The Potential Alleviating Property Against NAFLD by Ganoderma lucidum With Bacteria‐Enzyme Synergistic Fermentation

ABSTRACT Ganoderma lucidum is an edible and medicinal fungus. Triterpenoids, particularly ganoderic acids, represent the principal bioactive constituents in Ganoderma lucidum . Bacteria‐enzyme synergistic fermentation broth of Ganoderma lucidum (FBG) was optimized as a potential alternative to traditional water‐extracted Ganoderma lucidum (WEG). The optimized parameters with Lactobacillus rhamnosus fermentation exhibited the highest content of ganoderic acid F (GAF). Administration of FBG led to a pronounced decline in lipid deposition and contents of intracellular total cholesterol (TC), triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), reactive oxygen species (ROS), and malonic dialdehyde (MDA). The FBG treatment also markedly increased the activities of high‐density lipoprotein cholesterol (HDL‐C), superoxide dismutase (SOD), and catalase (CAT). The results of network pharmacology analysis and molecular docking suggested that GAF exhibits a robust interaction with the core targets sodium leak channel, nonselective (NALCN) and eukaryotic translation elongation factor 1 alpha 2 (EEF1A2). Enzyme‐linked immunosorbent assay (ELISA) results demonstrated that GAF could effectively reduce lipid accumulation while upregulating EEF1A2, phosphorylated AMP‐activated protein kinase (p‐AMPK), and peroxisome proliferator‐activated receptor alpha (PPAR‐α) protein expression. Collectively, these findings indicate that GAF alleviates free fatty acid (FFA)‐induced hepatic lipid accumulation through activation of the EEF1A2/p‐AMPK/PPAR‐α signaling pathway, suggesting a potential mechanism involving AMPK‐related pathways.