Integrative Peptidomics and Bioinformatic Analysis of Four Wasp Venoms Reveals Diverse Peptides and Novel Cryptides

Bee venom therapy has been officially integrated into traditional Chinese medicine and is widely used as an adjunct treatment for various diseases. In comparison, wasp venom, with its complex composition and potent biological activities, remains a valuable yet underexplored source of bioactive molecules. Systematic investigation of wasp venom peptides and their pharmacological potential is therefore essential for new drug discovery and the rational utilization of venom-derived resources. In this study, venoms from four wasp species (Vespa mandarinia, V. velutina, V. basalis, and Provespa barthelemyi) were collected by electrical stimulation and analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). A total of 681 peptides were identified, nearly 90% of which represent novel sequences. Comparative analysis revealed that most peptides were species-specific, while only a few were shared among species. These results indicate notable differences and an apparent species-dependent pattern in wasp venom peptidomes. Further analysis suggested that peptide release in wasp venom may be regulated by specific proteolytic cleavage patterns, which could contribute to structural and functional diversity. Bioinformatic predictions indicated that 291 peptides possess potential pharmacological activities, including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP4) inhibition, suggesting possible therapeutic applications in hypertension and diabetes. In addition, ten novel cryptides were identified, highlighting potential for venom derived drug discovery. Overall, this study provides the first comprehensive, side-by-side analysis of the peptidome from four wasp venoms. It characterizes their peptide diversity, generation mechanisms, and predicted bioactivities, offering valuable insights for future pharmaceutical and biotechnological development.