Elucidating the therapeutic mechanisms of Huatan Qushi decoction in reducing obesity: Insights from a high-fat diet mouse model

The global surge in obesity prevalence poses a substantial health burden, as obesity is closely associated with a panel of metabolic comorbidities including type 2 diabetes, dyslipidemia, and hypertension. This study aimed to elucidate the underlying mechanisms by which Huatan Qushi Decoction (HTQSD) modulates inflammation-associated responses in a high-fat diet (HFD)-induced obese mouse model. We first assessed the therapeutic efficacy of HTQSD on body weight gain and blood glucose homeostasis in HFD-fed mice. An integrated untargeted metabolomic approach was then employed to screen and identify HTQSD-regulated differential metabolites. Complementary Mendelian randomization and proteomic analyses were performed to pinpoint obesity-related inflammatory proteins and their associated signaling pathways. Furthermore, molecular docking and molecular dynamics simulations were utilized to investigate the intrinsic molecular mechanisms governing HTQSD-mediated regulation of inflammatory responses. HTQSD treatment significantly attenuated body weight gain and ameliorated glucose dysregulation in obese mice. Notably, three key metabolites were identified, namely deoxycholic acid (DCA), 11β-hydroxyprogesterone, and 3-(1-naphthalenylcarbonyl)-1H-indole-1-pentanoic acid. These metabolites not only modulated TNF and TNFSF-associated signaling pathways via GSTP1-mediated regulation, but also directly interacted with TNFSF12 to exert their regulatory effects. Molecular dynamics simulations further delineated the conformational characteristics and binding interaction mechanisms between these target proteins and the bioactive metabolites of HTQSD. This study is the first to systematically uncover the modulatory effects of HTQSD on obesity and glucose metabolism via an integrated multi-omics strategy. Our comprehensive profiling suggests that the therapeutic effects of HTQSD are likely mediated by the identified key metabolites and their downstream target proteins. These findings provide novel and valuable insights into the therapeutic potential of HTQSD for obesity management and its underlying molecular mechanisms.