14-kDa Phosphohistidine Phosphatase Is a Potential Therapeutic Target for Liver Fibrosis

Background: In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in cell migration. In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediated liver fibrosis in vivo. Methods: Liver fibrosis was induced in mice by carbon tetrachloride (CCl 4 ) administration. The preventive and therapeutic effect of PHP14 inhibition on liver fibrosis was evaluated by injection of the adeno-associated viral containing short hairpin RNA (shRNA) against Phpt1 (AAV- Phpt1) via tail vein into mice before or after 1 week of CCl4 treatment. The effect of AAV- Phpt1 on fibrosis was evaluated by real-time PCR, Western blotting, Immunohistochemistry and RNA sequencing (RNA-Seq). Flow cytometric, Transwell and adoptive transfer assays were used to assess the cell migration and infiltration. Finding: Liver fibrosis was significantly improved after AAV-Phpt1 administration in the CCl4 model. Notably, cell infiltration was significantly suppressed after PHP14 knockdown. Besides HSCs, we found the migration of macrophage was significantly inhibited by PHP14 knockdown, resulting in decreased accumulation of macrophages in the liver injury areas. RNA-seq results revealed that PHP14 knockdown in vivo influenced the environment of fibrogenesis and relevant signaling pathways, subsequently affecting myofibroblast activation. Interpretation: PHP14 inhibition can attenuate liver fibrosis and can be considered a potential therapeutic target for liver fibrosis. Funding Statement: Beijing Natural Science Foundation ( 7202034 to A. Xu), National Natural Science Foundation of China (81670539 and 81970524 to H. You, 81773800 to X. Zhang) Declaration of Interests: The authors disclose no conflicts. Ethics Approval Statement: All animal work was performed under the ethical guidelines of the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Beijing, China).