Microproteins encoded by short open reading frames: Vital regulators in neurological diseases

Short open reading frames (sORFs) are frequently overlooked because of their historical classification as non-coding elements or dismissed as “transcriptional noise”. However, advanced genomic and proteomic technologies have allowed for screening and validating sORFs-encoded peptides, revealing their fundamental regulatory roles in cellular processes and sparking a growing interest in microprotein biology. In neuroscience, microproteins serve as neurotransmitters in signal transmission and regulate metabolism and emotions, exerting pivotal effects on neurological conditions such as nerve injury, neurogenic tumors, inflammation, and neurodegenerative diseases. This review summarizes the origins, characteristics, classifications, and functions of microproteins, focusing on their molecular mechanisms in neurological disorders. Potential applications, future perspectives, and challenges are discussed.