Lack of ZBED6 causes harmful heart enlargement by disrupting cell cleaning through the MEOX1-ERK1/2 pathway

ZBED6 is markedly reduced in myocardial tissues from patients with cardiac hypertrophy.

• ZBED6 acts as a key suppressor of pathological cardiac hypertrophy.
• ZBED6-deficient pigs showed signs of cardiac hypertrophy along with diastolic dysfunction.
• MEOX1 is identified as a direct negative target of ZBED6, whose upregulation may contribute to cardiac hypertrophy.
• Increased MEOX1 transcription activates ERK1/2 signaling, impairing autophagy and promoting hypertrophy.
• Knockdown of MEOX1 can reduce ERK1/2 phosphorylation and lessens hypertrophy in ZBED6-deficient cardiomyocytes.
• Pharmacological inhibition of ERK1/2 may restore autophagy and alleviate hypertrophy in cardiomyocytes lacking ZBED6.

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