Activation of pregnane X receptor protects against cholestatic liver injury by inhibiting hepatocyte pyroptosis  

作　　者：Hang-fei Liang Xiao Yang Hui-lin Li Xuan Li Jia-ning Tian Hai-guo Su Min Huang Jian-hong Fang Hui-chang Bi 

机构地区：[1]NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening&Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Guandong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [3]The State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Shenzhen Graduate School of Peking University,Shenzhen 518055,China

出　　处：《Acta Pharmacologica Sinica》2025年第1期147-158,共12页中国药理学报(英文版)

基　　金：The work was supported by the National Key Research and Development Program of China(2022YFA1106700,2022YFA1104900);the National Natural Science Foundation of China(U23A20535,82025034,82274001,81973392,82204226);Guangdong Basic and Applied Basic Research Foundation(SL2022A04J01943);the Shenzhen Science and Technology Program(KQTD20190929174023858);the 111 project(B16047);the Key Laboratory Foundation of Guangdong Province(2017B030314030);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093).

摘　　要：Our previous study shows that activation of pregnane X receptor(PXR)exerts hepatoprotection against lithocholic acid(LCA)-induced cholestatic liver injury.In this study we investigated whether PXR activation could inhibit hepatocyte pyroptosis,as well as the underlying mechanisms.Male mice were treated with mouse PXR agonist pregnenolone 16a-carbonitrile(PCN,50 mg-kg^(-1).d^(-1),i.p.)for 7 days,and received LCA(125 mg/kg,i.p.,bid)from D4,then sacrificed 12 h after the last LCA injection.We showed that LCA injection resulted in severe cholestatic liver injury characterized by significant increases in gallbladder size,hepatocellular necrosis,and neutrophil infiltration with a mortality rate of 68%;PCN treatment significantly inhibited hepatocyte pyroptosis during LCAinduced cholestatic liver injury,as evidenced by reduced serum lactic dehydrogenase(LDH)levels,TUNEL-positive cells and hepatocyte membrane damage.Furthermore,PXR activation suppressed both the NOD-like receptor protein 3(NLRP3)inflammasome-induced canonical pyroptosis and the apoptosis protease activating factor-1(APAF-1)pyroptosome-induced noncanonical pyroptosis.Inhibition of the nuclear factor kappa B(NF-kB)and forkhead box O1(FOxO1)signaling pathways was also observed following PXR activation.Notably,dual luciferase reporter assay showed that PXR activation inhibited the transcriptional effects of NF-kB on NLRP3,as well as FOXO1 on APAF-1.Our results demonstrate that PXR activation protects against cholestatic liver injury by inhibiting the canonical pyroptosis through the NF-kB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis,providing new evidence for PXR as a prospective anti-cholestatic target.

关 键 词：cholestatic liver injury pregnane X receptor pregnenolone 16a-carbonitrile PYROPTOSIS NLRP3 APAF-1 

分 类 号：R96[医药卫生—药理学]