Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action. This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR. These findings elucidate that 80 mg kg of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.

中文翻译：

---

水飞蓟素通过微生物代谢物 7-酮脱氧胆酸靶向 FXR 蛋白治疗肥胖小鼠的 MASLD


水飞蓟素因其优异的保肝特性而闻名。最近的临床研究检查了水飞蓟素对代谢功能障碍相关的脂肪肝病 (MASLD) 的影响，强调了进一步探索最佳剂量、活性成分和作用机制的必要性。这项研究评估了水飞蓟素主要成分在细胞水平上的抗炎活性。还研究了不同水飞蓟素剂量和成分对高脂饮食 (HFD) 诱导的小鼠模型 MASLD 的治疗效果。这些研究结果表明，与 30 mg/kg 水飞蓟素或水飞蓟宾和异水飞蓟宾 A 的组合相比，80 mg/kg 水飞蓟素在减轻肝脏脂肪变性和减少脂质积累方面具有卓越功效。水飞蓟素的机制涉及调节肠道微生物群稳态和影响 TLR4/NF-通过 LPS 的 κB 信号通路。胆汁酸靶向代谢组学分析表明，水飞蓟素可显着降低 HFD 诱导的 7-酮脱氧胆酸 (7-KDCA) 增加。进一步的研究表明，7-KDCA 作为靶向法尼醇 X 受体 (FXR) 的拮抗剂，并且水飞蓟宾和异水飞蓟宾 A 都可以直接与 FXR 相互作用。这些研究结果阐明了80 mg·kg的水飞蓟素可以对MASLD小鼠产生治疗作用，并为水飞蓟素治疗MASLD的机制提供新的见解。特别是发现水飞蓟素可以调节胆汁酸代谢，降低7-KDCA浓度，从而对FXR进行负反馈调节。