Hidden proteins encoded by non-canonical open reading frames: A review
Jiang-Xue Li1, Yan-Xia Qin1, Zhao Li2
1Binzhou People's Hospital Affiliated to Shandong First Medical University/College of Medical Information and Artificial Intelligence, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Experimental and Molecular Pathology
|July 22, 2026
Summary
The human proteome is larger than previously thought, with functional peptides encoded by non-canonical open reading frames (ORFs). These hidden proteins, found in non-coding RNAs and mRNAs, play roles in cancer, immunity, and inflammation.
Area of Science:
- Genomics
- Proteomics
- Molecular Biology
Background:
- Evidence suggests translation extends beyond annotated protein-coding genes.
- Non-canonical open reading frames (ORFs) are increasingly identified as sources of translated peptides.
- These findings expand the concept of the functional proteome.
Purpose of the Study:
- To classify translated non-canonical ORFs based on transcriptional features and evidence.
- To review the origins, discovery methods, and classification of non-canonical ORFs.
- To explore the evolutionary origins and biological functions of non-canonical ORF-encoded peptides.
Main Methods:
- Ribosome profiling sequencing
- Mass spectrometry-based proteomics
- Immunopeptidomics
Main Results:
- Identified productive translation from non-canonical ORFs.
- These peptides originate from non-coding RNAs and canonical mRNAs.
- Non-canonical ORF-encoded peptides are implicated in cancer, immunity, and inflammation.
Conclusions:
- The functional proteome encompasses peptides from non-canonical ORFs.
- These peptides have potential as biomarkers and therapeutic targets.
- Understanding their roles is crucial for cancer and immunology research.
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