{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T11:20:20Z","timestamp":1782732020009,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder requiring safe, multitarget therapeutic strategies. Marine macroalgae represent an underexplored source of bioactives with pleiotropic metabolic effects. This study investigated the antidiabetic potential of an ultrasound-assisted ethanolic extract of Caulerpa racemosa (UAECr) and its key phytosterol, campesterol, through an integrative framework combining metabolomics, network pharmacology, molecular docking, molecular dynamics simulation, and in vitro validation. Untargeted ultra-high-performance liquid chromatography\u2013high-resolution mass spectrometry (UHPLC\u2013HRMS) metabolomics characterized UAECr constituents, followed by in silico bioactivity prediction, target-network analysis, molecular docking, and 100 ns molecular dynamics simulation of the peroxisome proliferator-activated receptor gamma (PPAR\u03b3)\u2013campesterol complex. Functional validation was performed in differentiated 3T3-L1 adipocytes assessing glucose uptake, PPAR\u03b3 expression, dipeptidyl peptidase 4 (DPP-4) inhibition, and cytotoxicity. Metabolomics identified campesterol as a prominent bioactive. Network pharmacology highlighted PPAR\u03b3 as a central hub, supported by strong docking affinity of campesterol toward PPAR\u03b3 (\u221211.4 kcal\/mol) and DPP-4 (\u22128.3 kcal\/mol). Molecular dynamics simulations demonstrated stable PPAR\u03b3\u2013campesterol interactions, with preserved protein compactness and low residue fluctuation. In vitro, UAECr and campesterol significantly enhanced glucose uptake (up to 134% vs. control, p &lt; 0.001), upregulated PPAR\u03b3 expression (4-fold, p &lt; 0.0001), and moderately inhibited DPP-4 activity (p &lt; 0.01) without cytotoxicity. C. racemosa-derived extracts and campesterol exert antidiabetic effects primarily via stable PPAR\u03b3-mediated insulin sensitization with complementary DPP-4 modulation, supporting its potential as a marine-derived functional food candidate.<\/jats:p>","DOI":"10.3390\/md24020082","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:15:35Z","timestamp":1771334135000},"page":"82","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Metabolomics and Systems Pharmacology Reveal PPAR\u03b3-Centered Antidiabetic Mechanisms of Caulerpa racemosa and Its Bioactive Compounds"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-0854","authenticated-orcid":false,"given":"Fahrul","family":"Nurkolis","sequence":"first","affiliation":[{"name":"Master Program of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"},{"name":"Medical Research Center of Indonesia, Surabaya 60281, Indonesia"},{"name":"Institute for Research and Community Service, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta 55281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5412-9913","authenticated-orcid":false,"given":"Annette","family":"d\u2019Arqom","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1842-9714","authenticated-orcid":false,"given":"Evhy","family":"Apryani","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurmawati","family":"Fatimah","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izza","family":"Afkarina","sequence":"additional","affiliation":[{"name":"Corpora Science Research Laboratory, Yogyakarta 55223, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8165-2072","authenticated-orcid":false,"given":"Reggie","family":"Surya","sequence":"additional","affiliation":[{"name":"Department of Food Technology, Faculty of Engineering, Bina Nusantara University, Jakarta 11480, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4777-624X","authenticated-orcid":false,"given":"Happy Kurnia","family":"Permatasari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomolecular, Faculty of Medicine, Brawijaya University, Malang 65145, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante Saksono","family":"Harbuwono","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1349-5367","authenticated-orcid":false,"given":"Nurpudji Astuti","family":"Taslim","sequence":"additional","affiliation":[{"name":"Division of Clinical Nutrition, Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6461-5782","authenticated-orcid":false,"given":"Arifa","family":"Mustika","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond Rubianto","family":"Tjandrawinata","sequence":"additional","affiliation":[{"name":"School of Bioscience, Innovation and Technology, Atma Jaya Catholic University of Indonesia, Jakarta 12930, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43205","DOI":"10.1038\/s41598-025-27173-9","article-title":"Discovering Bioactive Pharmaceuticals from Natural Products for Type 2 Diabetes Mellitus Using Network Pharmacology, Molecular Docking, and Molecular Dynamics","volume":"15","author":"Rahmani","year":"2025","journal-title":"Sci. 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