FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes

Chi Qian Liang, Deng Cheng Zhou, Wen Tao Peng, Wu Yun Chen, Hai Yan Wu, Yi Min Zhou, Wei Li Gu, Kyu Sang Park, Hui Zhao, Long Quan Pi, Li Zheng, Shan Shan Feng, Dong Qing Cai, Xu Feng Qi

Research output: Contribution to journalArticlepeer-review


Upon injury, the liver is capable of substantial regeneration from the original tissue until an appropriate functional size. The underlying mechanisms controlling the liver regeneration processes are not well elucidated. Previous studies have proposed that the transcription factor FoxO3 is involved in various liver diseases, but its exact role in the regulation of liver regeneration remains largely unclear. To directly test the detailed role of FoxO3 in liver regeneration, both a constitutive Albumin-Cre driver line and adeno-associated virus serotype 8 (AAV8)-Tbg-Cre (AAV-Cre)-injected adult FoxO3fl/fl mice were subjected to 70% partial hepatectomy (PH). Our data demonstrate that FoxO3 deletion accelerates liver regeneration primarily by limiting polyploidization and promoting the proliferation of hepatocytes during liver regeneration. RNA-seq analysis indicates that FoxO3 deficiency greatly alters the expression of gene sets associated with cell proliferation and apoptosis during liver regeneration. Chromatin immunoprecipitation-PCR (ChIP-PCR) and luciferase reporter assays reveal that FoxO3 promotes the expression of Nox4 but suppresses the expression of Nr4a1 in hepatocytes. AAV8 virus-mediated overexpression of Nox4 and knockdown of Nr4a1 significantly suppressed hepatocyte proliferation and liver regeneration in FoxO3-deficient mice. We demonstrate that FoxO3 negatively controls hepatocyte proliferation through Nox4 upregulation and Nr4a1 downregulation, thereby ensuring appropriate functional regeneration of the liver. Our findings provide novel mechanistic insight into the therapeutic mechanisms of FoxO3 in liver damage and repair.

Original languageEnglish
Article number33
Journalnpj Regenerative Medicine
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
This work was supported by grants from the National Key R&D Program of China (2017YFA0103302 and 2016YFE0204700), the National Natural Science Foundation of China (91649203, 82070257, 81770240, 81570222, 31802025, and 81270183), the Guangdong Natural Science Funds for Distinguished Young Scholar (2014A030306011), the Guangdong Science and Technology Planning Project (2014A050503043), the New Star of Pearl River on Science and Technology of Guangzhou (2014J2200002), the Top Young Talents of Guangdong Province Special Support Program (87315007), the Fundamental Research Funds for the Central Universities (21617436), and the Research Grant of Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University (ZSYX-M-2019-00009, ZSYXM202004, and ZSYXM202104), China.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Developmental Biology
  • Cell Biology


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