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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Wolffia globosa, the world\u2019s smallest flowering plant, is a sustainable protein- and phytochemical-rich food source with emerging neuroprotective potential. This study presents the first comprehensive characterization that integrates extraction optimization, multitarget bioactivity profiling, drug synergy assessment, high-resolution metabolomics, molecular docking, and in vivo validation in Drosophila melanogaster. Ethanol-based extraction was optimized using a Box\u2013Behnken design and response surface methodology (RSM), yielding optimal conditions of 32% ethanol, 1:40 (g\/mL) solid-to-solvent ratio, 60 \u00b0C, and 28 min. The optimized extract exhibited a total phenolic content (TPC) of 15.17 \u00b1 0.27 mg GAE\/g DW, a total flavonoid content (TFC) of 22.34 \u00b1 1.71 mg QE\/g DW, and an exceptional ORAC antioxidant activity of 4374.33 \u00b1 395.65 \u00b5mol TE\/g DW. Potent and selective BACE-1 inhibition was observed (IC50: 1.59 \u00b1 0.11 mg\/mL), alongside moderate AChE (IC50: 7.42 mg\/mL) and BChE (IC50: 6.55 mg\/mL) inhibition. Synergistic interactions with donepezil were confirmed by the Chou\u2013Talalay combination index method, with combined AChE, BChE, and BACE-1 inhibitions reaching 60.3%, 77.0%, and 82.2%, respectively\u2014substantially exceeding theoretical additive values. Multi-platform metabolite profiling by HPLC-QTOF-MS\/MS and LC-ESI-MS\/MS identified luteolin, apigenin, caffeic acid, isovitexin, schaftoside, and pinolenic acid as the principal bioactives. Molecular docking predicted favorable binding of luteolin (delta-G: \u221210.24 kcal\/mol, AChE) and naringenin (delta-G: \u22128.76 kcal\/mol, BACE-1) against crystal structures of human AChE (PDB: 7E3H), BChE (PDB: 4TPK), and BACE-1 (PDB: 6EQM). In vivo, the W. globosa extract significantly improved locomotor performance and suppressed brain BACE-1 activity in an Drosophila AD model over 28 days. These findings establish W. globosa as a multifunctional nutraceutical candidate for neurodegenerative disease prevention.<\/jats:p>","DOI":"10.3390\/ijms27188266","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:59:03Z","timestamp":1789639143000},"page":"8266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization and Metabolomic Profiling of Wolffia globosa Extract Reveal Multitarget Neuroprotective Activity Against Alzheimer\u2019s Disease with In Vitro, In Silico, and In Vivo Validation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7590-7024","authenticated-orcid":false,"given":"Piya","family":"Temviriyanukul","sequence":"first","affiliation":[{"name":"Food and Nutrition Academic and Research Cluster, Institute of Nutrition, Mahidol University, Nakhon Pathom 73170, 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Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5887-6329","authenticated-orcid":false,"given":"Uthaiwan","family":"Suttisansanee","sequence":"additional","affiliation":[{"name":"Food and Nutrition Academic and Research Cluster, Institute of Nutrition, Mahidol University, Nakhon Pathom 73170, 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