{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:50:33Z","timestamp":1779177033757,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Penelitian Inovasi Teknologi Program of UIN Sunan Kalijaga Yogyakarta","award":["3268.5.1\/Un.02\/PPK.3\/TL\/07\/2025"],"award-info":[{"award-number":["3268.5.1\/Un.02\/PPK.3\/TL\/07\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, oxidative\/nitrosative stress, and neuroinflammation. Marine green algae Caulerpa racemosa are rich in neuroactive lipids and fatty acid derivatives with reported antioxidant and anti-inflammatory properties. However, their integrated mechanistic potential against AD remains largely underexplored. This study aimed to elucidate the neuroprotective mechanisms of C. racemosa metabolites against AD using integrative metabolomics, network pharmacology, molecular docking, and in vitro validation assays. Untargeted LC\u2013HRMS profiling was performed to identify major metabolites in the ethanolic extract of C. racemosa. Neuroprotective targets were predicted via TargetNet, STRING, and Cytoscape (MCODE, CytoNCA). Functional enrichment was conducted using KEGG, GO (BP, MF, CC), and ClueGO. Molecular docking (CB-Dock2) validated compound\u2013target interactions with ACHE, CHRM1, NOS1, and NOS2. Antioxidant (DPPH) and cholinesterase (AChE\/BChE) inhibitory activities were evaluated in vitro. Metabolomic profiling identified lipid-dominant metabolites\u2014oleamide, hexadecanamide, palmitoyl ethanolamide, \u03b1-linolenic acid, \u03b1-eleostearic acid, and 9-oxo-octadecadienoic acid. Network analysis revealed key AD-related hubs (ACHE, CHRM1, NOS1, NOS2) enriched in cholinergic regulation, arachidonic-acid metabolism, oxidative stress response, and nitric oxide signaling. Docking showed moderate multi-target affinities (\u22126.0 to \u22128.4 kcal\/mol), with \u03b1-linolenic acid, \u03b1-eleostearic acid, and oxidized C18 lipids exhibiting the strongest interactions\u2014particularly with ACHE and NOS isoforms. In vitro assays showed moderate antioxidant activity (IC50 = 120.97 \u00b1 10.93 \u00b5g\/mL) and cholinesterase inhibition (AChE IC50 = 136.48 \u00b1 1.70 \u00b5g\/mL; BChE IC50 = 145.98 \u00b1 3.28 \u00b5g\/mL), aligning with predicted multi-target interactions. C. racemosa extract exhibits neuroprotective potential through a synergistic combination of cholinergic modulation, antioxidant activity, NOS-mediated nitrosative stress reduction, and suppression of arachidonic-acid inflammatory pathways. These findings support C. racemosa as a promising marine-derived multi-target candidate for AD intervention, warranting further mechanistic and in vivo evaluation.<\/jats:p>","DOI":"10.3390\/md23120475","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T15:43:43Z","timestamp":1765467823000},"page":"475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrative Metabolomics, Pharmacoinformatics and Experimental Studies Reveal the Neuroprotective Potential of Caulerpa racemosa Metabolites Against Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"given":"Nita","family":"Handayani","sequence":"first","affiliation":[{"name":"Department of Physics, Faculty of Science and Technology, Universitas Islam Negeri (UIN) Sunan Kalijaga Yogyakarta, Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4162-2151","authenticated-orcid":false,"given":"Dhecella Winy Cintya","family":"Ningrum","sequence":"additional","affiliation":[{"name":"Master\u2019s Program in Pharmaceutical Science, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9222-1173","authenticated-orcid":false,"given":"Adha Fauzi","family":"Hendrawan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anis","family":"Yuniati","sequence":"additional","affiliation":[{"name":"Department of Physics, Faculty of Science and Technology, Universitas Islam Negeri (UIN) Sunan Kalijaga Yogyakarta, Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, University of Napoli Federico II, Piazza Carlo di Borbone 1, 80055 Portici, NA, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-3633","authenticated-orcid":false,"given":"Lucia","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, University of Napoli Federico II, Piazza Carlo di Borbone 1, 80055 Portici, NA, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5505-3327","authenticated-orcid":false,"given":"Antonello","family":"Santini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-0854","authenticated-orcid":false,"given":"Fahrul","family":"Nurkolis","sequence":"additional","affiliation":[{"name":"Master of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60286, Indonesia"},{"name":"Medical Research Center of Indonesia, Surabaya 60286, Indonesia"},{"name":"Institute for Research and Community Service, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","unstructured":"Kumar, A., Sidhu, J., Lui, F., and Tsao, J.W. 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