METTL7B attenuates pathological cardiac hypertrophy via m6A-associated regulation of HK3.

Pathological cardiac hypertrophy is a major contributor to heart failure, yet the epitranscriptomic mechanisms that restrain maladaptive remodeling remain incompletely understood. In this study, we investigated the role of METTL7B and its association with m6A-related regulation of HK3 in pathological cardiac hypertrophy. By integrating RNA-seq and MeRIP-seq data from human hypertrophic and failing hearts, we identified coordinated downregulation of METTL7B and HK3, accompanied by reduced m6A enrichment of HK3 transcripts. Additional analysis of an independent human hypertrophic cardiomyopathy dataset showed a positive correlation between METTL7B and HK3 expression. These findings were further validated in angiotensin II-treated AC16 cardiomyocytes. Functional studies showed that overexpression of either METTL7B or HK3 attenuated cardiomyocyte hypertrophy in vitro and alleviated transverse aortic constriction-induced cardiac remodeling and dysfunction in vivo. RNA pull-down assays showed enrichment of METTL7B in HK3 RNA pull-down complexes, and METTL7B overexpression was accompanied by increased HK3 m6A enrichment and restored HK3 expression under hypertrophic stress. In vitro rescue experiments showed that HK3 silencing partially counteracted the anti-hypertrophic effect of METTL7B overexpression, supporting HK3 as a functional downstream effector of METTL7B in cardiomyocytes. We also identified YTHDC1 as a candidate HK3 RNA-associated factor. YTHDC1 knockdown stabilized HK3 mRNA, increased HK3 abundance, and reduced hypertrophic marker expression in METTL7B-overexpressing cardiomyocytes. Collectively, these findings identify a METTL7B-HK3 regulatory relationship in pathological cardiac hypertrophy and implicate YTHDC1 as a potential modulator of HK3 regulation. Our study suggests that METTL7B suppresses hypertrophic remodeling, at least in part, in association with m6A-associated regulation of HK3.