Wang, Yun-HanYun-HanWangLiu, Ta-WeiTa-WeiLiuHsiao, Sui-WenSui-WenHsiaoChu, Man-HsiuMan-HsiuChuTZONG-HUEI LEEHsu, Su-JungSu-JungHsuChen, Shih YinShih YinChenLee, Ching-KuoChing-KuoLee2025-06-162025-06-162025-05-21https://www.scopus.com/record/display.uri?eid=2-s2.0-105005579681&origin=resultslisthttps://scholars.lib.ntu.edu.tw/handle/123456789/730005Background Mangosteen (Garcinia mangostana L.) pericarp extract has demonstrated potential against Alzheimer’s disease (AD) and diabetes mellitus (DM). This study introduces a rapid dereplication and comparative approach to identify and characterize acetylcholinesterase (AChE) and α-glucosidase inhibitors in mangosteen pericarp. Using protein-subtraction, MS profiling, and computational modeling is effective for screening, identifying, and analyzing enzyme-inhibiting compounds from plant sources, and quantitative analysis of the main components has been performed. Results The Mangosteen pericarp extract observed significant inhibitory activity against α-glucosidase and AChE, with IC50 values of 31.02 and 70.56 µg/mL, respectively. By comparing profiles of protein-subtracted extracts with non-treated extracts, eight potential inhibitors for each enzyme were identified: 8-desoxygartanin, gartanin, 3-isomangostin, β-mangostin, 9-hydroxycalabaxanthone, γ-mangostin, α-mangostin, and garcinone E. The α-mangostin was the most abundant, comprising 39.589% of the extract. Molecular docking revealed these inhibitors target the peripheral anionic site of AChE and the active site of α-glucosidase, forming key hydrogen bonds and pi-pi stacking interactions. Conclusion This study emphasizes mangosteen pericarp as a promising natural source of these inhibitors, with potential for use in developing nutraceuticals and pharmaceuticals. The study validated a systems biology approach by applying dereplication and comparative UPLC-ESI-MS/MS metabolomics profiling to identify target-binding molecules in both protein-treated and untreated plant extracts. Further confirmation was obtained through molecular docking predictions, mechanism analysis, and compound quantification assays.enAcetylcholinesteraseComparative metabolomicsDereplicationMangosteen (Garciniaman gostana L)α-glucosidase[SDGs]SDG3journal article10.1186/s40529-025-00460-4