Fahrul Nurkolis, Annette d’Arqom, Evhy Apryani, Nurmawati Fatimah, Adha Fauzi Hendrawan, Izza Afkarina, Reggie Surya, Happy Kurnia Permatasari, Dante Saksono Harbuwono, Nurpudji Astuti Taslim, Arifa Mustika, Raymond Rubianto Tjandrawinata
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–high-resolution mass spectrometry (UHPLC–HRMS) 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 (PPARγ)–campesterol complex. Functional validation was performed in differentiated 3T3-L1 adipocytes assessing glucose uptake, PPARγ expression, dipeptidyl peptidase 4 (DPP-4) inhibition, and cytotoxicity. Metabolomics identified campesterol as a prominent bioactive. Network pharmacology highlighted PPARγ as a central hub, supported by strong docking affinity of campesterol toward PPARγ (−11.4 kcal/mol) and DPP-4 (−8.3 kcal/mol). Molecular dynamics simulations demonstrated stable PPARγ–campesterol interactions, with preserved protein compactness and low residue fluctuation. In vitro, UAECr and campesterol significantly enhanced glucose uptake (up to 134% vs. control, p < 0.001), upregulated PPARγ expression (4-fold, p < 0.0001), and moderately inhibited DPP-4 activity (p < 0.01) without cytotoxicity. C. racemosa-derived extracts and campesterol exert antidiabetic effects primarily via stable PPARγ-mediated insulin sensitization with complementary DPP-4 modulation, supporting its potential as a marine-derived functional food candidate. © 2026 by the authors.
Master Program of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, 60131, Indonesia; Medical Research Center of Indonesia, Surabaya, 60281, Indonesia; Institute for Research and Community Service, State Islamic University of Sunan Kalijaga, UIN Sunan Kalijaga, Yogyakarta, 55281, Indonesia; Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, 60131, Indonesia; Department of Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia; Corpora Science Research Laboratory, Yogyakarta, 55223, Indonesia; Department of Food Technology, Faculty of Engineering, Bina Nusantara University, Jakarta, 11480, Indonesia; Department of Biochemistry and Biomolecular, Faculty of Medicine, Brawijaya University, Malang, 65145, Indonesia; Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta, 10430, Indonesia; Division of Clinical Nutrition, Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar, 90245, Indonesia; School of Bioscience, Innovation and Technology, Atma Jaya Catholic University of Indonesia, Jakarta, 12930, Indonesia
