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

Authors

Xiao Zhang, Xiaopeng Liu, Ruirui Pan, Huan Liu, Junying Xiao, Xiangkai Leng, Hongmei Zhang, Dengke Pan, Shengzhong Duan, Jiangwei Wu

Published in

PLoS genetics. Volume 22. Issue 10. Pages e1012329. Epub Oct 08, 2026.

Abstract

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.

PMID:
42848794
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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