Background: Chemotherapy-induced liver damage (CILD) represents a significant clinical challenge in cancer treatment, with cyclophosphamide and doxorubicin being among the most commonly implicated agents. Despite their therapeutic efficacy, these drugs can cause severe hepatotoxicity through distinct molecular mechanisms, necessitating comprehensive understanding for optimal patient management.

Methods: We conducted a comprehensive literature review analyzing preclinical and clinical studies on cyclophosphamide and doxorubicin-induced hepatotoxicity published between 2010-2024. Data sources included PubMed, EMBASE, and clinical trial registries. We synthesized findings on mechanisms, clinical manifestations, risk factors, biomarkers, and hepatoprotective strategies.

Results: Cyclophosphamide induces hepatotoxicity primarily through CYP450-mediated metabolism producing toxic metabolites (acrolein, phosphoramide mustard), causing oxidative stress and inflammation. Clinical incidence ranges from 5-15% (mild) to 1-3% (severe), with delayed onset (6-127 days post-treatment). Doxorubicin causes liver damage through ROS generation and mitochondrial dysfunction, with higher incidence rates (10-25% mild, 2-5% severe) and earlier onset (days to weeks). Both drugs demonstrate dose-dependent toxicity patterns with cumulative dose thresholds of >1200 mg/m² (cyclophosphamide) and >450-550 mg/m² (doxorubicin). Multiple hepatoprotective strategies show promise, including N-acetylcysteine, silymarin, and various natural compounds targeting oxidative stress pathways.

Conclusion: Understanding the distinct temporal and mechanistic profiles of cyclophosphamide and doxorubicin hepatotoxicity is crucial for developing targeted prevention and management strategies. Future research should focus on biomarker-guided therapy and personalized hepatoprotective approaches.

Keywords: Chemotherapy, Hepatotoxicity, Cyclophosphamide, Doxorubicin, Drug-induced liver injury, Hepatoprotection.