Decoding multi-target effects of Sichuan Shai vinegar on metabolic syndrome with network analysis-molecular simulations and in vitro bioactivity

Abstract This study presents a comprehensive profiling of 23 bioactive compounds in Sichuan Shai vinegar (SSV) utilizing UPLC-MS/MS. The findings elucidate its multi-target mechanism of action against metabolic syndrome (MetS) through the integration of multi-component interaction network analysis and molecular simulations. Computational analyses identified 304 MetS-associated genes modulated via eight core targets (HSP90AA1, EGFR, EP300, TP53, NCOR2, CTNNB1, ESR1, HDAC1), with molecular docking and 100 ns dynamics simulations supporting stable binding of (S)-Coriolic acid and α-eleostearic acid (ΔG < -5.0 kcal/mol) that concurrently suggesting possible involvement nuclear factor kappa B (NF-κB) while may be associated with phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways. In vitro digestion demonstrated SSV's preserved inhibition of α-glucosidase, α-amylase and pancreatic lipase (IC50 (17.76-97.65) μL/mL), with a bile-salt-micelle–associated enhancement observed for BNV and ZJV, whereas SSV showed only a non-significant IC50 shift, suggesting that its intestinal-phase inhibition is mainly driven by hydrophilic inhibitors. These findings provide mechanistic hypothese SSV's potential relevance through coordinated regulation of inflammatory, oxidative and metabolic networks, providing novel insights for fermented food-based strategies in MetS management.