KLF1 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through Regulation of Wnt/β‐Catenin Signaling Pathway

Abstract Innovative therapeutic approaches for heart failure, a leading cause of mortality worldwide, are urgently needed. In this study, the important role of Krüppel‐like factor 1 (KLF1) in cardiomyocyte proliferation and heart regeneration is explored, and revealed its ability to regulate the Wnt/β‐catenin signaling pathway as well as exploring a feasible strategy to target KLF1 for the treatment of heart failure. Postnatally, a marked decrease in KLF1 expression occurred almost simultaneously with a reduction in myocardial regenerative capacity. Through comprehensive in vivo and in vitro studies, it is demonstrated that in neonatal and adult mice, KLF1 overexpression significantly increased cardiomyocyte proliferation and promoted myocardial repair following infarction, whereas KLF1 knockout abolished these effects. Mechanistically, through RNA sequencing (RNA‐seq) and ATAC sequencing (ATAC‐seq) analyses, it is revealed that the promotion of cardiomyocyte proliferation by KLF1 is associated with the Wnt/β‐catenin signaling pathway, mitochondrial function, and fatty acid metabolism. These findings highlight the important role of KLF1 in cardiomyocyte proliferation and heart regeneration, which provides novel insights into therapeutic targets for heart failure.