Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration
Abstract Promoting endogenous cardiomyocyte proliferation is a promising strategy for cardiac repair. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here, we identify Foxk1 and Foxk2 as key regulators of cardio...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57996-z |
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| author | Dongcheng Cai Chungeng Liu Haotong Li Chiyin Wang Lina Bai Jie Feng Miaoqing Hu Hao Wang Shen Song Yifan Xie Ziwei Chen Jiajun Zhong Hong Lian Zhiwei Yang Yuhui Zhang Yu Nie |
| author_facet | Dongcheng Cai Chungeng Liu Haotong Li Chiyin Wang Lina Bai Jie Feng Miaoqing Hu Hao Wang Shen Song Yifan Xie Ziwei Chen Jiajun Zhong Hong Lian Zhiwei Yang Yuhui Zhang Yu Nie |
| author_sort | Dongcheng Cai |
| collection | DOAJ |
| description | Abstract Promoting endogenous cardiomyocyte proliferation is a promising strategy for cardiac repair. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here, we identify Foxk1 and Foxk2 as key regulators of cardiomyocyte proliferation, whose expression declines during postnatal heart development. Cardiomyocyte-specific knockout of Foxk1 or Foxk2 impairs neonatal heart regeneration after myocardial infarction (MI) injury. AAV9-mediated Foxk1 or Foxk2 overexpression extends the postnatal cardiomyocyte proliferative window and enhances cardiac repair in adult mice after MI. Mechanistically, Foxk1 and Foxk2 drive cardiomyocyte cell cycle progression by directly activating CCNB1 and CDK1 expression, forming the CCNB1/CDK1 complex that facilitates G2/M transition. Moreover, Foxk1 and Foxk2 promote cardiomyocyte proliferation by upregulating HIF1α expression, which enhances glycolysis and the pentose phosphate pathway (PPP), which further favors cardiomyocyte proliferation. These findings establish Foxk1 and Foxk2 as promising therapeutic targets for cardiac injury. |
| format | Article |
| id | doaj-art-e2e41d7b403c4967a5967b1d297985b5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e2e41d7b403c4967a5967b1d297985b52025-08-20T03:40:45ZengNature PortfolioNature Communications2041-17232025-03-0116111710.1038/s41467-025-57996-zFoxk1 and Foxk2 promote cardiomyocyte proliferation and heart regenerationDongcheng Cai0Chungeng Liu1Haotong Li2Chiyin Wang3Lina Bai4Jie Feng5Miaoqing Hu6Hao Wang7Shen Song8Yifan Xie9Ziwei Chen10Jiajun Zhong11Hong Lian12Zhiwei Yang13Yuhui Zhang14Yu Nie15State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeNational Health Commission Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Promoting endogenous cardiomyocyte proliferation is a promising strategy for cardiac repair. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here, we identify Foxk1 and Foxk2 as key regulators of cardiomyocyte proliferation, whose expression declines during postnatal heart development. Cardiomyocyte-specific knockout of Foxk1 or Foxk2 impairs neonatal heart regeneration after myocardial infarction (MI) injury. AAV9-mediated Foxk1 or Foxk2 overexpression extends the postnatal cardiomyocyte proliferative window and enhances cardiac repair in adult mice after MI. Mechanistically, Foxk1 and Foxk2 drive cardiomyocyte cell cycle progression by directly activating CCNB1 and CDK1 expression, forming the CCNB1/CDK1 complex that facilitates G2/M transition. Moreover, Foxk1 and Foxk2 promote cardiomyocyte proliferation by upregulating HIF1α expression, which enhances glycolysis and the pentose phosphate pathway (PPP), which further favors cardiomyocyte proliferation. These findings establish Foxk1 and Foxk2 as promising therapeutic targets for cardiac injury.https://doi.org/10.1038/s41467-025-57996-z |
| spellingShingle | Dongcheng Cai Chungeng Liu Haotong Li Chiyin Wang Lina Bai Jie Feng Miaoqing Hu Hao Wang Shen Song Yifan Xie Ziwei Chen Jiajun Zhong Hong Lian Zhiwei Yang Yuhui Zhang Yu Nie Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration Nature Communications |
| title | Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration |
| title_full | Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration |
| title_fullStr | Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration |
| title_full_unstemmed | Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration |
| title_short | Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration |
| title_sort | foxk1 and foxk2 promote cardiomyocyte proliferation and heart regeneration |
| url | https://doi.org/10.1038/s41467-025-57996-z |
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