The Effects and Mechanisms of Ti-Fu-Kang Decoction in Alleviating Central Fatigue: Insights from Network Pharmacology and Metabolomics

<b>Background:</b> Although Ti-Fu-Kang (TFK) decoction has been clinically used for fatigue management, the systematic understanding of its mechanisms, particularly against central fatigue, remains largely unknown. This study is the first to employ an integrative approach of network pharmacology and metabolomics to explore the mechanisms of TFK against central fatigue. <b>Methods:</b> The central fatigue rat model was established using the modified multiple platform method in conjunction with alternate-day fasting. Behavioral alterations were evaluated through six behavioral tests, while brain injury was assessed through HE and Nissl staining. Serum metabolic indicators were analyzed to identify fatigue-related metabolic disturbances. Western blot analysis was used to assess the protein phosphorylation level of PI3K and AKT1. Oxidative stress was assessed by measuring superoxide dismutase, malondialdehyde, and glutathione peroxidase activities. Network pharmacology and serum metabolomics investigated the molecular mechanisms and metabolic pathways. <b>Results:</b> TFK significantly ameliorated behavioral abnormalities and brain pathological damage in central fatigue model rats. Network pharmacology analysis and in vivo experiment revealed that TFK may mediate biological processes such as oxidative stress and neuron death via the PI3K-AKT signaling pathway. Moreover, analysis of serum fatigue-related metabolic indicators indicated that TFK significantly modulated metabolic disruptions by elevating the levels of glucose, liver glycogen, and muscle glycogen and reducing the levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatine kinase, lactate, and lactate dehydrogenase in central fatigue rats. Serum metabolomics analysis revealed that TFK ameliorates central fatigue by modulating amino acid metabolism, specifically by altering the levels of leucine and L-tryptophan, which subsequently contributes to the restoration of 5-hydroxytryptamine and dopamine homeostasis. <b>Conclusions:</b> This study elucidates the potential therapeutic mechanism of TKF in alleviating central fatigue, providing a scientific and theoretical basis for broader application and development of TFK.