PXR triggers YAP-TEAD binding and Sirt2-driven YAP deacetylation and polyubiquitination to promote liver enlargement and regeneration in mice
Open accessAbstract
Pregnane X receptor (PXR) plays an important role in the regulation of metabolic homeostasis. Yes-associated protein (YAP) is a critical regulator of liver size and liver regeneration. Recently, we reported that PXR-induced liver enlargement and regeneration depend on YAP signalling, but the underlying mechanisms remain unclear. This study aimed to reveal how PXR regulates or interacts with YAP signalling during PXR-induced hepatomegaly and liver regeneration. Immunoprecipitation (IP), Co-IP and GST pull-down assays were performed in vitro to reveal the regulatory mechanisms involved in the PXR-YAP interaction. The roles of YAP-TEAD binding and Sirt2-driven deacetylation and polyubiquitination of YAP were further investigated in vitro and in vivo. The results showed that the ligand-binding domain (LBD) of PXR and the WW domain of YAP were critical for the PXR-YAP interaction. Furthermore, disruption of the YAP-TEAD interaction using the binding inhibitor verteporfin significantly decreased PXR-induced liver enlargement and regeneration after 70 % partial hepatectomy (PHx). Mechanistically, PXR activation significantly decreased YAP acetylation, which was interrupted by the sirtuin inhibitor nicotinamide (NAM). In addition, p300-induced YAP acetylation contributed to K48-linked YAP ubiquitination. Interestingly, PXR activation remarkably inhibited K48-linked YAP ubiquitination while inducing K63-linked YAP polyubiquitination. Sirt2 interference abolished the deacetylation and…
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PXR can accelerate regeneration.
“PXR can accelerate regeneration,57, 58, 59”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [59]
Cites
Hippo pathway in organ size control, tissue homeostasis, and cancer
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The Evolutionary History of YAP and the Hippo/YAP Pathway
Hilman, D., & Gat, U. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr065 · Cited by 166 · see citing works
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Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Zhou, W., Chembazhi, U. V., Huang, J., Bangru, S., Dean, A. E., Asokakumar, A., Kalsotra, A., Rudnick, D. A., & Anakk, S. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101858
- Authors
- Zhang, S., Guo, M., Jiang, X., Tang, L., Wu, T., Bi, G., Yang, X., Fan, S., & Bi, H.
- Affiliations
- Southern Medical University (CN)
- Corresponding author
- Bi, Huichang
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2023-02
- Volume
- 188
- Pages
- 106666
- ISSN
- 1043-6618 (ISSN-L)
- OpenAlex
- W4316497091
- Cited by
- 37
- References
- 3
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 11 · 2023: 1
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmacological Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Postdoctoral Research Foundation of China (2022M710067)
- National Key Research and Development Program of China (2022YFA110490)
- Shenzhen Science and Technology Innovation Program (KQTD20190929174023858)
- National Natural Science Foundation of China (82204500, 82025034, 81973392)
- China Postdoctoral Science Foundation
- Science, Technology and Innovation Commission of Shenzhen Municipality
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- pregnane X receptor, YAP, TEAD, SIRT2, K63-linked ubiquitination, K48-linked ubiquitination, liver regeneration, hepatomegaly, partial hepatectomy, P300, verteporfin, ligand-binding domain, WW domain
- MeSH terms
- Pregnane X Receptor, YAP-Signaling Proteins, Animals, Hepatomegaly, Liver, Mice, Ubiquitination, Sirtuin 2
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