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Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice

Acta Pharmacologica Sinica volume 46, pages 2423–2435 (2025)Cite this article

Abstract

The severity of sepsis is attributed to excessive inflammatory responses leading to liver injury. Pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, has been implicated in regulating inflammation and liver regeneration. This study aimed to investigate the role of PXR in sepsis-induced liver injury and the underlying mechanisms. Sepsis models were established in mice, the mice were administered the typical mouse PXR agonist PCN (100 mg·kg−1·d−1, i.p.) for 3 consecutive days in advance, then subjected to CLP operation or LPS administration 1 h after the last administration of PCN. The results showed that PCN pretreatment significantly increased the survival rate of septic mice, while the survival rate was reduced after the knockout of Pxr. In addition, PCN pretreatment effectively alleviated sepsis-induced liver injury. In Pxr knockout mice, liver injury was more severe, whereas the protective effects of PCN pretreatment were abolished. Mechanistically, PCN pretreatment significantly upregulated the expression of yes-associated protein (YAP) and its downstream targets and decreased the level of phosphorylated nuclear factor-κB (NF-κB). Moreover, liver-specific knockdown of Yap blocked the protective effects of PCN pretreatment against sepsis-induced liver injury and downregulated the phosphorylation level of NF-κB. In summary, this study demonstrated that PXR activation protects against sepsis-induced liver injury through activation of the YAP signaling pathway, providing a new strategy for the diagnosis and treatment of sepsis-induced liver injury.

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Fig. 1: Liver injury severity negatively correlates with the expression of PXR downstream target genes.
Fig. 2: PXR activation ameliorates CLP-induced liver injury.
Fig. 3: PXR activation ameliorates LPS-induced liver injury.
Fig. 4: Pxr knockdown aggravates the CLP-induced liver injury.
Fig. 5: Liver-specific knockdown of Pxr attenuates the effect of PXR activation on CLP-induced liver injury.
Fig. 6: PXR activation promotes liver Yes-associated protein and its downstream target protein expression in sepsis mice.
Fig. 7: Liver-specific knockdown of Yap attenuates the effect of PXR activation on CLP-induced liver injury.
Fig. 8: Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice.

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Acknowledgements

The research work was supported by the National Natural Science Foundation of China (Grants U23A20535, 82025034, 82274001, 82304603 and 82304457), the National Key R&D Program of China (Grant 2022YFA1104900, 2022YFA1106700), the Shenzhen Science and Technology Program (Grant KQTD20190929174023858), the Science and Technology Innovation Project of Guangdong Medical Products Administration (Grant 2023ZDZ06), the Guangdong Basic and Applied Basic Research Foundation (Grant SL2022A04J01943, 2023A1515012859) and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant 2017BT01Y093).

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  1. These authors contributed equally: Cheng-hua Wu, Shuang Hu

Authors and Affiliations

  1. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Cheng-hua Wu, Shuang Hu, Dan Li, Xiao-wen Jiang, Hui Ou-Yang, Guo-fang Bi, Peng Wang, Feng-ting Liang, Wen-hong Zhou, Xiao Yang, Jian-hong Fang & Hui-chang Bi

  2. The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518000, China

    Hui-chang Bi

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Contributions

HCB, JHF, and XY conceived and designed the project. CHW, SH, DL, XWJ, HOY, GFB, PW, FTL, and WHZ performed the experiments. HCB, CHW, and JHF wrote and revised the manuscript.

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Correspondence to Hui-chang Bi.

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Wu, Ch., Hu, S., Li, D. et al. Pregnane X receptor alleviates sepsis-induced liver injury through activation of yes-associated protein in mice. Acta Pharmacol Sin 46, 2423–2435 (2025). https://doi.org/10.1038/s41401-025-01552-4

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