{"gene":"HK1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"Mouse spermatogenic cell-specific HK1 (HK1-S) is encoded by alternative splicing from the single mHk1 gene using alternative exons; the resulting protein lacks the porin-binding domain (PBD) required for mitochondrial outer membrane binding and is localized to the fibrous sheath in the sperm tail rather than to mitochondria in the midpiece.","method":"Alternative exon identification by molecular cloning, immunolocalization by direct imaging/fractionation in mouse sperm","journal":"Molecular reproduction and development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (molecular cloning, alternative exon mapping, immunolocalization) in a focused study establishing both the transcriptional origin and subcellular localization with functional consequence","pmids":["9508088"],"is_preprint":false},{"year":2000,"finding":"A single human HK1 gene spanning at least 100 kb encodes multiple transcripts generated by alternative splicing of different 5' exons; testis-specific transcripts are produced by a separate upstream promoter and include a novel isoform (hHKI-td) with both a testis-specific 5' sequence and an additional unique sequence not present in somatic HK1.","method":"Cosmid library screening, genomic mapping, cDNA isolation and sequencing from human sperm","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct genomic and cDNA characterization with multiple orthogonal methods (cosmid mapping, direct sequencing, library screening) in a single dedicated study","pmids":["10978502"],"is_preprint":false},{"year":2001,"finding":"In the downeast anemia (dea) mouse model, a spontaneous early transposon (ETn) insertion in intron 4 of the Hk1 gene disrupts normal splicing, markedly decreases HK1 expression, and causes severe nonspherocytic hemolytic anemia due to hexokinase deficiency in erythroid tissues.","method":"Linkage analysis, Southern blotting, direct sequencing, hexokinase enzyme activity assay in mouse erythroid tissues","journal":"Blood cells, molecules & diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (linkage, Southern blot, sequencing, enzymatic activity) establishing both molecular defect and functional consequence in a dedicated model","pmids":["11783948"],"is_preprint":false},{"year":2012,"finding":"Mitochondrial hexokinase 1 (HKI) is a substrate of the Parkin E3 ubiquitin ligase; following dissipation of mitochondrial membrane potential, Parkin ubiquitylates HKI leading to its proteasomal degradation. Disease-relevant Parkin mutations hinder this ubiquitylation, and endogenous HKI is ubiquitylated upon membrane potential loss in cells expressing genuine Parkin.","method":"Substrate screen, co-immunoprecipitation, ubiquitylation assay in cells, Parkin mutant analysis, endogenous ubiquitylation confirmation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (substrate screen, Co-IP, functional ubiquitylation assay, disease mutant validation, endogenous confirmation) in a single dedicated mechanistic study","pmids":["23068103"],"is_preprint":false},{"year":2014,"finding":"A dominant HK1 missense mutation (p.Glu847Lys) causes autosomal dominant retinitis pigmentosa; the mutation is located outside the catalytic domains at a highly conserved position, and no systemic abnormalities in glycolysis were detected, suggesting the pathogenic effect is retina-specific and may not involve loss of enzymatic activity.","method":"Exome sequencing, linkage mapping, candidate gene screening, segregation analysis across five families, biochemical glycolysis assay","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping with functional biochemical assay (glycolysis normal), but mechanistic basis of retinal specificity not fully resolved; single lab","pmids":["25190649"],"is_preprint":false},{"year":2014,"finding":"The HK1 E847K missense mutation does not affect hexokinase enzymatic activity or protein stability, suggesting the mutation causes retinitis pigmentosa through an uncharacterized non-catalytic function or gain of function, not via loss of glycolytic enzyme activity.","method":"Biochemical enzyme activity assay, protein stability assessment in mutant vs. wild-type HK1","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical assays establishing a negative result (no loss of catalytic activity), single lab, mechanistic basis of pathogenicity remains unresolved","pmids":["25316723"],"is_preprint":false},{"year":2015,"finding":"mTORC1-induced upregulation of HK1-dependent glycolysis is required for NLRP3 inflammasome activation in macrophages; inhibition of Raptor/mTORC1 or HK1 suppresses both pro-IL-1β maturation and caspase-1 activation in response to LPS and ATP.","method":"Pharmacological inhibition (rapamycin, HK inhibitors), shRNA knockdown of HK1/Raptor, caspase-1 and IL-1β processing assays in macrophages","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic knockdown + pharmacological inhibition + downstream functional readouts) establishing pathway position of HK1 in NLRP3 inflammasome activation","pmids":["26119735"],"is_preprint":false},{"year":2022,"finding":"TGF-β stimulates palmitoylation of HK1 in hepatic stellate cells (HSCs), facilitating its secretion via large extracellular vesicles in a TSG101-dependent manner; the secreted HK1 is taken up by hepatocellular carcinoma (HCC) cells to accelerate glycolysis and HCC progression. The nuclear receptor Nur77 transcriptionally activates depalmitoylase ABHD17B to inhibit HK1 palmitoylation, and TGF-β-activated Akt phosphorylates and degrades Nur77 to repress this inhibitory axis.","method":"Co-IP, extracellular vesicle isolation and proteomic analysis, palmitoylation assay, TSG101 knockdown, Nur77/ABHD17B functional assays, Akt inhibition, xenograft models","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, vesicle fractionation, palmitoylation assays, genetic knockdown, in vivo xenografts) in a single rigorous study establishing a novel secretory mechanism for HK1","pmids":["36192599"],"is_preprint":false},{"year":2022,"finding":"Non-coding de novo variants in a 42-bp conserved cis-regulatory element in intron 2 of HK1 cause loss of repression of HK1 in pancreatic beta-cells (a 'disallowed gene' context), leading to inappropriate HK1 expression, insulin secretion during hypoglycemia, and congenital hyperinsulinism.","method":"Gene-agnostic non-coding region screening, epigenomic analysis of regulatory elements, functional demonstration of loss of beta-cell repression, identification of 14 de novo variants","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genomic screening, epigenomic regulatory element mapping, functional loss-of-repression assay) with replication across 14 independent de novo variants","pmids":["36333503"],"is_preprint":false},{"year":2016,"finding":"Simultaneous shRNA-mediated inactivation of HK1 and HK2 in colorectal cancer and melanoma cells leads to decreased cell viability and proliferation; HK2 inactivation alone induces compensatory upregulation of HK1, demonstrating functional redundancy between HK1 and HK2 in sustaining glycolysis in these cancers.","method":"shRNA lentiviral knockdown of HK1, HK2, and HK3 individually and in combination; cell viability and apoptosis assays","journal":"BMC genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with defined cellular phenotype, single lab, demonstrates functional redundancy and compensation between HK1 and HK2","pmids":["28105937"],"is_preprint":false},{"year":2024,"finding":"Oridonin forms a covalent bond with Cys-813 of HK1, located adjacent to the glucose-binding domain, suppressing HK1 enzymatic activity and reducing glycolysis in bladder cancer cells; this leads to apoptosis and inhibits lactate-induced PD-L1 expression.","method":"Human Proteome Microarray, streptavidin-agarose affinity assay, biolayer interferometry, mass spectrometry identifying Cys-813 adduct, cellular thermal shift assay, extracellular acidification rate measurement, xenograft models","journal":"Phytomedicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple rigorous biochemical methods (mass spectrometry adduct identification, CETSA, BLI binding, enzymatic assay) definitively identify covalent binding site and functional consequence, single lab","pmids":["38367425"],"is_preprint":false},{"year":2024,"finding":"PARP-1 activation during cerebral ischemia/reperfusion causes poly(ADP-ribosyl)ation (PARylation) of hexokinase-1, which inhibits HK1 enzymatic activity and contributes to energy metabolism collapse in neurons; PARP-1 inhibition restores hexokinase activity.","method":"Immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, 3D-modeling, hexokinase activity assay in MCAO/R mouse model","journal":"European journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, MS identification of PARylation, enzymatic activity assay, in vivo model) establishing PARylation as a PTM that inhibits HK1 activity","pmids":["38346469"],"is_preprint":false},{"year":2025,"finding":"FTO-mediated m6A demethylation of HK1 mRNA enhances the glycolytic pathway in osteoclasts, which stabilizes RANK protein via USP14 deubiquitinase activity, promoting osteoclastogenesis and alveolar bone resorption in apical periodontitis.","method":"m6A quantification, FTO knockdown/overexpression, HK1 manipulation, Co-IP for USP14/RANK interaction, glycolysis assays, BMDM-derived osteoclast models, rat AP model, pharmacological inhibition (Dac51, 2-DG)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (m6A assay, Co-IP, knockdown, in vivo model) but mechanistic link between HK1 m6A modification and RANK stabilization is indirect; single lab","pmids":["39934129"],"is_preprint":false},{"year":2023,"finding":"The RNA-binding protein hnRNP A1 directly binds to the 2605-2821 region of HK1 mRNA, stabilizing it; inhibition of hnRNP A1 downregulates HK1 mRNA and protein expression, impairs glycolysis in neurons, and overexpression of hnRNP A1 rescues Aβ-induced neuronal glycolytic dysfunction via the hnRNP A1/HK1/pyruvate pathway.","method":"RNA immunoprecipitation (RIP), CLIP-qPCR, hnRNP A1 inhibitor treatment, lentiviral hnRNP A1 overexpression, glycolysis assays in HT22 cells and AD mouse model","journal":"Frontiers in aging neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and CLIP-qPCR directly identify binding site on HK1 mRNA with functional rescue experiments; single lab","pmids":["37744386"],"is_preprint":false},{"year":2025,"finding":"NAT10-mediated N4-acetylcytosine (ac4C) modification of HK1 mRNA increases its stability and expression, thereby promoting glycolysis and retinoblastoma cell proliferation; NAT10 knockdown decreases ac4C modification and stability of HK1 mRNA, and HK1 overexpression reverses the glycolytic inhibition caused by NAT10 knockdown.","method":"Dot blot assay for ac4C levels, RNA immunoprecipitation, immunofluorescence, dual luciferase reporter, NAT10 knockdown, HK1 overexpression rescue, xenograft mouse model","journal":"Clinics (Sao Paulo, Brazil)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, reporter assay, rescue experiment, in vivo model) establishing ac4C as a PTM of HK1 mRNA that controls its stability; single lab","pmids":["40344913"],"is_preprint":false},{"year":2019,"finding":"HK1 and HK2 are functionally redundant for sustaining aerobic glycolysis and tumor growth; in HK1-expressing cancers, HK2 knockdown does not inhibit proliferation or tumor progression, but in HK1-negative (HK1-HK2+) cancers, HK2 knockdown inhibits proliferation, colony formation, and xenograft tumor progression.","method":"HK2 shRNA knockdown and CRISPR knockout in HK1+ and HK1- cancer cell lines; cell proliferation, colony formation, xenograft tumor assays, 18F-FDG PET/CT; Cancer Cell Line Encyclopedia expression analysis","journal":"Journal of nuclear medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown and knockout with multiple functional readouts (proliferation, colony formation, xenograft, metabolic imaging) establishing functional redundancy of HK1 and HK2 across multiple cancer lines","pmids":["29880505"],"is_preprint":false},{"year":2016,"finding":"Four novel pathogenic HK1 missense and splice-site mutations cause red blood cell hexokinase deficiency with severe hemolytic anemia; structural modeling and biochemical analysis confirmed pathogenicity, and splice-site mutation c.873-2A>G was confirmed to disrupt pre-mRNA processing at the protein level.","method":"Molecular genetic analysis, 3D structural modeling, biochemical enzyme activity assays, pre-mRNA processing analysis","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sequencing, structural analysis, enzyme assay, mRNA processing) characterizing loss-of-function variants; single lab","pmids":["27282571"],"is_preprint":false},{"year":2022,"finding":"KLF2 directly interacts with HK1 and reduces HK1-mediated hyperactivation of glycolysis; BDNF acting through the TrkB/KLF2 pathway downregulates HK1 expression, thereby suppressing HK1-induced glucose metabolism reprogramming and the endothelial-to-mesenchymal transition (EndMT) process in vascular endothelial cells.","method":"Co-immunoprecipitation (KLF2-HK1 interaction), HK1 knockdown, KLF2 silencing/overexpression, BDNF/TrkB pathway inhibition, glycolysis assays (ECAR, glucose uptake, lactate), EndMT markers in HUVECs","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction plus functional knockdown experiments; single lab, interaction not reciprocally confirmed with full controls","pmids":["35364229"],"is_preprint":false},{"year":2023,"finding":"The transcription factor ZBTB10 directly binds to the HK1 promoter and regulates its transcriptional activity; knockdown of ZBTB10 decreases HK1 expression and reduces glycolysis in laryngeal cancer cells, whereas ZBTB10 overexpression increases HK1 expression.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), ZBTB10 knockdown/overexpression, HK1 mRNA/protein quantification, glycolysis assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate promoter binding and transcriptional regulation; single lab","pmids":["37834257"],"is_preprint":false},{"year":2025,"finding":"CircST6GALNAC6 promotes PRKN (Parkin)-mediated ubiquitination and degradation of HK1 in bladder cancer cells by recruiting FUS to stabilize PRKN mRNA; overexpression of circST6GALNAC6 reduces HK1 protein levels, inhibits glycolysis and proliferation, and the effect is reversed by PRKN knockdown.","method":"RNA immunoprecipitation, co-immunoprecipitation, colony formation assay, glycolysis assays (glucose intake, lactate, ATP, ECAR), xenograft mouse model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and Co-IP identify molecular interactions with functional rescue and in vivo confirmation; single lab, indirect circuit","pmids":["39960214"],"is_preprint":false},{"year":2024,"finding":"KIAA1429 (an m6A writer) directly binds HK1 mRNA and, cooperating with the m6A reader HuR, enhances HK1 mRNA stability and upregulates HK1 expression to promote the Warburg effect in liver cancer; KIAA1429 depletion decreases HK1 expression and increases sorafenib sensitivity.","method":"RNA-seq and MeRIP-seq (m6A-seq), RIP assay, KIAA1429 knockdown, HK1 mRNA stability assay, glycolysis functional assays, in vivo xenograft","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq and RIP establish m6A modification and direct binding; functional effects on HK1 confirmed with knockdown and in vivo; single lab","pmids":["38996929"],"is_preprint":false}],"current_model":"HK1 (hexokinase 1) is a ubiquitously expressed enzyme catalyzing the first step of glycolysis (glucose → glucose-6-phosphate); it is tethered to the outer mitochondrial membrane via a porin-binding domain (absent in spermatogenic and testis-specific splice isoforms that localize instead to the sperm fibrous sheath), undergoes post-translational regulation by Parkin-mediated ubiquitylation (leading to proteasomal degradation upon mitochondrial depolarization), PARP-1-mediated PARylation (inhibiting its enzymatic activity), palmitoylation (promoting its secretion from hepatic stellate cells via large extracellular vesicles in a TSG101-dependent manner), and m6A/ac4C mRNA modifications that control its expression; its promoter is transcriptionally activated by ZBTB10, and its mRNA is stabilized by hnRNP A1 binding; upstream, mTORC1 upregulates HK1-dependent glycolysis to drive NLRP3 inflammasome activation in macrophages, and a cis-regulatory element in intron 2 normally silences HK1 in pancreatic beta-cells and liver (disallowed gene), with loss-of-repression variants causing congenital hyperinsulinism; loss-of-function HK1 mutations cause nonspherocytic hemolytic anemia, and dominant missense variants (p.E847K, outside catalytic domains) cause autosomal dominant retinitis pigmentosa without affecting catalytic activity, implicating a non-catalytic retina-specific function."},"narrative":{"mechanistic_narrative":"HK1 (hexokinase 1) catalyzes the committed first step of glycolysis (glucose → glucose-6-phosphate) and is the rate-limiting glycolytic enzyme whose activity sustains cell viability and proliferation, acting redundantly with HK2 such that loss of one is buffered by compensatory upregulation of the other [PMID:28105937, PMID:29880505]. A single gene generates multiple transcripts through alternative splicing of distinct 5' exons, including a testis-specific isoform (HK1-S/hHKI-td) driven by a separate upstream promoter that lacks the porin-binding domain required for mitochondrial outer-membrane association and instead localizes to the sperm fibrous sheath [PMID:9508088, PMID:10978502]. HK1 is subject to extensive post-translational and post-transcriptional control: Parkin (PRKN) ubiquitylates mitochondrial HK1 upon loss of membrane potential to target it for proteasomal degradation [PMID:23068103], PARP-1-mediated PARylation inhibits its catalytic activity during cerebral ischemia/reperfusion [PMID:38346469], and TGF-β-induced palmitoylation promotes its secretion from hepatic stellate cells via TSG101-dependent large extracellular vesicles, after which it is imported by hepatocellular carcinoma cells to fuel glycolysis [PMID:36192599]. At the mRNA level, HK1 transcript stability and expression are governed by hnRNP A1 binding [PMID:37744386], m6A and ac4C modifications [PMID:38996929, PMID:40344913], and promoter activation by the transcription factor ZBTB10 [PMID:37834257], while KLF2 directly binds HK1 to restrain glycolytic hyperactivation [PMID:35364229]. Upstream, mTORC1 drives HK1-dependent glycolysis required for NLRP3 inflammasome activation in macrophages [PMID:26119735]. Loss-of-function HK1 mutations cause red-cell hexokinase deficiency and nonspherocytic hemolytic anemia [PMID:11783948, PMID:27282571], non-coding variants in an intron 2 cis-regulatory element derepress HK1 in pancreatic beta-cells to cause congenital hyperinsulinism [PMID:36333503], and a dominant missense variant (p.E847K) located outside the catalytic domains causes autosomal dominant retinitis pigmentosa without altering enzymatic activity, implicating a non-catalytic retina-specific function [PMID:25190649, PMID:25316723].","teleology":[{"year":1998,"claim":"Established that the single HK1 gene produces a spermatogenic isoform whose alternative splicing removes the porin-binding domain, redirecting localization from mitochondria to the sperm fibrous sheath and decoupling HK1 isoform identity from its canonical subcellular targeting.","evidence":"Alternative exon mapping by molecular cloning and immunolocalization in mouse sperm","pmids":["9508088"],"confidence":"High","gaps":["Functional consequence of fibrous-sheath localization for sperm metabolism not defined","Human isoform behavior inferred from mouse"]},{"year":2000,"claim":"Showed the human HK1 locus uses a separate upstream promoter to generate testis-specific transcripts including a unique hHKI-td isoform, defining the genomic basis for tissue-restricted HK1 variants.","evidence":"Cosmid mapping, genomic mapping, and cDNA sequencing from human sperm","pmids":["10978502"],"confidence":"High","gaps":["Protein-level function of hHKI-td not characterized","Regulation of the alternative promoter unknown"]},{"year":2001,"claim":"Linked reduced HK1 expression to disease by showing a transposon insertion disrupting Hk1 splicing causes erythroid hexokinase deficiency and hemolytic anemia, establishing HK1 as essential for red-cell glycolysis.","evidence":"Linkage, Southern blot, sequencing, and enzyme activity assays in the dea mouse model","pmids":["11783948"],"confidence":"High","gaps":["Erythroid-specific transcript regulation not detailed","Translation to human variants pending"]},{"year":2014,"claim":"Identified a dominant non-catalytic disease mechanism: the p.E847K mutation outside catalytic domains causes retinitis pigmentosa without altering enzymatic activity or protein stability, implying a retina-specific function distinct from glycolysis.","evidence":"Exome sequencing, segregation across five families, and biochemical glycolysis/stability assays","pmids":["25190649","25316723"],"confidence":"Medium","gaps":["The non-catalytic retinal function remains uncharacterized","Gain-of-function versus dominant-negative mechanism unresolved","Single lab"]},{"year":2015,"claim":"Positioned HK1 within innate immune signaling by demonstrating mTORC1-driven HK1-dependent glycolysis is required for NLRP3 inflammasome activation, connecting metabolic flux to caspase-1/IL-1β processing.","evidence":"Pharmacologic inhibition and shRNA knockdown of HK1/Raptor with caspase-1/IL-1β readouts in macrophages","pmids":["26119735"],"confidence":"High","gaps":["Direct molecular link between HK1 metabolite output and NLRP3 assembly not defined","In vivo relevance not addressed here"]},{"year":2017,"claim":"Defined functional redundancy between HK1 and HK2 in cancer, showing dual inactivation reduces viability and that HK2 loss triggers compensatory HK1 upregulation, explaining glycolytic resilience in tumors.","evidence":"shRNA knockdown of HK1/HK2/HK3 individually and combined with viability/apoptosis assays in colorectal cancer and melanoma cells","pmids":["28105937"],"confidence":"Medium","gaps":["Mechanism of compensatory HK1 induction unknown","Single lab"]},{"year":2012,"claim":"Revealed regulated turnover of mitochondrial HK1 by identifying it as a Parkin substrate ubiquitylated upon mitochondrial depolarization for proteasomal degradation, linking HK1 stability to mitochondrial quality control.","evidence":"Substrate screen, Co-IP, ubiquitylation assay, Parkin mutant analysis, and endogenous confirmation in cells","pmids":["23068103"],"confidence":"High","gaps":["Ubiquitylation site mapping not reported","Physiological setting of HK1 degradation in vivo not defined"]},{"year":2019,"claim":"Extended HK1/HK2 redundancy to therapeutic logic, showing HK2 dependence emerges only in HK1-negative cancers, with HK1 status predicting response to HK2 targeting.","evidence":"HK2 knockdown/CRISPR knockout in HK1+ and HK1- lines with proliferation, xenograft, and 18F-FDG PET assays","pmids":["29880505"],"confidence":"High","gaps":["Determinants of HK1 expression status across tumors unclear","Does not address combined HK1/HK2 inhibition therapeutically"]},{"year":2022,"claim":"Uncovered a secretory, non-canonical role for HK1: TGF-β-induced palmitoylation enables TSG101-dependent vesicular secretion from hepatic stellate cells and paracrine glycolytic support of hepatocellular carcinoma, with the Nur77/ABHD17B axis controlling palmitoylation.","evidence":"Co-IP, EV proteomics, palmitoylation assays, TSG101/Nur77/ABHD17B perturbation, and xenografts","pmids":["36192599"],"confidence":"High","gaps":["Palmitoylation site(s) on HK1 not mapped","Mechanism of HK1 uptake by recipient cells undefined"]},{"year":2022,"claim":"Established a regulatory-element disease mechanism by showing de novo variants in an intron 2 cis-element derepress HK1 in pancreatic beta-cells, causing inappropriate insulin secretion and congenital hyperinsulinism.","evidence":"Gene-agnostic non-coding screening, epigenomic mapping, loss-of-repression assays, and 14 de novo variants","pmids":["36333503"],"confidence":"High","gaps":["Identity of the repressor binding the element not determined","Mechanism of beta-cell-specific silencing not fully resolved"]},{"year":2022,"claim":"Identified KLF2 as a direct HK1 interactor that restrains glycolytic hyperactivation, placing HK1 downstream of BDNF/TrkB/KLF2 signaling in endothelial-to-mesenchymal transition.","evidence":"Co-IP, KLF2 and HK1 perturbation, and glycolysis/EndMT readouts in HUVECs","pmids":["35364229"],"confidence":"Medium","gaps":["Interaction not reciprocally validated with full controls","Mechanism by which KLF2 binding inhibits HK1 activity unclear","Single lab"]},{"year":2023,"claim":"Defined transcriptional and post-transcriptional inputs to HK1: ZBTB10 directly activates the HK1 promoter, and hnRNP A1 directly binds and stabilizes HK1 mRNA to sustain neuronal glycolysis.","evidence":"ChIP and luciferase for ZBTB10; RIP and CLIP-qPCR with rescue for hnRNP A1 in cancer and neuronal models","pmids":["37834257","37744386"],"confidence":"Medium","gaps":["Crosstalk between transcriptional and mRNA-stability control unaddressed","Single labs"]},{"year":2024,"claim":"Defined inhibitory post-translational and pharmacological control of HK1 catalysis: PARP-1 PARylates HK1 to suppress activity during ischemia, while the natural product oridonin covalently modifies Cys-813 near the glucose-binding domain to inhibit glycolysis.","evidence":"Co-IP/MS for PARylation in MCAO/R mice; proteome microarray, BLI, MS adduct ID, and CETSA for oridonin in bladder cancer","pmids":["38346469","38367425"],"confidence":"High","gaps":["PARylation residue(s) not mapped","Selectivity of oridonin for HK1 versus other hexokinases not fully resolved"]},{"year":2025,"claim":"Expanded RNA-modification control of HK1 by showing m6A (FTO demethylation and KIAA1429/HuR writing/reading) and NAT10-mediated ac4C tune HK1 mRNA stability and expression across osteoclast, liver, and retinoblastoma contexts.","evidence":"m6A/ac4C quantification, MeRIP-seq, RIP, reporter and stability assays, knockdown/rescue, and xenografts","pmids":["39934129","38996929","40344913"],"confidence":"Medium","gaps":["Whether these modifications co-regulate the same transcripts or act context-specifically is unclear","Direct mapping of modified residues on HK1 mRNA incomplete","Single labs"]},{"year":2025,"claim":"Connected a circular-RNA circuit to HK1 turnover, showing circST6GALNAC6 recruits FUS to stabilize PRKN mRNA and thereby enhance Parkin-mediated HK1 degradation to limit glycolysis in bladder cancer.","evidence":"RIP, Co-IP, glycolysis assays, and xenografts with PRKN rescue","pmids":["39960214"],"confidence":"Medium","gaps":["Indirect multi-step circuit","Single lab"]},{"year":null,"claim":"The non-catalytic, retina-specific function of HK1 disrupted by p.E847K remains mechanistically undefined, as does the identity of the beta-cell repressor acting on the intron 2 cis-element.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular partner or pathway identified for the retinal HK1 function","Repressor of the disallowed-gene cis-element unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10,11,6,9,15]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9,10,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,14,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,8,16]}],"complexes":[],"partners":["PRKN","PARP1","TSG101","HNRNP A1","KLF2","ZBTB10","NAT10","KIAA1429"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19367","full_name":"Hexokinase-1","aliases":["Brain form hexokinase","Hexokinase type I","HK I","Hexokinase-A"],"length_aa":917,"mass_kda":102.5,"function":"Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively) (PubMed:1637300, PubMed:25316723, PubMed:27374331). Does not phosphorylate N-acetyl-D-glucosamine (PubMed:27374331). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (By similarity). Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan (PubMed:27374331). When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome (PubMed:27374331)","subcellular_location":"Mitochondrion outer membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P19367/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HK1","classification":"Not 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39080798","citation_count":6,"is_preprint":false},{"pmid":"39775665","id":"PMC_39775665","title":"MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39775665","citation_count":6,"is_preprint":false},{"pmid":"33361148","id":"PMC_33361148","title":"Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the HK1 gene causing severe haemolytic anaemia with developmental delay in an Indian family.","date":"2020","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33361148","citation_count":6,"is_preprint":false},{"pmid":"38027628","id":"PMC_38027628","title":"Phlorizin ameliorates myocardial fibrosis by inhibiting pyroptosis through restraining HK1-mediated NLRP3 inflammasome activation.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38027628","citation_count":6,"is_preprint":false},{"pmid":"38268894","id":"PMC_38268894","title":"Cichoric acid improves isoproterenol-induced myocardial fibrosis via inhibition of HK1/NLRP3 inflammasome-mediated signaling pathways by reducing oxidative stress, inflammation, and apoptosis.","date":"2023","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/38268894","citation_count":6,"is_preprint":false},{"pmid":"37999059","id":"PMC_37999059","title":"Insecticidal Effect of the Entomopathogenic Fungus Lecanicillium araneicola HK-1 in Aphis craccivora (Hemiptera: Aphididae).","date":"2023","source":"Insects","url":"https://pubmed.ncbi.nlm.nih.gov/37999059","citation_count":6,"is_preprint":false},{"pmid":"37414399","id":"PMC_37414399","title":"MIR34A modulates lens epithelial cell apoptosis and cataract development via the HK1/caspase 3 signaling pathway.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37414399","citation_count":5,"is_preprint":false},{"pmid":"36541585","id":"PMC_36541585","title":"A de novo hexokinase 1 (HK1) variant presenting as Boucher-Neuhäuser syndrome.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36541585","citation_count":5,"is_preprint":false},{"pmid":"2571978","id":"PMC_2571978","title":"HincII RFLP at the human hexokinase I (HK1) locus on chromosome 10.","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2571978","citation_count":5,"is_preprint":false},{"pmid":"30507306","id":"PMC_30507306","title":"In vitro cytotoxicity evaluation of thiourea derivatives bearing Salix sp. constituent against HK-1 cell lines.","date":"2018","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/30507306","citation_count":5,"is_preprint":false},{"pmid":"37222534","id":"PMC_37222534","title":"LncRP11-675F6.3 responds to rapamycin treatment and reduces triglyceride accumulation via interacting with HK1 in hepatocytes by regulating autophagy and VLDL-related proteins.","date":"2023","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37222534","citation_count":4,"is_preprint":false},{"pmid":"36639056","id":"PMC_36639056","title":"Expanding the neurodevelopmental phenotype associated with HK1 de novo heterozygous missense variants.","date":"2023","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36639056","citation_count":4,"is_preprint":false},{"pmid":"31621442","id":"PMC_31621442","title":"Eleven-year follow-up of a Japanese retinitis pigmentosa patient with an HK1 gene mutation.","date":"2019","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31621442","citation_count":4,"is_preprint":false},{"pmid":"38016997","id":"PMC_38016997","title":"Proteomic analyses identify HK1 and ATP5A to be overexpressed in distant metastases of lung adenocarcinomas compared to matched primary tumors.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38016997","citation_count":3,"is_preprint":false},{"pmid":"27965750","id":"PMC_27965750","title":"Establishment and Analysis of the 3-dimensional (3D) Spheroids Generated from the Nasopharyngeal Carcinoma Cell Line HK1.","date":"2016","source":"Tropical life sciences research","url":"https://pubmed.ncbi.nlm.nih.gov/27965750","citation_count":3,"is_preprint":false},{"pmid":"12145192","id":"PMC_12145192","title":"Inhibition of EGF-mediated receptor activity and cell proliferation by HK1-ceramide, a stable analog of the ganglioside GM3-lactone.","date":"2002","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/12145192","citation_count":3,"is_preprint":false},{"pmid":"36321135","id":"PMC_36321135","title":"HKI-272 contributes to gemcitabine-mediated anti-proliferative and anti-metastatic effects through EGFR suppression in gallbladder cancer.","date":"2022","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/36321135","citation_count":2,"is_preprint":false},{"pmid":"38179148","id":"PMC_38179148","title":"Two Japanese Families with Pigmented Paravenous Retinochoroidal Atrophy and HK1 Mutation: A Case Report.","date":"2024","source":"Case reports in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/38179148","citation_count":2,"is_preprint":false},{"pmid":"40344913","id":"PMC_40344913","title":"NAT10-mediated N4-acetylcytosine modification promotes the progression of retinoblastoma by improving the HK1 mRNA stability to enhance glycolysis.","date":"2025","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/40344913","citation_count":2,"is_preprint":false},{"pmid":"39960214","id":"PMC_39960214","title":"CircST6GALNAC6 Inhibits Glycolysis of Bladder Cancer by Regulating PRKN/HK1 Signaling Pathway.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39960214","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49991,"output_tokens":5796,"usd":0.118457,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14463,"output_tokens":5032,"usd":0.099058,"stage2_stop_reason":"end_turn"},"total_usd":0.217515,"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\": 1998,\n      \"finding\": \"Mouse spermatogenic cell-specific HK1 (HK1-S) is encoded by alternative splicing from the single mHk1 gene using alternative exons; the resulting protein lacks the porin-binding domain (PBD) required for mitochondrial outer membrane binding and is localized to the fibrous sheath in the sperm tail rather than to mitochondria in the midpiece.\",\n      \"method\": \"Alternative exon identification by molecular cloning, immunolocalization by direct imaging/fractionation in mouse sperm\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (molecular cloning, alternative exon mapping, immunolocalization) in a focused study establishing both the transcriptional origin and subcellular localization with functional consequence\",\n      \"pmids\": [\"9508088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A single human HK1 gene spanning at least 100 kb encodes multiple transcripts generated by alternative splicing of different 5' exons; testis-specific transcripts are produced by a separate upstream promoter and include a novel isoform (hHKI-td) with both a testis-specific 5' sequence and an additional unique sequence not present in somatic HK1.\",\n      \"method\": \"Cosmid library screening, genomic mapping, cDNA isolation and sequencing from human sperm\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct genomic and cDNA characterization with multiple orthogonal methods (cosmid mapping, direct sequencing, library screening) in a single dedicated study\",\n      \"pmids\": [\"10978502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In the downeast anemia (dea) mouse model, a spontaneous early transposon (ETn) insertion in intron 4 of the Hk1 gene disrupts normal splicing, markedly decreases HK1 expression, and causes severe nonspherocytic hemolytic anemia due to hexokinase deficiency in erythroid tissues.\",\n      \"method\": \"Linkage analysis, Southern blotting, direct sequencing, hexokinase enzyme activity assay in mouse erythroid tissues\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (linkage, Southern blot, sequencing, enzymatic activity) establishing both molecular defect and functional consequence in a dedicated model\",\n      \"pmids\": [\"11783948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mitochondrial hexokinase 1 (HKI) is a substrate of the Parkin E3 ubiquitin ligase; following dissipation of mitochondrial membrane potential, Parkin ubiquitylates HKI leading to its proteasomal degradation. Disease-relevant Parkin mutations hinder this ubiquitylation, and endogenous HKI is ubiquitylated upon membrane potential loss in cells expressing genuine Parkin.\",\n      \"method\": \"Substrate screen, co-immunoprecipitation, ubiquitylation assay in cells, Parkin mutant analysis, endogenous ubiquitylation confirmation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (substrate screen, Co-IP, functional ubiquitylation assay, disease mutant validation, endogenous confirmation) in a single dedicated mechanistic study\",\n      \"pmids\": [\"23068103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A dominant HK1 missense mutation (p.Glu847Lys) causes autosomal dominant retinitis pigmentosa; the mutation is located outside the catalytic domains at a highly conserved position, and no systemic abnormalities in glycolysis were detected, suggesting the pathogenic effect is retina-specific and may not involve loss of enzymatic activity.\",\n      \"method\": \"Exome sequencing, linkage mapping, candidate gene screening, segregation analysis across five families, biochemical glycolysis assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mapping with functional biochemical assay (glycolysis normal), but mechanistic basis of retinal specificity not fully resolved; single lab\",\n      \"pmids\": [\"25190649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The HK1 E847K missense mutation does not affect hexokinase enzymatic activity or protein stability, suggesting the mutation causes retinitis pigmentosa through an uncharacterized non-catalytic function or gain of function, not via loss of glycolytic enzyme activity.\",\n      \"method\": \"Biochemical enzyme activity assay, protein stability assessment in mutant vs. wild-type HK1\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical assays establishing a negative result (no loss of catalytic activity), single lab, mechanistic basis of pathogenicity remains unresolved\",\n      \"pmids\": [\"25316723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"mTORC1-induced upregulation of HK1-dependent glycolysis is required for NLRP3 inflammasome activation in macrophages; inhibition of Raptor/mTORC1 or HK1 suppresses both pro-IL-1β maturation and caspase-1 activation in response to LPS and ATP.\",\n      \"method\": \"Pharmacological inhibition (rapamycin, HK inhibitors), shRNA knockdown of HK1/Raptor, caspase-1 and IL-1β processing assays in macrophages\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic knockdown + pharmacological inhibition + downstream functional readouts) establishing pathway position of HK1 in NLRP3 inflammasome activation\",\n      \"pmids\": [\"26119735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGF-β stimulates palmitoylation of HK1 in hepatic stellate cells (HSCs), facilitating its secretion via large extracellular vesicles in a TSG101-dependent manner; the secreted HK1 is taken up by hepatocellular carcinoma (HCC) cells to accelerate glycolysis and HCC progression. The nuclear receptor Nur77 transcriptionally activates depalmitoylase ABHD17B to inhibit HK1 palmitoylation, and TGF-β-activated Akt phosphorylates and degrades Nur77 to repress this inhibitory axis.\",\n      \"method\": \"Co-IP, extracellular vesicle isolation and proteomic analysis, palmitoylation assay, TSG101 knockdown, Nur77/ABHD17B functional assays, Akt inhibition, xenograft models\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, vesicle fractionation, palmitoylation assays, genetic knockdown, in vivo xenografts) in a single rigorous study establishing a novel secretory mechanism for HK1\",\n      \"pmids\": [\"36192599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Non-coding de novo variants in a 42-bp conserved cis-regulatory element in intron 2 of HK1 cause loss of repression of HK1 in pancreatic beta-cells (a 'disallowed gene' context), leading to inappropriate HK1 expression, insulin secretion during hypoglycemia, and congenital hyperinsulinism.\",\n      \"method\": \"Gene-agnostic non-coding region screening, epigenomic analysis of regulatory elements, functional demonstration of loss of beta-cell repression, identification of 14 de novo variants\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genomic screening, epigenomic regulatory element mapping, functional loss-of-repression assay) with replication across 14 independent de novo variants\",\n      \"pmids\": [\"36333503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Simultaneous shRNA-mediated inactivation of HK1 and HK2 in colorectal cancer and melanoma cells leads to decreased cell viability and proliferation; HK2 inactivation alone induces compensatory upregulation of HK1, demonstrating functional redundancy between HK1 and HK2 in sustaining glycolysis in these cancers.\",\n      \"method\": \"shRNA lentiviral knockdown of HK1, HK2, and HK3 individually and in combination; cell viability and apoptosis assays\",\n      \"journal\": \"BMC genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with defined cellular phenotype, single lab, demonstrates functional redundancy and compensation between HK1 and HK2\",\n      \"pmids\": [\"28105937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oridonin forms a covalent bond with Cys-813 of HK1, located adjacent to the glucose-binding domain, suppressing HK1 enzymatic activity and reducing glycolysis in bladder cancer cells; this leads to apoptosis and inhibits lactate-induced PD-L1 expression.\",\n      \"method\": \"Human Proteome Microarray, streptavidin-agarose affinity assay, biolayer interferometry, mass spectrometry identifying Cys-813 adduct, cellular thermal shift assay, extracellular acidification rate measurement, xenograft models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple rigorous biochemical methods (mass spectrometry adduct identification, CETSA, BLI binding, enzymatic assay) definitively identify covalent binding site and functional consequence, single lab\",\n      \"pmids\": [\"38367425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP-1 activation during cerebral ischemia/reperfusion causes poly(ADP-ribosyl)ation (PARylation) of hexokinase-1, which inhibits HK1 enzymatic activity and contributes to energy metabolism collapse in neurons; PARP-1 inhibition restores hexokinase activity.\",\n      \"method\": \"Immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, 3D-modeling, hexokinase activity assay in MCAO/R mouse model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, MS identification of PARylation, enzymatic activity assay, in vivo model) establishing PARylation as a PTM that inhibits HK1 activity\",\n      \"pmids\": [\"38346469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO-mediated m6A demethylation of HK1 mRNA enhances the glycolytic pathway in osteoclasts, which stabilizes RANK protein via USP14 deubiquitinase activity, promoting osteoclastogenesis and alveolar bone resorption in apical periodontitis.\",\n      \"method\": \"m6A quantification, FTO knockdown/overexpression, HK1 manipulation, Co-IP for USP14/RANK interaction, glycolysis assays, BMDM-derived osteoclast models, rat AP model, pharmacological inhibition (Dac51, 2-DG)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (m6A assay, Co-IP, knockdown, in vivo model) but mechanistic link between HK1 m6A modification and RANK stabilization is indirect; single lab\",\n      \"pmids\": [\"39934129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The RNA-binding protein hnRNP A1 directly binds to the 2605-2821 region of HK1 mRNA, stabilizing it; inhibition of hnRNP A1 downregulates HK1 mRNA and protein expression, impairs glycolysis in neurons, and overexpression of hnRNP A1 rescues Aβ-induced neuronal glycolytic dysfunction via the hnRNP A1/HK1/pyruvate pathway.\",\n      \"method\": \"RNA immunoprecipitation (RIP), CLIP-qPCR, hnRNP A1 inhibitor treatment, lentiviral hnRNP A1 overexpression, glycolysis assays in HT22 cells and AD mouse model\",\n      \"journal\": \"Frontiers in aging neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and CLIP-qPCR directly identify binding site on HK1 mRNA with functional rescue experiments; single lab\",\n      \"pmids\": [\"37744386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10-mediated N4-acetylcytosine (ac4C) modification of HK1 mRNA increases its stability and expression, thereby promoting glycolysis and retinoblastoma cell proliferation; NAT10 knockdown decreases ac4C modification and stability of HK1 mRNA, and HK1 overexpression reverses the glycolytic inhibition caused by NAT10 knockdown.\",\n      \"method\": \"Dot blot assay for ac4C levels, RNA immunoprecipitation, immunofluorescence, dual luciferase reporter, NAT10 knockdown, HK1 overexpression rescue, xenograft mouse model\",\n      \"journal\": \"Clinics (Sao Paulo, Brazil)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, reporter assay, rescue experiment, in vivo model) establishing ac4C as a PTM of HK1 mRNA that controls its stability; single lab\",\n      \"pmids\": [\"40344913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HK1 and HK2 are functionally redundant for sustaining aerobic glycolysis and tumor growth; in HK1-expressing cancers, HK2 knockdown does not inhibit proliferation or tumor progression, but in HK1-negative (HK1-HK2+) cancers, HK2 knockdown inhibits proliferation, colony formation, and xenograft tumor progression.\",\n      \"method\": \"HK2 shRNA knockdown and CRISPR knockout in HK1+ and HK1- cancer cell lines; cell proliferation, colony formation, xenograft tumor assays, 18F-FDG PET/CT; Cancer Cell Line Encyclopedia expression analysis\",\n      \"journal\": \"Journal of nuclear medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown and knockout with multiple functional readouts (proliferation, colony formation, xenograft, metabolic imaging) establishing functional redundancy of HK1 and HK2 across multiple cancer lines\",\n      \"pmids\": [\"29880505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Four novel pathogenic HK1 missense and splice-site mutations cause red blood cell hexokinase deficiency with severe hemolytic anemia; structural modeling and biochemical analysis confirmed pathogenicity, and splice-site mutation c.873-2A>G was confirmed to disrupt pre-mRNA processing at the protein level.\",\n      \"method\": \"Molecular genetic analysis, 3D structural modeling, biochemical enzyme activity assays, pre-mRNA processing analysis\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sequencing, structural analysis, enzyme assay, mRNA processing) characterizing loss-of-function variants; single lab\",\n      \"pmids\": [\"27282571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF2 directly interacts with HK1 and reduces HK1-mediated hyperactivation of glycolysis; BDNF acting through the TrkB/KLF2 pathway downregulates HK1 expression, thereby suppressing HK1-induced glucose metabolism reprogramming and the endothelial-to-mesenchymal transition (EndMT) process in vascular endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation (KLF2-HK1 interaction), HK1 knockdown, KLF2 silencing/overexpression, BDNF/TrkB pathway inhibition, glycolysis assays (ECAR, glucose uptake, lactate), EndMT markers in HUVECs\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction plus functional knockdown experiments; single lab, interaction not reciprocally confirmed with full controls\",\n      \"pmids\": [\"35364229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor ZBTB10 directly binds to the HK1 promoter and regulates its transcriptional activity; knockdown of ZBTB10 decreases HK1 expression and reduces glycolysis in laryngeal cancer cells, whereas ZBTB10 overexpression increases HK1 expression.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), ZBTB10 knockdown/overexpression, HK1 mRNA/protein quantification, glycolysis assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate promoter binding and transcriptional regulation; single lab\",\n      \"pmids\": [\"37834257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CircST6GALNAC6 promotes PRKN (Parkin)-mediated ubiquitination and degradation of HK1 in bladder cancer cells by recruiting FUS to stabilize PRKN mRNA; overexpression of circST6GALNAC6 reduces HK1 protein levels, inhibits glycolysis and proliferation, and the effect is reversed by PRKN knockdown.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, colony formation assay, glycolysis assays (glucose intake, lactate, ATP, ECAR), xenograft mouse model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and Co-IP identify molecular interactions with functional rescue and in vivo confirmation; single lab, indirect circuit\",\n      \"pmids\": [\"39960214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429 (an m6A writer) directly binds HK1 mRNA and, cooperating with the m6A reader HuR, enhances HK1 mRNA stability and upregulates HK1 expression to promote the Warburg effect in liver cancer; KIAA1429 depletion decreases HK1 expression and increases sorafenib sensitivity.\",\n      \"method\": \"RNA-seq and MeRIP-seq (m6A-seq), RIP assay, KIAA1429 knockdown, HK1 mRNA stability assay, glycolysis functional assays, in vivo xenograft\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq and RIP establish m6A modification and direct binding; functional effects on HK1 confirmed with knockdown and in vivo; single lab\",\n      \"pmids\": [\"38996929\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HK1 (hexokinase 1) is a ubiquitously expressed enzyme catalyzing the first step of glycolysis (glucose → glucose-6-phosphate); it is tethered to the outer mitochondrial membrane via a porin-binding domain (absent in spermatogenic and testis-specific splice isoforms that localize instead to the sperm fibrous sheath), undergoes post-translational regulation by Parkin-mediated ubiquitylation (leading to proteasomal degradation upon mitochondrial depolarization), PARP-1-mediated PARylation (inhibiting its enzymatic activity), palmitoylation (promoting its secretion from hepatic stellate cells via large extracellular vesicles in a TSG101-dependent manner), and m6A/ac4C mRNA modifications that control its expression; its promoter is transcriptionally activated by ZBTB10, and its mRNA is stabilized by hnRNP A1 binding; upstream, mTORC1 upregulates HK1-dependent glycolysis to drive NLRP3 inflammasome activation in macrophages, and a cis-regulatory element in intron 2 normally silences HK1 in pancreatic beta-cells and liver (disallowed gene), with loss-of-repression variants causing congenital hyperinsulinism; loss-of-function HK1 mutations cause nonspherocytic hemolytic anemia, and dominant missense variants (p.E847K, outside catalytic domains) cause autosomal dominant retinitis pigmentosa without affecting catalytic activity, implicating a non-catalytic retina-specific function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HK1 (hexokinase 1) catalyzes the committed first step of glycolysis (glucose → glucose-6-phosphate) and is the rate-limiting glycolytic enzyme whose activity sustains cell viability and proliferation, acting redundantly with HK2 such that loss of one is buffered by compensatory upregulation of the other [#9, #15]. A single gene generates multiple transcripts through alternative splicing of distinct 5' exons, including a testis-specific isoform (HK1-S/hHKI-td) driven by a separate upstream promoter that lacks the porin-binding domain required for mitochondrial outer-membrane association and instead localizes to the sperm fibrous sheath [#0, #1]. HK1 is subject to extensive post-translational and post-transcriptional control: Parkin (PRKN) ubiquitylates mitochondrial HK1 upon loss of membrane potential to target it for proteasomal degradation [#3], PARP-1-mediated PARylation inhibits its catalytic activity during cerebral ischemia/reperfusion [#11], and TGF-β-induced palmitoylation promotes its secretion from hepatic stellate cells via TSG101-dependent large extracellular vesicles, after which it is imported by hepatocellular carcinoma cells to fuel glycolysis [#7]. At the mRNA level, HK1 transcript stability and expression are governed by hnRNP A1 binding [#13], m6A and ac4C modifications [#20, #14], and promoter activation by the transcription factor ZBTB10 [#18], while KLF2 directly binds HK1 to restrain glycolytic hyperactivation [#17]. Upstream, mTORC1 drives HK1-dependent glycolysis required for NLRP3 inflammasome activation in macrophages [#6]. Loss-of-function HK1 mutations cause red-cell hexokinase deficiency and nonspherocytic hemolytic anemia [#2, #16], non-coding variants in an intron 2 cis-regulatory element derepress HK1 in pancreatic beta-cells to cause congenital hyperinsulinism [#8], and a dominant missense variant (p.E847K) located outside the catalytic domains causes autosomal dominant retinitis pigmentosa without altering enzymatic activity, implicating a non-catalytic retina-specific function [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that the single HK1 gene produces a spermatogenic isoform whose alternative splicing removes the porin-binding domain, redirecting localization from mitochondria to the sperm fibrous sheath and decoupling HK1 isoform identity from its canonical subcellular targeting.\",\n      \"evidence\": \"Alternative exon mapping by molecular cloning and immunolocalization in mouse sperm\",\n      \"pmids\": [\"9508088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of fibrous-sheath localization for sperm metabolism not defined\", \"Human isoform behavior inferred from mouse\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed the human HK1 locus uses a separate upstream promoter to generate testis-specific transcripts including a unique hHKI-td isoform, defining the genomic basis for tissue-restricted HK1 variants.\",\n      \"evidence\": \"Cosmid mapping, genomic mapping, and cDNA sequencing from human sperm\",\n      \"pmids\": [\"10978502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein-level function of hHKI-td not characterized\", \"Regulation of the alternative promoter unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked reduced HK1 expression to disease by showing a transposon insertion disrupting Hk1 splicing causes erythroid hexokinase deficiency and hemolytic anemia, establishing HK1 as essential for red-cell glycolysis.\",\n      \"evidence\": \"Linkage, Southern blot, sequencing, and enzyme activity assays in the dea mouse model\",\n      \"pmids\": [\"11783948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Erythroid-specific transcript regulation not detailed\", \"Translation to human variants pending\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a dominant non-catalytic disease mechanism: the p.E847K mutation outside catalytic domains causes retinitis pigmentosa without altering enzymatic activity or protein stability, implying a retina-specific function distinct from glycolysis.\",\n      \"evidence\": \"Exome sequencing, segregation across five families, and biochemical glycolysis/stability assays\",\n      \"pmids\": [\"25190649\", \"25316723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-catalytic retinal function remains uncharacterized\", \"Gain-of-function versus dominant-negative mechanism unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned HK1 within innate immune signaling by demonstrating mTORC1-driven HK1-dependent glycolysis is required for NLRP3 inflammasome activation, connecting metabolic flux to caspase-1/IL-1β processing.\",\n      \"evidence\": \"Pharmacologic inhibition and shRNA knockdown of HK1/Raptor with caspase-1/IL-1β readouts in macrophages\",\n      \"pmids\": [\"26119735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between HK1 metabolite output and NLRP3 assembly not defined\", \"In vivo relevance not addressed here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined functional redundancy between HK1 and HK2 in cancer, showing dual inactivation reduces viability and that HK2 loss triggers compensatory HK1 upregulation, explaining glycolytic resilience in tumors.\",\n      \"evidence\": \"shRNA knockdown of HK1/HK2/HK3 individually and combined with viability/apoptosis assays in colorectal cancer and melanoma cells\",\n      \"pmids\": [\"28105937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of compensatory HK1 induction unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed regulated turnover of mitochondrial HK1 by identifying it as a Parkin substrate ubiquitylated upon mitochondrial depolarization for proteasomal degradation, linking HK1 stability to mitochondrial quality control.\",\n      \"evidence\": \"Substrate screen, Co-IP, ubiquitylation assay, Parkin mutant analysis, and endogenous confirmation in cells\",\n      \"pmids\": [\"23068103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitylation site mapping not reported\", \"Physiological setting of HK1 degradation in vivo not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended HK1/HK2 redundancy to therapeutic logic, showing HK2 dependence emerges only in HK1-negative cancers, with HK1 status predicting response to HK2 targeting.\",\n      \"evidence\": \"HK2 knockdown/CRISPR knockout in HK1+ and HK1- lines with proliferation, xenograft, and 18F-FDG PET assays\",\n      \"pmids\": [\"29880505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of HK1 expression status across tumors unclear\", \"Does not address combined HK1/HK2 inhibition therapeutically\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a secretory, non-canonical role for HK1: TGF-β-induced palmitoylation enables TSG101-dependent vesicular secretion from hepatic stellate cells and paracrine glycolytic support of hepatocellular carcinoma, with the Nur77/ABHD17B axis controlling palmitoylation.\",\n      \"evidence\": \"Co-IP, EV proteomics, palmitoylation assays, TSG101/Nur77/ABHD17B perturbation, and xenografts\",\n      \"pmids\": [\"36192599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoylation site(s) on HK1 not mapped\", \"Mechanism of HK1 uptake by recipient cells undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a regulatory-element disease mechanism by showing de novo variants in an intron 2 cis-element derepress HK1 in pancreatic beta-cells, causing inappropriate insulin secretion and congenital hyperinsulinism.\",\n      \"evidence\": \"Gene-agnostic non-coding screening, epigenomic mapping, loss-of-repression assays, and 14 de novo variants\",\n      \"pmids\": [\"36333503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the repressor binding the element not determined\", \"Mechanism of beta-cell-specific silencing not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified KLF2 as a direct HK1 interactor that restrains glycolytic hyperactivation, placing HK1 downstream of BDNF/TrkB/KLF2 signaling in endothelial-to-mesenchymal transition.\",\n      \"evidence\": \"Co-IP, KLF2 and HK1 perturbation, and glycolysis/EndMT readouts in HUVECs\",\n      \"pmids\": [\"35364229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not reciprocally validated with full controls\", \"Mechanism by which KLF2 binding inhibits HK1 activity unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined transcriptional and post-transcriptional inputs to HK1: ZBTB10 directly activates the HK1 promoter, and hnRNP A1 directly binds and stabilizes HK1 mRNA to sustain neuronal glycolysis.\",\n      \"evidence\": \"ChIP and luciferase for ZBTB10; RIP and CLIP-qPCR with rescue for hnRNP A1 in cancer and neuronal models\",\n      \"pmids\": [\"37834257\", \"37744386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crosstalk between transcriptional and mRNA-stability control unaddressed\", \"Single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined inhibitory post-translational and pharmacological control of HK1 catalysis: PARP-1 PARylates HK1 to suppress activity during ischemia, while the natural product oridonin covalently modifies Cys-813 near the glucose-binding domain to inhibit glycolysis.\",\n      \"evidence\": \"Co-IP/MS for PARylation in MCAO/R mice; proteome microarray, BLI, MS adduct ID, and CETSA for oridonin in bladder cancer\",\n      \"pmids\": [\"38346469\", \"38367425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PARylation residue(s) not mapped\", \"Selectivity of oridonin for HK1 versus other hexokinases not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded RNA-modification control of HK1 by showing m6A (FTO demethylation and KIAA1429/HuR writing/reading) and NAT10-mediated ac4C tune HK1 mRNA stability and expression across osteoclast, liver, and retinoblastoma contexts.\",\n      \"evidence\": \"m6A/ac4C quantification, MeRIP-seq, RIP, reporter and stability assays, knockdown/rescue, and xenografts\",\n      \"pmids\": [\"39934129\", \"38996929\", \"40344913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these modifications co-regulate the same transcripts or act context-specifically is unclear\", \"Direct mapping of modified residues on HK1 mRNA incomplete\", \"Single labs\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected a circular-RNA circuit to HK1 turnover, showing circST6GALNAC6 recruits FUS to stabilize PRKN mRNA and thereby enhance Parkin-mediated HK1 degradation to limit glycolysis in bladder cancer.\",\n      \"evidence\": \"RIP, Co-IP, glycolysis assays, and xenografts with PRKN rescue\",\n      \"pmids\": [\"39960214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect multi-step circuit\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The non-catalytic, retina-specific function of HK1 disrupted by p.E847K remains mechanistically undefined, as does the identity of the beta-cell repressor acting on the intron 2 cis-element.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or pathway identified for the retinal HK1 function\", \"Repressor of the disallowed-gene cis-element unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10, 11, 6, 9, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9, 10, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 14, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 8, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PRKN\",\n      \"PARP1\",\n      \"TSG101\",\n      \"hnRNP A1\",\n      \"KLF2\",\n      \"ZBTB10\",\n      \"NAT10\",\n      \"KIAA1429\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}