Non-canonical Protein Synthesis: Mechanisms, Regulation, and Therapeutic Potential

The classical view of one gene giving rise to one protein through canonical, AUG-initiated translation is being steadily rewritten. A growing body of work reveals that cells routinely produce proteins through non-canonical routes, including translation from non-AUG start codons, small and alternative open reading frames (sORFs and altORFs), upstream ORFs, stop-codon readthrough, ribosomal frameshifting, and translation from RNAs previously annotated as non-coding. These events expand the coding potential of genomes far beyond the annotated proteome and are emerging as important regulators of cellular function, stress responses, and disease.The products of these events — variously described as microproteins, micropeptides, alt-proteins, translons, or peptideins — remain inconsistently named and annotated, and establishing a shared nomenclature is now a central challenge for the field. Beyond their regulatory roles, non-canonical translation products are also emerging as tumour neoantigens, immunopeptidome components, and targets for cancer immunotherapy, adding a clear translational and clinical dimension to their study.This Research Topic aims to bring together advances in the discovery, mechanisms, and regulation of non-canonical protein synthesis, and to explore how these hidden proteins shape physiology and open new therapeutic avenues. We welcome original research, reviews, and perspectives spanning experimental, computational, and translational approaches, including work on the identification and annotation of novel proteins, the molecular machinery and regulation underlying their synthesis, their roles in health and disease, and their potential in immunotherapy and other therapeutic applications. Topic editors: Maxime WERY, Xavier Roucou Source: https://www.frontiersin.org/research-topics/84594/non-canonical-protein-synthesis-mechanisms-regulation-and-therapeutic-potential