M6A-modified circArhgap26 attenuates cardiac ischemia‒reperfusion injury by suppressing plakophilin-1 palmitoylation

Cardiac ischemia‒reperfusion (I/R) injury is a leading cause of disability and mortality worldwide, but the underlying mechanism remains largely unknown. Despite the emerging recognition of circular RNAs (circRNAs) as pivotal regulators of cardiac development and disease, their roles in cardiac I/R injury have yet to be thoroughly investigated. In this study, we identified a circRNA named circArhgap26, which is regulated by m6A modification. The expression of circArhgap26 was significantly decreased in the I/R myocardium. Cardiac-specific overexpression of circArhgap26 ameliorated cardiac dysfunction and reduced the infarct area and cardiomyocyte apoptosis in I/R model mice. Mechanistically, circArhgap26 directly bound to PKP1, thereby inhibiting the interaction between PKP1 and the palmitoyltransferase ZDHHC1. The subsequent palmitoylation of PKP1 and its protein stability are subsequently diminished, leading to a reduction in APAF1 protein synthesis and the inhibition of the Caspase-9/Caspase-3 signaling pathway, thereby mitigating cardiomyocyte apoptosis. Most importantly, the expression of circArhgap26 in the plasma of patients undergoing percutaneous coronary intervention (PCI) was decreased. This study not only elucidates the dual regulatory mechanisms of circArhgap26, m6A modification and posttranslational modification (palmitoylation), in combating I/R injury but also provides a theoretical foundation for circRNA-based therapies. Its dual value as a prognostic biomarker and therapeutic target holds promise for advancing precision cardiovascular medicine and improving outcomes in globally prevalent I/R-related diseases.