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

Author

Listed:
  • 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
    Harvard Stem Cell Institute
    Dana-Farber/Harvard Cancer Center)

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.

Suggested Citation

  • Yuchen Liu & Juanjuan Zhu & Yu Jin & Zhonghe Sun & Xiaolin Wu & Huiping Zhou & Yingzi Yang, 2025. "Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58809-z
    DOI: 10.1038/s41467-025-58809-z
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