P2Y14R activation facilitates liver regeneration via CREB/DNMT3b/Dact-2/β-Catenin signals in acute liver failure.
10.1016/j.apsb.2025.01.004
- Author:
Mengze ZHOU
1
;
Yehong LI
1
;
Jialong QIAN
1
;
Xinli DONG
1
;
Yanshuo GUO
1
;
Li YIN
1
;
Chunxiao LIU
1
;
Kun HAO
1
;
Qinghua HU
1
Author Information
1. State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
- Publication Type:Journal Article
- Keywords:
Acute liver failure;
Dact-2;
Hepatocyte;
Liver regeneration;
P2Y14R;
Partial hepatectomy;
UDP-Glucose;
β-Catenin
- From:
Acta Pharmaceutica Sinica B
2025;15(2):919-933
- CountryChina
- Language:English
-
Abstract:
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 (P2Y14R) in ALF remains unknown. The present study aims to investigate the role and underlying mechanisms of UDP-G/P2Y14R axis in ALF. In this study, hepatic P2Y14R is significantly increased in TAA-induced and partial hepatectomy-induced ALF, while knockout of whole-body P2Y14R aggravates liver failure, manifested by inhibiting β-Catenin-mediated liver regeneration. Consistently, P2Y14R deficiency exhibits impaired liver regeneration in mice suffer partial hepatectomy. Importantly, only hepatocellular specific deletion of P2Y14R (P2Y14R flox/flox Alb cre/+ ) mice shows a similar phenomenon, rather than stellate cell specific deletion of P2Y14R (P2Y14R flox/flox Lrat cre/+ ) mice. Mechanistically, P2Y14R induction regulates methylation of Dact-2 through CREB/DNMT3b signals in hepatocytes, subsequently inhibiting the expression of Dact-2 which is a stabilizer of β-Catenin degradation complex, leading to the activation of β-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 P2Y14R in ALF and provide an effective adjuvant strategy for treatment of ALF.
