Noncoding RNA encoded peptides in tumors from discovery to mechanism and clinical translation

Abstract

Summary Transcripts annotated as noncoding can produce peptides, but detecting translation does not establish peptide function. The central problem is to determine which instances of ribosome engagement lead to productive translation, which cancer phenotypes depend on the peptide rather than the source RNA, and which validated products are clinically relevant. This Review addresses that problem through a graded evidence framework that proceeds from transcript architecture and ribosome engagement to endogenous peptide detection and causal attribution to the peptide. Under this standard, validated peptides act at molecular control points where local concentration or enzymatic amplification can reconcile low abundance with biological effect. On that basis, we define the conditions required for actionability: tumor-enriched expression, reproducible endogenous measurement, a defined mechanism, and an intervention matched to that mechanism. Progress therefore depends on causal attribution, not on longer candidate lists.