Small open reading frame-encoded peptides (SEPs) as hidden treasures: a review

INTRODUCTION: Small open reading frame-encoded peptides (SEPs) are short peptides translated from small open reading frames (sORFs) that were previously overlooked in genome annotations. SEPs have relatively small molecular sizes, fewer than 100 amino acids, some SEPs can be as short as a dozen amino acids. Recent studies have revealed their widespread presence across plants, animals, and microorganisms, as well as their diverse biological functions and potential applications. AREAS COVERED: This review introduces the characteristics and biogenesis of SEPs, the processes and methods for their identification and validation, and their functional roles and target sites, highlighting the significant potential of SEPs in biological research and therapeutic development. Relevant literature was identified on PubMed (2010-2025) by searching for 'SEP,' 'sORF,' and 'Microprotein.' EXPERT OPINION: The revolutionary advances in high-throughput omics technologies - particularly mass spectrometry and ribosome profiling - combined with computational prediction methods such as machine learning, have enabled the discovery of an increasing number of SEPs. Research on SEP is currently in a phase of rapid development, and this suggests that the field of peptide drugs may gain many promising molecular candidate.