Xue Xiaoyong, Wang Le, Wu Ruiyu, Li Yufei, Liu Runping, Ma Zhi, Jia Kexin, Zhang Yinhao, Li Xiaojiaoyang
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China.
Chin Med. 2024 Jun 6;19(1):79. doi: 10.1186/s13020-024-00953-7.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver disease worldwide. Si-Wu-Tang (SWT), a traditional Chinese medicine decoction has shown therapeutic effects on various liver diseases. However, the hepatoprotective effects and underlying mechanism of SWT on MAFLD remain unclear.
First, a methionine-choline-deficient (MCD) diet-fed mice model was used and lipidomic analysis and transcriptomic analysis were performed. The contents of total iron ions, ferrous ions, and lipid peroxidation were detected and Prussian blue staining was performed to confirm the protective effects of SWT against ferroptosis. Finally, chemical characterization and network pharmacological analysis were employed to identify the potential active ingredients.
Serological and hepatic histopathological findings indicated SWT's discernible therapeutic impact on MCD diet-induced MAFLD. Lipidomic analysis revealed that SWT improved intrahepatic lipid accumulation by inhibiting TG synthesis and promoting TG transport. Transcriptomic analysis suggested that SWT ameliorated abnormal FA metabolism by inhibiting FA synthesis and promoting FA β-oxidation. Then, ferroptosis phenotype experiments revealed that SWT could effectively impede hepatocyte ferroptosis, which was induced by long-chain acyl-CoA synthetase 4 (ACSL4)-mediated esterification of arachidonic acid (AA). Finally, chemical characterization and network pharmacological analysis identified that paeoniflorin and other active ingredients might be responsible for the regulative effects against ferroptosis and MAFLD.
In conclusion, our study revealed the intricate mechanism through which SWT improved MCD diet-induced MAFLD by targeting FA metabolism and ferroptosis in hepatocytes, thus offering a novel therapeutic approach for the treatment of MAFLD and its complications.
代谢功能障碍相关脂肪性肝病（MAFLD）是一种在全球范围内普遍存在的慢性肝病。四物汤（SWT），一种中药汤剂，已显示出对各种肝病的治疗作用。然而，SWT对MAFLD的肝保护作用及其潜在机制仍不清楚。
首先，使用蛋氨酸-胆碱缺乏（MCD）饮食喂养的小鼠模型，并进行脂质组学分析和转录组学分析。检测总铁离子、亚铁离子和脂质过氧化的含量，并进行普鲁士蓝染色以确认SWT对铁死亡的保护作用。最后，采用化学表征和网络药理学分析来鉴定潜在的活性成分。
血清学和肝脏组织病理学结果表明SWT对MCD饮食诱导的MAFLD具有明显的治疗作用。脂质组学分析显示，SWT通过抑制甘油三酯（TG）合成和促进TG转运来改善肝内脂质蓄积。转录组学分析表明，SWT通过抑制脂肪酸（FA）合成和促进FAβ-氧化来改善异常的FA代谢。然后，铁死亡表型实验表明，SWT可以有效阻止由长链酰基辅酶A合成酶4（ACSL4）介导的花生四烯酸（AA）酯化所诱导的肝细胞铁死亡。最后，化学表征和网络药理学分析确定芍药苷和其他活性成分可能是对铁死亡和MAFLD发挥调节作用的原因。
总之，我们的研究揭示了SWT通过靶向肝细胞中的FA代谢和铁死亡来改善MCD饮食诱导的MAFLD的复杂机制，从而为MAFLD及其并发症的治疗提供了一种新的治疗方法。
