{"gene":"FOXK1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2018,"finding":"mTORC1 suppresses GSK3-dependent phosphorylation of FOXK1; when mTORC1 is inhibited, GSK3 phosphorylates FOXK1, triggering 14-3-3 binding, reduced DNA binding, and nuclear exclusion of FOXK1. Active mTORC1 thus keeps FOXK1 nuclear and transcriptionally active, driving expression of glycolytic and HIF-1α-dependent anabolic genes.","method":"Phosphoproteomics, 14-3-3 co-IP, nuclear/cytoplasmic fractionation, ChIP, gene-expression analysis, GSK3 inhibitor and mTOR inhibitor treatments, mutagenesis of phosphorylation sites","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (phosphoproteomics, Co-IP, fractionation, ChIP, mutagenesis) in a single rigorous study with mechanistic depth","pmids":["29861159"],"is_preprint":false},{"year":2018,"finding":"PP2A regulatory subunit B56 shuttles between nucleus and cytoplasm and is required for mTORC1-dependent dephosphorylation of nuclear FOXK1, providing the mechanistic link between lysosomal mTORC1 activity and nuclear FOXK1 regulation.","method":"Nuclear-cytoplasmic fractionation, PP2AB56 knockdown, co-immunoprecipitation, phosphorylation assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, reciprocal Co-IP and fractionation with functional rescue, extending a prior mechanistic study","pmids":["29845697"],"is_preprint":false},{"year":2017,"finding":"mTORC1 activation induces PP2A-mediated dephosphorylation of FOXK1, leading to its nuclear accumulation and direct transactivation of the CCL2 gene independently of NF-κB, thereby promoting recruitment of tumor-associated macrophages.","method":"Multiple phosphoproteomics approaches, ChIP, luciferase reporter assay, FOXK1 knockdown/overexpression, rapamycin treatment, in vivo macrophage accumulation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphoproteomics, ChIP, reporter assay, and in vivo rescue in a single study with multiple orthogonal methods","pmids":["29186685"],"is_preprint":false},{"year":2019,"finding":"FOXK1 and FOXK2 induce aerobic glycolysis by transcriptionally upregulating glycolytic enzymes (HK2, PFK, PKM, LDHA) and pyruvate dehydrogenase kinases 1 and 4 while suppressing pyruvate dehydrogenase phosphatase 1, leading to increased phosphorylation of the PDC E1α subunit and diversion of pyruvate to lactate rather than mitochondrial oxidation.","method":"ChIP, luciferase reporter, RNA-seq, FOXK1/K2 knockdown and overexpression in cell lines and primary human cells, in vivo metabolic measurements, enzyme activity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods, primary human cells, and in vivo validation across multiple labs/cell types in one study","pmids":["30700909"],"is_preprint":false},{"year":2019,"finding":"Following insulin stimulation, FOXK1 and FOXK2 translocate from the cytoplasm to the nucleus (reciprocal to FoxO1 nuclear export) in an Akt-mTOR-dependent manner; basal cytoplasmic retention requires GSK3. Knockdown of FoxK1/K2 in liver cells downregulates cell-cycle and lipid-metabolism genes and alters mitochondrial fatty acid metabolism.","method":"Immunofluorescence localization, nuclear/cytoplasmic fractionation, Akt/mTOR and GSK3 inhibitor treatments, siRNA knockdown, RNA-seq, metabolic flux analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal fractionation/imaging with pharmacological pathway dissection, replicated across multiple cell types in a single comprehensive study","pmids":["30952843"],"is_preprint":false},{"year":2002,"finding":"Foxk1 is required for myogenic progenitor cell (MPC) cycle progression; Foxk1-null mice show G0/G1 arrest and elevated p21CIP expression. Genetic ablation of p21CIP in Foxk1-/- mice fully restores MPC number, cell cycle progression, skeletal muscle regeneration, and growth, placing p21CIP downstream of FOXK1.","method":"Foxk1 knockout mice, combinatorial Foxk1/p21CIP double-knockout epistasis, cell cycle analysis, immunostaining, histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with double-mutant rescue across multiple phenotypic readouts","pmids":["12446708"],"is_preprint":false},{"year":2007,"finding":"Sox15 binds to an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally coactivate Foxk1 gene expression in myogenic progenitor cells. Sox15 knockout mice display decreased Foxk1 expression and impaired skeletal muscle regeneration.","method":"Transgenic reporter assays (4.6 kb Foxk1 promoter-LacZ), ChIP, Sox15 knockdown, Sox15 knockout mouse phenotyping","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, transgenic reporter, and genetic knockout with multiple orthogonal readouts","pmids":["17363903"],"is_preprint":false},{"year":2012,"finding":"FOXK1 physically interacts with both FOXO4 and MEF2, repressing their transcriptional activities; this repression promotes MPC proliferation and inhibits myogenic differentiation respectively.","method":"Co-IP, GST pull-down, luciferase transcriptional reporter assays, Foxk1 knockdown in C2C12 cells (cell cycle arrest), Foxk1 overexpression in C2C12CAR cells (impaired differentiation)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, GST pull-down, reporter assays, and loss/gain-of-function cellular phenotypes in one study","pmids":["22956541"],"is_preprint":false},{"year":2010,"finding":"The LIM-only protein Fhl2 interacts with Foxk1 through a yeast two-hybrid screen and GST pull-down, and in a dose-dependent manner promotes Foxk1-mediated transcriptional repression of Foxo4 activity. Fhl2 knockdown causes MPC cell cycle arrest; Fhl2-null mice have impaired skeletal muscle regeneration.","method":"Yeast two-hybrid screen, GST pull-down, transcriptional reporter assays, Fhl2 knockdown, Fhl2 knockout mice","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid + GST pull-down + reporter assays + genetic knockout with multiple readouts","pmids":["20013826"],"is_preprint":false},{"year":2012,"finding":"Sin3 (Sin3A and Sin3B) interacts with Foxk1; the Foxk1 N-terminal residues 1–40 (SID) bind the PAH2 domain of Sin3. Sin3A or Sin3B knockdown causes MPC cell cycle arrest and upregulates cell cycle inhibitor genes.","method":"Yeast two-hybrid screen, GST pull-down, domain-mapping mutagenesis, Sin3 knockdown with cell cycle analysis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid + GST pull-down + domain mapping, single lab, functional KD phenotype","pmids":["22476904"],"is_preprint":false},{"year":2007,"finding":"FOXK1 interacts with SRF in human cells; FOXK1 binding to the SM alpha-actin and PPGB promoters is dependent on SRF occupancy, and FOXK1 acts as a transcriptional repressor of these SRF target genes.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assays, FOXK1 overexpression/knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and reporter assays in a single lab study","pmids":["17670796"],"is_preprint":false},{"year":2010,"finding":"Adenovirus E1A C-terminus interacts with FOXK1/K2 via a Ser/Thr-containing motif; E1A mutants deficient in this interaction show enhanced cell proliferation and oncogenic transformation. Beta-HPV E6 proteins also interact with FOXK1/K2 through a similar motif and suppress E1A-induced transformation, indicating FOXK1/K2 as shared targets that suppress cell transformation.","method":"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, mutagenesis of the Ser/Thr motif, cell transformation assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — TAP-MS identification, Co-IP validation, mutagenesis, and functional transformation assays in one study","pmids":["20053746"],"is_preprint":false},{"year":2020,"finding":"FOXK1 and FOXK2 are integral components of the mammalian PR-DUB complex (containing BAP1, HCFC1, FOXK1/2, OGT, and ASXL1/2/3); FOXK1/2 and ASXL proteins mediate BAP1 recruitment to chromatin to remove H2AK119ub1 and maintain expression of metabolic and homeostatic genes.","method":"Co-IP, ChIP-seq, H2AK119ub1 ChIP, FOXK1/2 and ASXL knockouts in embryonic stem cells, RNA-seq","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP-seq, KO) defining complex composition and genome-wide function","pmids":["32747411"],"is_preprint":false},{"year":2020,"finding":"ASXL1 interacts with FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes (involved in glucose metabolism, oxygen sensing, JAK-STAT3 signaling). C-terminally truncated mutant ASXL1 (leukemia-associated) loses the ability to interact with FOXK1/K2, impairing BAP1-ASXL1-FOXK1/K2 target gene regulation.","method":"Co-IP, mass spectrometry, ChIP, gene expression analysis in ASXL1 heterozygous leukemia cells with specific deletion of mutant allele","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS, ChIP, and allele-specific deletion experiment, single lab","pmids":["32683582"],"is_preprint":false},{"year":2020,"finding":"FOXK1 associates with 53BP1, and this interaction is enhanced during S phase upon DNA damage in an ATM/CHK2-dependent manner. FOXK1-53BP1 interaction reduces 53BP1 association with its downstream effectors RIF1 and PTIP, thereby negatively regulating 53BP1 foci formation, impairing NHEJ and promoting HR. FOXK1 overexpression causes PARPi resistance in BRCA1-deficient cells.","method":"Co-IP, proximity ligation assay, laser micro-irradiation/live imaging, siRNA depletion, PARP inhibitor sensitivity assays, telomere fusion assay, cell cycle synchronization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, imaging, and multiple functional assays (PARPi resistance, telomere fusion, HR measurement) in one study","pmids":["32783940"],"is_preprint":false},{"year":2022,"finding":"HDAC3 interacts with FOXK1, co-localizes with it at the promoters of STAT1 and STAT2, and protects FOXK1 from lysosomal degradation. This HDAC3-FOXK1 complex is required for STAT1/STAT2 expression and macrophage antiviral innate immunity.","method":"Co-IP, ChIP, HDAC3 and FOXK1 knockout macrophages, viral infection assays, lysosomal inhibitor experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, and genetic KO with clear functional (antiviral) readout, multiple orthogonal methods","pmids":["35081346"],"is_preprint":false},{"year":2016,"finding":"c-jun directly binds to and activates the human FOXK1 gene promoter, stimulating FOXK1 expression. TGF-β1 treatment also induces FOXK1 expression and EMT; siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reverses EMT, proliferation, and metastatic phenotypes.","method":"Promoter reporter assay, ChIP, siRNA knockdown, in vivo orthotopic implantation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirming direct binding, single lab, with in vivo validation","pmids":["27882939"],"is_preprint":false},{"year":2018,"finding":"FOXK1 physically interacts with Snail; Snail directly binds to and activates the FOXK1 gene promoter. FOXK1 in turn directly transactivates Cyr61, driving EMT-mediated invasion and metastasis in colorectal cancer.","method":"Luciferase reporter assay, ChIP, co-immunoprecipitation, siRNA knockdown, invasion assays, in vivo metastasis model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter, and Co-IP, single lab, with in vivo validation","pmids":["29794466"],"is_preprint":false},{"year":2016,"finding":"FOXK1 physically interacts with FHL2 in colorectal cancer cells; co-expression of FOXK1 and FHL2 enhances cell proliferation and metastasis through EMT induction. siRNA-mediated repression of FHL2 in FOXK1-overexpressing cells reverses EMT and proliferative/metastatic phenotypes.","method":"Co-IP, immunofluorescence, shRNA knockdown, in vitro invasion assays, in vivo xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and functional rescue in vitro and in vivo, single lab","pmids":["27892920"],"is_preprint":false},{"year":2018,"finding":"FOXK1 physically interacts with vimentin and stabilizes it; co-expression of FOXK1 and vimentin promotes EMT, migration, and invasion in gastric cancer. siRNA-mediated knockdown of vimentin in FOXK1-overexpressing cells reverses EMT and reduces invasion.","method":"Co-IP, western blot, immunofluorescence, siRNA knockdown, in vitro and in vivo invasion/metastasis assays","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional rescue in vitro and in vivo, single lab","pmids":["30483822"],"is_preprint":false},{"year":2017,"finding":"RUFY3 physically interacts with FOXK1 in colorectal cancer; siRNA repression of FOXK1 in RUFY3-overexpressing cells reverses EMT and metastatic phenotypes, placing FOXK1 downstream of RUFY3.","method":"Co-IP, immunofluorescence, siRNA knockdown, in vitro and in vivo invasion/metastasis assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, epistasis inferred from rescue experiments only","pmids":["28623323"],"is_preprint":false},{"year":2020,"finding":"Nuclear DLC1 interacts with FOXK1 (identified by mass spectrometry) and is retained in the nucleus through this interaction; together DLC1 and FOXK1 cooperate at the MMP9 promoter to activate MMP9 transcription and promote melanoma invasion.","method":"Mass spectrometry, Co-IP, RNA-seq, ChIP, FOXK1/DLC1 knockdown, invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, Co-IP validation, ChIP, and functional knockdown, single lab","pmids":["32214200"],"is_preprint":false},{"year":2018,"finding":"FOXK1 directly binds and activates the CCDC43 gene promoter; CCDC43 is required for FOXK1-mediated EMT and metastasis in colorectal cancer.","method":"Luciferase reporter assay, ChIP, siRNA knockdown, EMT markers, invasion assays in vitro and in vivo","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay identifying direct promoter binding, functional rescue, single lab","pmids":["30562730"],"is_preprint":false},{"year":2018,"finding":"FOXK1 directly binds the Snail promoter and activates its transcription in glioblastoma cells, thereby promoting EMT and cell proliferation.","method":"Luciferase reporter assay, ChIP, FOXK1 knockdown/overexpression, cell cycle and invasion assays","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirming direct promoter binding, single lab","pmids":["29456714"],"is_preprint":false},{"year":2017,"finding":"FOXK1 facilitates cell cycle progression in ovarian cancer by directly regulating p21 expression; ChIP and luciferase assays demonstrated FOXK1 binds the p21 promoter and suppresses its transcription, promoting S-phase entry.","method":"ChIP, luciferase reporter assay, colony formation, CCK-8, flow cytometry","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay, single lab, consistent with established p21/Foxk1 axis","pmids":["29050292"],"is_preprint":false},{"year":2023,"finding":"FOXK1 directly activates CDC25A and CDK4 transcription by binding to their promoter regions in esophageal squamous cell carcinoma; this drives G1/S progression. Silencing FOXK1 increases radiosensitivity by impairing DNA damage repair and inducing G1 arrest.","method":"ChIP, luciferase reporter assay, FOXK1 knockdown/overexpression, γ-H2AX foci imaging, flow cytometry, colony survival assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for direct promoter binding plus functional cellular readouts, single lab","pmids":["37173384"],"is_preprint":false},{"year":2023,"finding":"FOXK1 regulates cardiogenesis by repressing the Wnt/β-catenin signaling pathway; Foxk1 KO embryoid bodies show impaired cardiac progenitor specification, reduced cardiac gene program (RNA-seq), closed chromatin at cardiogenesis loci (ATAC-seq), and loss of cardiomyocyte contractility.","method":"Foxk1 KO ES cell-derived embryoid bodies, flow cytometry, RNA-seq, ATAC-seq, ChIP-qPCR, cardiac beating assay, immunohistochemistry","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with RNA-seq, ATAC-seq, ChIP, and functional cardiac readout, multiple orthogonal methods in one study","pmids":["37036809"],"is_preprint":false},{"year":2025,"finding":"Foxk1 and Foxk2 directly activate CCNB1 and CDK1 transcription, forming a CCNB1/CDK1 complex that facilitates G2/M transition in cardiomyocytes; they also upregulate HIF1α to enhance glycolysis and the pentose phosphate pathway, supporting cardiomyocyte proliferation. Cardiomyocyte-specific KO impairs neonatal heart regeneration after MI; AAV9-mediated overexpression extends the proliferative window and enhances adult cardiac repair.","method":"Cardiomyocyte-specific KO mice, AAV9 overexpression, ChIP, RNA-seq, flow cytometry, MI model, cell cycle analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiomyocyte-specific KO, ChIP, and AAV rescue with in vivo cardiac phenotype, multiple orthogonal methods","pmids":["40128196"],"is_preprint":false},{"year":2024,"finding":"Foxk1 directly binds promoter regions of glycolytic enzyme genes in osteoblasts (identified by CUT&Tag), and conditional Foxk1 KO in preosteoblasts reduces aerobic glycolysis, osteoblast differentiation, bone mass, and mechanical strength. Glycolysis inhibition by 2-DG blocks Foxk1-overexpression-induced osteoblast effects, confirming glycolysis as the mechanistic effector.","method":"Conditional Foxk1 KO mice, CUT&Tag, glycolysis assays, 2-DG inhibition, Osterix-Cre overexpression, bone histomorphometry","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, genome-wide CUT&Tag, pharmacological rescue, and in vivo bone phenotype","pmids":["39232134"],"is_preprint":false},{"year":2024,"finding":"FOXK1 is O-GlcNAcylated; this modification peaks at G1/S and is required for FOXK1 to promote E2F target gene transcription, cell proliferation, and cellular transformation. O-GlcNAcylation-defective FOXK1 shows reduced BAP1 recruitment to gene regulatory regions, accompanied by increased H2AK119ub and decreased H3K4me1, creating a repressive chromatin state. OGT-dependent O-GlcNAcylation is promoted by insulin resistance/nuclear OGT elevation.","method":"O-GlcNAc modification assay, OGT inhibition/knockdown, mutagenesis of O-GlcNAcylation sites, ChIP-seq, H2AK119ub ChIP, Co-IP with BAP1, cell transformation assays, xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM identification, mutagenesis, ChIP-seq, Co-IP, and in vivo transformation assays in one peer-reviewed study","pmids":["40593803"],"is_preprint":false},{"year":2024,"finding":"FOXK1 O-GlcNAcylation (same finding as above, initially reported as preprint) co-opts BAP1 to the E2F pathway to promote oncogenesis; loss of O-GlcNAcylation reduces BAP1 occupancy, increases H2AK119ub, and impairs E2F target gene expression.","method":"O-GlcNAc mass spectrometry, site mutagenesis, ChIP-seq, Co-IP, cell proliferation/transformation assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — same mechanistic findings as peer-reviewed paper (PMID 40593803); included for completeness as the preprint source","pmids":["38463952"],"is_preprint":true},{"year":2023,"finding":"FoxK1 binds to the Pparγ2 promoter and stimulates its transcriptional activity in mesenchymal progenitor cells; adipogenic stimulation induces nuclear translocation of Foxk1 via mTOR and PI3K signaling, and Foxk1 overexpression promotes adipocyte differentiation while Foxk1 silencing impairs it.","method":"ChIP, luciferase reporter assay, Foxk1 overexpression/knockdown in C3H/10T1/2, ST2 and primary BMSCs, nuclear translocation imaging, PI3K/mTOR inhibitor treatment","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirming direct promoter binding, functional OE/KD, single lab","pmids":["37889840"],"is_preprint":false},{"year":2023,"finding":"FoxK1 directly binds the genome at >4,000 gene promoters/enhancers in hepatocytes; insulin enhances this interaction for ~75% of sites. FoxK1 ChIP-seq binding overlaps with that of the insulin receptor at genes including LARS1 and TIMM22, suggesting FoxK1 acts as a transcriptional partner for some IR-mediated gene regulation.","method":"ChIP-seq for FoxK1, IR and FoxO1 in liver cells; siRNA knockdown; gene expression analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with knockdown validation, single lab, mechanistic inference from overlap","pmids":["37852413"],"is_preprint":false},{"year":2025,"finding":"USP28 interacts with FOXK1 and deubiquitinates it, stabilizing FOXK1 protein. Stabilized FOXK1 activates the Hippo signaling pathway, promoting cell proliferation and radioresistance in lung cancer.","method":"In vitro ubiquitination assay, Co-IP, USP28 knockdown, RNA-seq pathway analysis, xenograft model, immunohistochemistry","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitination assay plus Co-IP and functional KD, single lab","pmids":["39983825"],"is_preprint":false},{"year":2025,"finding":"GARS protein binds to FOXK1 and reduces its ubiquitination, thereby stabilizing FOXK1. Stable FOXK1 then directly transactivates LDHA, PKM2, and GLUT1 promoters to promote glycolysis in hepatocellular carcinoma.","method":"Co-IP, ubiquitination assay, ChIP (FOXK1 on glycolytic gene promoters), KLF16 KD/OE, in vitro and in vivo glycolysis assays","journal":"The Tohoku journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and ChIP confirming direct promoter binding, single lab","pmids":["40603105"],"is_preprint":false},{"year":2024,"finding":"FOXK1 recruits multiple transcriptional corepressor complexes (NCoR/SMRT, SIN3A, NuRD, and REST/CoREST); the FOXK1/NCoR/SIN3A complex transcriptionally represses circadian clock genes including CLOCK, PER2, and CRY2 to promote breast cancer cell proliferation. Insulin resistance elevates OGT, causing nuclear translocation and increased FOXK1 expression.","method":"Co-IP (silver staining and mass spectrometry for complex members), ChIP-seq, qChIP, western blot, TUNEL and colony assay, xenograft, FOXK1 OE/KD","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex identification, ChIP-seq, and functional assays in single lab","pmids":["39094826"],"is_preprint":false},{"year":2024,"finding":"FOXK1 interacts with the REST/CoREST complex (confirmed by Co-IP) to transcriptionally repress apoptotic pathway genes in ER+ breast cancer cells, preventing apoptosis and promoting tumor growth in vivo.","method":"Co-IP, ChIP-seq, qChIP, western blot, TUNEL, cell counting and colony assays, xenograft","journal":"Animal models and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP-seq identifying complex and genomic targets, functional KO/OE, single lab","pmids":["38238876"],"is_preprint":false},{"year":2024,"finding":"HDAC1 and FOXK1 interact; the HDAC1-FOXK1 complex silences miR-33a expression, leading to upregulation of ABCB7 and p70S6K1 and conferring EGFR-TKI resistance in non-small cell lung cancer.","method":"Co-IP, HDAC1 knockdown/overexpression, miR-33a reporter assay, flow cytometry, Transwell, xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and functional knockdown with in vivo validation, single lab","pmids":["39198847"],"is_preprint":false},{"year":2023,"finding":"In renal tubular cells, TGF-β1 induces Foxk1 expression; Foxk1 functions as a transcriptional repressor of the N-cadherin gene. JLP (JNK-associated leucine zipper protein) restrains Foxk1 induction; loss of JLP leads to Foxk1-driven N-cadherin downregulation and a partial EMT state during renal fibrosis.","method":"TGF-β1 treatment, Foxk1 overexpression/knockdown, ChIP, luciferase reporter assay (N-cadherin promoter), JLP KO fibrosis model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay identifying direct promoter repression plus genetic epistasis, single lab","pmids":["37013185"],"is_preprint":false},{"year":2024,"finding":"KSHV ORF45 binds to FoxK1 and FoxK2 through their FHA domains using a conserved S/T linear motif; ORF45 augments FoxK1/K2 promoter occupancy and transcriptional activity at late viral gene promoters to promote KSHV lytic replication. A single-point mutation in the ORF45 S/T motif abolishes the ORF45-FOXK1/2 interaction.","method":"Co-IP, ChIP, luciferase reporter, FHA domain mutagenesis, point mutation of ORF45 S/T motif, FoxK1/K2 siRNA depletion, virion production assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mutagenesis defining the FHA-binding motif, ChIP, and functional viral replication assay, multiple orthogonal methods","pmids":["39287387","39494902"],"is_preprint":false},{"year":2016,"finding":"FOXK1 methylation at its promoter influences FOXK1 gene expression (dual luciferase reporter assay). Paternal age correlates with decreased FOXK1 sperm methylation, and this epigenetic change is transmitted to offspring cord blood on the paternal allele (allele-specific pyrosequencing with informative SNP).","method":"Bisulfite pyrosequencing, allele-specific pyrosequencing with informative SNP, dual luciferase reporter assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct reporter assay for methylation-dependent expression; allele-specific transmission established by deep bisulfite sequencing, single lab","pmids":["28171595"],"is_preprint":false}],"current_model":"FOXK1 is a forkhead/winged-helix transcription factor and FHA-domain protein that functions as a nutrient- and growth-factor-regulated transcriptional activator or repressor: it is kept nuclear by active mTORC1 (which suppresses GSK3-dependent phosphorylation and 14-3-3-mediated nuclear export) and drives aerobic glycolysis by directly transactivating genes encoding glycolytic enzymes and PDKs while suppressing mitochondrial pyruvate oxidation; it regulates cell-cycle progression partly through p21 and the E2F pathway (the latter requiring O-GlcNAcylation for BAP1 co-recruitment and H2AK119 deubiquitination); it interacts with partners including SRF, Fhl2/FHL2, Sin3, Foxo4/MEF2, 53BP1 (inhibiting NHEJ), HDAC3 (stabilizing FOXK1 for STAT1/2 transcription), REST/CoREST and NCoR/SIN3A repressor complexes, and ASXL1 within the BAP1 PR-DUB complex; it is post-translationally regulated by GSK3 phosphorylation (nuclear exclusion), PP2A/B56 dephosphorylation (nuclear activation downstream of mTORC1), USP28-mediated deubiquitination (stabilization), and O-GlcNAcylation (BAP1 recruitment and E2F activation); and it plays essential developmental roles in myogenic progenitor cell cycling, cardiogenesis (repressing Wnt/β-catenin), osteoblast bone formation, and adipogenesis (transactivating Pparγ2)."},"narrative":{"mechanistic_narrative":"FOXK1 is a forkhead/winged-helix transcription factor and FHA-domain protein that couples nutrient and growth-factor signaling to a transcriptional program governing cellular metabolism, cell-cycle progression, and chromatin state [PMID:30700909, PMID:30952843]. Its activity is controlled chiefly by regulated nuclear access: active mTORC1 suppresses GSK3-dependent phosphorylation of FOXK1, preventing 14-3-3 binding and nuclear exclusion, while PP2A-B56 dephosphorylates nuclear FOXK1 to license its transcriptional output, so that insulin/Akt-mTOR signaling drives FOXK1 into the nucleus reciprocally to FoxO1 export [PMID:29861159, PMID:29845697, PMID:30952843]. Once nuclear, FOXK1 (with FOXK2) directly transactivates glycolytic enzyme genes (HK2, PFK, PKM, LDHA) and pyruvate dehydrogenase kinases while suppressing pyruvate dehydrogenase phosphatase, diverting pyruvate to lactate and enforcing aerobic glycolysis—an axis it uses in hepatocytes, osteoblasts, and cardiomyocytes [PMID:30700909, PMID:39232134, PMID:40128196]. FOXK1 promotes cell-cycle progression by repressing the CDK inhibitor p21 (genetically epistatic in myogenic progenitors) and by directly activating cell-cycle drivers including CDC25A, CDK4, CCNB1, and CDK1 [PMID:12446708, PMID:29050292, PMID:37173384, PMID:40128196]. FOXK1 is also a chromatin-regulatory factor: it is an integral subunit of the BAP1 PR-DUB complex (with HCFC1, OGT, and ASXL proteins), recruiting BAP1 to chromatin to remove H2AK119ub1, and O-GlcNAcylation of FOXK1 peaking at G1/S is required for BAP1 co-recruitment and E2F target activation [PMID:32747411, PMID:40593803]. It additionally nucleates corepressor complexes (Sin3, NCoR/SIN3A, REST/CoREST) to repress target genes and interacts with 53BP1 to inhibit NHEJ and bias repair toward homologous recombination [PMID:22476904, PMID:39094826, PMID:38238876, PMID:32783940]. Protein levels are stabilized by deubiquitination (USP28) and by HDAC3, which protects FOXK1 from lysosomal degradation to sustain STAT1/2 expression in antiviral immunity [PMID:39983825, PMID:35081346]. FOXK1 has essential developmental roles in myogenic progenitor cycling, cardiogenesis through repression of Wnt/β-catenin, osteoblast bone formation, and adipogenesis via Pparγ2 [PMID:12446708, PMID:37036809, PMID:39232134, PMID:37889840].","teleology":[{"year":2002,"claim":"Established FOXK1 as a required driver of progenitor cell-cycle progression and placed a defined cell-cycle inhibitor downstream of it, the first genetic dissection of FOXK1 function.","evidence":"Foxk1 knockout and Foxk1/p21CIP double-knockout epistasis with cell-cycle and regeneration readouts in mice","pmids":["12446708"],"confidence":"High","gaps":["Did not establish whether p21 repression is direct DNA binding versus indirect","Restricted to myogenic progenitors"]},{"year":2007,"claim":"Defined upstream transcriptional control of the Foxk1 gene and identified FOXK1 as an SRF-dependent transcriptional repressor, framing its dual coactivator/corepressor behavior.","evidence":"Sox15/Fhl3 promoter studies with transgenic reporter and ChIP; SRF Co-IP and ChIP at SM alpha-actin/PPGB promoters","pmids":["17363903","17670796"],"confidence":"High","gaps":["Mechanism converting FOXK1 between activator and repressor not defined","Cofactor requirements at SRF sites unresolved"]},{"year":2012,"claim":"Identified the corepressor partners and protein interactions through which FOXK1 represses myogenic differentiation and promotes proliferation, mapping a partner network (Sin3, FHL2, FOXO4, MEF2).","evidence":"Yeast two-hybrid, GST pull-down, domain mapping, Co-IP, and reporter assays with knockdown phenotypes in C2C12 cells","pmids":["22956541","20013826","22476904"],"confidence":"High","gaps":["Genome-wide target sets not defined","Several interactions characterized only in myogenic context"]},{"year":2010,"claim":"Showed FOXK1/K2 are shared targets of viral oncoproteins via a conserved Ser/Thr motif, implicating them in suppression of cell transformation and foreshadowing FHA-domain recognition of phosphomotifs.","evidence":"TAP-MS, Co-IP, motif mutagenesis, and transformation assays with adenovirus E1A and beta-HPV E6","pmids":["20053746"],"confidence":"High","gaps":["Endogenous phosphomotif partners not identified at this stage","Transcriptional consequences of viral engagement undefined"]},{"year":2018,"claim":"Resolved how nutrient/growth-factor signaling controls FOXK1, defining the mTORC1–GSK3–14-3-3 and PP2A-B56 circuit that gates its nuclear localization and transcriptional activity.","evidence":"Phosphoproteomics, 14-3-3 Co-IP, nuclear/cytoplasmic fractionation, ChIP, mutagenesis, and PP2A-B56 knockdown rescue","pmids":["29861159","29845697","29186685"],"confidence":"High","gaps":["Full set of GSK3/PP2A target residues incompletely mapped","How dephosphorylation alters DNA binding affinity mechanistically not resolved"]},{"year":2019,"claim":"Established FOXK1/K2 as master inducers of aerobic glycolysis and showed insulin-driven nuclear translocation reciprocal to FoxO1, connecting signaling input to a metabolic transcriptional output.","evidence":"ChIP, RNA-seq, reporter assays, enzyme activity, metabolic flux, and knockdown/overexpression in cell lines, primary cells, and in vivo","pmids":["30700909","30952843"],"confidence":"High","gaps":["Co-activators required for glycolytic gene activation not fully defined","Relationship between metabolic and cell-cycle gene programs left open"]},{"year":2020,"claim":"Defined FOXK1 as a chromatin-regulatory factor by establishing it as an integral PR-DUB subunit that recruits BAP1 to remove H2AK119ub1, and revealed an ASXL1 mutation that disrupts this recruitment in leukemia.","evidence":"Co-IP, ChIP-seq, H2AK119ub1 ChIP, RNA-seq, and FOXK1/2 and ASXL knockouts in ES cells; allele-specific ASXL1 deletion","pmids":["32747411","32683582"],"confidence":"High","gaps":["Determinants of PR-DUB targeting to specific loci incompletely defined","ASXL1 finding rests on single-lab allele-specific experiments"]},{"year":2020,"claim":"Extended FOXK1 function into genome stability, showing a cell-cycle/DNA-damage-regulated interaction with 53BP1 that biases double-strand-break repair and confers PARP-inhibitor resistance.","evidence":"Co-IP, proximity ligation, laser micro-irradiation, telomere fusion, HR/NHEJ and PARPi sensitivity assays","pmids":["32783940"],"confidence":"High","gaps":["Whether the 53BP1 effect requires FOXK1 DNA binding or is purely protein-scaffolding unresolved","Generality across cell types beyond BRCA1-deficient models untested"]},{"year":2022,"claim":"Showed FOXK1 stability is regulated by HDAC3, which protects it from lysosomal degradation to sustain STAT1/2 transcription and antiviral immunity, adding a degradation-control layer.","evidence":"Co-IP, ChIP, HDAC3/FOXK1 knockout macrophages, viral infection and lysosomal-inhibitor experiments","pmids":["35081346"],"confidence":"High","gaps":["E3 ligase routing FOXK1 to lysosomal degradation not identified","Whether HDAC3 catalytic activity is required unclear"]},{"year":2023,"claim":"Defined developmental and regenerative roles of FOXK1 in heart and bone, linking its glycolytic and cell-cycle programs to cardiac progenitor specification, cardiomyocyte proliferation, and osteoblast bone formation.","evidence":"Foxk1 KO embryoid bodies and cardiomyocyte/preosteoblast conditional KO with RNA-seq, ATAC-seq, CUT&Tag, ChIP, glycolysis and 2-DG rescue, and in vivo cardiac/bone phenotypes","pmids":["37036809","39232134","40128196"],"confidence":"High","gaps":["Direct targets mediating Wnt/β-catenin repression in cardiogenesis not fully enumerated","Crosstalk between metabolic and cell-cycle target sets in vivo not dissected"]},{"year":2024,"claim":"Identified O-GlcNAcylation as the modification gating FOXK1's chromatin output, required for BAP1 co-recruitment and E2F target activation and linking insulin resistance to FOXK1-driven oncogenesis.","evidence":"O-GlcNAc mass spectrometry, site mutagenesis, OGT inhibition, ChIP-seq, H2AK119ub ChIP, BAP1 Co-IP, transformation and xenograft assays","pmids":["40593803","38463952"],"confidence":"High","gaps":["Interplay between O-GlcNAcylation and the phospho-regulated nuclear localization switch not integrated","Whether all FOXK1 functions depend on O-GlcNAcylation unknown"]},{"year":2024,"claim":"Expanded the FOXK1 corepressor repertoire (NCoR/SIN3A, NuRD, REST/CoREST) and showed repression of circadian and apoptotic gene programs in breast cancer, with USP28-mediated deubiquitination as an additional stabilization route.","evidence":"MS-based complex identification, ChIP-seq, Co-IP, TUNEL/colony assays, xenografts; in vitro ubiquitination and USP28 knockdown","pmids":["39094826","38238876","39983825"],"confidence":"Medium","gaps":["Determinants selecting among multiple corepressor complexes at given loci unknown","Several interactions rest on single-lab Co-IP/ChIP"]},{"year":null,"claim":"How the phospho-regulated nuclear-access switch, O-GlcNAc-dependent chromatin recruitment, and the choice between coactivator versus corepressor complexes are integrated into a single context-specific FOXK1 output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling PTM state to target selection","Structural basis of FHA-domain phosphomotif recognition of endogenous partners not defined","In vivo causal hierarchy among metabolic, cell-cycle, and chromatin functions unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,24,25,27,35]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12,14,29]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,28]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,24,25,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,35,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,26,28,31]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14]}],"complexes":["BAP1 PR-DUB complex","NCoR/SIN3A corepressor complex","REST/CoREST complex"],"partners":["FOXK2","BAP1","ASXL1","53BP1","HDAC3","FHL2","SRF","USP28"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P85037","full_name":"Forkhead box protein K1","aliases":["Myocyte nuclear factor","MNF"],"length_aa":733,"mass_kda":75.5,"function":"Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy (By similarity). Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context (PubMed:17670796). Together with FOXK2, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen (By similarity). Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4 (By similarity). Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate (By similarity). Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism (By similarity). Together with FOXK2, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins (By similarity). Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle (By similarity). Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population (By similarity). Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation (By similarity). Involved in remodeling processes of adult muscles that occur in response to physiological stimuli (By similarity). Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair (By similarity). Represses myogenic differentiation by inhibiting MEFC activity (By similarity). Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus (PubMed:25805136). Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression (PubMed:25852164). Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK1-bound genes (PubMed:24634419, PubMed:30664650). Acts as an indirect positive regulator of ferroptosis following phosphorylation by isoform Beta-II of PRKCB by promoting expression and subsequent secretion of LGALS13 (PubMed:40246981)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P85037/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOXK1","classification":"Not Classified","n_dependent_lines":227,"n_total_lines":1208,"dependency_fraction":0.1879139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPM1G","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FOXK1","total_profiled":1310},"omim":[{"mim_id":"616302","title":"FORKHEAD BOX K1; FOXK1","url":"https://www.omim.org/entry/616302"},{"mim_id":"147685","title":"FORKHEAD BOX K2; FOXK2","url":"https://www.omim.org/entry/147685"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FOXK1"},"hgnc":{"alias_symbol":["IMAGE:5164497"],"prev_symbol":[]},"alphafold":{"accession":"P85037","domains":[{"cath_id":"2.60.200.20","chopping":"104-204","consensus_level":"high","plddt":91.6686,"start":104,"end":204},{"cath_id":"1.10.10.10","chopping":"311-395","consensus_level":"high","plddt":93.3774,"start":311,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P85037","model_url":"https://alphafold.ebi.ac.uk/files/AF-P85037-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P85037-F1-predicted_aligned_error_v6.png","plddt_mean":56.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOXK1","jax_strain_url":"https://www.jax.org/strain/search?query=FOXK1"},"sequence":{"accession":"P85037","fasta_url":"https://rest.uniprot.org/uniprotkb/P85037.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P85037/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P85037"}},"corpus_meta":[{"pmid":"30700909","id":"PMC_30700909","title":"FOXK1 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Active mTORC1 thus keeps FOXK1 nuclear and transcriptionally active, driving expression of glycolytic and HIF-1α-dependent anabolic genes.\",\n      \"method\": \"Phosphoproteomics, 14-3-3 co-IP, nuclear/cytoplasmic fractionation, ChIP, gene-expression analysis, GSK3 inhibitor and mTOR inhibitor treatments, mutagenesis of phosphorylation sites\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (phosphoproteomics, Co-IP, fractionation, ChIP, mutagenesis) in a single rigorous study with mechanistic depth\",\n      \"pmids\": [\"29861159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PP2A regulatory subunit B56 shuttles between nucleus and cytoplasm and is required for mTORC1-dependent dephosphorylation of nuclear FOXK1, providing the mechanistic link between lysosomal mTORC1 activity and nuclear FOXK1 regulation.\",\n      \"method\": \"Nuclear-cytoplasmic fractionation, PP2AB56 knockdown, co-immunoprecipitation, phosphorylation assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, reciprocal Co-IP and fractionation with functional rescue, extending a prior mechanistic study\",\n      \"pmids\": [\"29845697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1 activation induces PP2A-mediated dephosphorylation of FOXK1, leading to its nuclear accumulation and direct transactivation of the CCL2 gene independently of NF-κB, thereby promoting recruitment of tumor-associated macrophages.\",\n      \"method\": \"Multiple phosphoproteomics approaches, ChIP, luciferase reporter assay, FOXK1 knockdown/overexpression, rapamycin treatment, in vivo macrophage accumulation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphoproteomics, ChIP, reporter assay, and in vivo rescue in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"29186685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXK1 and FOXK2 induce aerobic glycolysis by transcriptionally upregulating glycolytic enzymes (HK2, PFK, PKM, LDHA) and pyruvate dehydrogenase kinases 1 and 4 while suppressing pyruvate dehydrogenase phosphatase 1, leading to increased phosphorylation of the PDC E1α subunit and diversion of pyruvate to lactate rather than mitochondrial oxidation.\",\n      \"method\": \"ChIP, luciferase reporter, RNA-seq, FOXK1/K2 knockdown and overexpression in cell lines and primary human cells, in vivo metabolic measurements, enzyme activity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods, primary human cells, and in vivo validation across multiple labs/cell types in one study\",\n      \"pmids\": [\"30700909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Following insulin stimulation, FOXK1 and FOXK2 translocate from the cytoplasm to the nucleus (reciprocal to FoxO1 nuclear export) in an Akt-mTOR-dependent manner; basal cytoplasmic retention requires GSK3. Knockdown of FoxK1/K2 in liver cells downregulates cell-cycle and lipid-metabolism genes and alters mitochondrial fatty acid metabolism.\",\n      \"method\": \"Immunofluorescence localization, nuclear/cytoplasmic fractionation, Akt/mTOR and GSK3 inhibitor treatments, siRNA knockdown, RNA-seq, metabolic flux analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal fractionation/imaging with pharmacological pathway dissection, replicated across multiple cell types in a single comprehensive study\",\n      \"pmids\": [\"30952843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Foxk1 is required for myogenic progenitor cell (MPC) cycle progression; Foxk1-null mice show G0/G1 arrest and elevated p21CIP expression. Genetic ablation of p21CIP in Foxk1-/- mice fully restores MPC number, cell cycle progression, skeletal muscle regeneration, and growth, placing p21CIP downstream of FOXK1.\",\n      \"method\": \"Foxk1 knockout mice, combinatorial Foxk1/p21CIP double-knockout epistasis, cell cycle analysis, immunostaining, histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with double-mutant rescue across multiple phenotypic readouts\",\n      \"pmids\": [\"12446708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sox15 binds to an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally coactivate Foxk1 gene expression in myogenic progenitor cells. Sox15 knockout mice display decreased Foxk1 expression and impaired skeletal muscle regeneration.\",\n      \"method\": \"Transgenic reporter assays (4.6 kb Foxk1 promoter-LacZ), ChIP, Sox15 knockdown, Sox15 knockout mouse phenotyping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, transgenic reporter, and genetic knockout with multiple orthogonal readouts\",\n      \"pmids\": [\"17363903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOXK1 physically interacts with both FOXO4 and MEF2, repressing their transcriptional activities; this repression promotes MPC proliferation and inhibits myogenic differentiation respectively.\",\n      \"method\": \"Co-IP, GST pull-down, luciferase transcriptional reporter assays, Foxk1 knockdown in C2C12 cells (cell cycle arrest), Foxk1 overexpression in C2C12CAR cells (impaired differentiation)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, GST pull-down, reporter assays, and loss/gain-of-function cellular phenotypes in one study\",\n      \"pmids\": [\"22956541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The LIM-only protein Fhl2 interacts with Foxk1 through a yeast two-hybrid screen and GST pull-down, and in a dose-dependent manner promotes Foxk1-mediated transcriptional repression of Foxo4 activity. Fhl2 knockdown causes MPC cell cycle arrest; Fhl2-null mice have impaired skeletal muscle regeneration.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, transcriptional reporter assays, Fhl2 knockdown, Fhl2 knockout mice\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid + GST pull-down + reporter assays + genetic knockout with multiple readouts\",\n      \"pmids\": [\"20013826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sin3 (Sin3A and Sin3B) interacts with Foxk1; the Foxk1 N-terminal residues 1–40 (SID) bind the PAH2 domain of Sin3. Sin3A or Sin3B knockdown causes MPC cell cycle arrest and upregulates cell cycle inhibitor genes.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, domain-mapping mutagenesis, Sin3 knockdown with cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid + GST pull-down + domain mapping, single lab, functional KD phenotype\",\n      \"pmids\": [\"22476904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FOXK1 interacts with SRF in human cells; FOXK1 binding to the SM alpha-actin and PPGB promoters is dependent on SRF occupancy, and FOXK1 acts as a transcriptional repressor of these SRF target genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assays, FOXK1 overexpression/knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and reporter assays in a single lab study\",\n      \"pmids\": [\"17670796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Adenovirus E1A C-terminus interacts with FOXK1/K2 via a Ser/Thr-containing motif; E1A mutants deficient in this interaction show enhanced cell proliferation and oncogenic transformation. Beta-HPV E6 proteins also interact with FOXK1/K2 through a similar motif and suppress E1A-induced transformation, indicating FOXK1/K2 as shared targets that suppress cell transformation.\",\n      \"method\": \"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, mutagenesis of the Ser/Thr motif, cell transformation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — TAP-MS identification, Co-IP validation, mutagenesis, and functional transformation assays in one study\",\n      \"pmids\": [\"20053746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXK1 and FOXK2 are integral components of the mammalian PR-DUB complex (containing BAP1, HCFC1, FOXK1/2, OGT, and ASXL1/2/3); FOXK1/2 and ASXL proteins mediate BAP1 recruitment to chromatin to remove H2AK119ub1 and maintain expression of metabolic and homeostatic genes.\",\n      \"method\": \"Co-IP, ChIP-seq, H2AK119ub1 ChIP, FOXK1/2 and ASXL knockouts in embryonic stem cells, RNA-seq\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP-seq, KO) defining complex composition and genome-wide function\",\n      \"pmids\": [\"32747411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASXL1 interacts with FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes (involved in glucose metabolism, oxygen sensing, JAK-STAT3 signaling). C-terminally truncated mutant ASXL1 (leukemia-associated) loses the ability to interact with FOXK1/K2, impairing BAP1-ASXL1-FOXK1/K2 target gene regulation.\",\n      \"method\": \"Co-IP, mass spectrometry, ChIP, gene expression analysis in ASXL1 heterozygous leukemia cells with specific deletion of mutant allele\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS, ChIP, and allele-specific deletion experiment, single lab\",\n      \"pmids\": [\"32683582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXK1 associates with 53BP1, and this interaction is enhanced during S phase upon DNA damage in an ATM/CHK2-dependent manner. FOXK1-53BP1 interaction reduces 53BP1 association with its downstream effectors RIF1 and PTIP, thereby negatively regulating 53BP1 foci formation, impairing NHEJ and promoting HR. FOXK1 overexpression causes PARPi resistance in BRCA1-deficient cells.\",\n      \"method\": \"Co-IP, proximity ligation assay, laser micro-irradiation/live imaging, siRNA depletion, PARP inhibitor sensitivity assays, telomere fusion assay, cell cycle synchronization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, imaging, and multiple functional assays (PARPi resistance, telomere fusion, HR measurement) in one study\",\n      \"pmids\": [\"32783940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC3 interacts with FOXK1, co-localizes with it at the promoters of STAT1 and STAT2, and protects FOXK1 from lysosomal degradation. This HDAC3-FOXK1 complex is required for STAT1/STAT2 expression and macrophage antiviral innate immunity.\",\n      \"method\": \"Co-IP, ChIP, HDAC3 and FOXK1 knockout macrophages, viral infection assays, lysosomal inhibitor experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, and genetic KO with clear functional (antiviral) readout, multiple orthogonal methods\",\n      \"pmids\": [\"35081346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"c-jun directly binds to and activates the human FOXK1 gene promoter, stimulating FOXK1 expression. TGF-β1 treatment also induces FOXK1 expression and EMT; siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reverses EMT, proliferation, and metastatic phenotypes.\",\n      \"method\": \"Promoter reporter assay, ChIP, siRNA knockdown, in vivo orthotopic implantation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirming direct binding, single lab, with in vivo validation\",\n      \"pmids\": [\"27882939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 physically interacts with Snail; Snail directly binds to and activates the FOXK1 gene promoter. FOXK1 in turn directly transactivates Cyr61, driving EMT-mediated invasion and metastasis in colorectal cancer.\",\n      \"method\": \"Luciferase reporter assay, ChIP, co-immunoprecipitation, siRNA knockdown, invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter, and Co-IP, single lab, with in vivo validation\",\n      \"pmids\": [\"29794466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXK1 physically interacts with FHL2 in colorectal cancer cells; co-expression of FOXK1 and FHL2 enhances cell proliferation and metastasis through EMT induction. siRNA-mediated repression of FHL2 in FOXK1-overexpressing cells reverses EMT and proliferative/metastatic phenotypes.\",\n      \"method\": \"Co-IP, immunofluorescence, shRNA knockdown, in vitro invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and functional rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"27892920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 physically interacts with vimentin and stabilizes it; co-expression of FOXK1 and vimentin promotes EMT, migration, and invasion in gastric cancer. siRNA-mediated knockdown of vimentin in FOXK1-overexpressing cells reverses EMT and reduces invasion.\",\n      \"method\": \"Co-IP, western blot, immunofluorescence, siRNA knockdown, in vitro and in vivo invasion/metastasis assays\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"30483822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RUFY3 physically interacts with FOXK1 in colorectal cancer; siRNA repression of FOXK1 in RUFY3-overexpressing cells reverses EMT and metastatic phenotypes, placing FOXK1 downstream of RUFY3.\",\n      \"method\": \"Co-IP, immunofluorescence, siRNA knockdown, in vitro and in vivo invasion/metastasis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, epistasis inferred from rescue experiments only\",\n      \"pmids\": [\"28623323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear DLC1 interacts with FOXK1 (identified by mass spectrometry) and is retained in the nucleus through this interaction; together DLC1 and FOXK1 cooperate at the MMP9 promoter to activate MMP9 transcription and promote melanoma invasion.\",\n      \"method\": \"Mass spectrometry, Co-IP, RNA-seq, ChIP, FOXK1/DLC1 knockdown, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, Co-IP validation, ChIP, and functional knockdown, single lab\",\n      \"pmids\": [\"32214200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 directly binds and activates the CCDC43 gene promoter; CCDC43 is required for FOXK1-mediated EMT and metastasis in colorectal cancer.\",\n      \"method\": \"Luciferase reporter assay, ChIP, siRNA knockdown, EMT markers, invasion assays in vitro and in vivo\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay identifying direct promoter binding, functional rescue, single lab\",\n      \"pmids\": [\"30562730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 directly binds the Snail promoter and activates its transcription in glioblastoma cells, thereby promoting EMT and cell proliferation.\",\n      \"method\": \"Luciferase reporter assay, ChIP, FOXK1 knockdown/overexpression, cell cycle and invasion assays\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirming direct promoter binding, single lab\",\n      \"pmids\": [\"29456714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXK1 facilitates cell cycle progression in ovarian cancer by directly regulating p21 expression; ChIP and luciferase assays demonstrated FOXK1 binds the p21 promoter and suppresses its transcription, promoting S-phase entry.\",\n      \"method\": \"ChIP, luciferase reporter assay, colony formation, CCK-8, flow cytometry\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay, single lab, consistent with established p21/Foxk1 axis\",\n      \"pmids\": [\"29050292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXK1 directly activates CDC25A and CDK4 transcription by binding to their promoter regions in esophageal squamous cell carcinoma; this drives G1/S progression. Silencing FOXK1 increases radiosensitivity by impairing DNA damage repair and inducing G1 arrest.\",\n      \"method\": \"ChIP, luciferase reporter assay, FOXK1 knockdown/overexpression, γ-H2AX foci imaging, flow cytometry, colony survival assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for direct promoter binding plus functional cellular readouts, single lab\",\n      \"pmids\": [\"37173384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXK1 regulates cardiogenesis by repressing the Wnt/β-catenin signaling pathway; Foxk1 KO embryoid bodies show impaired cardiac progenitor specification, reduced cardiac gene program (RNA-seq), closed chromatin at cardiogenesis loci (ATAC-seq), and loss of cardiomyocyte contractility.\",\n      \"method\": \"Foxk1 KO ES cell-derived embryoid bodies, flow cytometry, RNA-seq, ATAC-seq, ChIP-qPCR, cardiac beating assay, immunohistochemistry\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with RNA-seq, ATAC-seq, ChIP, and functional cardiac readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37036809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Foxk1 and Foxk2 directly activate CCNB1 and CDK1 transcription, forming a CCNB1/CDK1 complex that facilitates G2/M transition in cardiomyocytes; they also upregulate HIF1α to enhance glycolysis and the pentose phosphate pathway, supporting cardiomyocyte proliferation. Cardiomyocyte-specific KO impairs neonatal heart regeneration after MI; AAV9-mediated overexpression extends the proliferative window and enhances adult cardiac repair.\",\n      \"method\": \"Cardiomyocyte-specific KO mice, AAV9 overexpression, ChIP, RNA-seq, flow cytometry, MI model, cell cycle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiomyocyte-specific KO, ChIP, and AAV rescue with in vivo cardiac phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"40128196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxk1 directly binds promoter regions of glycolytic enzyme genes in osteoblasts (identified by CUT&Tag), and conditional Foxk1 KO in preosteoblasts reduces aerobic glycolysis, osteoblast differentiation, bone mass, and mechanical strength. Glycolysis inhibition by 2-DG blocks Foxk1-overexpression-induced osteoblast effects, confirming glycolysis as the mechanistic effector.\",\n      \"method\": \"Conditional Foxk1 KO mice, CUT&Tag, glycolysis assays, 2-DG inhibition, Osterix-Cre overexpression, bone histomorphometry\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, genome-wide CUT&Tag, pharmacological rescue, and in vivo bone phenotype\",\n      \"pmids\": [\"39232134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 is O-GlcNAcylated; this modification peaks at G1/S and is required for FOXK1 to promote E2F target gene transcription, cell proliferation, and cellular transformation. O-GlcNAcylation-defective FOXK1 shows reduced BAP1 recruitment to gene regulatory regions, accompanied by increased H2AK119ub and decreased H3K4me1, creating a repressive chromatin state. OGT-dependent O-GlcNAcylation is promoted by insulin resistance/nuclear OGT elevation.\",\n      \"method\": \"O-GlcNAc modification assay, OGT inhibition/knockdown, mutagenesis of O-GlcNAcylation sites, ChIP-seq, H2AK119ub ChIP, Co-IP with BAP1, cell transformation assays, xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM identification, mutagenesis, ChIP-seq, Co-IP, and in vivo transformation assays in one peer-reviewed study\",\n      \"pmids\": [\"40593803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 O-GlcNAcylation (same finding as above, initially reported as preprint) co-opts BAP1 to the E2F pathway to promote oncogenesis; loss of O-GlcNAcylation reduces BAP1 occupancy, increases H2AK119ub, and impairs E2F target gene expression.\",\n      \"method\": \"O-GlcNAc mass spectrometry, site mutagenesis, ChIP-seq, Co-IP, cell proliferation/transformation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — same mechanistic findings as peer-reviewed paper (PMID 40593803); included for completeness as the preprint source\",\n      \"pmids\": [\"38463952\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FoxK1 binds to the Pparγ2 promoter and stimulates its transcriptional activity in mesenchymal progenitor cells; adipogenic stimulation induces nuclear translocation of Foxk1 via mTOR and PI3K signaling, and Foxk1 overexpression promotes adipocyte differentiation while Foxk1 silencing impairs it.\",\n      \"method\": \"ChIP, luciferase reporter assay, Foxk1 overexpression/knockdown in C3H/10T1/2, ST2 and primary BMSCs, nuclear translocation imaging, PI3K/mTOR inhibitor treatment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirming direct promoter binding, functional OE/KD, single lab\",\n      \"pmids\": [\"37889840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FoxK1 directly binds the genome at >4,000 gene promoters/enhancers in hepatocytes; insulin enhances this interaction for ~75% of sites. FoxK1 ChIP-seq binding overlaps with that of the insulin receptor at genes including LARS1 and TIMM22, suggesting FoxK1 acts as a transcriptional partner for some IR-mediated gene regulation.\",\n      \"method\": \"ChIP-seq for FoxK1, IR and FoxO1 in liver cells; siRNA knockdown; gene expression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with knockdown validation, single lab, mechanistic inference from overlap\",\n      \"pmids\": [\"37852413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP28 interacts with FOXK1 and deubiquitinates it, stabilizing FOXK1 protein. Stabilized FOXK1 activates the Hippo signaling pathway, promoting cell proliferation and radioresistance in lung cancer.\",\n      \"method\": \"In vitro ubiquitination assay, Co-IP, USP28 knockdown, RNA-seq pathway analysis, xenograft model, immunohistochemistry\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitination assay plus Co-IP and functional KD, single lab\",\n      \"pmids\": [\"39983825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GARS protein binds to FOXK1 and reduces its ubiquitination, thereby stabilizing FOXK1. Stable FOXK1 then directly transactivates LDHA, PKM2, and GLUT1 promoters to promote glycolysis in hepatocellular carcinoma.\",\n      \"method\": \"Co-IP, ubiquitination assay, ChIP (FOXK1 on glycolytic gene promoters), KLF16 KD/OE, in vitro and in vivo glycolysis assays\",\n      \"journal\": \"The Tohoku journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and ChIP confirming direct promoter binding, single lab\",\n      \"pmids\": [\"40603105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 recruits multiple transcriptional corepressor complexes (NCoR/SMRT, SIN3A, NuRD, and REST/CoREST); the FOXK1/NCoR/SIN3A complex transcriptionally represses circadian clock genes including CLOCK, PER2, and CRY2 to promote breast cancer cell proliferation. Insulin resistance elevates OGT, causing nuclear translocation and increased FOXK1 expression.\",\n      \"method\": \"Co-IP (silver staining and mass spectrometry for complex members), ChIP-seq, qChIP, western blot, TUNEL and colony assay, xenograft, FOXK1 OE/KD\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex identification, ChIP-seq, and functional assays in single lab\",\n      \"pmids\": [\"39094826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 interacts with the REST/CoREST complex (confirmed by Co-IP) to transcriptionally repress apoptotic pathway genes in ER+ breast cancer cells, preventing apoptosis and promoting tumor growth in vivo.\",\n      \"method\": \"Co-IP, ChIP-seq, qChIP, western blot, TUNEL, cell counting and colony assays, xenograft\",\n      \"journal\": \"Animal models and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP-seq identifying complex and genomic targets, functional KO/OE, single lab\",\n      \"pmids\": [\"38238876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC1 and FOXK1 interact; the HDAC1-FOXK1 complex silences miR-33a expression, leading to upregulation of ABCB7 and p70S6K1 and conferring EGFR-TKI resistance in non-small cell lung cancer.\",\n      \"method\": \"Co-IP, HDAC1 knockdown/overexpression, miR-33a reporter assay, flow cytometry, Transwell, xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and functional knockdown with in vivo validation, single lab\",\n      \"pmids\": [\"39198847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In renal tubular cells, TGF-β1 induces Foxk1 expression; Foxk1 functions as a transcriptional repressor of the N-cadherin gene. JLP (JNK-associated leucine zipper protein) restrains Foxk1 induction; loss of JLP leads to Foxk1-driven N-cadherin downregulation and a partial EMT state during renal fibrosis.\",\n      \"method\": \"TGF-β1 treatment, Foxk1 overexpression/knockdown, ChIP, luciferase reporter assay (N-cadherin promoter), JLP KO fibrosis model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay identifying direct promoter repression plus genetic epistasis, single lab\",\n      \"pmids\": [\"37013185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KSHV ORF45 binds to FoxK1 and FoxK2 through their FHA domains using a conserved S/T linear motif; ORF45 augments FoxK1/K2 promoter occupancy and transcriptional activity at late viral gene promoters to promote KSHV lytic replication. A single-point mutation in the ORF45 S/T motif abolishes the ORF45-FOXK1/2 interaction.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter, FHA domain mutagenesis, point mutation of ORF45 S/T motif, FoxK1/K2 siRNA depletion, virion production assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mutagenesis defining the FHA-binding motif, ChIP, and functional viral replication assay, multiple orthogonal methods\",\n      \"pmids\": [\"39287387\", \"39494902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXK1 methylation at its promoter influences FOXK1 gene expression (dual luciferase reporter assay). Paternal age correlates with decreased FOXK1 sperm methylation, and this epigenetic change is transmitted to offspring cord blood on the paternal allele (allele-specific pyrosequencing with informative SNP).\",\n      \"method\": \"Bisulfite pyrosequencing, allele-specific pyrosequencing with informative SNP, dual luciferase reporter assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct reporter assay for methylation-dependent expression; allele-specific transmission established by deep bisulfite sequencing, single lab\",\n      \"pmids\": [\"28171595\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXK1 is a forkhead/winged-helix transcription factor and FHA-domain protein that functions as a nutrient- and growth-factor-regulated transcriptional activator or repressor: it is kept nuclear by active mTORC1 (which suppresses GSK3-dependent phosphorylation and 14-3-3-mediated nuclear export) and drives aerobic glycolysis by directly transactivating genes encoding glycolytic enzymes and PDKs while suppressing mitochondrial pyruvate oxidation; it regulates cell-cycle progression partly through p21 and the E2F pathway (the latter requiring O-GlcNAcylation for BAP1 co-recruitment and H2AK119 deubiquitination); it interacts with partners including SRF, Fhl2/FHL2, Sin3, Foxo4/MEF2, 53BP1 (inhibiting NHEJ), HDAC3 (stabilizing FOXK1 for STAT1/2 transcription), REST/CoREST and NCoR/SIN3A repressor complexes, and ASXL1 within the BAP1 PR-DUB complex; it is post-translationally regulated by GSK3 phosphorylation (nuclear exclusion), PP2A/B56 dephosphorylation (nuclear activation downstream of mTORC1), USP28-mediated deubiquitination (stabilization), and O-GlcNAcylation (BAP1 recruitment and E2F activation); and it plays essential developmental roles in myogenic progenitor cell cycling, cardiogenesis (repressing Wnt/β-catenin), osteoblast bone formation, and adipogenesis (transactivating Pparγ2).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOXK1 is a forkhead/winged-helix transcription factor and FHA-domain protein that couples nutrient and growth-factor signaling to a transcriptional program governing cellular metabolism, cell-cycle progression, and chromatin state [#3, #4]. Its activity is controlled chiefly by regulated nuclear access: active mTORC1 suppresses GSK3-dependent phosphorylation of FOXK1, preventing 14-3-3 binding and nuclear exclusion, while PP2A-B56 dephosphorylates nuclear FOXK1 to license its transcriptional output, so that insulin/Akt-mTOR signaling drives FOXK1 into the nucleus reciprocally to FoxO1 export [#0, #1, #4]. Once nuclear, FOXK1 (with FOXK2) directly transactivates glycolytic enzyme genes (HK2, PFK, PKM, LDHA) and pyruvate dehydrogenase kinases while suppressing pyruvate dehydrogenase phosphatase, diverting pyruvate to lactate and enforcing aerobic glycolysis—an axis it uses in hepatocytes, osteoblasts, and cardiomyocytes [#3, #28, #27]. FOXK1 promotes cell-cycle progression by repressing the CDK inhibitor p21 (genetically epistatic in myogenic progenitors) and by directly activating cell-cycle drivers including CDC25A, CDK4, CCNB1, and CDK1 [#5, #24, #25, #27]. FOXK1 is also a chromatin-regulatory factor: it is an integral subunit of the BAP1 PR-DUB complex (with HCFC1, OGT, and ASXL proteins), recruiting BAP1 to chromatin to remove H2AK119ub1, and O-GlcNAcylation of FOXK1 peaking at G1/S is required for BAP1 co-recruitment and E2F target activation [#12, #29]. It additionally nucleates corepressor complexes (Sin3, NCoR/SIN3A, REST/CoREST) to repress target genes and interacts with 53BP1 to inhibit NHEJ and bias repair toward homologous recombination [#9, #35, #36, #14]. Protein levels are stabilized by deubiquitination (USP28) and by HDAC3, which protects FOXK1 from lysosomal degradation to sustain STAT1/2 expression in antiviral immunity [#33, #15]. FOXK1 has essential developmental roles in myogenic progenitor cycling, cardiogenesis through repression of Wnt/β-catenin, osteoblast bone formation, and adipogenesis via Pparγ2 [#5, #26, #28, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established FOXK1 as a required driver of progenitor cell-cycle progression and placed a defined cell-cycle inhibitor downstream of it, the first genetic dissection of FOXK1 function.\",\n      \"evidence\": \"Foxk1 knockout and Foxk1/p21CIP double-knockout epistasis with cell-cycle and regeneration readouts in mice\",\n      \"pmids\": [\"12446708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether p21 repression is direct DNA binding versus indirect\", \"Restricted to myogenic progenitors\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined upstream transcriptional control of the Foxk1 gene and identified FOXK1 as an SRF-dependent transcriptional repressor, framing its dual coactivator/corepressor behavior.\",\n      \"evidence\": \"Sox15/Fhl3 promoter studies with transgenic reporter and ChIP; SRF Co-IP and ChIP at SM alpha-actin/PPGB promoters\",\n      \"pmids\": [\"17363903\", \"17670796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism converting FOXK1 between activator and repressor not defined\", \"Cofactor requirements at SRF sites unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the corepressor partners and protein interactions through which FOXK1 represses myogenic differentiation and promotes proliferation, mapping a partner network (Sin3, FHL2, FOXO4, MEF2).\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, domain mapping, Co-IP, and reporter assays with knockdown phenotypes in C2C12 cells\",\n      \"pmids\": [\"22956541\", \"20013826\", \"22476904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target sets not defined\", \"Several interactions characterized only in myogenic context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed FOXK1/K2 are shared targets of viral oncoproteins via a conserved Ser/Thr motif, implicating them in suppression of cell transformation and foreshadowing FHA-domain recognition of phosphomotifs.\",\n      \"evidence\": \"TAP-MS, Co-IP, motif mutagenesis, and transformation assays with adenovirus E1A and beta-HPV E6\",\n      \"pmids\": [\"20053746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous phosphomotif partners not identified at this stage\", \"Transcriptional consequences of viral engagement undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how nutrient/growth-factor signaling controls FOXK1, defining the mTORC1–GSK3–14-3-3 and PP2A-B56 circuit that gates its nuclear localization and transcriptional activity.\",\n      \"evidence\": \"Phosphoproteomics, 14-3-3 Co-IP, nuclear/cytoplasmic fractionation, ChIP, mutagenesis, and PP2A-B56 knockdown rescue\",\n      \"pmids\": [\"29861159\", \"29845697\", \"29186685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of GSK3/PP2A target residues incompletely mapped\", \"How dephosphorylation alters DNA binding affinity mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established FOXK1/K2 as master inducers of aerobic glycolysis and showed insulin-driven nuclear translocation reciprocal to FoxO1, connecting signaling input to a metabolic transcriptional output.\",\n      \"evidence\": \"ChIP, RNA-seq, reporter assays, enzyme activity, metabolic flux, and knockdown/overexpression in cell lines, primary cells, and in vivo\",\n      \"pmids\": [\"30700909\", \"30952843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-activators required for glycolytic gene activation not fully defined\", \"Relationship between metabolic and cell-cycle gene programs left open\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined FOXK1 as a chromatin-regulatory factor by establishing it as an integral PR-DUB subunit that recruits BAP1 to remove H2AK119ub1, and revealed an ASXL1 mutation that disrupts this recruitment in leukemia.\",\n      \"evidence\": \"Co-IP, ChIP-seq, H2AK119ub1 ChIP, RNA-seq, and FOXK1/2 and ASXL knockouts in ES cells; allele-specific ASXL1 deletion\",\n      \"pmids\": [\"32747411\", \"32683582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of PR-DUB targeting to specific loci incompletely defined\", \"ASXL1 finding rests on single-lab allele-specific experiments\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FOXK1 function into genome stability, showing a cell-cycle/DNA-damage-regulated interaction with 53BP1 that biases double-strand-break repair and confers PARP-inhibitor resistance.\",\n      \"evidence\": \"Co-IP, proximity ligation, laser micro-irradiation, telomere fusion, HR/NHEJ and PARPi sensitivity assays\",\n      \"pmids\": [\"32783940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the 53BP1 effect requires FOXK1 DNA binding or is purely protein-scaffolding unresolved\", \"Generality across cell types beyond BRCA1-deficient models untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed FOXK1 stability is regulated by HDAC3, which protects it from lysosomal degradation to sustain STAT1/2 transcription and antiviral immunity, adding a degradation-control layer.\",\n      \"evidence\": \"Co-IP, ChIP, HDAC3/FOXK1 knockout macrophages, viral infection and lysosomal-inhibitor experiments\",\n      \"pmids\": [\"35081346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase routing FOXK1 to lysosomal degradation not identified\", \"Whether HDAC3 catalytic activity is required unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined developmental and regenerative roles of FOXK1 in heart and bone, linking its glycolytic and cell-cycle programs to cardiac progenitor specification, cardiomyocyte proliferation, and osteoblast bone formation.\",\n      \"evidence\": \"Foxk1 KO embryoid bodies and cardiomyocyte/preosteoblast conditional KO with RNA-seq, ATAC-seq, CUT&Tag, ChIP, glycolysis and 2-DG rescue, and in vivo cardiac/bone phenotypes\",\n      \"pmids\": [\"37036809\", \"39232134\", \"40128196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets mediating Wnt/β-catenin repression in cardiogenesis not fully enumerated\", \"Crosstalk between metabolic and cell-cycle target sets in vivo not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified O-GlcNAcylation as the modification gating FOXK1's chromatin output, required for BAP1 co-recruitment and E2F target activation and linking insulin resistance to FOXK1-driven oncogenesis.\",\n      \"evidence\": \"O-GlcNAc mass spectrometry, site mutagenesis, OGT inhibition, ChIP-seq, H2AK119ub ChIP, BAP1 Co-IP, transformation and xenograft assays\",\n      \"pmids\": [\"40593803\", \"38463952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between O-GlcNAcylation and the phospho-regulated nuclear localization switch not integrated\", \"Whether all FOXK1 functions depend on O-GlcNAcylation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the FOXK1 corepressor repertoire (NCoR/SIN3A, NuRD, REST/CoREST) and showed repression of circadian and apoptotic gene programs in breast cancer, with USP28-mediated deubiquitination as an additional stabilization route.\",\n      \"evidence\": \"MS-based complex identification, ChIP-seq, Co-IP, TUNEL/colony assays, xenografts; in vitro ubiquitination and USP28 knockdown\",\n      \"pmids\": [\"39094826\", \"38238876\", \"39983825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants selecting among multiple corepressor complexes at given loci unknown\", \"Several interactions rest on single-lab Co-IP/ChIP\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the phospho-regulated nuclear-access switch, O-GlcNAc-dependent chromatin recruitment, and the choice between coactivator versus corepressor complexes are integrated into a single context-specific FOXK1 output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling PTM state to target selection\", \"Structural basis of FHA-domain phosphomotif recognition of endogenous partners not defined\", \"In vivo causal hierarchy among metabolic, cell-cycle, and chromatin functions unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 24, 25, 27, 35]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12, 14, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 28]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 24, 25, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 35, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 26, 28, 31]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"BAP1 PR-DUB complex\", \"NCoR/SIN3A corepressor complex\", \"REST/CoREST complex\"],\n    \"partners\": [\"FOXK2\", \"BAP1\", \"ASXL1\", \"53BP1\", \"HDAC3\", \"FHL2\", \"SRF\", \"USP28\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}