CircRNA-regulated programmed cell death networks in cardiomyocytes: Molecular crosstalk and therapeutic translation

Cardiovascular diseases (CVDs) represent the predominant global health burden, where dysregulated programmed cell death (PCD) mechanisms critically drive myocardial injury pathogenesis. Circular RNAs (circRNAs), characterized by covalently closed structures conferring high stability, function as pivotal regulators coordinating cardiomyocyte fate through integrated networks encompassing ferroptosis, apoptosis, pyroptosis, autophagy, and necroptosis. This review synthesizes advances in understanding circRNA-mediated PCD modulation via molecular sponging, protein interactions, and epigenetic regulation. Key insights establish context-dependent circRNA functionality and validate circRNA-based diagnostic panels for CVDs stratification with enhanced accuracy. Therapeutically, viral vector-delivered protective circRNAs demonstrate significant efficacy in ameliorating post-infarction apoptosis and improving cardiac function. We further evaluate emerging CRISPR-based editing technologies and nanoplatform delivery systems for clinical translation, positioning circRNA networks as promising theranostic targets while highlighting unresolved questions regarding pathway crosstalk and tissue-specific delivery. Circular RNAs (circRNAs) function as central regulators of programmed cell death incardiomyocytes. Specific circular RNAs have different regulatory effects on fivedifferent cell death pathways, including ferroptosis, necrotic apoptosis, apoptosis, autophagy and pyroptosis. Key regulatory mechanisms include miRNA spongeing, interaction with cell death signaling pathways (such as RIPK1-RIPK3-MLKL in necroptosis and inflammasome activation in pyroptosis), and modulation of oxidativestress markers like lipid ROS. The complex interactions between circRNAs and celldeath patterns highlight their potential value in cardiovascular disease treatment. • CircRNAs coordinate cardiomyocyte death through integrated networks. • CircRNAs exhibit significant diagnostic potential for cardiovascular diseases. • Targeting circRNAs enables novel therapeutic strategies for cardiac injury.