Affinage

ITIH4

Inter-alpha-trypsin inhibitor heavy chain H4 · UniProt Q14624

Length
930 aa
Mass
103.4 kDa
Annotated
2026-06-10
53 papers in source corpus 21 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITIH4 is a liver-restricted, IL-6-inducible type II acute-phase plasma glycoprotein that acts as a protease inhibitor and modulator of inflammatory signaling (PMID:10486281, PMID:10712621, PMID:33348064, PMID:7775381). Its inhibitory activity follows a bait mechanism: proteases cleave ITIH4 within a susceptible proline-rich region (an Arg-Arg-Leu site yielding 85- and 35-kDa fragments), inducing a noncovalent inhibitory complex dependent on the ITIH4 von Willebrand factor A domain that sterically excludes large protein substrates from the protease active site while leaving small substrates accessible, thereby inhibiting MASP-1, MASP-2, and plasma kallikrein (PMID:33523981, PMID:7775381). Hepatic expression is driven specifically by IL-6 through the JAK/STAT pathway, not by IL-1β or TNF-α, and the gene carries liver-specific transcription factor binding sites in its promoter (PMID:10486281, PMID:10712621, PMID:33348064, PMID:8797089, PMID:7587397). ITIH4 cleavage tracks ongoing proteolytic activity in vivo, as intact ITIH4 is depleted and recombinant ITIH4 is rapidly cleaved in serum from hereditary angioedema patients with C1 inhibitor deficiency, consistent with a compensatory inhibitory role in plasma protease cascades (PMID:38657796). Beyond protease inhibition, ITIH4 binds actin to inhibit polymerization and suppress PMN phagocytosis (PMID:10939621), and acts as an anti-inflammatory and cytoprotective factor in epithelial, macrophage, and smooth muscle contexts—restraining oxidative-stress and pathogen-induced apoptosis and cytokine release via JNK, NF-κB, NLRP3, and Hippo/YAP-TAZ signaling (PMID:39069151, PMID:40404214, PMID:41998424, PMID:40682224, PMID:41735691). PGK1 binds ITIH4 and blocks kallikrein-mediated cleavage, stabilizing the intact protein (PMID:36841032).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    Established the molecular identity of ITIH4, defining its domain architecture and the proteolytic cleavage behavior that would later prove central to its function.

    Evidence cDNA cloning, peptide sequencing of plasma cleavage fragments, and tissue Northern blot

    PMID:7775381

    Open questions at the time
    • The protease responsible for physiological cleavage was not identified
    • Functional consequence of cleavage was unknown at this stage
  2. 1996 Medium

    Resolved the gene structure and identified liver-specific promoter elements, explaining the hepatic restriction of ITIH4 expression.

    Evidence Genomic cloning, exon-intron mapping, FISH to 3p21-p14, and promoter sequence analysis

    PMID:7587397 PMID:8797089

    Open questions at the time
    • Promoter elements identified by sequence only; functional transcription assays not performed
  3. 1998 Medium

    Cross-species comparison revealed divergence in the proline-rich region and showed acute-phase regulation differs between rat and human, while mouse work tied ITIH4 to embryonic liver development.

    Evidence Comparative cDNA/mRNA analysis (rat vs human), splice variant RT-PCR, and developmental expression profiling in mouse

    PMID:9480842 PMID:9602042

    Open questions at the time
    • Functional significance of the proline-rich repeats and predicted EF-hand motifs not tested
    • Species differences in inflammatory induction not mechanistically explained
  4. 1999 High

    Defined ITIH4 as a type II acute-phase protein by showing its hepatic induction is specific to IL-6.

    Evidence Dose-response IL-6 treatment of HepG2 cells with mRNA and 35S-labeled protein readouts

    PMID:10486281 PMID:10712621 PMID:33348064

    Open questions at the time
    • Signaling pathway downstream of IL-6 not yet defined
  5. 2000 Medium

    Provided the first functional activity for ITIH4 beyond an acute-phase marker—actin binding and suppression of PMN phagocytosis—framing it as anti-inflammatory.

    Evidence In vitro actin polymerization and phagocytosis assays with purified IHRP

    PMID:10939621

    Open questions at the time
    • No mutagenesis or structural mapping of the actin-binding interface
    • In vivo relevance not established
  6. 2002 Medium

    Connected ITIH4 induction to liver regeneration and tested predicted ligand interactions, finding the unmodified protein does not bind calcium or hyaluronic acid.

    Evidence IL-6-treated liver explants, partial hepatectomy time course, and GST-fusion binding assays

    PMID:11803570

    Open questions at the time
    • Whether posttranslational modification enables calcium/HA binding untested
    • Causal role in hepatocyte cell-cycle entry not demonstrated
  7. 2020 Medium

    Identified JAK/STAT as the signaling route for IL-6-driven ITIH4 induction, completing the regulatory pathway upstream of the protein.

    Evidence JAK/STAT inhibitor pretreatment before IL-6/LPS in HepG2 and mouse liver, with protein and mRNA readouts

    PMID:33348064

    Open questions at the time
    • Specific STAT factor and direct promoter binding not defined
  8. 2021 High

    Established the central mechanism: ITIH4 is a substrate-cleavage-activated, vWFA-domain-dependent steric protease inhibitor of MASP-1, MASP-2, and plasma kallikrein.

    Evidence In vitro protease inhibition, domain mutagenesis, substrate competition assays, and reconstitution of the noncovalent inhibitory complex

    PMID:33523981

    Open questions at the time
    • Full structural model of the inhibitory complex not resolved
    • In vivo contribution to complement/kallikrein control not quantified
  9. 2023 Medium

    Identified PGK1 as an ITIH4 binding partner that stabilizes intact ITIH4 by blocking kallikrein-mediated cleavage.

    Evidence Co-IP with MALDI-TOF/MS identification and Western blot cleavage assays

    PMID:36841032

    Open questions at the time
    • Single Co-IP without reciprocal structural validation
    • Mechanism by which PGK1 blocks cleavage unresolved
  10. 2024 Medium

    Extended ITIH4 function to tissue and disease contexts—VSMC stiffness via ERK/JNK, CXCR4-linked PI3K/Akt signaling in arthritis, and in vivo evidence of compensatory protease inhibition in hereditary angioedema.

    Evidence Gain/loss-of-function with pharmacological pathway dissection in VSMCs, siRNA and CIA rat model for CXCR4, and immunoassay/Western/recombinant-protein cleavage in HAE patient serum

    PMID:38657796 PMID:39069151 PMID:40608509

    Open questions at the time
    • Whether ITIH4-CXCR4 is a direct physical interaction beyond computational modeling untested
    • Mechanism linking ITIH4 to cytoskeletal acetylation not defined
  11. 2025 Medium

    Defined ITIH4 as a cytoprotective, anti-inflammatory factor in epithelial and lung-injury models, acting through JNK/β-catenin, NLRP3, and Hippo/YAP-TAZ signaling.

    Evidence Gain/loss-of-function in airway epithelial and A549 cells, NLRP3 rescue epistasis, and rITIH4 treatment in particulate-matter and OVA-asthma mouse models with scRNA-seq

    PMID:40404214 PMID:40410722 PMID:40437524 PMID:40682224

    Open questions at the time
    • Direct molecular link between ITIH4 and these pathways not established (mostly correlative)
    • Receptor mediating extracellular rITIH4 effects unknown
  12. 2026 Medium

    Showed that full-length ITIH4 accumulates under pro-inflammatory conditions and acts cell-non-autonomously, dampening macrophage NF-κB responses and supporting epithelial barrier integrity, and dynamically tuning Hippo signaling during lung repair.

    Evidence Quantitative proteomics of BMDMs, ITIH4 overexpression/knockdown in macrophage lines with RNA-seq, and Hippo pathway readouts in A549 and LPS-ARDS mice

    PMID:41735691 PMID:41998424

    Open questions at the time
    • Mechanism coupling intracellular/secreted ITIH4 to NF-κB and Hippo not defined
    • Whether protease-inhibition and signaling functions are mechanistically linked unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ITIH4's defined plasma protease-inhibitor mechanism relates to its diverse intracellular and cell-non-autonomous signaling roles (NF-κB, Hippo/YAP-TAZ, NLRP3, CXCR4/PI3K-Akt) remains unresolved.
  • No receptor identified for extracellular ITIH4 signaling effects
  • Unclear whether cleaved versus intact ITIH4 drives the signaling phenotypes
  • No structural model unifying the bait mechanism with the signaling functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
ACTBCXCR4KLKB1PGK1

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 ITIH4 functions as a protease inhibitor by a novel bait mechanism: proteases cleave ITIH4 within a protease-susceptible region, enabling ITIH4 to form a noncovalent, inhibitory complex with the executing protease that depends on the ITIH4 von Willebrand factor A domain. ITIH4 inhibits MASP-1, MASP-2, and plasma kallikrein by sterically preventing larger protein substrates from accessing their active sites while leaving the active site accessible to small substrates. In vitro protease inhibition assays, domain mutagenesis (vWFA domain dependence), substrate competition assays, biochemical reconstitution of inhibitory complex Science advances High 33523981
1999 ITIH4 expression in hepatocytes is specifically up-regulated by IL-6 (but not by IL-1β or TNF-α), establishing it as a type II acute-phase protein. This was demonstrated by dose-response IL-6 treatment of HepG2 cells showing increased ITIH4 mRNA and 35S-labeled secreted protein. Northern blot / RT-PCR for mRNA, 35S metabolic labeling of secreted protein, dose-response cytokine treatment of HepG2 cells Biochemical and biophysical research communications High 10486281 10712621 33348064
2000 ITIH4 (IHRP) binds actin and inhibits actin polymerization, and also suppresses phagocytic activity of polymorphonuclear (PMN) cells, suggesting it functions as an anti-inflammatory protein by neutralizing actin released from damaged cells and by binding cell-surface actin on PMN cells. In vitro actin polymerization assay, phagocytosis assay with PMN cells in presence of purified IHRP Inflammation research Medium 10939621
1995 ITIH4 (IHRP) is encoded by a 2,977 bp cDNA in human liver encoding 930 amino acids including a 28-residue signal peptide. The N-terminal ~600 residues show homology to ITI heavy chains while the C-terminal ~300 residues show homology to ATP-dependent proteases. The protein is cleaved into 85- and 35-kDa fragments at a proline-rich region (Arg-Arg-Leu site) when plasma is incubated at 37°C. Expression is liver-restricted. cDNA cloning, amino acid sequencing of proteolytic fragments, Northern blot of human tissues, SDS-PAGE of cleavage products Journal of biochemistry High 7775381
1996 The ITIH4 (ITIHL1) gene spans 15 kb, is composed of 24 exons, maps to chromosome 3p21→p14, and contains hepatocyte nuclear factor binding sites (LF-A1, HNF-5, NF-IL6, C/EBP) in the 5'-flanking region that likely confer liver-specific transcription. Two major transcription initiation sites were identified with no typical TATA box. Genomic cloning of three overlapping clones, exon-intron mapping, fluorescence in situ hybridization (FISH), promoter element identification by sequence analysis Journal of biochemistry Medium 7587397 8797089
1998 Rat and human ITIH4 differ substantially in their proline-rich region (PRR): rat PRR contains 6 repeats of Gly-X-Pro collagen-like motifs absent in human. Human ITIH4 also produces two alternative splice variants of the PRR. Rat ITIH4 mRNA is up-regulated by acute systemic inflammation, whereas neither human ITIH4 mRNA variant is up-regulated in human liver under the same conditions. cDNA cloning, sequence comparison of rat vs human H4P, RT-PCR splice variant analysis, Northern blot of inflamed vs control tissue Biochemical and biophysical research communications Medium 9480842
1998 Mouse itih-4 encodes a 942 amino acid protein containing two EF-hand (helix-loop-helix) calcium-binding motifs, is expressed prominently in embryonic liver (as early as E9) and is developmentally regulated, suggesting a role as a scaffolding/extracellular matrix regulatory protein in early liver development. Subtraction hybridization of embryonic liver cDNA, full-length cDNA sequencing, RT-PCR across developmental stages and tissues Biochimica et biophysica acta Medium 9602042
2002 Itih-4 expression in liver is induced by IL-6 in hepatocyte explant cultures and peaks in a bimodal manner (at 30 min and 12 hr) after partial hepatectomy, correlating with immediate-early gene expression and suggesting Itih-4 contributes to entry of quiescent hepatocytes into the cell cycle. A GST-fusion Itih-4 protein showed no detectable binding to calcium or hyaluronic acid, indicating posttranslational modifications may be required for these proposed interactions. IL-6 treatment of liver explant cultures, immunohistochemistry at developmental stages, partial hepatectomy model, GST-fusion protein binding assay for calcium and hyaluronic acid Developmental dynamics Medium 11803570
2023 Phosphoglycerate kinase 1 (PGK1) was identified as a binding partner of ITI-H4. PGK1 increases ITI-H4 expression levels and blocks KLKB1 (kallikrein B1)-mediated cleavage of ITI-H4. PGK1 also inhibits pro-inflammatory JAK2/STAT3 signaling. Immunoprecipitation of ITIH4-associated proteins from cell lysates, MALDI-TOF/MS identification of binding partners, Western blot validation of PGK1 interaction and effect on ITIH4 cleavage Biomedicine & pharmacotherapy Medium 36841032
2020 IL-6-mediated induction of ITIH4 in HepG2 cells operates through the JAK/STAT signaling pathway, as demonstrated by significant reduction of ITIH4 protein and mRNA levels upon JAK/STAT inhibitor treatment before IL-6 or LPS stimulation. JAK/STAT inhibitor pretreatment, Western blot, real-time PCR, immunohistochemistry in mouse liver and HepG2 cell model Cytokine Medium 33348064
2024 ITIH4 regulates vascular smooth muscle cell (VSMC) stiffness: ITIH4 overexpression increases VSMC stiffness and acetylated α-tubulin while inhibiting ERK1/2 and JNK (but not p38 MAPK). Thrombin downregulates ITIH4, and ITIH4 partially reverses thrombin-induced changes in acetylated α-tubulin and VSMC stiffness through JNK and ERK signaling. ITIH4 expression vector and siRNA transfection in VSMCs, atomic force microscopy for cell stiffness, Western blot for signaling molecules, ERK inhibitor (PD98059) and JNK inhibitor (SP600125) treatment Experimental cell research Medium 39069151
2025 ITIH4 deficiency in airway epithelial cells exacerbates oxidative-stress-induced apoptosis, while ITIH4 overexpression inhibits it. Mechanistically, ITIH4 attenuates JNK activation and prevents β-catenin decrease upon oxidative stress. Acute hydrogen peroxide exposure causes rapid ITIH4 protein degradation with no effect at the transcriptional level. ITIH4 overexpression in primary COPD small airway epithelial cells and normal cells, siRNA knockdown, human apoptosis antibody array, Western blot, clinical cohort ITIH4 measurements The European respiratory journal Medium 40404214
2024 ITIH4 interacts with CXCR4 in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS): siRNA-mediated knockdown of ITIH4 led to significant downregulation of CXCR4 protein expression. In a CIA rat model, ITIH4 knockdown inhibited arthritis progression, decreased cellular infiltration, cytokine production, and pannus formation. The ITIH4-CXCR4 interaction was linked to PI3K/Akt signaling modulation of apoptosis and inflammation. siRNA knockdown in RA-FLS, Western blot validation, in vivo CIA rat model, molecular dynamics simulation of ITIH4-CXCR4 interaction Rheumatology (Oxford, England) Medium 40608509
2024 ITIH4 is cleaved in hereditary angioedema (HAE) patients with C1 inhibitor deficiency (types 1 and 2), indicating ongoing enzymatic activity in the plasma of HAE patients. HAE patients have significantly lower intact ITIH4 levels compared to controls, and immediate cleavage of added recombinant ITIH4 was observed in serum lacking endogenous intact ITIH4, demonstrating a compensatory protease inhibitor role for ITIH4 in HAE-associated proteolytic pathways. Specific immunoassays for intact vs. total ITIH4, Western blot of cleavage products, recombinant ITIH4 addition to patient serum, clinical cohort of 80 HAE patients vs. 100 controls The Journal of allergy and clinical immunology Medium 38657796
2026 In macrophages, full-length ITIH4 increases under pro-inflammatory conditions due to decreased cleavage. 4-Octyl itaconate promotes synthesis and secretion of full-length ITIH4. ITIH4 overexpression in macrophages attenuates pro-inflammatory responses via the NF-κB signaling pathway, and macrophages with ITIH4 overexpression activate cAMP signaling to enhance viability and tight junction integrity of colonic epithelial cells. Quantitative proteomics (mass spectrometry) of BMDMs, ITIH4 overexpression and knockdown in Raw264.7 and THP-1 cells, RNA-seq, Western blot, qRT-PCR, CCK8 viability assay, scratch wound healing assay Inflammation research Medium 41998424
2025 ITIH4 knockdown in A549 cells increases MP-induced apoptosis and pro-inflammatory cytokine release, while overexpression of NLRP3 reverses the protective effects of ITIH4 knockdown. This places ITIH4 upstream of NLRP3 inflammasome activation in the context of Mycoplasma pneumoniae-induced lung epithelial cell inflammation. Lentiviral ITIH4 knockdown in A549 cells, NLRP3 reactivation rescue experiment, flow cytometry for apoptosis, ELISA for cytokines, Western blot for inflammasome proteins Allergologia et immunopathologia Medium 40682224
2025 Recombinant ITIH4 (rITIH4) attenuates acute lung injury in mice exposed to Fe-containing particulate matter by modulating the Hippo pathway in type II alveolar epithelial cells (AECII): rITIH4 restored Cdh1, Pdpn, Wwtr1, and Yap1 in AECII, increased α-catenin and p-YAP, and modulated pTAZ/TAZ and LC3BII/I ratios. Intratracheal DEP/FeCl3 instillation mouse model, intranasal rITIH4 treatment, single-cell RNA sequencing, single-cell ICP-MS for Fe, immunofluorescence, BALF cytokine measurement Respiratory research Medium 40437524
2026 ITIH4 regulates YAP/TAZ-mediated apoptosis in type II alveolar epithelial cells: ITIH4 knockdown decreases YAP and TAZ while increasing p-YAP and SIRT1; ITIH4 overexpression increases p-TAZ/TAZ and SIRT1 and decreases ATM and caspase-3. rITIH4 treatment of LPS-injured mice restored ITIH4 in SPC+ cells, reduced caspase-3, and transiently elevated YAP in damaged lung regions, indicating spatiotemporal Hippo pathway regulation during lung repair. ITIH4 knockdown and overexpression in A549 cells, rITIH4 treatment in LPS-ARDS mouse model, Western blot for Hippo pathway components, immunofluorescence in SPC+ cells, H&E with K-means clustering Pharmaceutical research Medium 41735691
2025 ITIH4 administration in an OVA-induced asthma mouse model significantly reduced Th2 cytokines (IL-4, IL-5, IL-13), IgE, and eosinophils/lymphocytes in BALF, modulated lung and gut microbiome composition (enriching Gram-positive taxa, depleting Helicobacteraceae), altered short-chain fatty acids, and proteomic analysis of intestinal tissue revealed dose-dependent granzyme A signaling activation and suppression of metabolic/solute transport pathways. Mouse OVA asthma model, lung function measurement, BALF cytokine ELISA, 16S rRNA microbiome profiling, GC-MS for SCFAs, intestinal tissue proteomics Molecular medicine Low 40410722

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 ITIH4 serum concentration increases during acute-phase processes in human patients and is up-regulated by interleukin-6 in hepatocarcinoma HepG2 cells. Biochemical and biophysical research communications 93 10486281
2004 ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4) is a new acute-phase protein isolated from cattle during experimental infection. Infection and immunity 68 15213118
2000 Pig MAP/ITIH4 and haptoglobin are interleukin-6-dependent acute-phase plasma proteins in porcine primary cultured hepatocytes. European journal of biochemistry 60 10712621
1995 Cloning and characterization of cDNA for inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP), a novel human plasma glycoprotein. Journal of biochemistry 53 7775381
2021 ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism. Science advances 51 33523981
2002 Itih-4, a serine protease inhibitor regulated in interleukin-6-dependent liver formation: role in liver development and regeneration. Developmental dynamics : an official publication of the American Association of Anatomists 51 11803570
2019 Long Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling. Molecular therapy. Nucleic acids 47 31557619
2020 ITIH4, as an inflammation biomarker, mainly increases in bacterial bloodstream infection. Cytokine 44 33348064
2019 Elevated levels of circulating ITIH4 are associated with hepatocellular carcinoma with nonalcoholic fatty liver disease: from pig model to human study. BMC cancer 40 31238892
2000 The novel acute phase protein, IHRP, inhibits actin polymerization and phagocytosis of polymorphonuclear cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 38 10939621
2011 ITI-H4, as a biomarker in the serum of recurrent pregnancy loss (RPL) patients. Molecular bioSystems 37 21331437
2019 Acute Anti-Inflammatory Markers ITIH4 and AHSG in Mice Brain of a Novel Alzheimer's Disease Model. Journal of Alzheimer's disease : JAD 33 30958362
2021 ITIH4 is a novel serum biomarker for early gastric cancer diagnosis. Clinica chimica acta; international journal of clinical chemistry 26 34687700
2013 ITIH4 and Gpx3 are potential biomarkers for amyotrophic lateral sclerosis. Journal of neurology 26 23436019
1996 Primary structure of the pig homologue of human IHRP: inter-alpha-trypsin inhibitor family heavy chain-related protein. Journal of biochemistry 26 8830057
2003 Hypercholesterolemia associated with splice-junction variation of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) gene. Journal of human genetics 25 14661079
1998 The H4P heavy chain of inter-alpha-inhibitor family largely differs in the structure and synthesis of its prolin-rich region from rat to human. Biochemical and biophysical research communications 25 9480842
2008 Liquid chromatography/tandem mass spectrometric method for the quantification of eight proteolytic fragments of ITIH4 with biomarker potential in human plasma and serum. Rapid communications in mass spectrometry : RCM 20 18752334
2013 ITIH4: A New Potential Biomarker of "Toxin Syndrome" in Coronary Heart Disease Patient Identified with Proteomic Method. Evidence-based complementary and alternative medicine : eCAM 19 24023573
2024 Translatome profiling reveals Itih4 as a novel smooth muscle cell-specific gene in atherosclerosis. Cardiovascular research 17 38289873
2014 The concentrations of EGFR, LRG1, ITIH4, and F5 in serum correlate with the number of colonic adenomas in ApcPirc/+ rats. Cancer prevention research (Philadelphia, Pa.) 15 25200834
2023 Gaining knowledge about biomarkers of the immune system and inflammation in the saliva of pigs: The case of myeloperoxidase, S100A12, and ITIH4. Research in veterinary science 14 37657394
2010 Sensitive liquid chromatography/tandem mass spectrometry assay for absolute quantification of ITIH4-derived putative biomarker peptides in clinical serum samples. Rapid communications in mass spectrometry : RCM 14 20533314
2001 Quantitative measurement of the novel human plasma protein, IHRP, by sandwich ELISA. Biological & pharmaceutical bulletin 14 11256472
1995 Mapping of human inter-alpha-trypsin inhibitor family heavy chain-related protein gene (ITIHL1) to human chromosome 3p21-->p14. Cytogenetics and cell genetics 14 7587397
2023 PGK1 modulates balance between pro- and anti-inflammatory cytokines by interacting with ITI-H4. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 13 36841032
2023 Serum ITIH4 in coronary heart disease: a potential anti-inflammatory biomarker related to stenosis degree and risk of major adverse cardiovascular events. Biomarkers in medicine 13 36891881
1998 Identification of mouse itih-4 encoding a glycoprotein with two EF-hand motifs from early embryonic liver. Biochimica et biophysica acta 13 9602042
2022 Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases. Journal of clinical and translational hepatology 11 36304505
2015 Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics. Clinical proteomics 9 26097443
2024 ITIH4 in Rheumatoid Arthritis Pathogenesis: Network Pharmacology and Molecular Docking Analysis Identify CXCR4 as a Potential Receptor. Pathophysiology : the official journal of the International Society for Pathophysiology 8 39311312
2004 Novel human plasma proteins, IHRP (acute phase protein) and PHBP (serine protease), which bind to glycosaminoglycans. Current medicinal chemistry. Cardiovascular and hematological agents 8 15320789
2019 Development and validation of an ELISA for the quantification of bovine ITIH4 in serum and milk. Veterinary immunology and immunopathology 6 31450165
1996 Isolation and characterization of the human inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene (ITIHL1). Journal of biochemistry 6 8797089
2020 Effects of Helicobacter pylori infection and interleukin 6 on the expression of ITIH4 in human gastric cancer cells. Translational cancer research 5 35117829
2017 Significant changes in ITIH4, AHSG, ORM1, and CD46 content in milk fat globule membrane proteins of ketotic dairy cows. The Journal of dairy research 5 29154737
2021 Prioritization of human well-being spectrum related GWAS-SNVs using ENCODE-based web-tools predict interplay between PSMC3, ITIH4, and SERPINC1 genes in modulating well-being. Journal of psychiatric research 4 34883412
2025 Particulate matter-related ITIH4 deficiency is associated with an emphysema phenotype of COPD through JNK-dependent and JNK-independent signalling. The European respiratory journal 3 40404214
2025 ITIH4 alleviates OVA-induced asthma by regulating lung-gut microbiota. Molecular medicine (Cambridge, Mass.) 3 40410722
2025 The role of ITIH4 in regulating the PI3K/Akt signalling in rheumatoid arthritis. Rheumatology (Oxford, England) 3 40608509
2024 Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) as a compensatory protease inhibitor in hereditary angioedema. The Journal of allergy and clinical immunology 3 38657796
2024 ITIH4 reversed the effects of thrombin on VSMCs stiffness via JNK and ERK signaling pathway. Experimental cell research 3 39069151
2025 Knockdown of ITIH4 reduces inflammatory damage and apoptosis of A549 cells induced by Mycoplasma pneumoniae through NLRP3 inflammation. Allergologia et immunopathologia 2 40682224
2024 ITIH4 is a predictor for coronary thrombus in coronary arteriography patients. Future cardiology 2 39041488
2024 Serum proteomic analysis identified ITIH4 as a potential novel biomarker for feline infectious peritonitis. Journal of proteomics 2 39454824
2021 Associations between KCNQ1 and ITIH4 gene polymorphisms and infant weight gain in early life. Pediatric research 2 34247200
2024 Linkage of serum ITIH4 with Th2 signature cytokine, inflammation, exacerbation risk and severity in childhood asthma. Biomarkers in medicine 1 39011671
2026 Role of ITIH4 in Modulating YAP/TAZ-Mediated Apoptosis of Type II Alveolar Epithelium during Acute Respiratory Distress Syndrome. Pharmaceutical research 0 41735691
2026 Bioinformatics and machine learning identify ITIH4 and ZC3H13 as novel mRNA biomarkers for major depressive disorder that promote microglial M1 polarization. Cytotechnology 0 41890272
2026 Macrophages with ITIH4 overexpression attenuate inflammatory responses and regulate intestinal epithelial cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 41998424
2025 ITIH4 attenuates acute lung injury by Fe-containing particulate matter in mice via Hippo pathway in type II alveolar epithelial cells. Respiratory research 0 40437524
2025 Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) in saliva of pigs: evaluation of two commercially available ELISA kits for its measurement and distribution of its main components. PloS one 0 41134855
2002 SNP analysis of the inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene by a fluorescence-adapted SSCP method. BMC medical genetics 0 12147176

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