Xinlikang Capsule Alleviates Chemotherapy‐Induced Fatigue by Inhibiting the PI3K/AKT‐mTOR‐FoxO Pathway

Objective Chemotherapy‐induced fatigue (CIF) remains a clinically challenging condition with limited therapeutic options. This study aimed to elucidate the therapeutic potential and underlying mechanisms of the multiherbal Xinlikang (XLK) capsule against CIF using an integrated strategy that combined network pharmacology prediction with experimental validation. Methods A murine CIF model was established using 5‐fluorouracil (5‐FU). XLK was administered at various doses to evaluate its efficacy through comprehensive assessments, including behavioral tests (weight‐bearing swimming, tail suspension, and grip strength), histopathology (hematoxylin–eosin H&E and periodic acid‐Schiff PAS staining), and metabolic indices (lactate and ATP levels). To investigate the mechanisms, an integrated network pharmacology approach was employed to identify bioactive components of XLK, predict their potential targets, and construct a “component‐target‐pathway” network. Core signaling pathways implicated in CIF were prioritized via protein–protein interaction (PPI) and KEGG enrichment analyses. Key predictions were subsequently verified by Western blot analysis. Results XLK treatment significantly ameliorated fatigue‐like behaviors, improved muscle glycogen storage, and restored lactate and ATP homeostasis in CIF mice (all p < 0.05). Network pharmacology predicted that the anti‐CIF effect of XLK was closely associated with the regulation of energy metabolism‐related pathways, particularly the PI3K/AKT‐mTOR‐FoxO signaling axis. Experimental validation confirmed that XLK significantly modulated the expression and phosphorylation levels of key proteins (e.g., p‐PI3K, p‐AKT, and p‐mTOR) within this pathway in the skeletal muscle or relevant tissues of CIF model mice (all p < 0.05). Conclusion XLK enhances cellular energy homeostasis by regulating the PI3K/AKT‐mTOR‐FoxO signaling axis, thereby alleviating CIF. These findings provide a mechanistic rationale for the clinical application of XLK against CIF.