Background: The discovery of translatable circular RNAs has fundamentally expanded the functional landscape of non-coding transcripts in colorectal cancer.
Objective: This review aims to synthesize current evidence on circRNA-encoded proteins and micropeptides in colorectal cancer, assess their functional dichotomy as oncogenic drivers or tumor suppressors, and evaluate the therapeutic opportunities and translational barriers in targeting these molecules.
Key Findings: A growing number of circRNA-encoded proteins and micropeptides exert distinct biological activities independent of their linear host genes. Specific subsets function as either oncogenic drivers or tumor suppressors, converging on key pathways such as Hippo-YES-associated protein (Hippo-YAP), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Mitogen-activated protein kinase (MAPK) signaling, while also contributing to metabolic reprogramming and therapy resistance. This functional dichotomy establishes a dual therapeutic framework: inhibiting oncogenic circRNA translation products while restoring tumor-suppressive ones.
Conclusion: Significant translational barriers remain, particularly in achieving efficient and tumor-selective in vivo delivery and systematically defining the full circRNA-encoded proteome. Addressing these challenges will require innovations in delivery platforms, functional screening technologies, and mechanistic characterization. circRNA-derived proteins are emerging as uniquely specific therapeutic targets owing to their cancer-restricted expression patterns and non-canonical regulation, positioning them to meaningfully contribute to precision oncology in colorectal cancer.
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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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