Mass spectrometry in the discovery of peptides involved in intercellular communication: From targeted to untargeted peptidomics approaches

Endogenous peptide hormones represent an essential class of biomolecules, which regulate cell–cell communications in diverse physiological processes of organisms. Mass spectrometry (MS) has been developed to be a powerful technology for identifying and quantifying peptides in a highly efficient manner. However, it is difficult to directly identify these peptide hormones due to their diverse characteristics, dynamic regulations, low abundance, and existence in a complicated biological matrix. Here, we summarize and discuss the roles of targeted and untargeted MS in discovering peptide hormones using bioassay‐guided purification, bioinformatics screening, or the peptidomics‐based approach. Although the peptidomics approach is expected to discover novel peptide hormones unbiasedly, only a limited number of successful cases have been reported. The critical challenges and corresponding measures for peptidomics from the steps of sample preparation, peptide extraction, and separation to the MS data acquisition and analysis are also discussed. We also identify emerging technologies and methods that can be integrated into the discovery platform toward the comprehensive study of endogenous peptide hormones.