Investigating the potential mechanism and therapeutic effects of SLXG for cholesterol gallstone treatment

BACKGROUND: Shugan Lidan Xiaoshi Granules (SLXG) is a traditional Chinese medicine (TCM) formulation frequently employed to prevent and treat cholesterol gallstones. SLXG is formulated based on the Chaihu Shugan Formula found in an ancient Chinese medical book, a traditional remedy in China for centuries, and has demonstrated successful treatment of numerous patients with gallbladder stones. PURPOSE: This research sought to clarify the therapeutic impact and molecular mechanisms of SLXG and its active components in the treatment of cholesterol gallbladder stones. METHODS: The study employed network pharmacology, UPLC-HRMS transcriptome sequencing, animal model experiments, molecular docking, and Surface Plasmon Resonance (SPR) to explore the molecular mechanisms of SLXG and its relationship with Traditional Chinese Medicines (TCMs) and potential targets. Furthermore, PPI network analysis, along with GO and KEGG enrichment analyses, were performed to explore the potential mechanisms through which SLXG and its active ingredient, naringenin, prevent and treat cholesterol gallstones. The mechanism of action was further elucidated using an animal model for gallbladder stone formation. RESULTS: The study employed a network pharmacology and UPLC-HRMS to investigate the active compounds of SLXG for the treatment of cholesterol gallbladder stones, and subsequently constructed a network of therapeutic targets of SLXG. The results from gene enrichment analyses indicated that SLXG targets the metabolic pathway of bile secretion and the cholesterol metabolism pathway in addressing cholesterol gallbladder stones. The molecular docking results confirmed the interaction between the genes enriched in the pathways and the active ingredients in SLXG. Transcriptome sequencing results demonstrated that SLXG exerts its therapeutic effect on gallstones by regulating cholesterol and bile acid synthesis and metabolism. Furthermore, animal model experiments and SPR provided evidence that SLXG and its active ingredient, naringenin, exert therapeutic effects on cholesterol gallbladder stones by targeting the genes HMGCR, SOAT2, and UGT1A1, and influencing substances associated with cholesterol synthesis and metabolism. CONCLUSIONS: Using systematic network pharmacology methods combined with in vivo validation experiments, we uncovered the fundamental pharmacological effects and potential mechanisms of SLXG and its active ingredient, naringenin, in the treatment of cholesterol gallstones. This research underscores the valuable role that traditional remedies can play in addressing medical challenges and suggests a promising direction for further exploration of natural treatments for the disease.