Xiang Yang, Kuang Ge, Gong Xia, Xie Huang, Lin Yan, Zhang Xijian, Chen Zhongpei, Wan Jingyuan, Li Zhenhan
Department of Endocrinology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China.
Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.
Phytother Res. 2025 Mar;39(3):1531-1548. doi: 10.1002/ptr.8443. Epub 2025 Jan 24.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, but effective therapeutic drugs are still lacking. Dihydrotanshinone I (DHTS), a natural product isolated from Salvia miltiorrhiza , has been shown to have ameliorative effects on NAFLD. The aim of this study was to investigate the hepatoprotective effect of DHTS on NAFLD and its mechanism. A model of NAFLD and DHTS treatment was established using a Western diet to observe the effect of DHTS on NAFLD, which were detected by immunohistochemical, immunofluorescence, and other experiments. The mechanism was further explored by constructing immune responsive gene 1 (IRG1) knockout mice, RNA sequence, and molecular docking. The results revealed that DHTS significantly improved diet-induced metabolic disorders in mice, notably alleviating liver inflammation, oxidative stress, and fibrosis. Further analysis revealed that the intervention of DHTS was associated with the activation of IRG1. Subsequent experiments confirmed that IRG1 gene deletion reversed the above protective effects of DHTS in NAFLD. Mechanistically, DHTS enhanced the antioxidant nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway through IRG1/itaconate and blocked the oxidative stress response in the liver. In addition, DHTS also inhibited the activation of NACHT-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome via IRG1/itaconate, blocking the inflammatory amplification effect in the liver. The study suggests that DHTS may be a potential drug for the treatment of NAFLD, which exerts protective regulatory effects mainly through the IRG1/itaconate molecular pathway.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，但仍缺乏有效的治疗药物。二氢丹参酮I（DHTS）是从丹参中分离出的一种天然产物，已被证明对NAFLD有改善作用。本研究的目的是探讨DHTS对NAFLD的肝保护作用及其机制。采用西方饮食建立NAFLD和DHTS治疗模型，以观察DHTS对NAFLD的影响，并通过免疫组织化学、免疫荧光等实验进行检测。通过构建免疫反应基因1（IRG1）敲除小鼠、RNA测序和分子对接进一步探索其机制。结果显示，DHTS显著改善了饮食诱导的小鼠代谢紊乱，尤其减轻了肝脏炎症、氧化应激和纤维化。进一步分析表明，DHTS的干预与IRG1的激活有关。随后的实验证实，IRG1基因缺失逆转了DHTS在NAFLD中的上述保护作用。机制上，DHTS通过IRG1/衣康酸增强抗氧化核因子红细胞2相关因子2（Nrf2）途径，阻断肝脏中的氧化应激反应。此外，DHTS还通过IRG1/衣康酸抑制含NACHT、富含亮氨酸重复序列（LRR）和吡啉结构域（PYD）的蛋白3（NLRP3）炎性小体的激活，阻断肝脏中的炎症放大效应。该研究表明，DHTS可能是一种治疗NAFLD的潜在药物，其主要通过IRG1/衣康酸分子途径发挥保护性调节作用。
