Authors
Zihao Wang, Lixia Zheng, Xiaokai Ma, Peng Gao, Yuanyuan Chen, Chenglu Xiao, Xin Zhao, Zhenyan Xiao, Xiaojun Zhu, Zhe Zhang, Jing-Wei Xiong
Published in
Cell regeneration (London, England). Volume 15. Issue 1. Aug 11, 2026. Epub Aug 11, 2026.
Abstract
Adult mammalian cardiomyocytes exhibit limited regenerative capacity, which remains a major challenge for functional recovery after myocardial infarction (MI). Our previous study identified a cocktail of five small molecules (5SM) that promotes cardiomyocyte proliferation and heart regeneration; however, the complexity of this five-compound mixture poses significant barriers to clinical translation and mechanistic studies. Here, we identified a simplified dual-compound cocktail (2SM) composed of phenylephrine hydrochloride (PE) and harmine (HM), which also robustly enhanced cardiomyocyte proliferation in vitro and in vivo. Transcriptomic and metabolomic analyses indicated that 2SM treatment activated cardiomyocyte cell-cycle programs and metabolic reprogramming. PE activated a fetal program and contributed to the up-regulation of CCND1 and WEE1 by activating mTOR signaling pathway, thus enabling cardiomyocytes to enter the G1/S phase but not G2/M phase. HM inhibited DYRK1A and activated MMB and FOXM1-MuvB complex, resulting in the upregulation of G2/M phase gene expression, of which the upregulated CDC25 proteins dephosphorylate CDK1, thereby relieving the inhibitory effect of PE. Sequential treatment of PE followed by HM was essential for completion of cytokinesis. In summary, we identified that 2SM, two compounds of 5SM, reprogrammed cardiomyocytes into an embryonic-like state, and precisely coordinated cell cycle progression for promoting cardiomyocyte proliferation.
PMID:
42579202
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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