Skip NavigationSkip to Content
Return Return to Search Results

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

  1. Author:
    Liu, Yuchen [ORCID]
    Zhu, Juanjuan
    Jin, Yu
    Sun,Zhonghe
    Wu,Xiaolin [ORCID]
    Zhou, Huiping [ORCID]
    Yang, Yingzi [ORCID]

  2. Author Address

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA., Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA., Department of Microbiology & Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA., Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA. yingzi_yang@hsdm.harvard.edu., Harvard Stem Cell Institute, Cambridge, MA, USA. yingzi_yang@hsdm.harvard.edu., Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA. yingzi_yang@hsdm.harvard.edu.,
    1. Year: 2025
    2. Date: Apr 15
    3. Epub Date: 2025 04 15
  2. Journal: Nature Communications
    1. 16
    2. 1
    3. Pages: 3583
  4. Type of Article: Article
  5. Article Number: 3583
  1. 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. © 2025. The Author(s).

    See More

External Sources

  1. View Full Text
  2. DOI: 10.1038/s41467-025-58809-z
  3. PMID: 40234449
  4. PMCID: PMC12000370
  5. PII : 10.1038/s41467-025-58809-z

Library Notes

  1. Fiscal Year: FY2024-2025
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel