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.

cancer cachexia  /  data mining  /  network pharmacology  /  molecular docking  /  HIF-1α  /  Poria  /  Atractylodis Macrocephalae Rhizoma  /  Astragali Radix  /  Dioscoreae Rhizoma  /  Glycyrrhizae Radix et Rhizoma Praeparata cum Melle  /  quercetin