• RBM4 acts as an endogenous protective factor against Ang II-induced cardiomyocyte hypertrophy, with its knockdown aggravating and overexpression suppressing hypertrophy.
• Mechanistically, RBM4 localizes in the nucleus and downregulates the pro-hypertrophic gene PTBP1, revealing a novel m6A-RBM4-PTBP1 axis.
• Ang II stimulation increases m6A methylation of RBM4 mRNA, enhancing YTHDF1-mediated translation of RBM4, which explains its upregulation during hypertrophy.
• These findings provide new insights into post-transcriptional regulation in cardiac hypertrophy and potential therapeutic targets for heart failure.