Translatable circular RNAs: Mechanism, function and clinical application

Recent advances in circular RNAs (circRNAs) research have significantly increased our understanding of their translational potential. Owing to their covalently closed structure, circRNAs undergo cap-independent translation initiation, distinguishing them from canonical linear mRNAs. Depending on different mechanisms, translatable circRNAs produce various functional proteins regulating different aspects of gene expression. Moreover, the circRNA-encoded proteins have been validated as critical regulators in the initiation and progression of various human diseases. In this review, we systematically introduce the cap-independent initiation mechanisms of translatable circRNAs, including the roles of cis-regulatory elements, trans-acting factors, and the emerging dimension of higher-order RNA structure. We also summarize the roles and molecular mechanisms of translatable circRNA in various diseases. CircRNAs have emerged as important regulators of gene expression, with their unique translational capabilities making them as promising candidates for RNA-based therapeutic strategy, including gene therapy and vaccine development. This multifunctional potential has established translatable circRNAs as a major focus in biomedical research.