Affinage

HHIP

Hedgehog-interacting protein · UniProt Q96QV1

Length
700 aa
Mass
78.9 kDa
Annotated
2026-06-10
63 papers in source corpus 23 papers cited in narrative 23 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

HHIP is a vertebrate cell-surface antagonist of Hedgehog (Hh) signaling that acts as a structural decoy receptor for all Hh ligands (PMID:19561609, PMID:19561611). Its ectodomain, built from two EGF domains and a six-bladed beta-propeller, inserts a critical loop into the pseudo active site groove of SHH/DHH and directly coordinates the ligand's Zn2+ cation, with Ca2+ preventing electrostatic repulsion at the interface, thereby competing with Patched for ligand binding in a tunable metal-dependent manner (PMID:19561609, PMID:19561611). At the cell surface HHIP colocalizes with Smoothened and internalizes with it in response to Hh; active Smoothened signaling drives HHIP internalization and degradation cell-autonomously, yet HHIP continues to sequester ligand to inhibit Hh signaling non-cell-autonomously in neighboring cells (PMID:25215859, PMID:16765934). HHIP expression is controlled by distal enhancer–promoter chromatin looping, where a COPD-risk SNP enhances repressor Sp3 binding to reduce HHIP levels (PMID:22140090), and by promoter CpG-island methylation and silencing histone marks that epigenetically inactivate HHIP in cancer cells (PMID:15970691, PMID:32710611). Through restraint of GLI-dependent Hh output, HHIP maintains tissue homeostasis: its loss in mice causes age-related emphysema driven by oxidative stress (PMID:27444019), airway smooth-muscle remodeling via glycolytic metabolic reprogramming (PKM2) (PMID:33907231), and protects bronchial epithelium against smoke-induced EMT (PMID:40192657), while HHIP is required for coronal suture development through a PTHLH–Ihh epistatic axis (PMID:34880220, PMID:41000054). In stromal and fibroblast contexts HHIP modulates paracrine Hh–VEGF angiogenesis (PMID:28127049, PMID:40875440) and constrains tumor cell proliferation and stemness (PMID:39553307). In lung cells HHIP physically interacts with CAVIN1 and TP53, linking it to oxidative stress response pathways (PMID:39945347).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Established the structural and biochemical basis for how HHIP antagonizes Hedgehog: not as a signaling receptor but as a decoy that occludes the ligand's functional surface.

    Evidence X-ray crystal structures of free HHIP and HHIP–SHH/DHH complexes with and without Ca2+, plus peptide binding and mutagenesis

    PMID:19561609 PMID:19561611

    Open questions at the time
    • Structures resolve the ectodomain interface but not the membrane-attachment or internalization machinery
    • Did not address how metal-dependent affinity is regulated in vivo
  2. 2006 High

    Showed HHIP regulates Hh not only by ligand sequestration but also by modulating Smoothened subcellular trafficking, refining the model of its cellular action.

    Evidence Morpholino knockdown, domain-deletion constructs, colocalization imaging and Smoothened internalization/muscle fate assays in zebrafish

    PMID:16765934

    Open questions at the time
    • Mechanism by which Hhip influences Smoothened localization unresolved
    • Role of the membrane-associated domain in Patched synergy not molecularly defined
  3. 2014 Medium

    Resolved the apparent paradox of how HHIP-expressing cells respond to Hh by distinguishing cell-autonomous degradation from non-cell-autonomous sequestration.

    Evidence Hhip overexpression in neural tube cells, live imaging of internalization, and Smo activation/inhibition with non-cell-autonomous inhibition assays

    PMID:25215859

    Open questions at the time
    • Degradation route and trafficking adaptors not identified
    • Single lab; quantitative thresholds for ligand sequestration unknown
  4. 2011 High

    Connected disease-associated genetic variation to HHIP regulation by demonstrating distal enhancer–promoter looping controls HHIP transcription.

    Evidence Chromatin conformation capture, luciferase reporters, EMSA for Sp3 binding, and analysis of COPD lung tissue

    PMID:22140090

    Open questions at the time
    • Other trans-acting factors at the enhancer not characterized
    • Cell-type specificity of looping not fully mapped
  5. 2005 Medium

    Identified epigenetic silencing as a mechanism of HHIP loss in cancer, linking reduced HHIP to elevated GLI activity.

    Evidence Bisulfite sequencing, methylation-specific PCR, demethylation rescue (5-aza-dC) and Gli reporter assay in pancreatic cancer cells; later extended to Cr(VI)-transformed bronchial cells with ChIP

    PMID:15970691 PMID:32710611

    Open questions at the time
    • Single-lab studies per context
    • Causal contribution of HHIP silencing to tumorigenesis in vivo not established
  6. 2016 High

    Demonstrated in vivo that HHIP dosage maintains lung homeostasis and that oxidative stress is a mechanistic mediator of emphysema upon HHIP loss.

    Evidence Hhip+/- mouse model with lung compliance, histology, oxidative stress markers and N-acetylcysteine rescue

    PMID:27444019

    Open questions at the time
    • Link between Hh derepression and oxidative stress not molecularly traced
    • Cell type responsible for emphysema not isolated
  7. 2021 Medium

    Extended HHIP's homeostatic role to metabolic and structural lung remodeling by linking it to glycolytic control in airway smooth muscle.

    Evidence OCR and lactate assays, PKM2 activity after HHIP knockdown, overexpression in COPD-derived ASMCs, and α-SMA staining in Hhip+/- mice

    PMID:33907231

    Open questions at the time
    • Mechanistic link between Hh signaling and PKM2/glycolysis not defined
    • Single lab
  8. 2021 High

    Identified HHIP as a tissue-specific guardian of cranial suture mesenchyme acting through restraint of Hedgehog signaling.

    Evidence scRNA-seq of murine coronal suture, Hhip-/- analysis, lineage tracing and osteogenic front histology

    PMID:34880220

    Open questions at the time
    • Effector genes downstream of derepressed Hh not yet defined at this stage
  9. 2025 High

    Defined the epistatic hierarchy by which HHIP maintains suture patency, placing PTHLH downstream of HHIP to negatively regulate Ihh.

    Evidence Hhip-/- and Hhip-/-;Pthlh-/- double-knockout mice with RNA-seq and suture fusion histology

    PMID:41000054

    Open questions at the time
    • Direct molecular link between HHIP/Hh output and Pthlh induction not resolved
    • Mechanism of paradoxical Ihh downregulation incomplete
  10. 2025 Medium

    Identified cell-type-specific physical partners of HHIP in lung cells, implicating it in oxidative stress response complexes.

    Evidence AP-MS in IMR90 and 16HBE cells with validation of CAVIN1 and TP53 interactions

    PMID:39945347

    Open questions at the time
    • Functional consequence of CAVIN1/TP53 binding not mechanistically dissected
    • Reciprocal validation and stoichiometry not established
  11. 2025 Medium

    Showed HHIP overexpression protects bronchial epithelium against smoke-induced EMT and supports epithelial regeneration via stromal crosstalk.

    Evidence HHIP overexpression in 16HBE with CSE treatment, CDH1 readout, and organoid co-culture with control vs COPD stromal cells (FGF10/GLI1)

    PMID:40192657

    Open questions at the time
    • Mechanism linking HHIP to FGF10/CDH1 not defined
    • Single lab; in vitro organoid system

Open questions

Synthesis pass · forward-looking unresolved questions
  • Beyond ligand sequestration, the diverse context-specific roles attributed to HHIP — paracrine angiogenesis, adipocyte/beta-cell/renal effects, JAK-STAT and YAP axes — lack a unifying molecular mechanism connecting decoy receptor activity to these downstream pathways.
  • No structural or biochemical link between HHIP ectodomain function and intracellular signaling axes reported
  • Most non-developmental contexts rest on single-lab overexpression/knockdown studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CAVIN1DHHPTCH1SHHSMOTP53

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Crystal structures of human HHIP alone and bound to Sonic hedgehog (SHH) reveal that HHIP comprises two EGF domains and a six-bladed beta-propeller domain. A critical loop from HHIP binds the pseudo active site groove of SHH and directly coordinates its Zn2+ cation, functioning as a structural decoy receptor that competes with Patched (PTC1) for binding to the SHH pseudo active site. X-ray crystallography (crystal structures of HHIP alone and HHIP-SHH complex), peptide binding studies, sequence comparisons Nature structural & molecular biology High 19561609
2009 Crystal structures of human HHIP ectodomain in complex with Desert hedgehog (DHH) and Sonic hedgehog (SHH), with and without Ca2+, reveal that Zn2+ makes a key contribution to the Hh-HHIP interface, while Ca2+ prevents electrostatic repulsion between the two proteins, suggesting a tunable metal-dependent mechanism for regulation of Hh signaling by HHIP. X-ray crystallography (multiple crystal structures), biophysical studies, mutagenesis Nature structural & molecular biology High 19561611
2014 Smoothened (Smo) activation drastically increases Hhip internalization and degradation in a cell-autonomous manner. Although Hhip cannot cell-autonomously inhibit Smo activation consequences, it can non-cell-autonomously inhibit Shh signaling in neighboring cells by sequestering Shh ligand. This provides a mechanism by which Shh can negate cell-autonomous Hhip inhibition while Hhip still induces non-cell-autonomous inhibition. Hhip overexpression in neural tube cells, live imaging of Hhip internalization, Smo activation/inhibition experiments, non-cell autonomous inhibition assays Nature communications Medium 25215859
2006 In zebrafish, Hhip regulates muscle development both by sequestering Hedgehog ligand and by modulating subcellular localization of Smoothened. Hhip and Smoothened colocalize at the cell surface and internalize together in response to Hedgehog. Knockdown of Hhip blocks Smoothened internalization while increasing Hedgehog signaling and slow muscle formation. Hhip lacking its membrane-associated domain still suppresses Hh activity but no longer acts synergistically with Patched. Hhip knockdown (morpholino), domain deletion constructs, colocalization imaging, Smoothened internalization assay, slow/fast muscle cell fate analysis Developmental biology High 16765934
2011 A genomic enhancer region ~85 kb upstream of HHIP interacts with the HHIP promoter through a chromatin loop. The COPD-risk SNP rs1542725C within this enhancer shows increased binding to the transcriptional repressor Sp3, leading to reduced HHIP promoter activity and decreased HHIP expression, linking distal transcriptional regulation to HHIP expression levels. Chromatin conformation capture (chromatin loop detection), promoter activity luciferase reporter assays, electrophoretic mobility shift assay (differential Sp3 binding), quantitative RT-PCR and protein analysis of COPD lung tissues Human molecular genetics High 22140090
2005 HHIP promoter CpG island methylation is associated with absent or reduced HHIP expression in pancreatic cancer cells. Restoration of HHIP expression by 5-aza-2'-deoxycytidine (demethylation) leads to decreased Gli reporter activity, consistent with HHIP functioning as a negative regulator of Hedgehog signaling through an epigenetic silencing mechanism. Bisulfite sequencing, methylation-specific PCR, real-time RT-PCR, epigenetic modifier drug treatment (5-aza-2'-deoxycytidine), Gli reporter assay Cancer biology & therapy Medium 15970691
2016 Hhip haploinsufficiency in mice (Hhip+/-) leads to increased lung compliance and spontaneous emphysema starting at 10 months of age, preceded by increased oxidative stress in lungs. Antioxidant N-acetylcysteine treatment starting at 5 months improved lung function and prevented emphysema, implicating oxidative stress as a mechanistic mediator of Hhip-dependent lung homeostasis. Hhip heterozygous mouse model, lung compliance measurement, histological emphysema assessment, oxidative stress markers, N-acetylcysteine intervention Proceedings of the National Academy of Sciences of the United States of America High 27444019
2017 Hhip haploinsufficiency in mice increases Hh signaling in tumor fibroblasts, which induces elevated VEGF expression, leading to increased endothelial cell proliferation and tumor angiogenesis via a paracrine mechanism. This establishes HHIP as a regulator of stromal Hedgehog signaling that controls tumor vascular density. B16F10 tumor implantation in Hhip+/- mice, tumor growth measurement, vascular density quantification, VEGF expression analysis, endothelial cell proliferation assay Experimental & molecular medicine Medium 28127049
2021 HHIP inhibits aerobic glycolysis (Warburg effect) and represses proliferation in COPD-derived airway smooth muscle cells (ASMCs). Knockdown of HHIP in normal ASMCs increased PKM2 activity. Hhip+/- mice demonstrated increased airway remodeling and increased α-SMA staining around airways compared to wild-type mice. Mitochondrial oxygen consumption rate measurement, lactate level assay, PKM2 activity assay after HHIP knockdown, HHIP overexpression in COPD-derived ASMCs, immunofluorescence staining for α-SMA in Hhip+/- mouse lung sections Scientific reports Medium 33907231
2019 Recombinant Hhip inhibits cell proliferation by downregulating cell cycle-related genes and reducing S-phase cell numbers. Hhip also promotes adipocyte differentiation by targeting canonical Hh signaling, increasing lipid accumulation and upregulating Glut4 and PPARγ expression. Recombinant Hhip protein treatment of porcine adipocytes, cell cycle analysis (S-phase), lipid accumulation assay, gene expression analysis (Glut4, PPARγ) Biochemical and biophysical research communications Medium 31027733
2019 In pancreatic beta cells, Hhip inhibits insulin secretion by promoting Nox2 gene expression and altering islet integrity. siRNA-mediated Hhip knockdown increased glucose-stimulated insulin secretion (GSIS) and abolished sodium palmitate-stimulated Nox2 expression. Recombinant Hhip increased Nox2 and NADPH activity and decreased insulin-positive beta cells in vitro. Hhip+/- mouse model fed high fat diet, GSIS assay, siRNA knockdown of Hhip, recombinant Hhip treatment, Nox2/NADPH activity assay, islet morphology analysis Scientific reports Medium 31371780
2021 Single-cell RNA-seq of embryonic murine coronal suture identifies an Hhip-expressing mesenchymal population distinct from other neurocranial sutures. In Hhip-/- mice, osteogenic fronts are closely apposed, suture mesenchyme is depleted, and hedgehog signaling is increased, demonstrating that Hhip is required for normal coronal suture development by maintaining suture mesenchyme through inhibition of hedgehog signaling. Single-cell RNA-seq of murine coronal suture, Hhip-/- knockout mouse analysis, lineage tracing of Hhip-expressing cells, histological analysis of osteogenic fronts Nature communications High 34880220
2014 In a murine model of maternal diabetes, augmented HHIP expression in developing kidney is associated with dysnephrogenesis. In vitro, HHIP overexpression decreased SHH and PAX2 proteins and increased NFκB (p50/p65), phospho-p53, and TGF-β1 expression. PAX2 overexpression inhibited HHIP and NFκB and activated SHH, N-myc, and p27Kip1, revealing a negative autocrine feedback loop. High glucose stimulated HHIP expression and targeted TGF-β1 signaling. Murine maternal diabetes model, HHIP overexpression in vitro, PAX2 overexpression, Western blotting for pathway components, ureteric bud branching morphogenesis quantification Diabetologia Medium 24957663
2021 HHIP overexpression in Cr(VI)-transformed bronchial epithelial cells suppressed Hh signaling (reduced GLI1-3 and PTCH1) and inhibited cell proliferation and anchorage-independent growth. Cr(VI)-transformed cells showed DNA hypermethylation and silencing histone marks at the HHIP promoter, establishing epigenetic silencing of HHIP as a mechanism of Cr(VI)-induced lung carcinogenesis. Ectopic HHIP expression in Cr(VI)-transformed cells, cell proliferation assay, soft agar colony formation assay, chromatin immunoprecipitation (silencing histone marks), methylation analysis Carcinogenesis Medium 32710611
2025 Affinity purification mass spectrometry (AP-MS) identified cell type-specific protein-protein interactors of HHIP in lung cells. CAVIN1 was identified and validated as an HHIP interactor in IMR90 cells, and TP53 was identified and validated in 16HBE cells, implicating HHIP in oxidative stress response pathways relevant to COPD pathogenesis. Affinity purification mass spectrometry (AP-MS) in IMR90 and 16HBE lung cell lines, validation of CAVIN1 and TP53 interactions, protein-protein interaction network analysis Human molecular genetics Medium 39945347
2025 In renal proximal tubular cells (RPTCs), excessive Hhip triggers cellular senescence (polyploidization and cytoskeleton destabilization) and promotes release of extracellular vesicles carrying Hhip (EVsHhip), predominantly as apoptotic bodies and microvesicles. Hhip stimulates β2-microglobulin, which interacts with EVsHhip to facilitate RPTC transition from senescence to fibrosis and/or apoptosis. Canagliflozin prevented Hhip-mediated tubulopathy by inhibiting this mechanism. Akita/HhipRPTC-transgenic mouse model, in vivo and in vitro extracellular vesicle characterization, β2-microglobulin interaction analysis, canagliflozin pharmacological intervention Translational research : the journal of laboratory and clinical medicine Medium 39756674
2025 HHIP overexpression in bronchial epithelial cells (16HBE) attenuated cigarette smoke extract-induced reduction in CDH1 (E-cadherin) expression, suggesting HHIP protects against epithelial-to-mesenchymal transition. Additionally, HHIP overexpression promoted formation of more and larger organoids in co-culture with lung mesenchymal stromal cells from non-COPD controls, but this effect was impaired in COPD-derived stromal cells, associated with lower FGF10 expression. HHIP overexpression in 16HBE cells, cigarette smoke extract treatment, CDH1 expression measurement, lung organoid formation assay with mesenchymal stromal cells, GLI1 suppression assay American journal of physiology. Lung cellular and molecular physiology Medium 40192657
2025 In Gli1+ osteogenic progenitors in a temporomandibular joint osteoarthritis mouse model, YAP activity increase was associated with reduced Hhip expression and subsequent excessive osteogenesis. Specific inhibition of YAP in Gli1+ cells maintained Hhip expression, inhibited excessive osteogenesis, and mitigated OA phenotype. Additional Hh-Gli1 signaling activation aggravated the rescued phenotype, establishing a YAP-Hhip-Hh signaling axis in subchondral bone remodeling. Gli1-CreERT2;YAPfl/fl conditional knockout mice, partial discectomy OA model, Smoothened agonist treatment, micro-CT, histology, immunofluorescence, RNA-seq Osteoarthritis and cartilage Medium 40447254
2025 In Hhip-/- mice, both coronal and lambdoid suture development is disrupted: the lambdoid suture fuses by E18.5 while coronal suture mesenchyme is depleted. RNA-seq shows HH target genes including Pthlh are upregulated while Ihh is paradoxically downregulated in Hhip-/- sutures. In Hhip-/-;Pthlh-/- double knockout embryos, coronal sutures also fuse by E18.5, revealing that PTHLH acts downstream of HHIP to maintain coronal suture patency through negative regulation of Ihh expression. Hhip-/- and Hhip-/-;Pthlh-/- double knockout mouse models, RNA-seq of isolated sutures, histological analysis of suture fusion at E18.5 Development (Cambridge, England) High 41000054
2013 A novel activating variant c.-1G>C in HHIP was identified in a CPHD patient, and in vitro assays demonstrated that this variant increases HHIP's inhibiting function on the Hh pathway, suggesting gain-of-function HHIP variants can cause combined pituitary hormone deficiency. Direct sequencing of HHIP coding regions in CPHD patients, in vitro Hh pathway activity assay in Hep3B transfected cells comparing wild-type and mutant HHIP Clinical endocrinology Low 22897141
2024 In zebrafish, hhip mutations lead to an increase in radial bones specifically in a localized region of pectoral fins. Shh gene expression coincides with notable hhip expression during early development, and hhip acts as a negative feedback component of Hedgehog signaling to constrain anterior-posterior patterning of pectoral fin radials. This notable hhip expression during early fin development is specific to zebrafish compared to basal species. hhip mutant zebrafish generation, skeletal preparation and quantification of radial bones, in situ hybridization for Shh and hhip, comparative expression analysis across species, Hox13 expression analysis Development (Cambridge, England) Medium 39417578
2025 In vascular smooth muscle cells, the lncRNA CARMN maintains expression levels that prevent accumulation of miR-143-3p; when CARMN is lost, miR-143-3p targets and suppresses HHIP (an antagonist of Hedgehog signaling), leading to reduced Hedgehog pathway activity and impaired angiogenesis. Delivery of HHIP-specific siRNA or miR-143-3p mimics rescued endothelial cell angiogenic defects and improved blood flow recovery in CARMN-KO mice. CARMN-KO mouse model, limb ischemia model, RNA-seq, miR-143-3p mimic delivery, HHIP-specific siRNA delivery, endothelial cell sprouting and proliferation assays, blood flow measurement The Journal of clinical investigation Medium 40875440
2024 In cancer-associated fibroblasts (CAFs), HHIP overexpression inhibits the JAK1/STAT3 pathway and reduces secretion of inflammatory factors, thereby suppressing proliferation and stemness of prostate cancer cells in paracrine fashion. Knockdown of HHIP in CAFs partially reversed the inhibitory effects of JAK1/STAT3 pathway inhibitor AG490 on prostate cancer cell stemness. HHIP overexpression and knockdown in primary CAFs, ELISA for inflammatory factors, JAK1/STAT3 pathway inhibitor (AG490) treatment, spheroid formation assay, flow cytometry for cancer stem cell markers, mouse subcutaneous tumor model Journal of inflammation research Medium 39553307

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Human molecular genetics 136 22140090
2009 The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nature structural & molecular biology 119 19561609
2009 Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nature structural & molecular biology 113 19561611
2005 Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer biology & therapy 71 15970691
2016 Hhip haploinsufficiency sensitizes mice to age-related emphysema. Proceedings of the National Academy of Sciences of the United States of America 65 27444019
2016 Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A. The Journal of allergy and clinical immunology 45 27612410
2006 Comparative genomics on HHIP family orthologs. International journal of molecular medicine 43 16391842
2014 Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling. Nature communications 36 25215859
2006 Hhip regulates zebrafish muscle development by both sequestering Hedgehog and modulating localization of Smoothened. Developmental biology 33 16765934
2021 Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells. Scientific reports 31 33907231
2013 Association of HHIP polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population. Gene 31 23994291
2021 Single-cell analysis identifies a key role for Hhip in murine coronal suture development. Nature communications 30 34880220
2020 Long Noncoding RNA DIO3OS Hinders Cell Malignant Behaviors of Hepatocellular Carcinoma Cells Through the microRNA-328/Hhip Axis. Cancer management and research 27 32547226
2018 Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 29539620
2022 The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors. Nature communications 26 35831316
2019 A novel long noncoding RNA HHIP-AS1 suppresses hepatocellular carcinoma progression through stabilizing HHIP mRNA. Biochemical and biophysical research communications 26 31604528
2017 Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis. Experimental & molecular medicine 24 28127049
2019 Hhip inhibits proliferation and promotes differentiation of adipocytes through suppressing hedgehog signaling pathway. Biochemical and biophysical research communications 23 31027733
2020 Exosomes secreted by chronic hepatitis B patients with PNALT and liver inflammation grade ≥ A2 promoted the progression of liver cancer by transferring miR-25-3p to inhibit the co-expression of TCF21 and HHIP. Cell proliferation 22 32525231
2021 MiR-199b-5p Promotes Gastric Cancer Progression by Regulating HHIP Expression. Frontiers in oncology 17 34532291
2021 Downregulation of hedgehog-interacting protein (HHIP) contributes to hexavalent chromium-induced malignant transformation of human bronchial epithelial cells. Carcinogenesis 16 32710611
2019 HHIP overexpression inhibits the proliferation, migration and invasion of non-small cell lung cancer. PloS one 16 31765425
2013 Altered expression of PTCH and HHIP in gastric cancer through their gene promoter methylation: novel targets for gastric cancer. Molecular medicine reports 16 23440386
2021 lncRNA HHIP-AS1 Promotes the Osteogenic Differentiation Potential and Inhibits the Migration Ability of Periodontal Ligament Stem Cells. Stem cells international 15 34721591
2014 Occurrence of HHIP gene CpG island methylation in gastric cancer. Oncology letters 15 25295121
2017 Metabolomic profiling in a Hedgehog Interacting Protein (Hhip) murine model of chronic obstructive pulmonary disease. Scientific reports 13 28566717
2014 Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP). Diabetologia 13 24957663
2020 HHIP Overexpression Suppresses Human Gastric Cancer Progression and Metastasis by Reducing Its CpG Island Methylation. Frontiers in oncology 12 33415068
2023 LncRNA HHIP-AS1 suppresses lung squamous cell carcinoma by stabilizing HHIP mRNA. Life sciences 10 36958438
2020 The SNP rs13147758 in the HHIP Gene Is Associated With COPD Susceptibility, Serum, and Sputum Protein Levels in Smokers. Frontiers in genetics 10 33193570
2013 Genetic variants in HHIP are associated with FEV1 in subjects with chronic obstructive pulmonary disease. Respirology (Carlton, Vic.) 10 23731023
2020 Participation of HHIP Gene Variants in COPD Susceptibility, Lung Function, and Serum and Sputum Protein Levels in Women Exposed to Biomass-Burning Smoke. Diagnostics (Basel, Switzerland) 9 32977420
2018 Correlation between lung cancer and the HHIP polymorphisms of chronic obstructive pulmonary disease (COPD) in the Chinese Han population. Genes and immunity 9 29915314
2025 Canagliflozin inhibits hedgehog interacting protein (Hhip) induction of tubulopathy in diabetic Akita mice. Translational research : the journal of laboratory and clinical medicine 8 39756674
2023 CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR-630/HHIP axis. Cancer medicine 8 37039160
2019 Hedgehog Interacting Protein (Hhip) Regulates Insulin Secretion in Mice Fed High Fat Diets. Scientific reports 8 31371780
2022 Differential promoter usages of PTCH1 and down regulation of HHIP are associated with HNSCC progression. Pathology, research and practice 7 35276608
2021 Long non‑coding RNA HHIP‑AS1 inhibits lung cancer epithelial‑mesenchymal transition and stemness by regulating PCDHGA9. Molecular medicine reports 7 34643245
2021 MicroRNA-221 promotes tumor progression by targeting HHIP in human glioblastoma. Translational cancer research 7 35116434
2013 Single-nucleotide variants in two Hedgehog genes, SHH and HHIP, as genetic cause of combined pituitary hormone deficiency. Clinical endocrinology 7 22897141
2024 Anterior-posterior constraint on Hedgehog signaling by hhip in teleost fin elaboration. Development (Cambridge, England) 6 39417578
2022 Natural Antisense Long Noncoding RNA HHIP-AS1 Suppresses Non-Small-Cell Lung Cancer Progression by Increasing HHIP Stability via Interaction with CELF2. Critical reviews in eukaryotic gene expression 6 36374812
2019 Evaluation Of HHIP Polymorphisms And Their Relationship With Chronic Obstructive Pulmonary Disease Phenotypes. International journal of chronic obstructive pulmonary disease 6 31631996
2017 Comparison of the role of HHIP SNPs in susceptibility to chronic obstructive pulmonary disease between Chinese Han and Mongolian populations. Gene 6 28939338
2022 lncRNA HHIP-AS1/HHIP modulates osteogenic differentiation of BM-MSCs by regulating Hedgehog signaling pathway. Aging 5 36375472
2020 HHIP gene overexpression inhibits the growth, migration and invasion of human liver cancer cells. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 4 33277865
2025 HHIP protein interactions in lung cells provide insight into COPD pathogenesis. Human molecular genetics 3 39945347
2023 Circulating HHIP Levels in Women with Insulin Resistance and PCOS: Effects of Physical Activity, Cold Stimulation and Anti-Diabetic Drug Therapy. Journal of clinical medicine 3 36769536
2021 Variants associated with HHIP expression have sex-differential effects on lung function. Wellcome open research 3 33728380
2025 Targeting YAP-Hhip-mediated osteogenesis in Gli1+ osteogenic progenitors suppresses aberrant subchondral bone remodeling in osteoarthritis. Osteoarthritis and cartilage 2 40447254
2025 A smooth muscle cell lncRNA controls angiogenesis in chronic limb-threatening ischemia through miR-143-3p/HHIP signaling. The Journal of clinical investigation 2 40875440
2023 Hhip hits the brakes on lung tissue resident lymphocytes. Immunity 2 36921570
2021 Retraction Note to: HHIP gene overexpression inhibits the growth, migration and invasion of human liver cancer cells. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 2 34565049
2025 COPD susceptibility gene HHIP regulates repair genes in airway epithelial cells and repair within the epithelial-mesenchymal trophic unit. American journal of physiology. Lung cellular and molecular physiology 1 40192657
2024 HHIP protein interactions in lung cells provide insight into COPD pathogenesis. bioRxiv : the preprint server for biology 1 38617310
2024 HHIP's Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility. bioRxiv : the preprint server for biology 1 39416045
2024 The Mechanism by Which Hedgehog Interacting Protein (HHIP) in Cancer-Associated Fibroblasts Regulate the Secretion of Inflammatory Factors Through the JAK1/STAT3 Pathway Affecting Prostate Cancer Stemness. Journal of inflammation research 1 39553307
2024 Downregulation of Hedgehog Interacting Protein (HHIP) in Gastric Cancer: Implications for Tumorigenesis. Indian journal of clinical biochemistry : IJCB 1 39835242
2026 HHIP's dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility. Proceedings of the National Academy of Sciences of the United States of America 0 42190016
2025 Erratum: The Mechanism by Which Hedgehog Interacting Protein (HHIP) in Cancer-Associated Fibroblasts Regulate the Secretion of Inflammatory Factors Through the JAK1/STAT3 Pathway Affecting Prostate Cancer Stemness [Corrigendum]. Journal of inflammation research 0 40687152
2025 Differential regulation of coronal and lambdoid suture patency by PTHLH and HHIP activity in mice. Development (Cambridge, England) 0 41000054
2024 Impact of HHIP gene polymorphisms on phenotypes, serum IL-17 and IL-18 in COPD patients of the Chinese Han population. Respiratory research 0 39468530
2024 Elevated circulating HHIP levels in patients with metabolic syndrome. Biochemical and biophysical research communications 0 39490156

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