(1) Background: Soyasapogenol C (SSC), a derivative of soyasapogenol B (SSB), is specifically found high in many fermented soybean (Glycine max) products, including Cheonggukjang (in Korean). However, the biological activities for preventing and treating hepatic steatosis, and the precise underlying mechanisms of SSC, remain to be explored. (2) Methods: A novel SANDA (structural screening, ADMET prediction, network pharmacology, docking validation, and activity evaluation) methodology was used to examine whether SSC exerts hepatoprotective effects in silico and in vitro. (3) Results: SSC had better ADMET characteristics and a higher binding affinity with predicted targets chosen from network pathway analysis than SSB. SSC induced the phosphorylation of AMP-activated protein kinase (AMPK) and stimulated the nuclear translocation of peroxisome proliferator-activated receptor alpha (PPARα), further enhancing PPAR response element (PPRE) binding activity in HepG2 cells. Concurrently, SSC significantly inhibited triglyceride accumulation, which was associated with the suppression of lipogenesis genes and the enhancement of fatty acid oxidation gene expression in HepG2 cells. (4) Conclusions: Soyasapogenol C, discovered using a novel SANDA methodology from fermented soybean, is a novel AMPK/PPARα dual activator that is effective against hepatic steatosis. Dietary supplementation with soyasapogenol C may prevent the development of hepatic steatosis and other diseases associated with fat accumulation in the liver.
Keywords: AMP-activated protein kinase; SANDA methodology; fermented soybean; hepatic steatosis; peroxisome proliferator-activated receptors alpha; soyasapogenol C.