Britanin improved high-fat diet-induced obesity by regulating the MAPK signaling pathway

Abstract: Background: The escalating prevalence of obesity has made it a critical public health concern. There is an urgent need to identify naturally derived compounds with anti-obesity potential. Britanin (BRI), a bioactive sesquiterpene lactone derived from Inula species, has shown promise in metabolic disorder management, but its anti-obesity mechanisms remain uncharacterized. Objectives: Combining animal experiments and network pharmacology analysis to explore the effect of BRI in high-fat diet-induced obesity. Methods: C57BL/6J male mice were used for experiment. A high-fat diet (HFD)-induced obese mouse model was treated with BRI (5/15 mg/kg, i.p.) to validate lipid metabolism and weight loss. Network pharmacology identified potential targets via SwissTargetPrediction, GeneCards and OMIM databases, with molecular docking (CB-DOCK) and PPI network analysis (STRING/Cytoscape). Relevant validations were conducted based on the screened targets. Additionally, a biosafety assessment was performed. Results: In-vivo, 15 mg/kg BRI reduced body weight by 18%, decreased serum TG (-45%, p<0.001), TC (-37%, p<0.001) and LDL-C (-32%, p<0.01) and reversed adipocyte hypertrophy. Thirty-nine intersection targets were identified, with MAPK1, EGFR, PTGS2, MAP2K1 and MAPK8 as top hubs (degree centrality >15). BRI exhibited strong binding affinity (-7.7 to -10.3 kcal/mol) to these targets. Mechanistically, BRI exerts its anti-obesity effects by regulating key targets within the MAPK signaling pathway, particularly MAPK1 and inhibited the PPARγ, thereby blocking adipogenesis and promoting the transition of adipose tissue. Conclusion: BRI may alleviate obesity by regulating the Mitogen-Activated Protein Kinase signaling pathway, providing a rationale for natural compound-based obesity therapy.