Liu Yuchen, Zhu Juanjuan, Jin Yu, Sun Zhonghe, Wu Xiaolin, Zhou Huiping, Yang Yingzi
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA.
Nat Commun. 2025 Apr 15;16(1):3583. doi: 10.1038/s41467-025-58809-z.
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.
胆汁酸（BA）代谢紊乱会引发包括肝细胞癌（HCC）在内的各种肝脏疾病。然而，其潜在的分子机制仍不清楚。在此，我们报告BA代谢直接受YAP的抑制功能控制，YAP通过抑制关键生理性BA传感器Fxr的转录活性来改变BA水平和组成，从而诱导胆汁淤积。升高的BA水平进一步激活肝脏YAP，导致一个前馈循环，进而引发HCC。从机制上讲，发现Teads以不依赖DNA结合的方式与Fxr结合，并招募YAP以表观遗传方式抑制Fxr。促进BA排泄，或通过药理学激活Fxr和抑制HDAC1来减轻YAP抑制功能，或过表达Fxr靶基因Bsep以促进BA输出，均可减轻由YAP激活引起的胆汁淤积和HCC。我们的结果确定了YAP在BA代谢中的转录抑制作用是HCC的关键驱动因素，并表明其作为治疗靶点的潜力。
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