目的 基于网络药理学研究探讨红景天苷治疗癌因性疲乏的作用机制，并通过动物实验进行验证。方法 利用HERB、ChEMBL、PubChem数据库搜集红景天苷的潜在作用靶点，通过GeneCards和DisGeNET数据库筛选癌因性疲乏相关疾病靶点，取二者的交集，进一步行基因本体（GO）功能和京都基因和基因组百科全书（KEGG）通路富集分析。利用STRING数据库构建蛋白质相互作用（PPI）网络，利用CytoHuba插件确定核心靶点，关键靶点与红景天苷进行分子对接。动物实验部分通过构建氟尿嘧啶化疗诱导的荷瘤小鼠疲乏模型，通过力竭游泳实验、悬尾实验观察红景天苷干预后对疲劳的缓解程度，并采用免疫组化对骨骼肌靶蛋白蛋白激酶B1（Akt1）的表达水平进行验证。结果 筛选出红景天苷与癌因性疲乏共134个交集靶点。GO分析表明，这些靶点显著富集于凋亡调控、细胞迁移、营养应激反应及细胞因子信号传导等生物学过程；KEGG通路分析提示其核心机制涉及磷酸肌醇3-激酶（PI3K）/Akt信号通路、内分泌抵抗及神经退行性疾病相关通路。通过拓扑分析进一步筛选出Akt1、促分裂原活化蛋白激酶（MAPK）3、MAPK1等10个核心靶点。分子对接结果显示，红景天苷与Akt1具有高亲和力。动物实验证实，红景天苷组小鼠力竭游泳时间较模型组显著延长，悬尾不动时间显著缩短（P＜0.05、0.001）。免疫组化分析显示，红景天苷能逆转氟尿嘧啶诱导的骨骼肌Akt1蛋白表达下调（P＜0.01）。结论 红景天苷可通过多靶点、多通路的作用机制改善癌因性疲乏，其中Akt1可能是其主要作用靶点之一。

Objective To investigate the mechanism of salidroside in treatment of cancer-related fatigue based on network pharmacology and to validate these findings through animal experiments. Methods Targets of salidroside were retrieved from databases including HERB, ChEMBL, and PubChem, while cancer-related fatigue-related targets were collected from GeneCards and DisGeNET. The common targets were identified by intersecting the two sets. GO functional enrichment and KEGG pathway analyses were subsequently performed. A PPI network was constructed using the STRING database, and core targets were identified using the CytoHubba plugin. Molecular docking was conducted between salidroside and the key target. In the animal experiments, a cancer-related fatigue model was established in tumor-bearing mice induced by fluorouracil chemotherapy. Through exhaustive swimming experiments and tail suspension experiments, the degree of fatigue alleviation after the intervention with salidroside was observed. Immunohistochemistry was used to verify the expression level of the target protein Akt1 in skeletal muscle. Results A total of 134 overlapping targets of salidroside and cancer-related fatigue were identified. GO analysis indicated that these targets were significantly enriched in biological processes such as regulation of apoptosis, cell migration, response to nutrient stress, and cytokine-mediated signaling. KEGG pathway analysis suggested that the core mechanisms involved the PI3K/Akt signaling pathway, endocrine resistance, and pathways related to neurodegenerative diseases. Through topological analysis, 10 core targets including Akt1, MAPK3, and MAPK1 were further selected. Molecular docking results showed that salidroside has a high affinity for Akt1. Animal experiments have confirmed that salidroside group of mice had a significantly longer time for exhaustive swimming compared to the model group, and a significantly shorter immobility time on the tail suspension test (P < 0.05, 0.001). Immunohistochemical analysis showed that salidroside could reverse the downregulation of Akt1 protein expression in skeletal muscle induced by fluorouracil (P < 0.01). Conclusion Salidroside can ameliorate cancer-related fatigue through multi-target and multi-pathway mechanisms, with Akt1 serving as one of the main targets.

R965;R979.1

湖北省时珍人才工程科研项目资助（鄂卫函[2024]256号）；武汉市中医药科研面上项目（WZ22A07）；武汉市中心医院院级科研项目（23YJ09）