CircRNA-RBAC induces cardiac repair by promoting ribosome biogenesis and cell cycle progression in cardiomyocytes

Ribosome biogenesis (RiBi) is an essential process that controls the protein synthesis rate, but its function in regulating endogenous cardiac regeneration remains unknown. Herein, we investigated the function and underlying mechanism of RiBi-associated circRNAs in cardiomyocyte (CM) proliferation and cardiac regeneration. We used high-throughput sequencing, quantitative PCR and in situ hybridization techniques to identify an adult downregulated circRNA, RiBi-associated circRNA (RBAC), in CMs. A functional study further revealed that RBAC overexpression increased ribosome biogenesis activity and cell cycle progression in CMs, while silencing RBAC decreased ribosome biogenesis activity and cell cycle progression. Moreover, RBAC overexpression induced adult CM proliferation and improved cardiac function after myocardial infarction in adult mice. Mechanistically, RBAC controlled ribosome biogenesis and cell proliferation by regulating the proteasome-dependent degradation of Ddx21, thereby altering the localization of Rps14 and reducing Rb expression. Our findings indicate that RBAC upregulation might be a plausible therapeutic strategy to induce endogenous cardiac regeneration.