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FoxO3 controls cardiomyocyte proliferation and heart regeneration by regulating Sfrp2 expression in postnatal mice

Author

Listed:
  • Jing-Bo Xia

    (Jinan University
    Jinan University)

  • Kun Liu

    (Jinan University
    Zhongshan Torch Development Zone People’s Hospital)

  • Xiao-Lin Lin

    (Jinan University)

  • Hong-Ji Li

    (Jinan University)

  • Jin-Hua Lin

    (Jinan University)

  • Li Li

    (Jinan University)

  • Chi-Qian Liang

    (Jinan University)

  • Yan Cao

    (Jinan University)

  • Na Wen

    (Jinan University)

  • Zhao-Fu Liao

    (Guangdong Medical University)

  • Hui Zhao

    (The Chinese University of Hong Kong)

  • Kyu-Sang Park

    (Yonsei University)

  • Guo-Hua Song

    (Shandong First Medical University & Shandong Academy of Medical Science)

  • Ze-Bing Ye

    (Jinan University)

  • Dong-Qing Cai

    (Jinan University)

  • Zhen-Yu Ju

    (Jinan University)

  • Xu-Feng Qi

    (Jinan University
    Jinan University)

Abstract

The Forkhead box O3 (FoxO3) transcription factor is crucial to controlling heart growth in adulthood, but its exact role in cardiac repair and regeneration in postnatal mice remains unclear. Here, we show that FoxO3 deficiency promotes cardiomyocyte proliferation in postnatal mice and improves cardiac function in homeostatic adult mice. Moreover, FoxO3 deficiency accelerates heart regeneration following injury in postnatal mice at the regenerative and non-regenerative stages. We reveal that FoxO3 directly promotes the expression of secreted frizzled-related protein 2 (Sfrp2) and suppresses the activation of canonical Wnt/β-catenin signaling during heart regeneration. The increased activation of β-catenin in FoxO3-deficient cardiomyocytes can be blocked by Sfrp2 overexpression. In addition, Sfrp2 overexpression suppressed cardiomyocyte proliferation and heart regeneration in FoxO3-deficient mice. These findings suggest that FoxO3 negatively controls cardiomyocyte proliferation and heart regeneration in postnatal mice at least in part by promoting Sfrp2 expression, which leading to the inactivation of canonical Wnt/β-catenin signaling.

Suggested Citation

  • Jing-Bo Xia & Kun Liu & Xiao-Lin Lin & Hong-Ji Li & Jin-Hua Lin & Li Li & Chi-Qian Liang & Yan Cao & Na Wen & Zhao-Fu Liao & Hui Zhao & Kyu-Sang Park & Guo-Hua Song & Ze-Bing Ye & Dong-Qing Cai & Zhen, 2025. "FoxO3 controls cardiomyocyte proliferation and heart regeneration by regulating Sfrp2 expression in postnatal mice," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57962-9
    DOI: 10.1038/s41467-025-57962-9
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    References listed on IDEAS

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    1. Xiang Li & Fan Wu & Stefan Günther & Mario Looso & Carsten Kuenne & Ting Zhang & Marion Wiesnet & Stephan Klatt & Sven Zukunft & Ingrid Fleming & Gernot Poschet & Astrid Wietelmann & Ann Atzberger & M, 2023. "Publisher Correction: Inhibition of fatty acid oxidation enables heart regeneration in adult mice," Nature, Nature, vol. 623(7986), pages 7-7, November.
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    3. Xiang Li & Fan Wu & Stefan Günther & Mario Looso & Carsten Kuenne & Ting Zhang & Marion Wiesnet & Stephan Klatt & Sven Zukunft & Ingrid Fleming & Gernot Poschet & Astrid Wietelmann & Ann Atzberger & M, 2023. "Inhibition of fatty acid oxidation enables heart regeneration in adult mice," Nature, Nature, vol. 622(7983), pages 619-626, October.
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