ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1-ERK1/2-dependent autophagy dysfunction.

Pathological cardiac hypertrophy, a major risk factor for heart failure, is regulated by complex transcriptional networks. We previously identified the transcription factor ZBED6 as a key regulator for skeletal muscle hypertrophy, its role in the cardiac hypertrophy remains unexplored. Here, we report that ZBED6 is a key suppressor of pathological cardiac hypertrophy. ZBED6 is markedly reduced in myocardial tissues from patients with cardiac hypertrophy. ZBED6-deficient pigs exhibited cardiac hypertrophy with diastolic dysfunction. Integrative transcriptomic and ChIP-seq analyses identified MEOX1 as a direct negative target of ZBED6. Loss of ZBED6 upregulates MEOX1 transcription, which subsequently activated ERK1/2 signaling, leading to impaired autophagy-induced hypertrophy. Knockdown of MEOX1 reduced ERK1/2 phosphorylation and mitigated cardiomyocyte hypertrophy induced by ZBED6 deficiency. Similarly, pharmacological inhibition of ERK1/2 restored autophagy and alleviated hypertrophy in ZBED6-depleted cardiomyocytes. Collectively, these findings define a previously unrecognized ZBED6-MEOX1-ERK1/2 axis that critically regulates cardiac hypertrophy and represents a potential therapeutic target.