Integrative Metabolomics and Systems Pharmacology Reveal PPARγ-Centered Antidiabetic Mechanisms of Caulerpa racemosa and Its Bioactive Compounds

Abstract

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 <i>Caulerpa racemosa</i> (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, <i>p</i> < 0.001), upregulated PPARγ expression (4-fold, <i>p</i> < 0.0001), and moderately inhibited DPP-4 activity (<i>p</i> < 0.01) without cytotoxicity. <i>C. racemosa</i>-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.

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