Li Yue, Li Hailan, Sun Minhui, Chen Hong, Xiao Yao, Wang Jieman, Zhang Yuanyuan, Fang Shuhua, Kou Junping
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, P. R. China.
The Public Laboratory Platform, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 9. doi: 10.1007/s00210-024-03760-x.
Silibinin (Sil) is a major bioactive component of silymarin, extracted from the fruit and seeds of Silybum marianum. Silibinin meglumine (SM) is a water-soluble derivative of silibinin that has shown significant potential in liver fibrosis. However, the potential effects and underlying mechanisms of SM on acute liver failure (ALF) are still not fully understood. This study aims to find the likely mechanism. An ALF mouse model and a cell model were established with GalN/LPS. SM was administered to mice via the tail vein or to a hepatocyte line (alpha mouse liver 12, AML12). The results showed that SM particularly lowered the mortality and improved liver pathological lesions in ALF mice. Meanwhile, SM improved the levels of GSH, SOD, TNF-α, IL-6, IL-1β, and IL-10 in the liver tissues and serum. Additionally, SM enhanced cell viability and reduced oxidative stress in vitro. In the AKT/GSK3β/Nrf2/GPX4 pathway, the subpathway of AKT/GSK3β was inhibited, and the subpathway of Nrf2/GPX4 was activated by SM both in vivo and in vitro. In addition, ferrostatin-1, a ferroptosis inhibitor, and the silencing of AKT using siRNA weakened the protective effect of SM, indicating that this process is mediated in an AKT-dependent manner. All the results suggested that SM inhibits inflammation and oxidative stress by modulating the AKT/GSK3β/Nrf2/GPX4 pathway.
水飞蓟宾（Sil）是水飞蓟素的主要生物活性成分，从水飞蓟的果实和种子中提取。水飞蓟宾葡甲胺（SM）是水飞蓟宾的水溶性衍生物，在肝纤维化方面已显示出显著潜力。然而，SM对急性肝衰竭（ALF）的潜在影响及潜在机制仍未完全明确。本研究旨在探寻可能的机制。采用GalN/LPS建立了ALF小鼠模型和细胞模型。通过尾静脉给小鼠注射SM，或对肝细胞系（α小鼠肝脏12，AML12）给予SM。结果显示，SM尤其降低了ALF小鼠的死亡率并改善了肝脏病理损伤。同时，SM提高了肝组织和血清中谷胱甘肽（GSH）、超氧化物歧化酶（SOD）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和白细胞介素-10（IL-10）的水平。此外，SM在体外增强了细胞活力并降低了氧化应激。在AKT/糖原合成酶激酶3β（GSK3β）/核因子E2相关因子2（Nrf2）/谷胱甘肽过氧化物酶4（GPX4）通路中，体内和体外实验均表明，SM抑制了AKT/GSK3β子通路，并激活了Nrf2/GPX4子通路。此外，铁死亡抑制剂铁抑素-1以及使用小干扰RNA（siRNA）沉默AKT减弱了SM的保护作用，表明该过程以AKT依赖的方式介导。所有结果表明，SM通过调节AKT/GSK3β/Nrf2/GPX4通路抑制炎症和氧化应激。
