YTHDF1-mediated m6A RNA regulation controls cardiomyocyte remodeling through KLF11-HIF1α.

Cardiovascular disease remains the leading cause of mortality globally. Although cardiac hypertrophy initially serves as a compensatory adaptation to stress, physiological and pathological hypertrophy are governed by distinct mechanisms and lead to divergent outcomes. However, how cardiomyocytes differentially respond to diverse stimuli remains incompletely understood. Here, we demonstrate that YTHDF1-mediated RNA m6A regulation modulates cardiomyocyte metabolic adaptation under different stress conditions and, in this context, directs hypertrophic response toward distinct remodeling outcomes. Cardiomyocyte-specific YTHDF1 deficiency leads to maladaptive cardiac remodeling in response to swimming exercise and additionally exacerbates pathological cardiac remodeling under pressure overload stimulation in vivo. In vitro, YTHDF1 functions as a switch to regulate the type of cardiomyocyte hypertrophy in an RNA m6A-dependent manner. Mechanistically, the YTHDF1-KLF11-HIF1α axis contributes to metabolic adaptation during cardiomyocyte hypertrophy. Cardiac-specific overexpression of YTHDF1 alleviates pathological cardiac remodeling. Together, our findings reveal a previously unrecognized YTHDF1-KLF11-HIF1α regulatory pathway linking m6A RNA recognition to cardiomyocyte remodeling. These findings provide valuable insight into how m6A-dependent signaling coordinates stress-responsive cardiac adaptation and establish YTHDF1 as an important regulator of cardiomyocyte remodeling.