YTHDF1-mediated m6A RNA regulation controls cardiomyocyte remodeling through KLF11-HIF1α [RIP-Seq]

While cardiac hypertrophy initially arises as a compensatory adaptation of cardiomyocytes to stress, physiological and pathological cardiac hypertrophy exhibit distinct underlying mechanisms and prognoses. However, the precise mechanisms by which cardiomyocytes differentially respond to various stimuli, resulting in distinct forms of hypertrophy thereby ultimately determining divergent cell fates, remain unclear.

Here, we demonstrate that metabolic flexibility governs cardiomyocyte fate during cardiac hypertrophy and identified that this metabolic governance is mediated through YTHDF1-dependent RNA epigenetic regulation. In vivo, cardiomyocyte-specific YTHDF1 deficiency leads to maladaptive cardiac remodeling in response to swimming exercise and additionally exacerbates pathological cardiac remodeling under pressure overload stimulation.