Multi-target mechanisms of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Syzygium nervosum DC. flower buds in alleviating obesity and metabolic complications: An integrated study combining network pharmacology and experimental validation.

The flower buds of Syzygium nervosum DC., a traditional herbal tea in southern China, contain the principal chalcone 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC). DMC exhibits multiple pharmacological activities, yet its impact on obesity and related metabolic diseases (ORD) remains to be fully explored. To systematically characterise the therapeutic targets and mechanisms of DMC against ORD, network pharmacology was applied to predict DMC targets, followed by protein-protein interaction (PPI) network construction and GO/KEGG enrichment analysis. Molecular docking was performed using MOE software. For in vivo validation, high-fat diet (HFD)-induced obese rats were administered DMC for 8 weeks, and metabolic phenotyping, histopathology, ELISA, qRT-PCR, and western blotting were evaluated. Analysis identified 92 common targets, with IL-6, IL1B, TNF, MMP9, and PTGS2 confirmed as core targets. KEGG analysis revealed significant enrichment of pathways in cancer, lipid and atherosclerosis, and endocrine resistance pathways. DMC intervention effectively alleviated metabolic profiles, reduced adiposity and hepatic steatosis, promoted mitochondrial β-oxidation, and maintained intestinal barrier integrity through anti-inflammatory and antioxidant mechanisms. Molecular docking confirmed stable binding between DMC and 12 key proteins involved in inflammation, oxidative stress, and energy homeostasis. Collectively, these findings indicate that DMC ameliorates ORD through multi-target mechanisms involving metabolic regulation, intestinal barrier protection, and anti-inflammatory actions, supporting its potential as a natural therapeutic agent.