Microproteins: novel multi-functional regulators in health and disease

Microproteins, once overlooked due to their small size and non-canonical origins, have been recently identified as essential regulators of diverse biological processes, including mitochondrial function, cell signaling, and immune responses. Their study has been propelled by recent technological advances in identifying and characterizing microproteins, revealing their significant role in health and disease. This review comprehensively summarizes these advances and recent insights into the epigenetic, transcriptional, translational, and proteostatic regulation of microproteins and their regulatory effects on oncogenic targets such as KRAS and EGFR. We emphasize clinical and translational opportunities, including using microproteins as therapeutic targets and as templates for modality design (e.g., stabilized therapeutic peptides and molecular glues), alongside their value as biomarkers and potential companion diagnostics. Finally, we outline key challenges that must be addressed to enable therapeutic development, especially in microprotein detection, structure and interaction analysis, context-specific expression prediction, and functional characterization in vivo. Addressing these gaps will help convert microprotein biology more effectively into translational medicine.