Beyond non-coding: peptide translation and bifunctional RNA biology in cardiovascular disease

Non-coding RNAs (ncRNAs) have traditionally been regarded as functional transcripts lacking protein-coding capacity. However, advances in translatomics and proteomics have revealed that a subset of ncRNAs harbor small open reading frames capable of generating biologically active peptides. Recent studies indicate that these peptides participate in diverse cardiovascular processes, including calcium handling, mitochondrial metabolism, tissue repair, fibrosis, inflammation, and vascular remodeling. Importantly, the significance of these discoveries extends beyond the identification of a new class of peptides. Increasing studies demonstrate that RNA transcripts and encoded peptides can coexist within the same genetic locus and contribute to biological regulation through independent, parallel, cooperative, or antagonistic mechanisms. This dual-output architecture challenges the traditional binary distinction between coding and non-coding transcripts and suggests that some peptide-producing ncRNAs function as bifunctional regulatory units. In this Review, we summarize current evidence supporting peptide translation from ncRNAs and discuss the emerging roles of ncRNA-derived peptides in cardiovascular physiology and disease. Furthermore, we explore how peptide translation expands the functional output of a genetic locus, enabling RNA transcripts and encoded peptides to participate in biological regulation through independent, parallel, cooperative, or antagonistic mechanisms. Based on these regulatory architectures, we propose a conceptual framework for understanding bifunctional RNAs. We further discuss how this dual-output mode of regulation may open new avenues for therapeutic intervention, biomarker development, and bioengineering applications in cardiovascular disease.