Salvianolic Acid B Alleviates MAFLD by Targeting PPAR-α: Mechanistic Insights From Network Pharmacology and...

Metabolic dysfunction-associated fatty liver disease (MAFLD) remains a global health burden with limited definitive therapies, highlighting the need for safe, food-derived interventions. Salvianolic acid B (SALB), a major water-soluble bioactive component of the traditional Asian health-promoting food Salvia miltiorrhiza Bunge, exhibits lipid-lowering, anti-inflammatory, and antioxidant properties, but its therapeutic potential and mechanisms in MAFLD remain unclear. Here, we employed an integrated approach combining network pharmacology, molecular docking, surface plasmon resonance affinity assays, lipidomics, and experiments in vitro and in vivo to address this gap. Network pharmacology combined with lipidomics identified PPAR-α as a key target of SALB. Molecular docking and SPR assays confirmed direct binding between SALB and PPAR-α. In vitro, SALB reduced triglyceride levels and lipid accumulation in HepG2 cells, enhanced fatty acid oxidation (FAO), and upregulated PPAR-α, PGC-1α, and FAO-related genes (CPT1, CPT2, ACADL, ACADVL). In HFD-fed mice, SALB decreased serum total cholesterol, triglycerides, LDL-C, ALT, AST, while increasing HDL-C. Additionally, SALB upregulated hepatic PPAR-α and FAO-related gene expression and suppressed hepatic reactive oxygen species production and inflammatory responses in both models. Collectively, our findings demonstrate that SALB, a natural food-derived bioactive compound, targets PPAR-α to ameliorate MAFLD by enhancing FAO, modulating lipid metabolism, and mitigating oxidative stress and inflammation. This work supports SALB's potential as a dietary supplement for MAFLD and metabolic disease management, reinforcing the value of exploring functional components from health-promoting food.