Zang B, Li JX, Liu QX, Yao Y, Li H, Wang Y, Wang JG, Yang YF, Liang RW, Xin XR, Liu B. Tumor necrosis factor alpha-induced protein 3: A key biomarker for response to ursodeoxycholic acid in primary biliary cholangitis. World J Hepatol 2025; 17(7): 107666 [DOI: 10.4254/wjh.v17.i7.107666]
Corresponding Author of This Article
Bin Liu, MD, PhD, Department of Rheumatology and Immunology, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266001, Shandong Province, China. binliu72314@163.com
Research Domain of This Article
Immunology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Jul 27, 2025; 17(7): 107666 Published online Jul 27, 2025. doi: 10.4254/wjh.v17.i7.107666
Tumor necrosis factor alpha-induced protein 3: A key biomarker for response to ursodeoxycholic acid in primary biliary cholangitis
Bo Zang, Jia-Xiu Li, Qi-Xuan Liu, Yuan Yao, Hua Li, Yan Wang, Ji-Gang Wang, Yi-Fei Yang, Rui-Wen Liang, Xin-Ran Xin, Bin Liu
Bo Zang, Jia-Xiu Li, Yuan Yao, Hua Li, Yi-Fei Yang, Rui-Wen Liang, Xin-Ran Xin, Bin Liu, Department of Rheumatology and Immunology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
Qi-Xuan Liu, Graduate Group of Epidemiology, University of California Davis, Davis, CA 95616, United States
Yan Wang, Ji-Gang Wang, Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266001, Shandong Province, China
Co-first authors: Bo Zang and Jia-Xiu Li.
Author contributions: Zang B, Li JX, and Liu B designed and conducted the study and wrote the article; Zang B and Li JX contributed equally to this article, they are the co-first authors of this manuscript; Yao Y and Li H corrected the details of the experimental design; Wang Y and Wang JG collected sample tissues; Yang YF, Liang RW, and Xin XR performed experiments and analyzed results; Zang B interpreted the data; Liu QX and Liu B supervised the experiment and revised the manuscript; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81671600 and No. 81241094; Natural Science Foundation of Shandong Province, China, No. ZR2016HM13 and No. ZR2023MH066; and Qingdao Medical and Health Scientific Research Project, China, No. 2024-WJKY160.
Institutional review board statement: This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Qingdao University. The patients/participants provided their written informed consent to participate in this study, approval No. QYFY WZLL 29650.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bin Liu, MD, PhD, Department of Rheumatology and Immunology, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266001, Shandong Province, China. binliu72314@163.com
Received: March 30, 2025 Revised: May 10, 2025 Accepted: June 25, 2025 Published online: July 27, 2025 Processing time: 118 Days and 15.7 Hours
Abstract
BACKGROUND
The pathogenesis of primary biliary cholangitis (PBC) remains unclear. Ursodeoxycholic acid (UDCA) is the only first-line clinical treatment, but approximately 40% of patients exhibit a poor response.
AIM
To identify novel biomarkers for PBC to predict the efficacy of UDCA and enhance treatment.
METHODS
Microarray expression profiling datasets were downloaded from the Gene Expression Omnibus and analyzed to identify differentially expressed genes between PBC patients and healthy controls. Immunohistochemistry was performed to validate key genes in liver tissues of the participants. Logistic regression was employed to evaluate prognostic risk factors, receiver operating characteristic curves were used to assess predictive performance, and correlations between key genes and clinicopathological characteristics were analyzed.
RESULTS
By bioinformatic analysis, 13 genes primarily associated with the progression of PBC were identified, and tumor necrosis factor alpha-induced protein 3 (TNFAIP3) was selected for further investigation. Then expression of TNFAIP3 in PBC patients was significantly elevated compared to healthy controls on immunohistochemistry (P < 0.0001). Multivariate Cox regression analysis indicated that both TNFAIP3 and fatigue were independent risk factors for response to UDCA in PBC patients (P < 0.05). The area under the curve for TNFAIP3 and fatigue were 0.691 and 0.704, respectively, while their combination showed a significantly higher area under the curve of 0.848. The expression of TNFAIP3 was also correlated with age, albumin, total bilirubin, alkaline phosphatase and splenomegaly (P < 0.05).
CONCLUSION
TNFAIP3 and fatigue are independent risk factors for response to UDCA in Chinese patients with PBC. TNFAIP3 may be a potential biomarker or therapeutic target for PBC. These findings offer new insights into the pathogenesis of PBC.
Core Tip: By bioinformatics analysis, we identified 13 differentially expressed genes linked to primary biliary cholangitis progression. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) was selected for validation via immunohistochemistry and confirmed as a promising biomarker for ursodeoxycholic acid response. Clinical validation further proved its significant correlation with treatment outcomes. Additionally, fatigue was identified as an independent predictor of ursodeoxycholic acid efficacy, and the combination of TNFAIP3 expression and fatigue exhibited superior predictive performance. The expression of TNFAIP3 was also associated with key clinicopathological features, including age, albumin levels, total bilirubin, alkaline phosphatase, and splenomegaly, providing new insights into disease progression.
