14-kDa phosphohistidine phosphatase is a potential therapeutic target for liver fibrosis

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2021-03, Vol.320 (3), p.G351-G365
• Main Authors: Xu, Anjian, Zhou, Jichao, Li, Yanmeng, Qiao, Luyao, Jin, Caicai, Chen, Wei, Sun, Lan, Wu, Shanna, Li, Xiaojin, Zhou, Donghu, Jia, Siyu, Zhang, Bei, Yao, Jingyi, Zhang, Xiaowei, You, Hong, Huang, Jian
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Bile; Carbon tetrachloride; Carbon Tetrachloride Poisoning; Coculture Techniques; Drug Delivery Systems; Fibrosis; Gene Knockdown Techniques; Infiltration; Inflammation; Lamellipodia; Leukocyte migration; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Macrophages; Mice; Mice, Inbred C57BL; Morbidity; Phosphatase; Phosphohistidine; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Pseudopodia; RAW 264.7 Cells; Stellate cells; Therapeutic applications; Therapeutic targets; Up-Regulation
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/AJPGI.00334.2020

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-sh administration significantly attenuates CCl -induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration, and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis. PHP14 inhibition via adeno-associated virus (AAV)-mediated gene silencing could potently attenuate carbon tetrachloride (CCl )-induced liver fibrosis. PHP14 could regulate the migration of macrophages to the site of injury in vivo. PHP14 knockdown in vivo influenced the environment of fibrogenesis and relevant signaling pathways, subsequently affecting myofibroblast activation.