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

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

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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 16α-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 LCA-induced 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 non-canonical pyroptosis.Inhibition of the nuclear factor kappa B(NF-κB)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-κB 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-κB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis,providing new evidence for PXR as a prospective anti-cholestatic target.

cholestatic liver injurypregnane X receptorpregnenolone 16α-carbonitrilepyroptosisNLRP3APAF-1

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

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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

Guandong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

The State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Shenzhen Graduate School of Peking University,Shenzhen 518055,China

The State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Bio

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2025

10.1038/s41401-024-01357-x

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926
ISSN：1671-4083
年,卷(期)：2025.46(1)