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Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells

Author

Listed:
  • Peng Zhang

    (Shandong University)

  • Xinying Li

    (Shandong University)

  • Jinyuan Liang

    (Shandong University)

  • Yuanwen Zheng

    (Shandong Provincial Hospital Affiliated to Shandong First Medical University)

  • Yao Tong

    (Chongqing University)

  • Jing Shen

    (Shandong University)

  • Yatai Chen

    (Shandong University)

  • Penghu Han

    (Shandong University)

  • Shuzheng Chu

    (Shandong University)

  • Ruirui Liu

    (Shandong University)

  • Mengqi Zheng

    (Shandong University)

  • Yunjiao Zhai

    (Shandong University)

  • Xiaolong Tang

    (Qilu Hospital of Shandong University)

  • Cuijuan Zhang

    (Shandong University)

  • Hui Qu

    (Qilu Hospital of Shandong University)

  • Ping Mi

    (Shandong University)

  • Jin Chai

    (The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University))

  • Detian Yuan

    (Shandong University)

  • Shiyang Li

    (Shandong University)

Abstract

Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.

Suggested Citation

  • Peng Zhang & Xinying Li & Jinyuan Liang & Yuanwen Zheng & Yao Tong & Jing Shen & Yatai Chen & Penghu Han & Shuzheng Chu & Ruirui Liu & Mengqi Zheng & Yunjiao Zhai & Xiaolong Tang & Cuijuan Zhang & Hui, 2025. "Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57351-2
    DOI: 10.1038/s41467-025-57351-2
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    References listed on IDEAS

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    1. Xinyang Song & Ximei Sun & Sungwhan F. Oh & Meng Wu & Yanbo Zhang & Wen Zheng & Naama Geva-Zatorsky & Ray Jupp & Diane Mathis & Christophe Benoist & Dennis L. Kasper, 2020. "Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis," Nature, Nature, vol. 577(7790), pages 410-415, January.
    2. Mohammad Arifuzzaman & Tae Hyung Won & Ting-Ting Li & Hiroshi Yano & Sreehaas Digumarthi & Andrea F. Heras & Wen Zhang & Christopher N. Parkhurst & Sanchita Kashyap & Wen-Bing Jin & Gregory Garbès Put, 2022. "Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation," Nature, Nature, vol. 611(7936), pages 578-584, November.
    3. Donggi Paik & Lina Yao & Yancong Zhang & Sena Bae & Gabriel D. D’Agostino & Minghao Zhang & Eunha Kim & Eric A. Franzosa & Julian Avila-Pacheco & Jordan E. Bisanz & Christopher K. Rakowski & Hera Vlam, 2022. "Human gut bacteria produce ΤΗ17-modulating bile acid metabolites," Nature, Nature, vol. 603(7903), pages 907-912, March.
    4. Bi-Sen Ding & Zhongwei Cao & Raphael Lis & Daniel J. Nolan & Peipei Guo & Michael Simons & Mark E. Penfold & Koji Shido & Sina Y. Rabbany & Shahin Rafii, 2014. "Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis," Nature, Nature, vol. 505(7481), pages 97-102, January.
    5. Saiyu Hang & Donggi Paik & Lina Yao & Eunha Kim & Jamma Trinath & Jingping Lu & Soyoung Ha & Brandon N. Nelson & Samantha P. Kelly & Lin Wu & Ye Zheng & Randy S. Longman & Fraydoon Rastinejad & A. Slo, 2019. "Bile acid metabolites control TH17 and Treg cell differentiation," Nature, Nature, vol. 576(7785), pages 143-148, December.
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