Affinage

ZHX2

Zinc fingers and homeoboxes protein 2 · UniProt Q9Y6X8

Length
837 aa
Mass
92.3 kDa
Annotated
2026-06-11
59 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZHX2 is a zinc-finger/homeodomain transcription factor that acts predominantly as a sequence-specific repressor of a developmentally silenced gene program in the liver while functioning as a context-dependent co-activator in cancer (PMID:15626755, PMID:30026228). It was originally identified as the gene responsible for hereditary persistence of alpha-fetoprotein and H19, with liver-specific transgenic complementation restoring postnatal silencing of these loci (PMID:15626755), and it likewise enforces postnatal repression of lipoprotein lipase to control hepatic lipoprotein metabolism (PMID:20160197). As a repressor it directly binds target promoters (GPC3, MDR1 via NF-YA, mitochondrial ETC genes) and additionally tunes lipid metabolism by driving miR-24-3p-mediated SREBP1c degradation and by destabilizing PGC-1α, thereby restraining de novo lipogenesis and mitochondrial OXPHOS (PMID:25473899, PMID:25195714, PMID:32770671, PMID:37980429). In clear-cell renal carcinoma ZHX2 switches to an oncogenic co-activator: VHL normally targets it for hydroxylation-dependent ubiquitination, so VHL loss stabilizes and nuclearizes ZHX2, which then associates with NF-κB p65 to activate NF-κB target genes (PMID:30026228). ZHX2 protein abundance is opposed by USP13-mediated deubiquitination (PMID:36037364), its promoter occupancy depends on NRMT1-catalyzed N-terminal methylation (PMID:35613330), and YAP both suppresses its expression and competes for p65 binding (PMID:40120683). Under hypoxia ZHX2 undergoes liquid-liquid phase separation through a proline-rich intrinsically disordered region, and phosphorylation at S625/S628 recruits CTCF into condensates to remodel chromatin looping and drive metastatic transcription (PMID:40185097). Beyond transcription, ZHX2 forms homo- and heterodimers with ZHX1 and ZHX3 (PMID:14659886), and in immune and metabolic settings controls macrophage glycolysis and polarization (Pfkfb3, Irf1/p65), NK cell maturation (Zeb2), and β-cell mass (Pax6) (PMID:32179636, PMID:37582865, PMID:34279541, PMID:37275527).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 Medium

    Established that ZHX2 is a member of a family of dimerizing transcriptional repressors, defining its structural basis for action before its physiological targets were known.

    Evidence cDNA cloning with in vitro and in vivo protein-protein interaction assays showing ZHX2-ZHX3 heterodimerization via HD1

    PMID:14659886

    Open questions at the time
    • No target genes or promoter specificity defined
    • Functional consequence of heterodimerization on repression not tested
  2. 2004 High

    Identified ZHX2 as the causal gene for hereditary persistence of AFP/H19, answering what enforces postnatal silencing of fetal liver genes.

    Evidence Positional cloning and liver-specific Zhx2 transgenic complementation in BALB/cJ mice

    PMID:15626755

    Open questions at the time
    • Direct promoter binding to AFP/H19 not shown
    • Cofactor requirements for repression undefined
  3. 2009 High

    Extended ZHX2's repressive role from oncofetal markers to metabolic genes and connected it to a quantitative lipid phenotype.

    Evidence QTL mapping with congenic strains plus transgenic complementation and hepatic microarray in BALB/cJ mice (LPL); Co-IP and functional assays in neural progenitors (ephrin-B1)

    PMID:19515908 PMID:20160197

    Open questions at the time
    • Direct LPL promoter occupancy not demonstrated in this work
    • Mechanism by which ephrin-B1 intracellular domain enhances repression unresolved
  4. 2014 Medium

    Demonstrated ZHX2 acts through direct promoter binding and partner transcription factors, clarifying its molecular mode of repression.

    Evidence ChIP and luciferase reporter assays for GPC3 core promoter binding and NF-YA-dependent MDR1 repression with nuclear translocation requirement

    PMID:25195714 PMID:25473899

    Open questions at the time
    • Genome-wide binding repertoire not defined
    • Determinants of nuclear translocation unknown at this stage
  5. 2018 High

    Revealed that ZHX2 protein stability is governed by the VHL E3 ligase, explaining its accumulation and oncogenic co-activator switch in ccRCC.

    Evidence Genome-wide VHL substrate screen, hydroxylation-dependent ubiquitination/stability assays, ChIP-seq, and in vivo tumor growth assays; cccDNA ChIP and miR-155 3'UTR studies for HBV regulation

    PMID:29580980 PMID:29752719 PMID:30026228

    Open questions at the time
    • Direct co-occupancy with p65 on NF-κB targets not mapped in this study
    • Hydroxylation site and prolyl hydroxylase identity not fully resolved
  6. 2020 High

    Showed ZHX2 acts bidirectionally as both repressor and activator across tissues, linking it to metabolism, immunity, and stemness.

    Evidence Myeloid- and liver-specific conditional KO mice with ChIP and genetic rescue for Pfkfb3 activation, miR-24-3p/SREBP1c repression, and KDM2A-mediated stemness control

    PMID:32114388 PMID:32179636 PMID:32382017 PMID:32770671 PMID:32780537

    Open questions at the time
    • Molecular switch dictating activator vs repressor mode not defined
    • How ZHX2 selects activating versus repressing promoters unclear
  7. 2021 High

    Defined ZHX2 as a HIF1α co-activator in TNBC and a repressor of NK maturation, broadening its transcription-factor partnerships and identifying functionally critical residues.

    Evidence Reciprocal Co-IP, ChIP-seq co-occupancy at active promoters, ZHX2 point mutagenesis (R491/R581/R674); NK-specific conditional KO with Zeb2 target identification

    PMID:34279541 PMID:34779768

    Open questions at the time
    • Structural basis of ZHX2-HIF1α interaction unknown
    • How the same factor partners with both p65 and HIF1α in different cancers unresolved
  8. 2022 High

    Identified post-translational controls that set ZHX2 abundance and chromatin activity, providing actionable nodes upstream of its function.

    Evidence DUB library screen with ubiquitination/enzymatic-mutant assays (USP13); in vitro Nα-methylation assay and methylation-deficient mutant with promoter occupancy readout (NRMT1)

    PMID:35613330 PMID:36037364

    Open questions at the time
    • Interplay between VHL ubiquitination and USP13 deubiquitination not kinetically resolved
    • Whether N-terminal methylation is regulated dynamically in disease unknown
  9. 2023 Medium

    Mapped ZHX2's reach into mitochondrial metabolism, macrophage polarization, β-cell maintenance, and epithelial state, while adding upstream YAP and Hippo control.

    Evidence Conditional KO and injury models with PGC-1α/ETC epistasis; Co-IP/ChIP for p65-Irf1, Pax6, CDH1, Elovl3; Co-IP showing YAP competes with ZHX2 for p65

    PMID:37275527 PMID:37460540 PMID:37582865 PMID:37847682 PMID:37980429 PMID:40120683

    Open questions at the time
    • Unified principle governing tissue-specific repressor/activator output still lacking
    • PGC-1α destabilization mechanism not molecularly resolved
  10. 2025 High

    Established a phase-separation mechanism that reframes ZHX2 as a hypoxia-responsive condensate-forming factor coupling chromatin architecture to metastasis, plus an m6A axis controlling its mRNA.

    Evidence LLPS/condensate assays with IDR deletion and S625/S628 phosphosite mutagenesis, CTCF Co-IP in condensates, chromatin-looping ChIP, in vivo metastasis; m6A-RIP/RIP and stability assays (METTL3/IGF2BP1, YTHDF2 loop); LLPS-dependent SLC3A2 activation in DLBCL

    PMID:39159608 PMID:39987125 PMID:40185097 PMID:40730912

    Open questions at the time
    • Kinase responsible for hypoxia-induced S625/S628 phosphorylation not identified
    • Relationship between condensate formation and classical dimerization/cofactor binding unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular determinant that switches ZHX2 between transcriptional repression and co-activation across tissues remains undefined.
  • No structure of ZHX2 on DNA or with its partners
  • No unified model reconciling repressor (liver) and activator (ccRCC/TNBC) functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CTCFHIF1ANRMT1RELAUSP13VHLZHX1ZHX3

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ZHX2 (Afr1) functions as a transcriptional repressor responsible for postnatal silencing of alpha-fetoprotein (AFP) and H19 in the liver. Liver-specific overexpression of a Zhx2 transgene in BALB/cJ mice (which carry a retroviral insertion disrupting Zhx2) restored wild-type H19 repression, directly demonstrating that Zhx2 is the gene responsible for hereditary persistence of AFP and H19. Transgenic complementation in BALB/cJ mice with liver-specific Zhx2 overexpression; positional cloning/mapping Proceedings of the National Academy of Sciences of the United States of America High 15626755
2003 ZHX2 forms a heterodimer with ZHX3 via a region containing homeodomain 1 (HD1), demonstrated by in vitro and in vivo protein-protein interaction assays. ZHX family members (ZHX1, ZHX2, ZHX3) act as ubiquitous transcriptional repressors and can form both homodimers and heterodimers. In vitro and in vivo protein-protein interaction assays (co-immunoprecipitation/pull-down); cDNA cloning and expression analysis Gene Medium 14659886
2009 ZHX2 is expressed specifically in neural progenitor cells during cortical neurogenesis and binds to the cytoplasmic domain of ephrin-B1. ZHX2 acts as a transcriptional repressor, and its repressor activity is enhanced by co-expression with the ephrin-B1 intracellular domain. Blocking ZHX2 function causes neuronal differentiation, while overexpression of ZHX2 with ephrin-B1 intracellular domain disrupts normal differentiation of cortical neural progenitor cells. Co-immunoprecipitation (ZHX2 binding ephrin-B1); loss-of-function and gain-of-function in cultured neural progenitor cells and embryonic cortex; transcriptional repressor assay The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 19515908
2009 Zhx2 functions as a novel developmental regulator of hepatic lipoprotein metabolism. Reduced Zhx2 expression in BALB/cJ mice causes failure to suppress lipoprotein lipase (LPL) expression in adult liver, a gene normally silenced postnatally; Zhx2 transgene in BALB/cJ mice normalized hepatic LPL expression. QTL mapping and transgenic complementation identified Zhx2 as the gene underlying a chromosome 15 QTL for HDL cholesterol and triglyceride levels. QTL mapping with congenic strains; transgenic complementation; microarray analysis of hepatic gene expression Circulation. Cardiovascular genetics High 20160197
2018 ZHX2 is a substrate of the VHL E3 ubiquitin ligase complex: VHL regulates ZHX2 protein stability via hydroxylation-dependent ubiquitination. Loss of VHL in ccRCC leads to increased ZHX2 abundance and nuclear localization. ZHX2 promotes NF-κB activation in ccRCC, as demonstrated by integrated ChIP-seq and microarray analysis, and ZHX2 depletion inhibits VHL-deficient ccRCC cell growth in vitro and in vivo. Genome-wide in vitro expression/binding screen for VHL substrates; protein stability assays; ChIP-seq; microarray; in vitro and in vivo tumor growth assays (knockdown) Science (New York, N.Y.) High 30026228
2015 ZHX2 represses MDR1 (multidrug resistance 1) transcription by interacting with NF-YA and reducing NF-Y binding to the MDR1 promoter. Co-IP and ChIP assays showed ZHX2 physically interacts with NF-YA; luciferase reporter assays showed ZHX2-mediated repression of MDR1 promoter is abolished by NF-YA knockdown or mutation of the NF-Y binding site. Increased ZHX2 enhances chemosensitivity in HCC cells in vitro and in vivo. Co-immunoprecipitation; ChIP assay; luciferase reporter assay; in vitro drug sensitivity assays; in vivo xenograft Oncotarget Medium 25473899
2014 ZHX2 directly binds the core promoter of GPC3 (glypican 3) and suppresses its transcription. Nuclear translocation of ZHX2 is required for this repression. Loss of nuclear ZHX2 in HCC is responsible for GPC3 reactivation. Dual luciferase reporter assay; ChIP assay; ZHX2 overexpression/knockdown in HCC cell lines; immunohistochemistry; nuclear translocation experiments The international journal of biochemistry & cell biology Medium 25195714
2018 ZHX2 restricts HBV replication by binding to HBV cccDNA and transcriptionally inhibiting HBV promoter activities. ZHX2 also suppresses expression of histone regulator genes including p300/CBP that bind cccDNA, leading to epigenetic repression of cccDNA transcription. Dual luciferase assay; cccDNA ChIP assay; ZHX2 overexpression/knockdown in vitro and in mouse liver models; immunohistochemistry; measurement of HBV antigens and DNA Antiviral research Medium 29580980
2018 HBV X protein (HBx) inhibits ZHX2 expression via upregulation of miR-155, which targets the ZHX2 3'UTR. miR-155 overexpression reduced ZHX2 levels through its seed sites in the ZHX2 3'UTR, and blocking miR-155 increased ZHX2 levels. This pathway links HBV oncogenic properties to ZHX2 suppression. miR-155 overexpression/blockade experiments; 3'UTR reporter assay; in vitro and in vivo HBV/HBx overexpression models; qPCR and Western blot International journal of cancer Medium 29752719
2019 ZHX2 inhibits lipid uptake in hepatocytes by transcriptionally suppressing lipoprotein lipase (LPL). ZHX2 overexpression decreased LPL transcription, inhibited exogenous lipid uptake, and reduced HCC cell proliferation; LPL overexpression reversed ZHX2-mediated inhibition. ZHX2 and LPL show inverse correlation in HCC patient samples. ZHX2 overexpression/knockdown in HCC cell lines; in vitro and in vivo lipid uptake assays; LPL rescue overexpression; xenograft tumor growth; IHC in patient cohort Cell death and differentiation Medium 31740790
2020 ZHX2 enhances macrophage glycolysis and promotes sepsis pathogenesis by directly binding to the Pfkfb3 promoter and enhancing Pfkfb3 transcription. Myeloid-specific Zhx2 deletion reduced Pfkfb3 expression and macrophage glycolytic rate; Pfkfb3 overexpression rescued the glycolysis defect caused by Zhx2 deficiency. This was demonstrated by RNA-seq and ChIP assays. Myeloid-specific conditional knockout mice; RNA sequencing; ChIP assay (Zhx2 binding Pfkfb3 promoter); Pfkfb3 rescue overexpression; extracellular acidification rate and lactate measurement; cecal ligation and puncture (CLP) and LPS sepsis models Journal of immunology (Baltimore, Md. : 1950) High 32179636
2020 ZHX2 suppresses HCC progression by inhibiting de novo lipogenesis via transcriptional upregulation of miR-24-3p, which targets and promotes degradation of SREBP1c. ZHX2 overexpression reduced FASN, ACL, ACC1, and SCD1; ZHX2-mediated effects were reversed by SREBP1c overexpression; liver-specific Zhx2 KO mice showed increased spontaneous tumor formation reversed by SREBP1c inhibitor fatostatin. ZHX2 overexpression/knockdown in HCC cells; miR-24-3p rescue/inhibition; SREBP1c overexpression rescue; Zhx2 liver-specific knockout mice; fatostatin treatment; qPCR and Western blot The Journal of pathology Medium 32770671
2020 ZHX2 suppresses liver cancer stem cell (CSC) traits by transcriptionally repressing KDM2A (a histone H3K36 demethylase). ZHX2 inhibits KDM2A-mediated demethylation of H3K36 at promoters of stemness transcription factors NANOG, SOX4, and OCT4, thereby restricting CSC self-renewal, tumor initiation, and sorafenib resistance. This was demonstrated by microarray, luciferase reporter, ChIP, and ChIP-on-chip analyses. ChIP; ChIP-on-chip; luciferase reporter assay; microarray; ZHX2 overexpression/knockdown in sorted CSC populations; in vivo tumor initiation assays EBioMedicine Medium 32114388
2020 ZHX2 overexpression drives ccRCC cell growth and migration through transcriptional activation of MEK/ERK1/2 signaling and its downstream targets, and also increases VEGF secretion. ZHX2 overexpression induces sunitinib resistance through activating autophagy. Lentiviral overexpression/knockdown in VHL-deficient (786-O) and VHL-normal (CAKI-1) cell lines; in vitro and in vivo growth/migration assays; Western blot for MEK/ERK pathway; autophagic flux measurement; drug sensitivity assay with chloroquine rescue Cell death & disease Low 32382017
2021 ZHX2 physically interacts with HIF family members (HIF1α) and positively regulates HIF1α transcriptional activity in triple-negative breast cancer (TNBC). ZHX2 and HIF1α co-occupy transcriptionally active promoters marked by H3K4me3 and H3K27ac, as shown by integrated ChIP-seq and gene expression profiling. Residues R491, R581, and R674 on ZHX2 are important for its transcriptional activity and oncogenic phenotype in TNBC. Co-immunoprecipitation (ZHX2-HIF1α); ChIP-seq; gene expression profiling; ZHX2 point mutant analysis; ZHX2 knockdown with in vitro and in vivo tumor growth assays; rescue by overexpression of target genes eLife High 34779768
2021 ZHX2 transcriptionally represses Zeb2 (a key transcription factor for NK cell terminal maturation) in NK cells, thereby restricting NK cell maturation and survival. Conditional deletion of Zhx2 in NK cells resulted in accumulation of mature NK cells and enhanced NK cell response to IL-15, with Zeb2 identified as a direct downstream target. NK cell-specific conditional Zhx2 knockout mice; transcriptomic analysis; in vivo tumor models with Zhx2-deficient NK cell transfer; assessment of NK cell maturation markers The Journal of experimental medicine Medium 34279541
2022 USP13 is a deubiquitinase (DUB) that binds ZHX2 and promotes ZHX2 deubiquitination and protein stability in an enzymatically dependent manner. USP13 depletion leads to ZHX2 downregulation in ccRCC and decreased tumor cell proliferation in vitro and in vivo; the effect of USP13 on ccRCC growth is partially mediated through ZHX2. DUB cDNA library binding screen; co-immunoprecipitation (USP13-ZHX2); ubiquitination assay; enzymatic mutant USP13 analysis; 2D colony formation and 3D anchorage-independent growth assays; in vivo tumor growth Proceedings of the National Academy of Sciences of the United States of America High 36037364
2022 ZHX2 is a substrate for N-terminal methylation (Nα-methylation) by the methyltransferase NRMT1. NRMT1 can methylate ZHX2 in vitro, and a methylation-deficient ZHX2 mutant shows reduced transcription factor activity and reduced promoter occupancy. Loss of NRMT1 in mice causes dysregulation of ZHX2 targets (CYP and MUP families) in liver, linking NRMT1-mediated Nα-methylation to ZHX2 function. In vitro methylation assay (NRMT1 + ZHX2); methylation-deficient ZHX2 mutant analysis; RNA-seq of NRMT1 knockout mouse livers; promoter occupancy assay; Western blot and qPCR Transcription Medium 35613330
2023 ZHX2 is a negative regulator of mitochondrial oxidative phosphorylation (OXPHOS) during acute liver injury. ZHX2 both transcriptionally inhibits expression of mitochondrial electron transport chain genes and decreases PGC-1α protein stability, leading to reduced mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery after partial hepatectomy or CCl4 injury by increasing mitochondrial OXPHOS; inhibition of PGC-1α or ETC abolishes these protective effects. Conditional Zhx2 knockout mice; partial hepatectomy and CCl4 liver injury models; measurement of mitochondrial mass and OXPHOS; transcriptional analysis of ETC genes; PGC-1α stability assay; shRNA delivery in vivo Nature communications High 37980429
2023 ZHX2 associates with NF-κB p65 and binds to the Irf1 promoter to transcriptionally activate Irf1 in macrophages, thereby controlling macrophage polarization. Myeloid-specific Zhx2 deletion suppresses LPS-induced proinflammatory polarization but promotes IL-4- and tumor microenvironment-induced pro-tumoral macrophage phenotype. Lactate from the tumor microenvironment decreases Zhx2 expression, leading to a switch toward pro-tumor TAM phenotype. Myeloid-specific Zhx2 conditional KO mice; co-immunoprecipitation (ZHX2-p65); ChIP/reporter assay (Irf1 promoter); murine liver tumor models; macrophage polarization assays; Western blot Cell death and differentiation Medium 37582865
2023 ZHX2 transcriptionally activates Pax6 by binding to the Pax6 promoter region (positions -1740 to -1563, -862 to -559, and -251 to +75). β-cell-specific Zhx2 knockout mice showed decreased β-cell proliferation, reduced β-cell mass, and impaired glucose homeostasis, demonstrating a role for Zhx2 in maintaining β-cell mass and function via Pax6 regulation. β-cell-specific Zhx2 knockout mice; ChIP assay (Zhx2 binding Pax6 promoter); luciferase reporter assay; glucose tolerance tests; insulin secretion measurements iScience Medium 37275527
2023 ZHX2 transcriptionally inhibits GADD34 expression by binding to its promoter, thereby enhancing endoplasmic reticulum stress-mediated anticancer effects of I-125 radiation in HCC. This was part of a circSEC11A/miR-3529-3p/ZHX2/GADD34 axis. Dual-luciferase reporter assay; RNA pull-down; RNA immunoprecipitation; FISH; in vitro and in vivo anticancer effect assays (CCK-8, flow cytometry, TUNEL, EdU, transwell) Cell death discovery Low 37563132
2023 ZHX2 directly binds the CDH1 promoter and represses E-cadherin (CDH1) expression in TNBC cells. Loss of ZHX2 reactivates CDH1, promoting a hybrid mesenchymal-to-epithelial (MET) state and inhibiting cancer cell migration and metastasis. E-cadherin restoration reverses the effects of ZHX2 loss. ChIP assay (ZHX2 binding CDH1 promoter); ZHX2 knockdown/overexpression; CDH1 rescue overexpression; cell migration assays; in vivo lung metastasis models; organoid culture Cell death & disease Medium 37460540
2023 ZHX2 positively regulates Elovl3 expression in the liver by directly activating its transcription. Zhx2 loss-of-function in mice reduces Elovl3 levels; Elovl3 expression is repressed during liver regeneration correlating with reduced very long chain fatty acids. Forced Elovl3 expression in human hepatoma cells reduces cell growth and blocks cell cycle progression in S-phase. Mouse models of Zhx2 loss-of-function; liver regeneration models (partial hepatectomy, CCl4); cell growth assays; cell cycle synchronization; mRNA and protein analysis; VLCFA measurements American journal of physiology. Gastrointestinal and liver physiology Medium 37847682
2025 ZHX2 undergoes liquid-liquid phase separation (LLPS) in response to hypoxia via a proline-rich intrinsically disordered region (IDR), which enhances chromatin occupancy. Hypoxia induces phosphorylation of ZHX2 at S625 and S628, incorporating CTCF into ZHX2 condensates and altering chromatin looping to activate metastatic gene transcription. This phase separation drives cancer metastasis in breast cancer cells and is distinct from HIF-dependent hypoxia responses. Phase separation/condensate formation assays; phosphorylation site identification and mutagenesis (S625, S628); CTCF co-immunoprecipitation in condensates; ChIP for chromatin looping; in vivo metastasis models; IDR deletion mutants Molecular cell High 40185097
2025 YAP (Hippo pathway effector) inhibits ZHX2 expression and competes with ZHX2 for binding to the NF-κB subunit p65. Elevated nuclear YAP blocks the cooperative interaction between ZHX2 and p65, leading to diminished NF-κB target gene expression and suppressed ccRCC cell growth. ZHX2 overexpression or p65 overexpression rescues the anti-proliferative effects of Hippo kinase inhibition. ZHX2 and p65 co-immunoprecipitation; YAP knockdown/overexpression; pharmacological Hippo kinase inhibition; ZHX2 and p65 overexpression rescue assays; NF-κB target gene expression analysis; ccRCC cell growth assays The Journal of biological chemistry Medium 40120683
2025 ZHX2 undergoes LLPS and binds to the SLC3A2 promoter through phase separation, activating SLC3A2 transcription to inhibit ferroptosis in DLBCL cells. ZHX2-siRNA lipid nanoparticles targeting this mechanism suppressed DLBCL tumor growth in vivo. LLPS assays; ChIP assay (ZHX2 binding SLC3A2 promoter); ZHX2 knockdown/overexpression; ferroptosis assays; in vivo tumor growth with siRNA-LNP Leukemia Medium 40730912
2025 METTL3-mediated m6A methylation of ZHX2 mRNA is recognized by the m6A reader IGF2BP1, which stabilizes ZHX2 mRNA. This m6A modification promotes ZHX2 expression and renal cell carcinoma progression. METTL3 silencing reduces ZHX2, and ZHX2 overexpression reverses the inhibitory effects of METTL3 depletion on RCC tumor growth. m6A RNA immunoprecipitation assay; RNA immunoprecipitation (IGF2BP1-ZHX2 mRNA); mRNA stability assay (Actinomycin D); METTL3 knockdown; ZHX2 overexpression rescue; xenograft mouse model Kidney & blood pressure research Medium 39159608
2025 ZHX2 transcriptionally inhibits YTHDF2 by binding to its promoter region, and in turn YTHDF2 recognizes m6A-modified ZHX2 mRNA to promote its degradation, forming a feedback regulatory loop. ZHX2 overexpression protects against diabetes-induced hepatic ferroptosis by suppressing YTHDF2, which otherwise promotes GPX4 and SLC7A11 degradation. Luciferase reporter assay; ChIP assay (ZHX2 at YTHDF2 promoter); RNA immunoprecipitation (YTHDF2 binding ZHX2 mRNA); ZHX2 knockdown/overexpression; in vivo HFD/STZ diabetes mouse model; ferroptosis assays Nutrition & diabetes Medium 39987125
2019 ZHX2 and ZHX3 form heterodimeric complexes in podocytes, with ZHX2-ZHX1 localized predominantly at the podocyte cell body membrane and ZHX2-ZHX3 at the slit diaphragm. ZHX2 interacts with aminopeptidase A (ENPEP) at the cell body membrane and with ephrin-B1 (EFNB1) at the slit diaphragm, as shown by co-immunoprecipitation. ZHX2 imbalance is a critical factor in glomerular diseases, with ZHX2 sequestering ZHX1 peripherally to regulate its nuclear access. Co-immunoprecipitation (ZHX2 with aminopeptidase A and ephrin-B1); subcellular fractionation/localization; Zhx2 knockout mice; podocyte-specific Zhx2 overexpressing transgenic rats; glomerular disease models; immunofluorescence Kidney international Medium 32059999
2020 ZHX2 mediates proteasome inhibitor (bortezomib) resistance in multiple myeloma cells by directly binding NF-κB and promoting nuclear translocation of NF-κB. ZHX2 knockdown reduced nuclear NF-κB, decreased NF-κB target gene expression, and enhanced bortezomib sensitivity in myeloma cell lines. Co-immunoprecipitation (ZHX2-NF-κB); Western blot and immunofluorescence for NF-κB nuclear localization; ZHX2 knockdown; flow cytometry for apoptosis; qRT-PCR for NF-κB target genes Cancer medicine Low 32780537
2022 ZHX2 transcriptionally represses S100A14 by binding to its promoter, inhibiting thyroid cancer cell migration and metastasis. S100A14 knockdown reverses ZHX2 depletion-induced enhanced metastasis. ChIP assay (ZHX2 at S100A14 promoter); ZHX2 knockdown/overexpression; S100A14 knockdown rescue; cell migration assays; in vivo lung metastasis model Cancer cell international Low 35151335
2026 ZHX2 transcriptionally represses CRABP1 by binding to its promoter, which modulates retinoid metabolism and enhances retinoic acid (RA) sensitivity in neuroblastoma cells. ZHX2 overexpression inhibited NB malignancy and augmented RA-induced neuronal differentiation in vitro and reduced tumor growth in vivo. CHIP-qPCR (ZHX2 at CRABP1 promoter); ZHX2 knockdown/overexpression; RNA-seq; cell proliferation, migration, apoptosis assays; in vivo xenograft; differentiation marker analysis Biomedicine & pharmacotherapy Low 42070457
2019 ZHX2 knockdown in dorsal root ganglion (DRG) neurons reverses CCI (chronic constriction injury)-induced downregulation of μ-opioid receptor expression and alleviates mechanical allodynia in mice. In primary DRG neurons, ZHX2 knockdown upregulated μ-opioid receptor mRNA and protein, indicating ZHX2 represses μ-opioid receptor expression in DRG neurons. In vivo siRNA microinjection into DRG; RT-qPCR and Western blot for μ-opioid receptor; behavioral testing (paw withdrawal frequency); primary DRG neuron culture with ZHX2 siRNA transfection Nan fang yi ke da xue xue bao = Journal of Southern Medical University Low 31511211
2025 ZHX2 transcriptionally inhibits FABP4 by binding to its promoter region, thereby blocking the AGEs/RAGE/NLRP3 pathway and inhibiting podocyte pyroptosis and inflammation in diabetic nephropathy. ChIP assay (ZHX2 at FABP4 promoter); luciferase reporter assay; ZHX2 overexpression/knockdown; in vitro high-glucose podocyte model; in vivo diabetic nephropathy mouse model; exosome delivery of ZHX2 FASEB journal : official publication of the Federation of American Societies for Experimental Biology Low 41603587

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science (New York, N.Y.) 159 30026228
2004 Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. Proceedings of the National Academy of Sciences of the United States of America 84 15626755
2018 HBV suppresses ZHX2 expression to promote proliferation of HCC through miR-155 activation. International journal of cancer 58 29752719
2019 Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake. Cell death and differentiation 53 31740790
2020 ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation. EBioMedicine 52 32114388
2011 Zhx2 and Zbtb20: novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer. Seminars in cancer biology 50 21216289
2020 Zhx2 Accelerates Sepsis by Promoting Macrophage Glycolysis via Pfkfb3. Journal of immunology (Baltimore, Md. : 1950) 48 32179636
2022 USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer. Proceedings of the National Academy of Sciences of the United States of America 47 36037364
2006 Promoter hypermethylation of a novel gene, ZHX2, in hepatocellular carcinoma. American journal of clinical pathology 46 16707376
2011 Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma. Leukemia research 42 22078940
2009 ZHX2 Interacts with Ephrin-B and regulates neural progenitor maintenance in the developing cerebral cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 19515908
2003 The mouse zinc-fingers and homeoboxes (ZHX) family; ZHX2 forms a heterodimer with ZHX3. Gene 39 14659886
2021 ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer. eLife 38 34779768
2020 ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p. The Journal of pathology 34 32770671
2020 ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma. Cell death & disease 33 32382017
2009 Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Circulation. Cardiovascular genetics 33 20160197
2015 ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA. Oncotarget 32 25473899
2014 Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma. The international journal of biochemistry & cell biology 30 25195714
2008 Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma. British journal of haematology 30 18353163
2011 t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2. Genes, chromosomes & cancer 29 21987443
2021 HNRNPD interacts with ZHX2 regulating the vasculogenic mimicry formation of glioma cells via linc00707/miR-651-3p/SP2 axis. Cell death & disease 28 33542193
2009 ZHX2 and ZHX3 repress cancer markers in normal hepatocytes. Frontiers in bioscience (Landmark edition) 26 19273305
2018 Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice. Arteriosclerosis, thrombosis, and vascular biology 25 30026271
2018 Tumor suppressor ZHX2 restricts hepatitis B virus replication via epigenetic and non-epigenetic manners. Antiviral research 24 29580980
2021 Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity. The Journal of experimental medicine 22 34279541
2023 Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response. Cell death and differentiation 21 37582865
2020 ZHX2 inhibits proliferation and promotes apoptosis of human lung cancer cells through targeting p38MAPK pathway. Cancer biomarkers : section A of Disease markers 19 31683461
2023 ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury. Nature communications 18 37980429
2025 Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis. Molecular cell 17 40185097
2022 ZHX2 inhibits thyroid cancer metastasis through transcriptional inhibition of S100A14. Cancer cell international 17 35151335
2007 Characterization of the ETnII-alpha endogenous retroviral element in the BALB/cJ Zhx2 ( Afr1 ) allele. Mammalian genome : official journal of the International Mammalian Genome Society 17 18066620
2010 Expression of RAN, ZHX-2, and CHC1L genes in multiple myeloma patients and in myeloma cell lines treated with HDAC and Dnmts inhibitors. Neoplasma 13 20568903
2019 The zinc fingers and homeoboxes 2 protein ZHX2 and its interacting proteins regulate upstream pathways in podocyte diseases. Kidney international 12 32059999
2022 Novel regulation of the transcription factor ZHX2 by N-terminal methylation. Transcription 11 35613330
2020 ZHX2 mediates proteasome inhibitor resistance via regulating nuclear translocation of NF-κB in multiple myeloma. Cancer medicine 11 32780537
2019 Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high-fat diet are due, in part, to Zhx2. Mammalian genome : official journal of the International Mammalian Genome Society 11 31321500
2022 Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward. The Journal of pharmacology and experimental therapeutics 10 35688478
2024 METTL3 and IGF2BP1-Mediated m6A Modification of ZHX2 Promotes Tumor Property of Renal Cell Carcinoma. Kidney & blood pressure research 9 39159608
2022 ZHX2 in health and disease. Frontiers in oncology 9 36465389
2025 ZHX2 inhibits diabetes-induced liver injury and ferroptosis by epigenetic silence of YTHDF2. Nutrition & diabetes 8 39987125
2025 The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2. The Journal of biological chemistry 6 40120683
2023 Characterization of circSEC11A as a novel regulator of Iodine-125 radioactive seed-induced anticancer effects in hepatocellular carcinoma via targeting ZHX2/GADD34 axis. Cell death discovery 5 37563132
2025 Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2. Leukemia 4 40730912
2023 ZHX2 deficiency enriches hybrid MET cells through regulating E-cadherin expression. Cell death & disease 4 37460540
2018 The role of Zhx2 transcription factor in bipolar cell differentiation during mouse retinal development. Biochemical and biophysical research communications 4 30146259
2023 Zhx2 maintains islet β-cell mass and function by transcriptionally regulating Pax6. iScience 3 37275527
2023 An intronic genetic variant of ZHX2 predicts response to pegylated interferon α therapy in HBeAg-positive chronic hepatitis B patients. Antiviral research 3 39492517
2011 Lack of association of G779A ZHX-2 gene variant with HbF levels in β-thalassemia major. European journal of haematology 3 21443521
2025 Validation studies and multiomics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior. The Journal of pharmacology and experimental therapeutics 2 40215834
2019 Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation. Neoplasma 2 30784286
2023 Elongation of very long chain fatty acids-3 (Elovl3) is activated by ZHX2 and is a regulator of cell cycle progression. American journal of physiology. Gastrointestinal and liver physiology 1 37847682
2023 Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype. Cancers 1 38201462
2026 GMSCs-Derived Exosome ZHX2 Improves Diabetes Nephropathy by Blocking AGEs/RAGE/NLRP3 Pathway to Inhibit Podocyte Pyroptosis and Inflammatory Response. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41603587
2026 Transcription factor zinc fingers and homeoboxes protein 2 (ZHX2) drives CRABP1 targeting to strengthen retinoic acid sensitivity and potentiate therapeutic response in neuroblastoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 42070457
2025 The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2. bioRxiv : the preprint server for biology 0 38979373
2025 Molecular mechanisms underlying the oncogenic and tumor-suppressive roles of ZHX2 in cancers. Cancer genetics 0 40991982
2024 Validation studies and multi-omics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior. bioRxiv : the preprint server for biology 0 39257803
2024 Relationship between ZHX2 Expression and VHL Gene Alteration in VHL-associated and Sporadic Hemangioblastomas of the Central Nervous System. Journal of kidney cancer and VHL 0 39850947
2019 [Role of ZHX2 in regulating dorsal root ganglion μ-opioid receptor expression in mice with peripheral nerve injuryinduced pain hypersensitivity]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 31511211

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