Itih4, also known as inter-α-trypsin inhibitor heavy chain 4, is a plasma protein with diverse functions. It acts as a protease inhibitor through a novel mechanism, inhibiting key proteases like mannan-binding lectin-associated serine protease-1 (MASP-1), MASP-2, and plasma kallikrein involved in intravascular host defense [1]. It is also expressed specifically in vascular smooth muscle cells (SMCs) in atherosclerosis, potentially linked to extracellular matrix stability [2].

In various disease contexts, Itih4 shows different associations. In bacterial bloodstream infection, its level increases, suggesting it could be an inflammation biomarker [3]. In early gastric cancer, it is a key serum biomarker with high specificity for diagnosis [4]. In coronary artery disease, its level is lower in patients, and it may predict coronary thrombus [5]. It can also regulate VSMCs stiffness, counteracting the effects of thrombin via JNK and ERK signaling pathways [6]. In coronary heart disease, it may serve as an anti-inflammatory biomarker related to stenosis degree and major adverse cardiovascular event risk [7]. In hereditary angioedema, it may have compensatory mechanisms and could be a diagnostic and prognostic biomarker [8]. In bitches with pyometra, it behaves as a moderate acute-phase protein [9]. In rheumatoid arthritis, network pharmacology and molecular docking suggest CXCR4 might be a potential receptor for Itih4 to activate the chemokine signaling, exacerbating the pathogenesis [10].

In conclusion, Itih4 has multiple functions including protease inhibition and is associated with various diseases such as infections, cancers, and cardiovascular and inflammatory diseases. Studies on Itih4 contribute to understanding disease mechanisms, with potential implications for diagnosis, prognosis, and treatment in these disease areas.

References:

1. Pihl, Rasmus, Jensen, Rasmus K, Poulsen, Emil C, Enghild, Jan J, Thiel, Steffen. 2021. ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism. In Science advances, 7, . doi:10.1126/sciadv.aba7381. https://pubmed.ncbi.nlm.nih.gov/33523981/

2. Ravindran, Aarthi, Holappa, Lari, Niskanen, Henri, Örd, Tiit, Kaikkonen, Minna U. . Translatome profiling reveals Itih4 as a novel smooth muscle cell-specific gene in atherosclerosis. In Cardiovascular research, 120, 869-882. doi:10.1093/cvr/cvae028. https://pubmed.ncbi.nlm.nih.gov/38289873/

3. Ma, Yating, Li, Ruibing, Wang, Jianan, Cui, Jiayue, Wang, Chengbin. 2020. ITIH4, as an inflammation biomarker, mainly increases in bacterial bloodstream infection. In Cytokine, 138, 155377. doi:10.1016/j.cyto.2020.155377. https://pubmed.ncbi.nlm.nih.gov/33348064/

4. Sun, Yingying, Jin, Jie, Jing, Hongyan, Zhang, Qinghua, Jing, Dadao. 2021. ITIH4 is a novel serum biomarker for early gastric cancer diagnosis. In Clinica chimica acta; international journal of clinical chemistry, 523, 365-373. doi:10.1016/j.cca.2021.10.022. https://pubmed.ncbi.nlm.nih.gov/34687700/

5. Tian, Lei, Zhao, Su, Zhang, Ruiyan. 2024. ITIH4 is a predictor for coronary thrombus in coronary arteriography patients. In Future cardiology, 20, 547-554. doi:10.1080/14796678.2024.2377924. https://pubmed.ncbi.nlm.nih.gov/39041488/

6. Tian, Lei, Zhao, Su, Ding, Fenghua, Zhang, Ruiyan. 2024. ITIH4 reversed the effects of thrombin on VSMCs stiffness via JNK and ERK signaling pathway. In Experimental cell research, 441, 114189. doi:10.1016/j.yexcr.2024.114189. https://pubmed.ncbi.nlm.nih.gov/39069151/

7. Huo, Yanfei, Lai, Yungang, Feng, Qiang, Wang, Qingxiang, Li, Junhua. 2023. Serum ITIH4 in coronary heart disease: a potential anti-inflammatory biomarker related to stenosis degree and risk of major adverse cardiovascular events. In Biomarkers in medicine, 16, 1279-1288. doi:10.2217/bmm-2022-0673. https://pubmed.ncbi.nlm.nih.gov/36891881/

8. Troldborg, Anne, Godnic-Polai, Zsofia, Cervenak, László, Farkas, Henriette, Thiel, Steffen. 2024. Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) as a compensatory protease inhibitor in hereditary angioedema. In The Journal of allergy and clinical immunology, 154, 468-479.e6. doi:10.1016/j.jaci.2024.03.028. https://pubmed.ncbi.nlm.nih.gov/38657796/

9. Soler, Lourdes, Szczubiał, Marek, Dąbrowski, Roman, Lampreave, Fermín, Piñeiro, Matilde. 2021. Measurement of ITIH4 and Hp levels in bitches with pyometra using newly developed ELISA methods. In Veterinary immunology and immunopathology, 235, 110221. doi:10.1016/j.vetimm.2021.110221. https://pubmed.ncbi.nlm.nih.gov/33730638/

10. Joshi, Lovely, Chakraborty, Debolina, Kumar, Vijay, Biswas, Sagarika. 2024. ITIH4 in Rheumatoid Arthritis Pathogenesis: Network Pharmacology and Molecular Docking Analysis Identify CXCR4 as a Potential Receptor. In Pathophysiology : the official journal of the International Society for Pathophysiology, 31, 514-530. doi:10.3390/pathophysiology31030038. https://pubmed.ncbi.nlm.nih.gov/39311312/