P2Y_(14)R activation facilitates liver regeneration via CREB/DNMT3b/Dact-2/β-Catenin signals in acute liver failure  

作　　者：Mengze Zhou Yehong Li Jialong Qian Xinli Dong Yanshuo Guo Li Yin Chunxiao Liu Kun Hao Qinghua Hu 

机构地区：[1]State Key Laboratory of Natural Medicines,School of Pharmacy,China Pharmaceutical University,Nanjing211198,China [2]School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期919-933,共15页药学学报(英文版)

基　　金：supported by National Natural Science Foundation of China(No.82373887 to Qinghua Hu,No.82304506 to Mengze Zhou);Natural Science Foundation of Jiangsu Province(BK20211223 to Qinghua Hu,BK20231022 to Mengze Zhou,China);China Postdoctoral Science Foundation(2022M723513 to Mengze Zhou);the Fundamental Research Funds for the Central Universities(2632024TD01 to Qinghua Hu,2632023GR23 to Mengze Zhou,China).

摘　　要：Acute liver failure(ALF)is lack of broadly approved therapeutic strategy except liver transplantation.As a glycogen metabolic intermediate,UDP-glucose(UDP-G)has been considered to accelerate liver repairment.Nevertheless,the role of UDP-G and its receptor P2Y purinoceptor 14(P2Y_(14)R)in ALF remains unknown.The present study aims to investigate the role and underlying mechanisms of UDP-G/P2Y_(14)R axis in ALF.In this study,hepatic P2Y_(14)R is significantly increased in TAA-induced and partial hepatectomy-induced ALF,while knockout of whole-body P2Y_(14)R aggravates liver failure,manifested by inhibitingβ-Catenin-mediated liver regeneration.Consistently,P2Y_(14)R deficiency exhibits impaired liver regeneration in mice suffer partial hepatectomy.Importantly,only hepatocellular specific deletion of P2Y_(14)R(P2Y_(14)R^(flox/flox)Alb^(cre/+))mice shows a similar phenomenon,rather than stellate cell specific deletion of P2Y_(14)R(P2Y_(14)R^(flox/flox)Lrat^(cre/+))mice.Mechanistically,P2Y_(14)R induction regulates methylation of Dact-2 through CREB/DNMT3b signals in hepatocytes,subsequently inhibiting the expression of Dact-2 which is a stabilizer ofβ-Catenin degradation complex,leading to the activation ofβ-Catenin-mediated liver regeneration.Interestingly,the administration of exogenous UDP-G can accelerate liver regeneration and liver function recovery after partial hepatectomy in hepatocellular carcinoma mice.Together,the findings propose an unrecognized role of P2Y_(14)R in ALF and provide an effective adjuvant strategy for treatment of ALF.

关 键 词：Acute liver failure UDP-GLUCOSE P2Y_(14)R Liver regeneration HEPATOCYTE Partial hepatectomy b-Catenin Dact-2 

分 类 号：R575.3[医药卫生—消化系统]