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

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-Yu Ju () and Xu-Feng Qi ()
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Jing-Bo Xia: Jinan University
Kun Liu: Jinan University
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57962-9

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