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

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 Qu (), Ping Mi (), Jin Chai (), Detian Yuan () and Shiyang Li ()
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57351-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57351-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57351-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().