Sharata Ehab E, Attya Mina Ezzat, Khalaf Marwa M, Rofaeil Remon Roshdy, Hemeida Ramadan A M, Abo-Youssef Amira M
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt.
Department of Pathology, Faculty of Medicine, Minia University, Minia, 61519, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep 27. doi: 10.1007/s00210-025-04583-0.
Cyclophosphamide (CPA) is an alkylating drug utilized in the treatment of several cancers and autoimmune illnesses. Liver injury is a serious adverse effect linked to the administration of CPA. Nonetheless, the mechanism behind this toxicity remains incompletely elucidated; mechanistic investigations have identified oxidative stress, inflammatory responses, and apoptosis as pivotal elements contributing to CPA-induced liver dysfunction. In addition, CPA triggers the production of reactive oxygen species that act as damage-associated molecular patterns that rapidly activate TLR4/MYD88/NF-κB and NLRP3 inflammasome signaling cascades. Additionally, Nrf2/HO-1, α-klotho, and P-AMPK, which have anti-inflammatory and antioxidative characteristics, are thought to be important signaling pathways that mitigate oxidative stress in CPA-induced liver dysfunction. This review comprehensively covers all aspects of liver injury, including its epidemiology of drug-induced liver injury, risk factors, clinical presentation, chemotherapy-induced liver injury severity index, pathogenesis of CPA-induced liver injury and molecular mechanisms, and therapeutic choices. This study seeks to consolidate all known data about CPA-evoked liver injury, focusing on the probable redox molecular pathways underlying CPA-induced liver injury and recent drugs that showed a protective impact. In conclusion, studying these molecular pathways might open the way for early alleviation of hepatic dysfunction.
