Ethnopharmacological relevanceHypericum perforatum L. is a traditional Chinese medicine used to sooth the liver, relieve depression, reduce body temperature, reduce sweating, and stimulate lactation. HP was extracted from Hypericum perforatum L. Aim of studyThe antifatigue effects of hypericin were assessed in a series of experiments. Materials and methodsSix-to eight-week-old male ICR mice were raised in our lab. Mice were subjected to swimming training for 2 h, 6 days/week for 6 weeks. One hour prior to each swimming session, intraperitoneal injection of saline or HP (2 or 4 mg/kg) was performed. ResultsCompared with the fatigue model control group, HP was found to significantly increase the swimming time in forced swimming tests. The molecular mechanisms underlying the antifatigue effects were further revealed by analysing energy metabolism, the oxidant–antioxidant system and the inflammatory response. HP normalized changes in BLA, LDH, BUN, and CK, LG in the liver. In addition, multiple assays have confirmed that HP improved the MDA, T-AOC, GSH-PX and SOD activity, and the relevant signalling pathways involved in the antifatigue effects were clarified. Furthermore, HP improves the expression of pro- and anti-inflammatory cytokines in skeletal muscle. ConclusionThese results suggested that the anti-chronic fatigue effects of HP are likely achieved by normalizing energy metabolism and attenuating oxidative and inflammatory responses. Consequently, this study supports HP use in the clinic to alleviate chronic fatigue.