Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy,which not only largely reduces the quality of life in patients,but also diminishes their physical and social function.At present,there is no effective drug for preventing and treating CRF.Ganoderic acid (GA),isolated from traditional Chinese medicine Ganoderma lucidum,has shown a variety of pharmacological activities such as anti-tumor,anti-inflammation,immunoregulation,etc.In this study,we investigated whether GA possessed anti-fatigue activity against CRF.CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU,30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days.Peripheral and central fatigue-related behaviors,energy metabolism and inflammatory factors were assessed.We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function,increasing glycogen content and ATP production,reducing lactic acid content and LDH activity,and inhibiting p-AMPK,IL-6 and TNF-α expression in skeletal muscle.Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6,iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-KB pathway.These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice,which provides evidence for GA as a potential drug for treatment of CRF in clinic.