ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is a common neurodegenerative disorder in the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. Hufeng Jiu from Vespa magnifica Smith, a traditional remedy used by the Chinese Jingpo minority, is documented in the Pharmacopoeia of China (2020) for treating rheumatic arthritis. Notably, recent research suggests that components of wasp venom (WV) from Vespa magnifica Smith, particularly polypeptides such as Mastoparan-M (Mast-M) and Vespakinin-M, may have potential therapeutic effects for neurological disorders. However, the specific polypeptide components of WV and their therapeutic effects on PD models remain insufficiently understood. AIM OF THE STUDY: This study aims to characterize the neuroactive polypeptides in Vespa magnifica Smith venom and investigate the therapeutic potential of Mast-M for PD. MATERIALS AND METHODS: Neuroactive polypeptides in WV were identified using LC/MS, and Mast-M derived from venom of Vespa magnifica Smith was verified with HPLC. The neuroprotective effects of WV and its peptides were assessed using the CCK-8 assay in 1-methyl-4- phenylpyridinium (MPP RESULTS: A total of 1007 peptides were identified in the WV, including 187 UniProtKB unreviewed, with 185 predicted to be BBB-permeability. Our results show that Mast-M exhibits a time-dependent distribution in mice, initially localizing in the peritoneal region and subsequently accumulating in the brain, liver, and kidney. Cellular uptake studies reveal that Mast-M penetrates cell membranes and accumulates intracellularly over time. In the MPP CONCLUSION: Mast-M emerges as a promising therapeutic candidate for PD, capable of crossing the BBB, enhancing autophagy, and providing neuroprotection in PD models. Further studies are warranted to optimize dosing and elucidate its full therapeutic potential.