Cai Dongcheng, Liu Chungeng, Li Haotong, Wang Chiyin, Bai Lina, Feng Jie, Hu Miaoqing, Wang Hao, Song Shen, Xie Yifan, Chen Ziwei, Zhong Jiajun, Lian Hong, Yang Zhiwei, Zhang Yuhui, Nie Yu
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Nat Commun. 2025 Mar 24;16(1):2877. doi: 10.1038/s41467-025-57996-z.
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.
促进内源性心肌细胞增殖是心脏修复的一种有前景的策略。识别调节心肌细胞增殖的关键因素可以推动心脏再生新疗法的发展。在此，我们确定Foxk1和Foxk2是心肌细胞增殖的关键调节因子，其表达在出生后心脏发育过程中下降。心肌细胞特异性敲除Foxk1或Foxk2会损害心肌梗死（MI）损伤后的新生心脏再生。腺相关病毒9（AAV9）介导的Foxk1或Foxk2过表达延长了出生后心肌细胞增殖窗口，并增强了成年小鼠MI后的心脏修复。机制上，Foxk1和Foxk2通过直接激活CCNB1和CDK1的表达来驱动心肌细胞的细胞周期进程，形成促进G2/M期转换的CCNB1/CDK1复合物。此外，Foxk1和Foxk2通过上调HIF1α表达促进心肌细胞增殖，HIF1α增强糖酵解和磷酸戊糖途径（PPP），进而更有利于心肌细胞增殖。这些发现确立了Foxk1和Foxk2作为心脏损伤有前景的治疗靶点。
