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Betulinic acid (BA) is a natural triterpenoid that protects against liver damage. However, the underlying mechanism has not yet been elucidated. The purpose of this study was to evaluate the ameliorative effects of BA on CYP\u2010induced hepatotoxicity and further clarify the underlying mechanism. BA pretreatment mitigated CYP\u2010induced liver oxidative damage by alleviating histopathological lesions, reducing reactive oxygen species (ROS) accumulation, and restoring the mRNA expression of antioxidant enzymes (<jats:italic>Cu\u2010Sod<\/jats:italic>, <jats:italic>Mn\u2010Sod<\/jats:italic>, <jats:italic>Cat<\/jats:italic>, and <jats:italic>Gsh\u2010Px<\/jats:italic>). BA treatment also suppressed CYP\u2010induced oxidative stress by activating the NRF2 pathway and inhibiting the MAPK signaling pathway. Moreover, BA attenuated CYP\u2010triggered hepatic apoptosis by suppressing excessive mitochondrial fission, boosting mitochondrial fusion, and ameliorating pro\u2010apoptotic protein expression (CASP9 and the ratio of BCL\u20102\/BAX) by blocking the oxidative stress\u2010activated mitochondrial apoptotic pathway. Furthermore, PD98059 (an inhibitor of ERK) and\/or BA abated CYP\u2010provoked hepatotoxicity by inhibiting the ERK\u2013MAPK and mitochondrial apoptotic pathways, implying that deactivation of the ERK\u2010mediated mitochondrial apoptotic pathway contributed to the hepatoprotective efficacy of BA against CYP\u2010induced oxidative stress. Therefore, BA could be used as a complementary medicine in patients undergoing CYP treatment owing to its hepatoprotective effects.<\/jats:p>","DOI":"10.1002\/tox.24444","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:12:59Z","timestamp":1732709579000},"page":"608-623","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Ameliorative Effect of Betulinic Acid on Oxidative Stress in Mice of Cyclophosphamide\u2010Induced Liver Damage"],"prefix":"10.1002","volume":"40","author":[{"given":"You","family":"Huang","sequence":"first","affiliation":[{"name":"Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine Hunan Agricultural University  Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center of 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