Single-cell transcriptome analysis uncovers underlying mechanisms of acute liver injury induced by tripterygium glycosides tablet in mice

• Published in: Journal of pharmaceutical analysis Vol. 13; no. 8; pp. 908 - 925
• Main Authors: Guo, Qiuyan, Wu, Jiangpeng, Wang, Qixin, Huang, Yuwen, Chen, Lin, Gong, Jie, Du, Maobo, Cheng, Guangqing, Lu, Tianming, Zhao, Minghong, Zhao, Yuan, Qiu, Chong, Xia, Fei, Zhang, Junzhe, Chen, Jiayun, Qiu, Feng, Wang, Jigang
• Format: Journal Article
• Language: English
• Published: Xi'an Elsevier B.V 01.08.2023; Xi'an Jiaotong University, Journal of Pharmaceutical Analysis; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs,Artemisinin Research Center,and Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing,100700,China%School of Chinese Materia Medica,and State Key Laboratory of Component-Based Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin,301617,China; Department of Nephrology,Shenzhen Key Laboratory of Kidney Diseases,Shenzhen Clinical Research Centre for Geriatrics,Shenzhen People's Hospital,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,Guangdong,518020,China%College of Food Science and Engineering,Institute of Ocean,Bohai University,Jinzhou,Liaoning,121013,China%State Key Laboratory of Infectious Disease Prevention and Control,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,National Institute for Communicable Disease Control and Prevention,Chinese Center for Disease Control and Prevention,Beijing,102206,China%Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing,100700,China%The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong,518033,China%School of Chinese Materia Medica,and State Key Laboratory of Component-Based Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin,301617,China%State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs,Artemisinin Research Center,and Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing,100700,China; School of Chinese Materia Medica,and State Key Laboratory of Component-Based Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin,301617,China; Department of Nephrology,Shenzhen Key Laboratory of Kidney Diseases,Shenzhen Clinical Research Centre for Geriatrics,Shenzhen People's Hospital,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,Guangdong,518020,China; Xi'an Jiaotong University; Elsevier
• Subjects: Acute liver injury; Alanine transaminase; Alkaline phosphatase; Apoptosis; Aspartate aminotransferase; Behcet's syndrome; Bilirubin; Cell activation; Cells; Endothelial cells; Enzymes; Gene expression; Genomics; Glycosides; Hepatitis; Hepatocytes; Inflammation; Kidney diseases; Laboratory animals; Leprosy; Liver; Liver diseases; Lymphocytes; Macrophages; Metabolism; Microenvironments; Nephrotic syndrome; Original; Phagocytosis; Phosphatase; Rheumatoid arthritis; scRNA-seq; Stellate cells; Therapeutic targets; Toxicity; Transcriptomes; Tripterygium glycosides tablet; Vein & artery diseases; Beijing China; United States > US; China; Germany; Tripterygium glycosides tablet; scRNA-seq; Acute liver injury
• ISSN: 2095-1779; 2214-0883; 2214-0883
• DOI: 10.1016/j.jpha.2023.03.004

Tripterygium glycosides tablet (TGT), the classical commercial drug of Tripterygium wilfordii Hook. F. has been effectively used in the treatment of rheumatoid arthritis, nephrotic syndrome, leprosy, Behcet's syndrome, leprosy reaction and autoimmune hepatitis. However, due to its narrow and limited treatment window, TGT-induced organ toxicity (among which liver injury accounts for about 40% of clinical reports) has gained increasing attention. The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing (scRNA-seq) technology. The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Using the mouse model, we identified 15 specific subtypes of cells in the liver tissue, including endothelial cells, hepatocytes, cholangiocytes, and hepatic stellate cells. Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations; led to marked inflammatory response, apoptosis and fatty acid metabolism dysfunction in hepatocytes; activated hepatic stellate cells; brought about the activation, inflammation, and phagocytosis of liver capsular macrophages cells; resulted in immune dysfunction of liver lymphocytes; disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways. Thus, these findings elaborate the mechanism underlying TGT-induced acute liver injury, provide new insights into the safe and rational applications in the clinic, and complement the identification of new biomarkers and therapeutic targets for liver protection. [Display omitted] •TGT induced acute liver injury via the regulation of inflammatory response.•TGT treatment resulted in hepatocyte apoptosis and HSC activation.•TGT treatment caused activated LCM cells and the immune dysfunction of lymphocyte.