整合网络药理学、分子对接并结合代谢组学以阐明解毒活血汤抗顺铂诱导急性肾损伤的药理机制。
Integrated network pharmacology and molecular docking combined with metabolomics to identify the pharmacological mechanisms of Jiedu Huoxue decoction against cisplatin-induced acute kidney injury.
作者信息
Wang Xiaowan, Guo Shan, Chen Jing, Cheng Ran, Zhou Fangqiang, Huang Lihua, Yang Le, Lu Zhaoyu, Li Shuju, Li Chuang, Mao Wei, Tian Ruimin, Xu Peng
机构信息
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China; Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China.
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
出版信息
J Ethnopharmacol. 2025 Jul 24;351:120088. doi: 10.1016/j.jep.2025.120088. Epub 2025 Jun 5.
ETHNOPHARMACOLOGICAL RELEVANCE
Jiedu Huoxue decoction (JHD), a classical Chinese herbal prescription that originated from Wang Qingren's Correction on Errors in Medical Works, has been shown to be effective in treating acute kidney injury (AKI), yet the mechanisms remain to be elucidated.
AIM OF THE STUDY
This study aimed to probe the efficacy of JHD on AKI and clarify its potential mechanism in cisplatin-induced AKI mice.
METHODS
An integrated tactic, including network pharmacology, molecular docking, pharmacodynamics, molecular biology, and metabolomics, was employed to illuminate the pharmacological mechanisms of JHD in treating AKI. Firstly, network pharmacology was adopted to predict potential drug targets and molecular pathways of AKI by utilizing the active ingredients in JHD. Secondly, molecular docking was used to explore the affinity between the active ingredients of JHD and AKI targets. Thirdly, biochemical analysis and histopathology were performed to estimate JHD's impact on cisplatin-induced AKI mice. Finally, quantitative real-time PCR, Western blot, lipid/immunofluorescence staining, and untargeted metabolomics were performed to understand the underlying mechanisms in vivo.
RESULTS
In silico analysis identified 184 active compounds and 394 targets of JHD. Topology analysis based on the PPI network indicated 7 main targets. The GO and KEGG enriched signaling pathways pointed to metabolic changes due to JHD's effects on AKI. Molecular docking screening revealed that TP53, SRC, MAPK1, MAPK2, and AKT1 were the key targets of JHD. Further molecular biology and untargeted metabolomics experiments revealed that fatty acid uptake (CD36) and lipogenesis (sphingolipids, phospholipids, and neutral lipids) mediated by the p53 and SRC-ERK/AKT signaling pathway may be involved in the protective effects of JHD against AKI in vivo.
CONCLUSION
JHD exerted therapeutic effects on AKI by regulating fatty acid uptake and lipogenesis via the p53 and SRC-ERK/AKT signaling pathway.
民族药理学相关性
解毒活血汤（JHD）是源自王清任《医林改错》的经典中药方剂，已被证明对治疗急性肾损伤（AKI）有效，但其作用机制仍有待阐明。
研究目的
本研究旨在探讨解毒活血汤对急性肾损伤的疗效，并阐明其在顺铂诱导的急性肾损伤小鼠中的潜在作用机制。
方法
采用网络药理学、分子对接、药效学、分子生物学和代谢组学等综合策略，阐明解毒活血汤治疗急性肾损伤的药理机制。首先，利用解毒活血汤中的活性成分，采用网络药理学预测急性肾损伤的潜在药物靶点和分子途径。其次，运用分子对接技术探索解毒活血汤活性成分与急性肾损伤靶点之间的亲和力。第三，进行生化分析和组织病理学检查，以评估解毒活血汤对顺铂诱导的急性肾损伤小鼠的影响。最后，进行定量实时PCR、蛋白质免疫印迹法、脂质/免疫荧光染色和非靶向代谢组学分析，以了解体内潜在机制。
结果
计算机分析确定了解毒活血汤的184种活性化合物和394个靶点。基于蛋白质-蛋白质相互作用网络的拓扑分析表明有7个主要靶点。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集的信号通路表明，解毒活血汤对急性肾损伤的作用导致了代谢变化。分子对接筛选显示，TP53、SRC、MAPK1、MAPK2和AKT1是解毒活血汤的关键靶点。进一步的分子生物学和非靶向代谢组学实验表明，由p53和SRC-ERK/AKT信号通路介导的脂肪酸摄取（CD36）和脂肪生成（鞘脂、磷脂和中性脂质）可能参与了解毒活血汤在体内对急性肾损伤的保护作用。
结论
解毒活血汤通过p53和SRC-ERK/AKT信号通路调节脂肪酸摄取和脂肪生成，从而对急性肾损伤发挥治疗作用。
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