Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation

Yuchen Liu, Juanjuan Zhu, Yu Jin, Zhonghe Sun, Xiaolin Wu, Huiping Zhou and Yingzi Yang ()
Additional contact information
Yuchen Liu: Harvard School of Dental Medicine
Juanjuan Zhu: Harvard School of Dental Medicine
Yu Jin: Harvard School of Dental Medicine
Zhonghe Sun: Frederick National Laboratory for Cancer
Xiaolin Wu: Frederick National Laboratory for Cancer
Huiping Zhou: Virginia Commonwealth University
Yingzi Yang: Harvard School of Dental Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP’s transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58809-z 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_s41467-025-58809-z

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

DOI: 10.1038/s41467-025-58809-z

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 ().