{"gene":"HKDC1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2015,"finding":"Purified HKDC1 protein has hexokinase activity in vitro; reducing or increasing HKDC1 expression correspondingly reduces or increases hexokinase activity in multiple cellular models.","method":"In vitro hexokinase activity assay with purified protein; cellular knockdown/overexpression with activity measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with purified protein plus cellular gain/loss-of-function, two orthogonal methods in one study","pmids":["25648650"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Heterozygous knockout mouse model; glucose tolerance tests; hepatic glycogen and peripheral glucose uptake measurements","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO mouse model with defined metabolic phenotype, multiple physiological readouts","pmids":["27459389"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Subcellular fractionation/localization; mitochondrial respiration assays (Seahorse); in vivo hepatic overexpression via adenoviral vector","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment tied to functional consequence, multiple orthogonal metabolic assays, in vitro and in vivo","pmids":["30517626"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Immunofluorescence/subcellular localization; Co-IP/pulldown for VDAC1 interaction; luciferase reporter assay and ChIP for PGC1β/SREBP1 transcriptional regulation; siRNA knockdown","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding (Co-IP) and ChIP/luciferase for transcriptional mechanism; single lab with multiple orthogonal methods","pmids":["31058090"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Peptide competition assay; mitochondrial function assays (ROS, membrane potential); EBV replication assay; xenograft mouse model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide-based functional disruption of HKDC1-VDAC1 interaction with multiple downstream readouts; single lab","pmids":["32203147"],"is_preprint":false},{"year":2020,"finding":"HKDC1 promotes glycolysis and tumor growth in lung adenocarcinoma by regulating the AMPK/mTOR signaling pathway.","method":"siRNA knockdown and overexpression; Western blotting for AMPK/mTOR pathway components; glycolysis assays; in vivo xenograft","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement inferred from phosphorylation western blots without direct mechanistic reconstitution","pmids":["32943998"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SELECT PCR for m6A site identification; m6A quantification by MS; siRNA knockdown of METTL3; cell and in vivo tumor models","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific m6A site identified by SELECT PCR with functional validation by METTL3 knockdown; single lab","pmids":["34763315"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Conditional intestinal HKDC1 knockout mouse model; oral glucose tolerance test; intestinal glucose transporter expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined phenotype and transporter expression readout; single lab","pmids":["35435980"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP identifies HKDC1-RNA interaction, Co-IP for protein binding; multiple orthogonal methods in single lab","pmids":["37423558"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Stable hepatic HKDC1 overexpression mouse model; metabolic flux analysis; YAP pathway Western blotting; liver histology and proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function model with metabolic and signaling pathway characterization; single lab","pmids":["37198225"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Comprehensive transcriptome analysis; ChIP-qPCR; TFEB knockdown/overexpression; PINK1 stabilization assays; mitophagy flux assays; lysosomal damage assays; Co-IP for VDAC interaction; senescence assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-qPCR for direct transcriptional target, multiple orthogonal functional assays (mitophagy, lysosomal repair, senescence), protein interaction, and genetic epistasis in one rigorous study","pmids":["38170752"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for multiple interactions, defined mechanistic pathway, in vitro and in vivo validation, clinical correlation; replicated across multiple approaches","pmids":["38351096"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Domain mapping by deletion mutagenesis; ubiquitination assays; Co-IP for PHB2 interaction; SP1 reporter assay; genetic knockout; glucose starvation experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis identifies key residues, ubiquitination assay, Co-IP for substrate/binding partner; multiple orthogonal methods in one study","pmids":["39375512"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Nuclear fractionation; in vitro kinase assay; site-directed mutagenesis (Ser497); Co-IP for MLL1 complex; ChIP for H3K4me3; cell proliferation assays; tumor xenograft","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, ChIP for downstream histone mark, and functional cellular/in vivo validation; multiple orthogonal methods","pmids":["39891906"],"is_preprint":false},{"year":2024,"finding":"HKDC1 is induced by hypoxia and binds glycogen synthase kinase 3β (GSK3β) to stabilize β-catenin, enhancing stemness of HCC cells and promoting metastasis.","method":"Co-IP for HKDC1-GSK3β interaction; β-catenin stability assay; hypoxia induction experiments; HCC orthotopic and tail-vein injection mouse models; stemness marker analysis","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, β-catenin stabilization with in vivo validation; single lab, multiple methods","pmids":["39250463"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RT-qPCR; siRNA knockdown of ATF4; ISRIB pharmacological inhibition; luciferase reporter assay identifying ATF4-responsive element in KRT16 promoter (analogous approach for HKDC1)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptional regulation confirmed by RNAi epistasis and pharmacological inhibitor in multiple cell lines; no direct ChIP for HKDC1 promoter reported","pmids":["29420561"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Whole-exome sequencing; in vitro hexokinase activity assay with mutant protein; CRISPR/Cas9 Hkdc1 knockout mouse; ERG; immunostaining; Western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with patient-variant mutant protein, CRISPR KO mouse with multiple phenotypic readouts; two orthogonal approaches","pmids":["30085091"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR identifies direct promoter binding, Co-IP for protein interactions, in vivo functional validation; single lab","pmids":["40692442"],"is_preprint":false},{"year":2025,"finding":"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.","method":"METTL3 knockout; m6A quantification; Co-IP for HKDC1-ATPB interaction; ubiquitination assay showing MuRF1 antagonism; NF-κB reporter; AAV9-mediated METTL3 silencing in vivo","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay for mechanistic interactions, in vivo AAV silencing; single lab with multiple methods","pmids":["40520008"],"is_preprint":false},{"year":2025,"finding":"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.","method":"ChIP for H3K18 lactylation at ORMDL3 promoter; ECAR/OCR metabolic assays; siRNA knockdown; in vivo CCl4 liver fibrosis model with Hkdc1 silencing","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies histone lactylation at specific promoter, in vitro and in vivo validation; single lab","pmids":["41418678"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-IP with domain mapping; ubiquitination assay; histone acetylation ChIP; dual-luciferase reporter; RNA-seq; metabolic assays; xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay for mechanistic interaction; multiple orthogonal methods; single lab","pmids":["41629949"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes binding, in vitro and in vivo functional validation; single lab","pmids":["40234623"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Quantitative proteomics; ChIP for JUN binding; ZMAT3 and JUN siRNA knockdown; mitochondrial respiration assay (Seahorse); genetic epistasis (double depletion rescue)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies transcription factor binding, genetic epistasis with functional rescue, quantitative proteomics; preprint, single lab","pmids":["bio_10.1101_2025.05.12.653341"],"is_preprint":true},{"year":2024,"finding":"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.","method":"Conditional intestinal epithelial HKDC1 knockout (ApcMin/+ mouse); organoid culture; mitochondrial respiration assay; immunoprecipitation/mass spectrometry; xenograft model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with multiple in vivo models and unbiased interactome by IP-MS; preprint, single lab","pmids":["bio_10.1101_2024.11.15.623798"],"is_preprint":true},{"year":2024,"finding":"HKDC1 promotes autophagy in pancreatic adenocarcinoma by directly interacting with PARP1 and enhancing PARP1's own poly(ADP-ribosyl)ation (PARylation) activity.","method":"Co-IP for HKDC1-PARP1 interaction; PARylation activity assay; LC3B autophagy marker Western blot; TEM for autophagic vesicles; HKDC1 knockdown/overexpression; in vivo xenograft","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes interaction, PARylation activity assay is functional; single lab with multiple methods","pmids":["39424110"],"is_preprint":false},{"year":2025,"finding":"Menin interacts with YBX1 and facilitates YBX1 nuclear translocation to enhance HKDC1 transcription; this Menin-YBX1-HKDC1 axis drives glycolysis in pancreatic ductal adenocarcinoma.","method":"Co-IP for Menin-YBX1 interaction; nuclear fractionation for YBX1 localization; HKDC1 promoter reporter; glycolysis assays; in vivo xenograft","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and subcellular fractionation for mechanistic pathway; single lab with multiple methods","pmids":["40894906"],"is_preprint":false},{"year":2025,"finding":"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.","method":"m5C methylation quantification; NSUN2 knockdown; YBX1 interaction assay; mRNA stability assay; glycolysis assays; in vivo tumor growth","journal":"Journal of bioenergetics and biomembranes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA methylation and stability assays; single lab, limited mechanistic detail in abstract","pmids":["40423890"],"is_preprint":false},{"year":2026,"finding":"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.","method":"HKDC1 knockdown; total hexokinase activity assay; glycolytic flux measurement (pyruvate/lactate); HCV subgenomic replicon reporter assay; subcellular localization by immunofluorescence","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay with KD, multiple functional readouts; single lab","pmids":["42043212"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for transcriptional regulation, multi-omics and in vivo genetic model; single lab","pmids":["41812646"],"is_preprint":false},{"year":2026,"finding":"P2-HNF4α directly binds the HKDC1 gene enhancer and upregulates HKDC1 expression, orchestrating a glycolytic metabolic rewiring that promotes gastric cancer migration and metastasis.","method":"ChIP for HNF4α-HKDC1 enhancer binding; transcriptome and metabolome analysis; HNF4α knockdown/overexpression; in vitro migration and in vivo metastasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies direct enhancer binding, multi-omic functional validation; single lab","pmids":["41866549"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Luciferase reporter assay for HKDC1 promoter; HNF1α ChIP (implied by transcriptional activity assay); AKT/AMPK Western blotting; HKDC1 knockdown epistasis; in vivo tumor model","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional activity assay and signaling western blots; limited mechanistic depth in abstract; single lab","pmids":["38986750"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-IP; mass spectrometry; immunofluorescence; HKDC1 knockdown/overexpression; Wnt/β-catenin pathway Western blotting; in vivo tumor model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and MS identify binding partner, functional pathway validated by KD/OE; single lab","pmids":["40209953"],"is_preprint":false}],"current_model":"HKDC1 is a fifth hexokinase with confirmed in vitro glucose-phosphorylating activity that localizes primarily to the mitochondrial outer membrane where it interacts with VDACs to regulate mitochondrial permeability, mitophagy (via PINK1 stabilization), and mitochondria-lysosome contact; it is transcriptionally controlled by TFEB, ATF4, USF1, HNF4α, HNF1α, and SREBP1/PGC1β, and post-transcriptionally regulated by METTL3-mediated m6A and NSUN2-mediated m5C modifications; beyond glycolysis, HKDC1 also functions as a nuclear protein kinase (phosphorylating RBBP5-Ser497 to drive H3K4me3), a glucose sensor (with Ser896 regulating Lys620 ubiquitination-dependent stability), an RNA-binding protein that stabilizes PRKDC mRNA via G3BP1, a STAT1 scaffold that couples cytoskeletal ACTA2 to IFNγ receptor signaling to promote PD-L1 expression, and a stabilizer of ASS1 and G6PC/G6PC2 proteins to reprogram lipid metabolism; collectively these canonical and noncanonical activities promote glycolysis, mitochondrial homeostasis, immune evasion, and tumor progression across multiple tissue contexts."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2015,"claim":"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","pmids":["25648650"],"confidence":"High","gaps":["Kinetic parameters versus other hexokinases not defined","Physiological substrate range beyond glucose untested"]},{"year":2016,"claim":"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","pmids":["27459389"],"confidence":"High","gaps":["Tissue origin of the phenotype not resolved","Homozygous null consequences not addressed in this study"]},{"year":2018,"claim":"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","pmids":["29420561","30085091"],"confidence":"High","gaps":["No direct ChIP confirming ATF4 occupancy at the HKDC1 promoter","Mechanism connecting reduced hexokinase activity to rhodopsin mislocalization unresolved"]},{"year":2019,"claim":"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","pmids":["30517626","31058090"],"confidence":"Medium","gaps":["Stoichiometry and direct versus indirect VDAC1 binding not resolved","Reconciliation between low glucose-phosphorylating ability and metabolic effects incomplete"]},{"year":2020,"claim":"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","pmids":["32203147"],"confidence":"Medium","gaps":["Peptide specificity for HKDC1 versus off-target effects not fully excluded","Structural detail of the C-terminal/VDAC interface absent"]},{"year":2023,"claim":"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","pmids":["37423558"],"confidence":"Medium","gaps":["RNA-binding domain not mapped","Breadth of the HKDC1 RNA interactome beyond PRKDC undefined"]},{"year":2024,"claim":"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","pmids":["38170752"],"confidence":"High","gaps":["Molecular mechanism by which HKDC1 stabilizes PINK1 not defined","How a single protein coordinates contact-site maintenance unresolved"]},{"year":2024,"claim":"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","pmids":["39891906"],"confidence":"High","gaps":["Kinase active-site architecture and ATP-binding determinants not characterized","Full nuclear substrate set beyond RBBP5 unknown"]},{"year":2024,"claim":"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","pmids":["39375512"],"confidence":"High","gaps":["Identity of the kinase/ligase acting on Ser896/Lys620 not established","Direct glucose-binding by the sensing domain not biochemically demonstrated"]},{"year":2024,"claim":"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","pmids":["38351096"],"confidence":"High","gaps":["Whether scaffolding requires HKDC1 catalytic activity untested","Generality of the STAT1-ACTA2 axis across tissues unconfirmed"]},{"year":2024,"claim":"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","pmids":["39424110","39250463"],"confidence":"Medium","gaps":["Direct versus indirect nature of these interactions not fully resolved","Whether these binding modes are mutually exclusive or context-restricted unknown"]},{"year":2025,"claim":"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","pmids":["41629949","40234623"],"confidence":"Medium","gaps":["Whether HKDC1 directly blocks ubiquitin transfer or competes for substrate sites unresolved","Overlap of stabilized substrates with its kinase/RNA functions not integrated"]},{"year":2025,"claim":"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","pmids":["35435980","34763315","40520008","41866549","38986750","41812646","40894906","40423890"],"confidence":"Medium","gaps":["Hierarchy among the many transcription factors in any single cell type unclear","Direct ChIP missing for some inferred promoter interactions"]},{"year":null,"claim":"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.","evidence":"No structural or domain-allocation study reconciling the catalytic, kinase, RNA-binding, and scaffolding activities within one polypeptide","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,3,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,27]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,14]}],"complexes":[],"partners":["VDAC1","STAT1","ACTA2","PHB2","G3BP1","ASS1","PARP1","GSK3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2TB90","full_name":"Hexokinase HKDC1","aliases":["Hexokinase domain-containing protein 1"],"length_aa":917,"mass_kda":102.5,"function":"Catalyzes the phosphorylation of hexose to hexose 6-phosphate, although at very low level compared to other hexokinases (PubMed:30517626). Has low glucose phosphorylating activity compared to other hexokinases (PubMed:30517626). Involved in glucose homeostasis and hepatic lipid accumulation. Required to maintain whole-body glucose homeostasis during pregnancy; however additional evidences are required to confirm this role (By similarity)","subcellular_location":"Cytoplasm; Mitochondrion membrane; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/Q2TB90/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HKDC1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HKDC1","total_profiled":1310},"omim":[{"mim_id":"619614","title":"RETINITIS PIGMENTOSA 92; RP92","url":"https://www.omim.org/entry/619614"},{"mim_id":"617221","title":"HEXOKINASE DOMAIN-CONTAINING PROTEIN 1; HKDC1","url":"https://www.omim.org/entry/617221"},{"mim_id":"268000","title":"RETINITIS PIGMENTOSA; RP","url":"https://www.omim.org/entry/268000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":50.4},{"tissue":"retina","ntpm":43.4}],"url":"https://www.proteinatlas.org/search/HKDC1"},"hgnc":{"alias_symbol":["FLJ37767","FLJ22761"],"prev_symbol":[]},"alphafold":{"accession":"Q2TB90","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TB90","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TB90-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TB90-F1-predicted_aligned_error_v6.png","plddt_mean":93.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HKDC1","jax_strain_url":"https://www.jax.org/strain/search?query=HKDC1"},"sequence":{"accession":"Q2TB90","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2TB90.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2TB90/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TB90"}},"corpus_meta":[{"pmid":"30005951","id":"PMC_30005951","title":"The Circadian Clock Regulates Metabolic Phenotype Rewiring Via 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Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37545422","citation_count":0,"is_preprint":false},{"pmid":"39651120","id":"PMC_39651120","title":"Hepatic HKDC1 Deletion Alleviates Western Diet-Induced MASH in Mice.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39651120","citation_count":0,"is_preprint":false},{"pmid":"40894906","id":"PMC_40894906","title":"Menin regulates YBX1 nucleus translocation to boost the HKDC1 transcription and affects pancreatic cancer glycolysis.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40894906","citation_count":0,"is_preprint":false},{"pmid":"42043212","id":"PMC_42043212","title":"Hepatitis C Virus (HCV)-Mediated Activation of Hexokinase Domain-Containing Protein 1 (HKDC1) Promotes Hexokinase Activity and Metabolic Reprogramming.","date":"2026","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/42043212","citation_count":0,"is_preprint":false},{"pmid":"42004071","id":"PMC_42004071","title":"Epigenetic reprogramming of hexokinase domain containing 1 (HKDC1) promotes proliferation in colorectal cancer.","date":"2026","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/42004071","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.12.653341","title":"p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.12.653341","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.15.623798","title":"Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis in mice","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.15.623798","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29848,"output_tokens":8025,"usd":0.104959,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17631,"output_tokens":5075,"usd":0.107515,"stage2_stop_reason":"end_turn"},"total_usd":0.212474,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Purified HKDC1 protein has hexokinase activity in vitro; reducing or increasing HKDC1 expression correspondingly reduces or increases hexokinase activity in multiple cellular models.\",\n      \"method\": \"In vitro hexokinase activity assay with purified protein; cellular knockdown/overexpression with activity measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with purified protein plus cellular gain/loss-of-function, two orthogonal methods in one study\",\n      \"pmids\": [\"25648650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Heterozygous knockout mouse model; glucose tolerance tests; hepatic glycogen and peripheral glucose uptake measurements\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse model with defined metabolic phenotype, multiple physiological readouts\",\n      \"pmids\": [\"27459389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation/localization; mitochondrial respiration assays (Seahorse); in vivo hepatic overexpression via adenoviral vector\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment tied to functional consequence, multiple orthogonal metabolic assays, in vitro and in vivo\",\n      \"pmids\": [\"30517626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence/subcellular localization; Co-IP/pulldown for VDAC1 interaction; luciferase reporter assay and ChIP for PGC1β/SREBP1 transcriptional regulation; siRNA knockdown\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding (Co-IP) and ChIP/luciferase for transcriptional mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31058090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Peptide competition assay; mitochondrial function assays (ROS, membrane potential); EBV replication assay; xenograft mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide-based functional disruption of HKDC1-VDAC1 interaction with multiple downstream readouts; single lab\",\n      \"pmids\": [\"32203147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HKDC1 promotes glycolysis and tumor growth in lung adenocarcinoma by regulating the AMPK/mTOR signaling pathway.\",\n      \"method\": \"siRNA knockdown and overexpression; Western blotting for AMPK/mTOR pathway components; glycolysis assays; in vivo xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement inferred from phosphorylation western blots without direct mechanistic reconstitution\",\n      \"pmids\": [\"32943998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SELECT PCR for m6A site identification; m6A quantification by MS; siRNA knockdown of METTL3; cell and in vivo tumor models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific m6A site identified by SELECT PCR with functional validation by METTL3 knockdown; single lab\",\n      \"pmids\": [\"34763315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional intestinal HKDC1 knockout mouse model; oral glucose tolerance test; intestinal glucose transporter expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined phenotype and transporter expression readout; single lab\",\n      \"pmids\": [\"35435980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP identifies HKDC1-RNA interaction, Co-IP for protein binding; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"37423558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Stable hepatic HKDC1 overexpression mouse model; metabolic flux analysis; YAP pathway Western blotting; liver histology and proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function model with metabolic and signaling pathway characterization; single lab\",\n      \"pmids\": [\"37198225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Comprehensive transcriptome analysis; ChIP-qPCR; TFEB knockdown/overexpression; PINK1 stabilization assays; mitophagy flux assays; lysosomal damage assays; Co-IP for VDAC interaction; senescence assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-qPCR for direct transcriptional target, multiple orthogonal functional assays (mitophagy, lysosomal repair, senescence), protein interaction, and genetic epistasis in one rigorous study\",\n      \"pmids\": [\"38170752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for multiple interactions, defined mechanistic pathway, in vitro and in vivo validation, clinical correlation; replicated across multiple approaches\",\n      \"pmids\": [\"38351096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Domain mapping by deletion mutagenesis; ubiquitination assays; Co-IP for PHB2 interaction; SP1 reporter assay; genetic knockout; glucose starvation experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis identifies key residues, ubiquitination assay, Co-IP for substrate/binding partner; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39375512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclear fractionation; in vitro kinase assay; site-directed mutagenesis (Ser497); Co-IP for MLL1 complex; ChIP for H3K4me3; cell proliferation assays; tumor xenograft\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, ChIP for downstream histone mark, and functional cellular/in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"39891906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HKDC1 is induced by hypoxia and binds glycogen synthase kinase 3β (GSK3β) to stabilize β-catenin, enhancing stemness of HCC cells and promoting metastasis.\",\n      \"method\": \"Co-IP for HKDC1-GSK3β interaction; β-catenin stability assay; hypoxia induction experiments; HCC orthotopic and tail-vein injection mouse models; stemness marker analysis\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, β-catenin stabilization with in vivo validation; single lab, multiple methods\",\n      \"pmids\": [\"39250463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RT-qPCR; siRNA knockdown of ATF4; ISRIB pharmacological inhibition; luciferase reporter assay identifying ATF4-responsive element in KRT16 promoter (analogous approach for HKDC1)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptional regulation confirmed by RNAi epistasis and pharmacological inhibitor in multiple cell lines; no direct ChIP for HKDC1 promoter reported\",\n      \"pmids\": [\"29420561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing; in vitro hexokinase activity assay with mutant protein; CRISPR/Cas9 Hkdc1 knockout mouse; ERG; immunostaining; Western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with patient-variant mutant protein, CRISPR KO mouse with multiple phenotypic readouts; two orthogonal approaches\",\n      \"pmids\": [\"30085091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR identifies direct promoter binding, Co-IP for protein interactions, in vivo functional validation; single lab\",\n      \"pmids\": [\"40692442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"METTL3 knockout; m6A quantification; Co-IP for HKDC1-ATPB interaction; ubiquitination assay showing MuRF1 antagonism; NF-κB reporter; AAV9-mediated METTL3 silencing in vivo\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay for mechanistic interactions, in vivo AAV silencing; single lab with multiple methods\",\n      \"pmids\": [\"40520008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP for H3K18 lactylation at ORMDL3 promoter; ECAR/OCR metabolic assays; siRNA knockdown; in vivo CCl4 liver fibrosis model with Hkdc1 silencing\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies histone lactylation at specific promoter, in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"41418678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP with domain mapping; ubiquitination assay; histone acetylation ChIP; dual-luciferase reporter; RNA-seq; metabolic assays; xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and ubiquitination assay for mechanistic interaction; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"41629949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes binding, in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"40234623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative proteomics; ChIP for JUN binding; ZMAT3 and JUN siRNA knockdown; mitochondrial respiration assay (Seahorse); genetic epistasis (double depletion rescue)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies transcription factor binding, genetic epistasis with functional rescue, quantitative proteomics; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.12.653341\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional intestinal epithelial HKDC1 knockout (ApcMin/+ mouse); organoid culture; mitochondrial respiration assay; immunoprecipitation/mass spectrometry; xenograft model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with multiple in vivo models and unbiased interactome by IP-MS; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.11.15.623798\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HKDC1 promotes autophagy in pancreatic adenocarcinoma by directly interacting with PARP1 and enhancing PARP1's own poly(ADP-ribosyl)ation (PARylation) activity.\",\n      \"method\": \"Co-IP for HKDC1-PARP1 interaction; PARylation activity assay; LC3B autophagy marker Western blot; TEM for autophagic vesicles; HKDC1 knockdown/overexpression; in vivo xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes interaction, PARylation activity assay is functional; single lab with multiple methods\",\n      \"pmids\": [\"39424110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Menin interacts with YBX1 and facilitates YBX1 nuclear translocation to enhance HKDC1 transcription; this Menin-YBX1-HKDC1 axis drives glycolysis in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-IP for Menin-YBX1 interaction; nuclear fractionation for YBX1 localization; HKDC1 promoter reporter; glycolysis assays; in vivo xenograft\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and subcellular fractionation for mechanistic pathway; single lab with multiple methods\",\n      \"pmids\": [\"40894906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"m5C methylation quantification; NSUN2 knockdown; YBX1 interaction assay; mRNA stability assay; glycolysis assays; in vivo tumor growth\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA methylation and stability assays; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40423890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"HKDC1 knockdown; total hexokinase activity assay; glycolytic flux measurement (pyruvate/lactate); HCV subgenomic replicon reporter assay; subcellular localization by immunofluorescence\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay with KD, multiple functional readouts; single lab\",\n      \"pmids\": [\"42043212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for transcriptional regulation, multi-omics and in vivo genetic model; single lab\",\n      \"pmids\": [\"41812646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"P2-HNF4α directly binds the HKDC1 gene enhancer and upregulates HKDC1 expression, orchestrating a glycolytic metabolic rewiring that promotes gastric cancer migration and metastasis.\",\n      \"method\": \"ChIP for HNF4α-HKDC1 enhancer binding; transcriptome and metabolome analysis; HNF4α knockdown/overexpression; in vitro migration and in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies direct enhancer binding, multi-omic functional validation; single lab\",\n      \"pmids\": [\"41866549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay for HKDC1 promoter; HNF1α ChIP (implied by transcriptional activity assay); AKT/AMPK Western blotting; HKDC1 knockdown epistasis; in vivo tumor model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional activity assay and signaling western blots; limited mechanistic depth in abstract; single lab\",\n      \"pmids\": [\"38986750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP; mass spectrometry; immunofluorescence; HKDC1 knockdown/overexpression; Wnt/β-catenin pathway Western blotting; in vivo tumor model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and MS identify binding partner, functional pathway validated by KD/OE; single lab\",\n      \"pmids\": [\"40209953\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HKDC1 is a fifth hexokinase with confirmed in vitro glucose-phosphorylating activity that localizes primarily to the mitochondrial outer membrane where it interacts with VDACs to regulate mitochondrial permeability, mitophagy (via PINK1 stabilization), and mitochondria-lysosome contact; it is transcriptionally controlled by TFEB, ATF4, USF1, HNF4α, HNF1α, and SREBP1/PGC1β, and post-transcriptionally regulated by METTL3-mediated m6A and NSUN2-mediated m5C modifications; beyond glycolysis, HKDC1 also functions as a nuclear protein kinase (phosphorylating RBBP5-Ser497 to drive H3K4me3), a glucose sensor (with Ser896 regulating Lys620 ubiquitination-dependent stability), an RNA-binding protein that stabilizes PRKDC mRNA via G3BP1, a STAT1 scaffold that couples cytoskeletal ACTA2 to IFNγ receptor signaling to promote PD-L1 expression, and a stabilizer of ASS1 and G6PC/G6PC2 proteins to reprogram lipid metabolism; collectively these canonical and noncanonical activities promote glycolysis, mitochondrial homeostasis, immune evasion, and tumor progression across multiple tissue contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#2, #3, #4]. 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 [#10]. 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 [#13], and it operates as a glucose sensor whose stability is governed by a Ser896-containing domain controlling Lys620 ubiquitination [#12]. 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 [#11], sequestering PHB2 to de-repress SP1 [#12], stabilizing ASS1 and G6PC/G6PC2 to reprogram lipid metabolism [#20, #21], and acting as an RNA-binding protein that cooperates with G3BP1 to stabilize PRKDC mRNA [#8]. HKDC1 expression is transcriptionally controlled by stress- and tissue-specific factors including ATF4, TFEB, HNF4\\u03b1, HNF1\\u03b1, USF1, and SREBP1/PGC1\\u03b2 [#15, #10, #29, #30, #28, #3], and post-transcriptionally by METTL3-mediated m6A modification [#6]. A patient hexokinase-deficient variant (p.T58M) and Hkdc1-null mice with photoreceptor dysfunction establish HKDC1 as required for retinal rod function [#16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that HKDC1 is a bona fide enzyme rather than a pseudogene-like fifth hexokinase, answering whether the protein has catalytic glucose-phosphorylating activity.\",\n      \"evidence\": \"In vitro hexokinase assay with purified protein plus cellular knockdown/overexpression\",\n      \"pmids\": [\"25648650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic parameters versus other hexokinases not defined\", \"Physiological substrate range beyond glucose untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Heterozygous knockout mouse with glucose tolerance tests and tissue glucose-uptake measurements\",\n      \"pmids\": [\"27459389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue origin of the phenotype not resolved\", \"Homozygous null consequences not addressed in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked HKDC1 expression to stress signaling and to a Mendelian retinal phenotype, establishing both an inducible regulatory input and a tissue-essential requirement.\",\n      \"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\",\n      \"pmids\": [\"29420561\", \"30085091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct ChIP confirming ATF4 occupancy at the HKDC1 promoter\", \"Mechanism connecting reduced hexokinase activity to rhodopsin mislocalization unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, Seahorse respirometry, Co-IP for VDAC1, and ChIP/luciferase for PGC1\\u03b2/SREBP1 transcriptional control\",\n      \"pmids\": [\"30517626\", \"31058090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct versus indirect VDAC1 binding not resolved\", \"Reconciliation between low glucose-phosphorylating ability and metabolic effects incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Peptide competition (Tf-D-HKC8) with mitochondrial ROS/membrane-potential readouts and xenograft in NK/T-cell lymphoma\",\n      \"pmids\": [\"32203147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide specificity for HKDC1 versus off-target effects not fully excluded\", \"Structural detail of the C-terminal/VDAC interface absent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an RNA-binding function for HKDC1, expanding its repertoire beyond enzymatic and mitochondrial roles by showing it stabilizes target mRNAs with G3BP1.\",\n      \"evidence\": \"RIP to identify HKDC1-bound PRKDC mRNA, Co-IP for G3BP1, and mRNA stability assays in gastric cancer\",\n      \"pmids\": [\"37423558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding domain not mapped\", \"Breadth of the HKDC1 RNA interactome beyond PRKDC undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established glycolysis-independent mitochondrial quality-control functions, showing HKDC1 is a TFEB-driven effector required for mitophagy, lysosomal repair, and mitochondria-lysosome contact.\",\n      \"evidence\": \"ChIP-qPCR for TFEB, PINK1-stabilization and mitophagy flux assays, Co-IP for VDACs, and senescence assays with genetic epistasis\",\n      \"pmids\": [\"38170752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which HKDC1 stabilizes PINK1 not defined\", \"How a single protein coordinates contact-site maintenance unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Nuclear fractionation, in vitro kinase assay with Ser497 mutagenesis, MLL1 Co-IP, and H3K4me3 ChIP in HCC\",\n      \"pmids\": [\"39891906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase active-site architecture and ATP-binding determinants not characterized\", \"Full nuclear substrate set beyond RBBP5 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Deletion mutagenesis (aa 751\\u2013917, Ser896), ubiquitination assays at Lys620, Co-IP for PHB2, and SP1 reporter with glucose starvation\",\n      \"pmids\": [\"39375512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase/ligase acting on Ser896/Lys620 not established\", \"Direct glucose-binding by the sensing domain not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed HKDC1 drives tumor immune evasion through a cytoskeletal scaffolding mechanism, linking IFN\\u03b3 receptor signaling to PD-L1 induction.\",\n      \"evidence\": \"Reciprocal Co-IP for STAT1 and ACTA2, proximity ligation, IFNGR1 membrane assays, and in vivo anti-PD-1/PD-L1 combination models\",\n      \"pmids\": [\"38351096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffolding requires HKDC1 catalytic activity untested\", \"Generality of the STAT1-ACTA2 axis across tissues unconfirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended HKDC1's interactome to PARP1 and GSK3\\u03b2, linking it to autophagy and \\u03b2-catenin-driven stemness in distinct cancer contexts.\",\n      \"evidence\": \"Co-IP for PARP1 with PARylation activity assays in PDAC; Co-IP for GSK3\\u03b2 with \\u03b2-catenin stability and hypoxia induction in HCC\",\n      \"pmids\": [\"39424110\", \"39250463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of these interactions not fully resolved\", \"Whether these binding modes are mutually exclusive or context-restricted unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"41629949\", \"40234623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HKDC1 directly blocks ubiquitin transfer or competes for substrate sites unresolved\", \"Overlap of stabilized substrates with its kinase/RNA functions not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the transcriptional and post-transcriptional control network of HKDC1, identifying additional tissue- and stress-specific inducers and RNA-modification inputs.\",\n      \"evidence\": \"ChIP/luciferase for HNF4\\u03b1, HNF1\\u03b1, USF1, YY1, Menin-YBX1 axis, ZMAT3-JUN repression; m6A (METTL3) and m5C (NSUN2/YBX1) modification assays\",\n      \"pmids\": [\"35435980\", \"34763315\", \"40520008\", \"41866549\", \"38986750\", \"41812646\", \"40894906\", \"40423890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among the many transcription factors in any single cell type unclear\", \"Direct ChIP missing for some inferred promoter interactions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No structural or domain-allocation study reconciling the catalytic, kinase, RNA-binding, and scaffolding activities within one polypeptide\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VDAC1\", \"STAT1\", \"ACTA2\", \"PHB2\", \"G3BP1\", \"ASS1\", \"PARP1\", \"GSK3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}