The Hidden Proteome of Cutaneous Repair: Emerging Roles of ncRNA-Encoded Micropeptides.

Abstract

The molecular mechanisms governing cutaneous repair have been largely understood through transcriptional and post-transcriptional regulatory networks. Recent discoveries, however, have challenged the long-held assumption that noncoding RNAs (ncRNAs) function exclusively as regulatory transcripts. Advances in translatomics have revealed that a subset of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) encode bioactive micropeptides, uncovering a hidden proteome involved in tissue repair. In this mini-review, we discuss the established and potential roles of ncRNA-derived micropeptides in processes relevant to cutaneous repair, including re-epithelialization, fibroblast plasticity and matrix remodeling, inflammatory resolution and vascular repair. Rather than acting as isolated molecular effectors, these micropeptides operate across multiple biological scales, from intracellular protein signaling and cell-intrinsic programs to tissue remodeling and the broader repair microenvironment. We further highlight the emerging concept that a single ncRNA locus can generate distinct RNA- and peptide-mediated functions, thereby expanding the regulatory capacity of the noncoding genome. Finally, we discuss key unanswered questions, including what licenses context-specific micropeptide translation during tissue repair and how RNA and micropeptide outputs cooperate to shape repair outcomes. Together, these advances support an emerging conceptual framework in which the ncRNA-encoded hidden proteome constitutes an additional regulatory layer in cutaneous repair, providing new insights into unconventional mechanisms of tissue repair and potential opportunities for therapeutic intervention.