目的 探讨中医药治疗癌症恶病质（cancer cachexia，CC）的用药规律、核心组方及其多维作用机制。方法 通过数据挖掘，从211篇文献中筛选出高频药物和核心组方，随后利用网络药理学方法，筛选核心处方的活性成分和靶点，构建“药物-成分-靶点”网络和蛋白质-蛋白质相互作用网络，并进行基因本体论（gene ontology，GO）和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）富集分析，并通过分子对接验证核心成分与靶点的结合能力。在A549荷瘤裸鼠CC模型上，通过检测体质量、摄食量、肌肉功能、炎症因子［白细胞介素-6（interleukin-6，IL-6）、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）］水平和关键蛋白［肌肉萎缩F-box蛋白（muscle atrophy F-box protein，Atrogin-1）、肌肉环指蛋白1（muscle ring-finger protein-1，MuRF1）、蛋白激酶B1（protein kinase B1，Akt1）、缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）等］表达量进行体内药效验证。结果 最终纳入方剂67首，涉及药物171味，确定核心组方为茯苓、白术、黄芪、山药、炙甘草。网络药理学预测出149个潜在靶点，涉及磷脂酰肌醇-3-羟激酶（phosphatidylinositol-3-hydroxykinase，PI3K）/蛋白激酶B（protein kinase B，Akt）、缺氧反应因子-1（hypoxia-inducible factor-1，HIF-1）、p53和凋亡等信号通路，分子对接显示槲皮素等核心成分与核心靶点结合良好。体内实验显示，核心处方高剂量组疗效最佳，显著改善了CC裸鼠的厌食症状、维持体质量、恢复握力峰值和股四头肌湿质量（均P＜0.05）。机制方面，核心组方显著降低了裸鼠血清IL-6和TNF-α水平；免疫荧光显示其显著抑制了腓肠肌中Atrogin-1和MuRF1的表达，同时上调了抗凋亡蛋白蛋白激酶B1（protein kinase B1，Akt1）和B淋巴细胞瘤-2（B-cell lymphoma-2，Bcl-2）的表达，并下调了HIF-1α、肿瘤蛋白p53（tumor protein p53，TP53）和原癌基因蛋白c-Myc（cellular-Myc，MYC）等促凋亡及代谢重编程蛋白的表达（均P＜0.05），调控结果与网络药理学预测的HIF-1α、PI3K-Akt信号通路调控一致。结论 中医药治疗CC的核心组方以健脾渗湿、益气扶正为主要法则，其机制可能通过PI3K-Akt/HIF-1α等通路，实现对代谢重编程、炎症反应及细胞凋亡的综合调节，并有效抑制泛素-蛋白酶体途径，从而发挥多维度、整体性的抗恶病质作用。

Objective To investigate the medication rules, core formula, and multi-dimensional mechanisms of traditional Chinese medicine (TCM) in the treatment of cancer cachexia (CC). Methods Medication rules and the core formula were screened from 211 publications through data mining. Network pharmacology was subsequently applied to identify the active components and potential targets of the core formula, followed by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses and molecular docking validation. Finally, the therapeutic efficacy and mechanisms were validated in vivo using an A549 tumor-bearing nude mouse CC model. Evaluation indicators included tumor-free body weight, food intake, muscle function, inflammatory cytokines [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)], and key proteins [muscle atrophy F-box protein (Atrogin-1), muscle RING-finger protein-1 (MuRF1), protein kinase B1 (Akt1), and hypoxia-inducible factor-1α (HIF-1α)]. Results A total of 67 prescriptions involving 171 drugs were identified, and the core formula was determined as Fuling (Poria), Baizhu (Atractylodis Macrocephalae Rhizoma), Huangqi (Astragali Radix), Shanyao (Dioscoreae Rhizoma), and Zhigancao (Glycyrrhizae Radix et Rhizoma Praeparata cum Melle). Network pharmacology predicted 149 potential targets involved in the PI3K-Akt, HIF-1α, p53, and apoptosis signaling pathways. Molecular docking showed that core components, such as quercetin, exhibited strong binding affinities with key targets. In vivo experiments demonstrated that the high-dose core formula exhibited the best therapeutic effect, significantly improving anorexia, maintaining tumor-free body weight, and restoring peak grip strength and quadriceps wet weight (all P < 0.05). Mechanistically, the core formula significantly reduced serum levels of IL-6 and TNF-α. Furthermore, it markedly inhibited the expression of muscle-atrophy-related proteins Atrogin-1 and MuRF1 in the gastrocnemius muscle. It also upregulated the expression of the anabolic protein Akt1 and anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), while downregulating the expression of metabolic reprogramming and pro-apoptotic proteins, including HIF-1α, tumor protein p53 (TP53), and cellular-Myc (MYC) (all P < 0.05). These results were consistent with the regulatory patterns predicted for the HIF-1α and PI3K-Akt signaling pathways. Conclusion The core TCM formula for treating CC follows the therapeutic principles of invigorating the spleen, resolving dampness, supplementing qi, and strengthening healthy qi. Its mechanism likely involves the modulation of the PI3K-Akt/HIF-1α signaling axis to comprehensively regulate metabolic reprogramming, inflammatory response, and cell apoptosis while effectively inhibiting the ubiquitin-proteasome pathway, thereby exerting a multi-dimensional and holistic anti-cachexia effect.

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国家科技重大专项（2024ZD0521301）；湖南省中医肿瘤临床研究中心平台项目（2021SK4023）；2024年湖南中医药大学研究生创新课题项目（2024CX111）