucose tolerance, hepatic energy storage, and peripheral glucose uptake (PMID:25648650, PMID:27459389). A defining feature is that its activities partition between metabolic and non-canonical functions: HKDC1 associates with the mitochondrial outer membrane and binds VDAC1 through a hexokinase-isoform-unique C-terminal 8-amino-acid motif, regulating mitochondrial permeability transition, respiration, and membrane potential (PMID:30517626, PMID:31058090, PMID:32203147). Through its VDAC interaction it sustains mitochondria-lysosome contact and is required for PINK1/Parkin-dependent mitophagy and clearance of damaged lysosomes, functions that are independent of its glycolytic activity and that protect against DNA-damage-induced senescence (PMID:38170752). Beyond mitochondria, nuclear HKDC1 acts as a protein kinase that phosphorylates RBBP5 at Ser497 to drive MLL1-complex assembly, H3K4me3, and cell-cycle gene transcription (PMID:39891906), and it operates as a glucose sensor whose stability is governed by a Ser896-containing domain controlling Lys620 ubiquitination (PMID:39375512). In cancer, HKDC1 promotes tumor growth and immune evasion through multiple protein-protein mechanisms: scaffolding cytosolic STAT1 to IFNGR1 via ACTA2 to upregulate PD-L1 (PMID:38351096), sequestering PHB2 to de-repress SP1 (PMID:39375512), stabilizing ASS1 and G6PC/G6PC2 to reprogram lipid metabolism (PMID:41629949, PMID:40234623), and acting as an RNA-binding protein that cooperates with G3BP1 to stabilize PRKDC mRNA (PMID:37423558). HKDC1 expression is transcriptionally controlled by stress- and tissue-specific factors including ATF4, TFEB, HNF4α, HNF1α, USF1, and SREBP1/PGC1β (PMID:29420561, PMID:38170752, PMID:41866549, PMID:38986750, PMID:41812646, PMID:31058090), and post-transcriptionally by METTL3-mediated m6A modification (PMID:34763315). A patient hexokinase-deficient variant (p.T58M) and Hkdc1-null mice with photoreceptor dysfunction establish HKDC1 as required for retinal rod function (PMID:30085091).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2015 High

    Established that HKDC1 is a bona fide enzyme rather than a pseudogene-like fifth hexokinase, answering whether the protein has catalytic glucose-phosphorylating activity.

    Evidence In vitro hexokinase assay with purified protein plus cellular knockdown/overexpression

    PMID:25648650

    Open questions at the time
    • Kinetic parameters versus other hexokinases not defined
    • Physiological substrate range beyond glucose untested
  2. 2016 High

    Showed that HKDC1 has a non-redundant in vivo role in systemic glucose handling, moving it from a biochemical curiosity to a physiologically relevant metabolic enzyme.

    Evidence Heterozygous knockout mouse with glucose tolerance tests and tissue glucose-uptake measurements

    PMID:27459389

    Open questions at the time
    • Tissue origin of the phenotype not resolved
    • Homozygous null consequences not addressed in this study
  3. 2018 High

    Linked HKDC1 expression to stress signaling and to a Mendelian retinal phenotype, establishing both an inducible regulatory input and a tissue-essential requirement.

    Evidence ATF4 RNAi/ISRIB epistasis for transcriptional control; whole-exome sequencing of patient p.T58M variant with mutant enzymatic assay and CRISPR Hkdc1-null mouse ERG/immunostaining

    PMID:29420561 PMID:30085091

    Open questions at the time
    • No direct ChIP confirming ATF4 occupancy at the HKDC1 promoter
    • Mechanism connecting reduced hexokinase activity to rhodopsin mislocalization unresolved
  4. 2019 Medium

    Defined the mitochondrial localization and VDAC1-binding behavior of HKDC1, establishing a structural basis for its influence on mitochondrial respiration and permeability beyond cytosolic glycolysis.

    Evidence Subcellular fractionation, Seahorse respirometry, Co-IP for VDAC1, and ChIP/luciferase for PGC1β/SREBP1 transcriptional control

    PMID:30517626 PMID:31058090

    Open questions at the time
    • Stoichiometry and direct versus indirect VDAC1 binding not resolved
    • Reconciliation between low glucose-phosphorylating ability and metabolic effects incomplete
  5. 2020 Medium

    Mapped the VDAC1 interaction to a hexokinase-isoform-unique C-terminal motif and demonstrated it is functionally targetable, distinguishing HKDC1's mitochondrial anchoring from other hexokinases.

    Evidence Peptide competition (Tf-D-HKC8) with mitochondrial ROS/membrane-potential readouts and xenograft in NK/T-cell lymphoma

    PMID:32203147

    Open questions at the time
    • Peptide specificity for HKDC1 versus off-target effects not fully excluded
    • Structural detail of the C-terminal/VDAC interface absent
  6. 2023 Medium

    Revealed an RNA-binding function for HKDC1, expanding its repertoire beyond enzymatic and mitochondrial roles by showing it stabilizes target mRNAs with G3BP1.

    Evidence RIP to identify HKDC1-bound PRKDC mRNA, Co-IP for G3BP1, and mRNA stability assays in gastric cancer

    PMID:37423558

    Open questions at the time
    • RNA-binding domain not mapped
    • Breadth of the HKDC1 RNA interactome beyond PRKDC undefined
  7. 2024 High

    Established glycolysis-independent mitochondrial quality-control functions, showing HKDC1 is a TFEB-driven effector required for mitophagy, lysosomal repair, and mitochondria-lysosome contact.

    Evidence ChIP-qPCR for TFEB, PINK1-stabilization and mitophagy flux assays, Co-IP for VDACs, and senescence assays with genetic epistasis

    PMID:38170752

    Open questions at the time
    • Molecular mechanism by which HKDC1 stabilizes PINK1 not defined
    • How a single protein coordinates contact-site maintenance unresolved
  8. 2024 High

    Demonstrated a nuclear protein-kinase activity for HKDC1, the most unexpected non-canonical function, coupling it directly to chromatin modification and cell-cycle gene transcription.

    Evidence Nuclear fractionation, in vitro kinase assay with Ser497 mutagenesis, MLL1 Co-IP, and H3K4me3 ChIP in HCC

    PMID:39891906

    Open questions at the time
    • Kinase active-site architecture and ATP-binding determinants not characterized
    • Full nuclear substrate set beyond RBBP5 unknown
  9. 2024 High

    Defined a glucose-sensing domain and stability switch and a chromatin-derepression mechanism via PHB2 sequestration, connecting nutrient status to HKDC1 abundance and to pro-oncogenic transcription.

    Evidence Deletion mutagenesis (aa 751–917, Ser896), ubiquitination assays at Lys620, Co-IP for PHB2, and SP1 reporter with glucose starvation

    PMID:39375512

    Open questions at the time
    • Identity of the kinase/ligase acting on Ser896/Lys620 not established
    • Direct glucose-binding by the sensing domain not biochemically demonstrated
  10. 2024 High

    Showed HKDC1 drives tumor immune evasion through a cytoskeletal scaffolding mechanism, linking IFNγ receptor signaling to PD-L1 induction.

    Evidence Reciprocal Co-IP for STAT1 and ACTA2, proximity ligation, IFNGR1 membrane assays, and in vivo anti-PD-1/PD-L1 combination models

    PMID:38351096

    Open questions at the time
    • Whether scaffolding requires HKDC1 catalytic activity untested
    • Generality of the STAT1-ACTA2 axis across tissues unconfirmed
  11. 2024 Medium

    Extended HKDC1's interactome to PARP1 and GSK3β, linking it to autophagy and β-catenin-driven stemness in distinct cancer contexts.

    Evidence Co-IP for PARP1 with PARylation activity assays in PDAC; Co-IP for GSK3β with β-catenin stability and hypoxia induction in HCC

    PMID:39250463 PMID:39424110

    Open questions at the time
    • Direct versus indirect nature of these interactions not fully resolved
    • Whether these binding modes are mutually exclusive or context-restricted unknown
  12. 2025 Medium

    Consolidated a recurrent theme of HKDC1 stabilizing metabolic enzymes by domain-specific binding, reprogramming lipid and gluconeogenic metabolism to drive therapy resistance and immune escape.

    Evidence Co-IP with domain mapping and ubiquitination assays for ASS1 (HKLS1 domain) and G6PC/G6PC2, with histone-acetylation ChIP and in vivo tumor models

    PMID:40234623 PMID:41629949

    Open questions at the time
    • Whether HKDC1 directly blocks ubiquitin transfer or competes for substrate sites unresolved
    • Overlap of stabilized substrates with its kinase/RNA functions not integrated
  13. 2025 Medium

    Broadened the transcriptional and post-transcriptional control network of HKDC1, identifying additional tissue- and stress-specific inducers and RNA-modification inputs.

    Evidence ChIP/luciferase for HNF4α, HNF1α, USF1, YY1, Menin-YBX1 axis, ZMAT3-JUN repression; m6A (METTL3) and m5C (NSUN2/YBX1) modification assays

    PMID:34763315 PMID:35435980 PMID:38986750 PMID:40423890 PMID:40520008 PMID:40894906 PMID:41812646 PMID:41866549

    Open questions at the time
    • Hierarchy among the many transcription factors in any single cell type unclear
    • Direct ChIP missing for some inferred promoter interactions

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein simultaneously functions as a cytosolic hexokinase, a mitochondrial VDAC partner, a nuclear protein kinase, an RNA-binding protein, and an enzyme-stabilizing scaffold remains mechanistically unintegrated.
  • No structure assigning distinct activities to distinct domains
  • Determinants of subcellular partitioning between cytosol, mitochondria, and nucleus unknown
  • Which functions require catalytic activity versus are purely scaffolding untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2 GO:0003723 RNA binding 1 GO:0140096 catalytic activity, acting on a protein 1 GO:0140299 molecular sensor activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-4839726 Chromatin organization 1
Partners
ACTA2ASS1G3BP1GSK3BPARP1PHB2STAT1VDAC1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Purified HKDC1 protein has hexokinase activity in vitro; reducing or increasing HKDC1 expression correspondingly reduces or increases hexokinase activity in multiple cellular models. In vitro hexokinase activity assay with purified protein; cellular knockdown/overexpression with activity measurement Nature communications High 25648650
2016 Heterozygous deletion of HKDC1 in mice impairs whole-body glucose tolerance and reduces hepatic energy storage and peripheral tissue glucose uptake, demonstrating HKDC1's in vivo role in glucose utilization. Heterozygous knockout mouse model; glucose tolerance tests; hepatic glycogen and peripheral glucose uptake measurements Endocrinology High 27459389
2019 HKDC1 associates with mitochondria in hepatocytes and has low glucose-phosphorylating ability; overexpression reduces glycolytic capacity, maximal mitochondrial respiration, glucose oxidation, and mitochondrial membrane potential, and induces mitochondrial dynamic changes in vivo. Subcellular fractionation/localization; mitochondrial respiration assays (Seahorse); in vivo hepatic overexpression via adenoviral vector Endocrinology High 30517626
2019 HKDC1 is located on the mitochondrial membrane and binds VDAC1, regulating mitochondrial permeability transition pore opening; HKDC1 expression is co-activated by PGC1β through SREBP1 binding to the HKDC1 promoter. Immunofluorescence/subcellular localization; Co-IP/pulldown for VDAC1 interaction; luciferase reporter assay and ChIP for PGC1β/SREBP1 transcriptional regulation; siRNA knockdown Frontiers in oncology Medium 31058090
2020 HKDC1 C-terminal 8 amino acids (unique among hexokinase isoforms) mediate its association with VDAC1; disrupting this interaction with a peptide (Tf-D-HKC8) causes mitochondrial dysfunction, ROS overgeneration, suppression of EBV replication, and P-gp expression reduction in NK/T-cell lymphoma cells. Peptide competition assay; mitochondrial function assays (ROS, membrane potential); EBV replication assay; xenograft mouse model Leukemia Medium 32203147
2020 HKDC1 promotes glycolysis and tumor growth in lung adenocarcinoma by regulating the AMPK/mTOR signaling pathway. siRNA knockdown and overexpression; Western blotting for AMPK/mTOR pathway components; glycolysis assays; in vivo xenograft Cancer cell international Low 32943998
2021 METTL3-mediated m6A modification at position 2854 of HKDC1 mRNA regulates HKDC1 expression; baicalin inhibits this modification, suppressing the HKDC1/JAK2/STAT1/caspase-3 pathway in liver cancer under high glucose. SELECT PCR for m6A site identification; m6A quantification by MS; siRNA knockdown of METTL3; cell and in vivo tumor models Phytomedicine Medium 34763315
2022 Intestine-specific HKDC1 knockout mice fed a high-fat diet exhibit increased glucose excursion after oral glucose load, associated with increased apical GLUT2 expression in fasting state, indicating HKDC1 modulates intestinal glucose transport under metabolic stress. Conditional intestinal HKDC1 knockout mouse model; oral glucose tolerance test; intestinal glucose transporter expression analysis Endocrinology Medium 35435980
2023 HKDC1 functions as an RNA-binding protein in gastric cancer; it cooperates with G3BP1 to enhance stability of PRKDC mRNA, promoting PRKDC-dependent lipid metabolism rewiring, invasion, migration, and cisplatin resistance. Transcriptomic sequencing; metabolomic analysis; RIP (RNA immunoprecipitation) to identify HKDC1-bound RNAs; Co-IP for G3BP1 interaction; mRNA stability assays; in vitro and in vivo functional assays Cancer letters Medium 37423558
2023 Liver-specific HKDC1 overexpression in mice causes impaired glucose homeostasis, shifts glucose metabolism toward anabolic pathways (increased nucleotide synthesis), and increases liver size through enhanced hepatocyte proliferative potential partly mediated by YAP signaling. Stable hepatic HKDC1 overexpression mouse model; metabolic flux analysis; YAP pathway Western blotting; liver histology and proliferation assays Scientific reports Medium 37198225
2024 TFEB directly binds the HKDC1 promoter (identified by ChIP-qPCR) and transcriptionally activates HKDC1; HKDC1 is upregulated by both mitochondrial and lysosomal stress in a TFEB-dependent manner and is essential for PINK1/Parkin-dependent mitophagy (specifically PINK1 stabilization) and clearance of damaged lysosomes; HKDC1 interacts with VDACs and this interaction is required for maintaining mitochondria-lysosome contact; loss of HKDC1 accelerates DNA damage-induced cellular senescence with accumulation of hyperfused mitochondria and damaged lysosomes; these functions are independent of HKDC1's glycolytic activity. Comprehensive transcriptome analysis; ChIP-qPCR; TFEB knockdown/overexpression; PINK1 stabilization assays; mitophagy flux assays; lysosomal damage assays; Co-IP for VDAC interaction; senescence assays Proceedings of the National Academy of Sciences of the United States of America High 38170752
2024 HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by binding cytosolic STAT1 and presenting it to IFNGR1 on the plasma membrane via association with cytoskeleton protein ACTA2 following IFNγ stimulation, resulting in STAT1 phosphorylation and nuclear translocation and subsequent PD-L1 upregulation. Co-IP for HKDC1-STAT1 and HKDC1-ACTA2 interactions; proximity ligation assay; IFNGR1 membrane localization assay; HKDC1 knockdown with STAT1 phosphorylation readout; in vivo liver cancer mouse models with anti-PD-1/PD-L1 combination Nature communications High 38351096
2024 HKDC1 contains a glucose-sensing domain between amino acids 751–917 with Ser896 as a key residue that regulates HKDC1 stability by affecting Lys620 ubiquitination; HKDC1 promotes tumor growth by sequestering prohibitin 2 (PHB2) to disable its suppressive effect on SP1, promoting pro-oncogenic gene expression; glucose depletion destabilizes HKDC1 and releases PHB2. Domain mapping by deletion mutagenesis; ubiquitination assays; Co-IP for PHB2 interaction; SP1 reporter assay; genetic knockout; glucose starvation experiments Cell death and differentiation High 39375512
2024 Nuclear-localized HKDC1 acts as a protein kinase, phosphorylating RBBP5 at Ser497, which is required for MLL1 complex assembly and H3K4me3 histone modification, leading to transcriptional activation of mitosis-related genes and cell cycle progression in HCC. Nuclear fractionation; in vitro kinase assay; site-directed mutagenesis (Ser497); Co-IP for MLL1 complex; ChIP for H3K4me3; cell proliferation assays; tumor xenograft Cell reports High 39891906
2024 HKDC1 is induced by hypoxia and binds glycogen synthase kinase 3β (GSK3β) to stabilize β-catenin, enhancing stemness of HCC cells and promoting metastasis. Co-IP for HKDC1-GSK3β interaction; β-catenin stability assay; hypoxia induction experiments; HCC orthotopic and tail-vein injection mouse models; stemness marker analysis Hepatology Medium 39250463
2018 HKDC1 is identified as a direct transcriptional target of ATF4 during the integrated stress response; mitochondrial respiration chain dysfunction and ER stress induce HKDC1 expression in an ATF4-dependent manner, reversible by ISRIB (ISR inhibitor) or ATF4 RNAi. RT-qPCR; siRNA knockdown of ATF4; ISRIB pharmacological inhibition; luciferase reporter assay identifying ATF4-responsive element in KRT16 promoter (analogous approach for HKDC1) PloS one Medium 29420561
2018 HKDC1 mutation (p.T58M) causes partial loss of hexokinase activity; Hkdc1 knockout mice exhibit reduced scotopic electroretinogram response, thinner outer nuclear layer, and mislocalization of rhodopsin in rods, establishing HKDC1 as necessary for retinal photoreceptor function. Whole-exome sequencing; in vitro hexokinase activity assay with mutant protein; CRISPR/Cas9 Hkdc1 knockout mouse; ERG; immunostaining; Western blot Human molecular genetics High 30085091
2024 LPS promotes binding of transcription factor YY1 to the HKDC1 promoter via TLR4 receptor activation, inducing HKDC1 transcription; HKDC1 interacts with HSCB and FDX1, leading to increased intracellular copper levels and suppression of cuproptosis; HKDC1 knockdown in vivo alleviates acute sepsis by activating copper-dependent cell death. ChIP-qPCR for YY1-HKDC1 promoter binding; Co-IP for HKDC1-HSCB and HKDC1-FDX1 interactions; copper level measurement; cuproptosis assays; in vivo sepsis model with HKDC1 knockdown Acta biochimica et biophysica Sinica Medium 40692442
2025 METTL3 mediates m6A modification of HKDC1 mRNA in renal tubular epithelial cells; HKDC1 binds to ATPB and antagonizes the ubiquitinase MuRF1, leading to increased ATPB expression and NF-κB signaling pathway activation, promoting renal inflammation in lead nephropathy. METTL3 knockout; m6A quantification; Co-IP for HKDC1-ATPB interaction; ubiquitination assay showing MuRF1 antagonism; NF-κB reporter; AAV9-mediated METTL3 silencing in vivo International journal of biological sciences Medium 40520008
2025 HKDC1 silencing in hepatic stellate cells reduces glycolysis and decreases H3K18 lactylation of the ORMDL3 promoter, suppressing ORMDL3 expression and thereby inhibiting HSC activation and liver fibrosis. ChIP for H3K18 lactylation at ORMDL3 promoter; ECAR/OCR metabolic assays; siRNA knockdown; in vivo CCl4 liver fibrosis model with Hkdc1 silencing Biochimica et biophysica acta. Molecular basis of disease Medium 41418678
2025 HKDC1 interacts with ASS1 via its HKLS1 domain (ASS1 residues 310–412), inhibiting ubiquitin-mediated ASS1 degradation and stabilizing it; this enhances glutamine-derived acetyl-CoA production, which drives H3K acetylation at the ACSBG2 locus and promotes lipid biosynthesis and lenvatinib resistance in HCC. Co-IP with domain mapping; ubiquitination assay; histone acetylation ChIP; dual-luciferase reporter; RNA-seq; metabolic assays; xenograft model Journal of translational medicine Medium 41629949
2025 HKDC1 promotes ovarian cancer cell proliferation and immune escape by interacting with and stabilizing glucose-6-phosphatase catalytic subunits (G6PC/G6PC2), supporting lipid accumulation and PD-L1 upregulation. Co-IP for HKDC1-G6PC/G6PC2 interaction; G6PC/G6PC2 stability assay; lipid metabolite quantification; PD-L1 and T cell function assays; in vivo ID8 mouse model Communications biology Medium 40234623
2025 ZMAT3 inhibits HKDC1 transcription by suppressing JUN transcription factor binding to the HKDC1 locus; ZMAT3 depletion enhances JUN binding and HKDC1 expression, increasing mitochondrial respiration that is rescued by simultaneous HKDC1 depletion. Quantitative proteomics; ChIP for JUN binding; ZMAT3 and JUN siRNA knockdown; mitochondrial respiration assay (Seahorse); genetic epistasis (double depletion rescue) bioRxivpreprint Medium bio_10.1101_2025.05.12.653341
2024 Epithelial HKDC1 deletion in intestinal cells reduces proliferation, impairs mitochondrial respiration, and protects from intestinal carcinogenesis in ApcMin/+ mice; immunoprecipitation and mass spectrometry reveal HKDC1 interacts with multiple mitochondria-related proteins. Conditional intestinal epithelial HKDC1 knockout (ApcMin/+ mouse); organoid culture; mitochondrial respiration assay; immunoprecipitation/mass spectrometry; xenograft model bioRxivpreprint Medium bio_10.1101_2024.11.15.623798
2024 HKDC1 promotes autophagy in pancreatic adenocarcinoma by directly interacting with PARP1 and enhancing PARP1's own poly(ADP-ribosyl)ation (PARylation) activity. Co-IP for HKDC1-PARP1 interaction; PARylation activity assay; LC3B autophagy marker Western blot; TEM for autophagic vesicles; HKDC1 knockdown/overexpression; in vivo xenograft Cellular signalling Medium 39424110
2025 Menin interacts with YBX1 and facilitates YBX1 nuclear translocation to enhance HKDC1 transcription; this Menin-YBX1-HKDC1 axis drives glycolysis in pancreatic ductal adenocarcinoma. Co-IP for Menin-YBX1 interaction; nuclear fractionation for YBX1 localization; HKDC1 promoter reporter; glycolysis assays; in vivo xenograft iScience Medium 40894906
2025 HKDC1 mRNA stability and expression in retinoblastoma are regulated by NSUN2-mediated m5C methylation, with YBX1 as the m5C reader, promoting HKDC1-dependent glycolysis and malignant progression. m5C methylation quantification; NSUN2 knockdown; YBX1 interaction assay; mRNA stability assay; glycolysis assays; in vivo tumor growth Journal of bioenergetics and biomembranes Low 40423890
2026 HCV infection selectively upregulates HKDC1 and enhances its cytoplasmic localization in hepatoma cells; HKDC1 depletion reduces total hexokinase activity, glycolytic flux (pyruvate/lactate production), and HCV replicon activity without compensatory upregulation of other hexokinases, establishing HKDC1 as the primary hexokinase linking HCV to glycolytic reprogramming. HKDC1 knockdown; total hexokinase activity assay; glycolytic flux measurement (pyruvate/lactate); HCV subgenomic replicon reporter assay; subcellular localization by immunofluorescence Viruses Medium 42043212
2026 USF1 transcriptionally activates HKDC1, which promotes SMS (spermine synthase)-mediated polyamine biosynthesis; this polyamine rewiring impairs CD8+ T cell metabolism and drives lenvatinib resistance in HCC. ChIP for USF1-HKDC1 promoter binding; luciferase reporter; RIP assay; polyamine metabolomics; scRNA-seq and flow cytometry for T cell profiling; hepatocyte-specific Hkdc1 deletion in immunocompetent HCC model Clinical and molecular hepatology Medium 41812646
2026 P2-HNF4α directly binds the HKDC1 gene enhancer and upregulates HKDC1 expression, orchestrating a glycolytic metabolic rewiring that promotes gastric cancer migration and metastasis. ChIP for HNF4α-HKDC1 enhancer binding; transcriptome and metabolome analysis; HNF4α knockdown/overexpression; in vitro migration and in vivo metastasis assays Cell death & disease Medium 41866549
2026 HNF1α binds the HKDC1 promoter to increase its transcriptional activity, thereby activating AKT/AMPK signaling and promoting colorectal cancer proliferation and metastasis; HKDC1 knockdown reverses the effects of HNF1α overexpression. Luciferase reporter assay for HKDC1 promoter; HNF1α ChIP (implied by transcriptional activity assay); AKT/AMPK Western blotting; HKDC1 knockdown epistasis; in vivo tumor model Gene Low 38986750
2025 HKDC1 interacts with RCOR1 (identified by Co-IP and mass spectrometry), and this interaction regulates the Wnt/β-catenin signaling pathway to promote CRC proliferation, migration, glycolysis, and EMT. Co-IP; mass spectrometry; immunofluorescence; HKDC1 knockdown/overexpression; Wnt/β-catenin pathway Western blotting; in vivo tumor model The Journal of biological chemistry Medium 40209953

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer. EBioMedicine 101 30005951
2015 Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nature communications 87 25648650
2016 HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use. Endocrinology 66 27459389
2019 Hepatic HKDC1 Expression Contributes to Liver Metabolism. Endocrinology 57 30517626
2021 Baicalin suppresses the progression of Type 2 diabetes-induced liver tumor through regulating METTL3/m6A/HKDC1 axis and downstream p-JAK2/STAT1/clevaged Capase3 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 56 34763315
2020 HKDC1 promotes the tumorigenesis and glycolysis in lung adenocarcinoma via regulating AMPK/mTOR signaling pathway. Cancer cell international 55 32943998
2019 PGC1β Regulates Breast Tumor Growth and Metastasis by SREBP1-Mediated HKDC1 Expression. Frontiers in oncology 48 31058090
2023 HKDC1 reprograms lipid metabolism to enhance gastric cancer metastasis and cisplatin resistance via forming a ribonucleoprotein complex. Cancer letters 45 37423558
2024 HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 41 38170752
2023 HKDC1 upregulation promotes glycolysis and disease progression, and confers chemoresistance onto gastric cancer. Cancer science 40 36519789
2024 HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression. Nature communications 39 38351096
2013 Inferring therapeutic targets from heterogeneous data: HKDC1 is a novel potential therapeutic target for cancer. Bioinformatics (Oxford, England) 36 24162464
2020 HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression. Leukemia 32 32203147
2024 Helicobacter pylori promotes gastric cancer progression by activating the TGF-β/Smad2/EMT pathway through HKDC1. Cellular and molecular life sciences : CMLS 31 39545942
2018 Studies on the Tissue Localization of HKDC1, a Putative Novel Fifth Hexokinase, in Humans. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 31 29401404
2022 The HOXC-AS2/miR-876-5p/HKDC1 axis regulates endometrial cancer progression in a high glucose-related tumor microenvironment. Cancer science 29 35485648
2023 Lactoferrin suppresses the progression of colon cancer under hyperglycemia by targeting WTAP/m6A/NT5DC3/HKDC1 axis. Journal of translational medicine 27 36855062
2018 Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response. PloS one 26 29420561
2016 Hexokinase Domain Containing 1 (HKDC1) Gene Variants and their Association with Gestational Diabetes Mellitus in a South Indian Population. Annals of human genetics 25 27346736
2018 Whole-exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa. Human molecular genetics 20 30085091
2024 HKDC1 promotes liver cancer stemness under hypoxia through stabilizing β-catenin. Hepatology (Baltimore, Md.) 17 39250463
2023 Liver-specific overexpression of HKDC1 increases hepatocyte size and proliferative capacity. Scientific reports 11 37198225
2024 Hepatitis B virus X protein promotes tumor glycolysis by downregulating lncRNA OIP5-AS1/HKDC1 in HCC. Cellular signalling 10 38636768
2023 CircVMP1 promotes glycolysis and disease progression by upregulating HKDC1 in colorectal cancer. Environmental toxicology 10 38009649
2024 HKDC1 functions as a glucose sensor and promotes metabolic adaptation and cancer growth via interaction with PHB2. Cell death and differentiation 9 39375512
2023 HKDC1 Silencing Inhibits Proliferation and Glycolysis of Gastric Cancer Cells. Journal of oncology 9 37153834
2024 New insights into the treatment of polycystic ovary syndrome: HKDC1 promotes the growth of ovarian granulocyte cells by regulating mitochondrial function and glycolysis. Journal of molecular histology 8 38478190
2025 HKDC1 promotes ovarian cancer progression through boosting lipid metabolism and immune escape by stabilizing G6PC/G6PC2. Communications biology 7 40234623
2022 Enterocyte HKDC1 Modulates Intestinal Glucose Absorption in Male Mice Fed a High-fat Diet. Endocrinology 7 35435980
2025 METTL3 mediated m6A modification of HKDC1 promotes renal injury and inflammation in lead nephropathy. International journal of biological sciences 6 40520008
2025 Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3. Cell reports 5 39891906
2022 Type XXVIII Collagen Regulates Renal Interstitial Fibrosis and Epithelial-Mesenchymal Transition by SREBP1-Mediated HKDC1 Expression. Journal of the renin-angiotensin-aldosterone system : JRAAS 4 36518326
2024 HNF1ɑ promotes colorectal cancer progression via HKDC1-mediated activation of AKT/AMPK signaling pathway. Gene 3 38986750
2025 HKDC1 promotes colorectal cancer progression by regulating RCOR1 expression to activate the Wnt/β-catenin pathway, enhancing proliferation, migration, and epithelial-mesenchymal transition. The Journal of biological chemistry 2 40209953
2025 NSUN2 contributes to the RB malignant progression and Glycolysis by mediating the m5C methylation modification of HKDC1. Journal of bioenergetics and biomembranes 2 40423890
2025 LPS mediates cuproptosis and inflammation in THP-1 macrophages through HKDC1. Acta biochimica et biophysica Sinica 2 40692442
2025 HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis. Biochimica et biophysica acta. Molecular basis of disease 2 41418678
2025 Hepatic HKDC1 deletion alleviates western diet-induced MASH in mice. Biochimica et biophysica acta. Molecular basis of disease 1 40020530
2025 HKDC1 in Cancer: Mechanisms, Clinical Applications, and Future. Journal of Cancer 1 41049000
2025 The regulatory and synergistic effects of FBP2 and HKDC1 on glucose metabolism and malignant progression in gastric cancer. Cell death & disease 1 41102152
2024 Mitochondrial HKDC1 suppresses oxidative stress and apoptosis by regulating mitochondrial function in goose fatty liver. International journal of biological macromolecules 1 39491705
2026 The HKDC1-ASS1-ACSBG2 axis reprograms lipid metabolism to drive therapeutic resistance in hepatocellular carcinoma. Journal of translational medicine 0 41629949
2026 The oncogenic role of U2AF2/HKDC1 cascade in colorectal cancer by promoting cancer cell glycolysis and malignant phenotypes. Mutation research 0 41671784
2026 Silencing of the Metabolic Gene HKDC1 Is Associated With Aging and Neurodegeneration in Mice and Humans. Aging cell 0 41736382
2026 HKDC1-Mediated Polyamine Rewiring Drives Lenvatinib Resistance and Immune Escape in Hepatocellular Carcinoma. Clinical and molecular hepatology 0 41812646
2026 HNF4α-HKDC1 axis orchestrates a metabolic rewiring to promote migration and metastasis in advanced gastric cancer. Cell death & disease 0 41866549
2026 Epigenetic reprogramming of hexokinase domain containing 1 (HKDC1) promotes proliferation in colorectal cancer. American journal of cancer research 0 42004071
2026 Hepatitis C Virus (HCV)-Mediated Activation of Hexokinase Domain-Containing Protein 1 (HKDC1) Promotes Hexokinase Activity and Metabolic Reprogramming. Viruses 0 42043212
2025 Hepatic HKDC1 Deletion Alleviates Western Diet-Induced MASH in Mice. bioRxiv : the preprint server for biology 0 39651120
2025 Menin regulates YBX1 nucleus translocation to boost the HKDC1 transcription and affects pancreatic cancer glycolysis. iScience 0 40894906
2024 HKDC1 promotes autophagy and proliferation in pancreatic adenocarcinoma through interaction with PARP1 and poly(ADP-ribosyl)ation. Cellular signalling 0 39424110
2023 Proteomics identifies the developmental regulation of HKDC1 in liver of pigs and mice. American journal of physiology. Regulatory, integrative and comparative physiology 0 37545422

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