Microproteins at the Frontiers of Biology and Medicine

Small proteins, known as microproteins, typically consisting of fewer than 150 amino acids, have recently emerged as a previously unrecognized class of functional genes in biology. Advances in ribosome profiling, proteogenomics, and genome-wide functional screens have revealed that thousands of small open reading frames are actively translated, producing microproteins, some of which regulate essential processes in metabolism, immunity, cancer, and neurodegeneration. These discoveries have challenged long-held assumptions that gene function is confined to large, conserved proteins and have underscored microproteins as critical modulators. Dysregulation or mutation of small open reading frame–encoding microproteins contributes to a diverse range of biology, and in some cases links the noncanonical proteome to pathophysiological biology. In this review, we summarize current knowledge of microprotein discovery and function, describe key examples connecting microproteins to human disease, and discuss the opportunities and challenges that define this rapidly evolving field.