Lipotoxicity is increasingly recognized as a potential cause of metabolic syndrome, yet effective treatments are still lacking. Boletus edulis (B. edulis) Bull: Fr., is a classical mushroom used in traditional Chinese medicine. Polysaccharides, its primary pharmacological components, are widely known to offer various health benefits, but their anti-lipotoxicity properties remain poorly understood. This study aimed to investigate a natural B. edulis Bull: Fr. polysaccharide (BP) for its effectiveness and underlying molecular mechanisms in mitigating hepatic lipotoxicity. In vitro, BP enhanced glucose uptake and reduced lipid accumulation and oxidative stress in Oleic acid (OA)-treated LO2 cells. It downregulated receptor for advanced glycation end-products (RAGE) expression, inhibited mitogen-activated protein kinase (MAPK) activation, and normalized key proteins involved in glucose and lipid metabolism, thereby alleviating OA-induced lipotoxicity. In vivo, high-fat diet-fed mice injected with BP exhibited similar metabolic improvements, with the reversal of RAGE/reactive oxygen species (ROS)/MAPK signaling in liver tissue, further supporting the molecular mechanisms observed in vitro in modulating lipotoxicity. Collectively, these findings underscore BP as a potent bioactive preparation with significant pharmacological potential in alleviating hepatic lipotoxicity.
