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This study clarified the protective effect of ganoderic acid A (GAA) on cyclophosphamide (CP)‐induced hepatotoxicity in mice. Hepatic injury mice were induced by a single intraperitoneal injection of CP (200 mg/kg). The results showed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and liver of the CP group mice were increased, and the levels of cytokines such as interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α in serum were increased. With the increase of the thioredoxin interaction protein (Txnip)/Trx/NF‐кB pathway, the histological structure of the liver has significantly changed as well as apoptosis events. On the contrary, the levels of ALT, AST, and cytokines in serum and liver in mice have been improved after GAA administration. Furthermore, the protein levels of the Txnip/Trx/NF‐кB pathway and apoptosis‐related protein including Bax, Bcl‐2, caspase‐3, and ‐9 were restored by GAA. In conclusion, GAA can be used as an effective drug to improve the hepatotoxicity caused by CP. [ABSTRACT FROM AUTHOR]