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Our goal was to identify a unique secretory protein for cholangiocarcinoma diagnosis and differentiation from other malignancies, benign hepatobiliary diseases, and chronic liver conditions. We conducted bulk RNA\u2010seq analysis to identify genes specifically upregulated in cholangiocarcinoma but not in most other cancers, benign hepatobiliary diseases, and chronic liver diseases focusing on exocrine protein\u2010encoding genes. Single\u2010cell RNA sequencing examined subcellular distribution. Immunohistochemistry and enzyme\u2010linked immunosorbent assays assessed tissue and serum expression. Diagnostic performance was evaluated via receiver\u2010operating characteristic (ROC) analysis. Inter\u2010alpha\u2010trypsin inhibitor heavy chain family member five (ITIH5), a gene encoding an extracellular protein, is notably upregulated in cholangiocarcinoma. This elevation is not observed in most other cancer types, benign hepatobiliary diseases, or chronic liver disorders. It is specifically expressed by malignant cholangiocytes. ITIH5 expression in cholangiocarcinoma tissues exceeded that in nontumorous bile duct, hepatocellular carcinoma, and nontumorous hepatic tissues. Serum ITIH5 levels were elevated in cholangiocarcinoma compared with controls (hepatocellular carcinoma, benign diseases, chronic hepatitis B, and healthy individuals). ITIH5 yielded areas under the ROC curve (AUCs) from 0.839 to 0.851 distinguishing cholangiocarcinoma from controls. Combining ITIH5 with carbohydrate antigen 19\u20109 (CA19\u20109) enhanced CA19\u20109's diagnostic effectiveness. In conclusion, serum ITIH5 may serve as a novel noninvasive cholangiocarcinoma diagnostic marker.<\/jats:p>","DOI":"10.1111\/cas.16143","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T05:20:03Z","timestamp":1710307203000},"page":"1665-1679","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Serum<scp>ITIH5<\/scp>as a novel diagnostic biomarker in cholangiocarcinoma"],"prefix":"10.1111","volume":"115","author":[{"given":"Meiru","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases Shijiazhuang Hebei Province China"},{"name":"Department of Gastroenterology Hengshui People's Hospital Hengshui Hebei Province 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