Cyclophosphamide, an alkylating chemotherapeutic agent, is extensively employed in clinical oncology. The therapeutic effectiveness is constrained by its systemic toxicity mediated by oxidative stress. The hepatic biotransformation of this prodrug via the cytochrome P450 system produces toxic metabolites, including acrolein and phosphor amide mustard, resulting in hepatocellular damage. Natural compound such as ellagic acid, have been made significant stride in reducing cyclophosphamide induced organ damage. The integration of natural bioactive substances with nanotechnology is a promising biomedical approach to augment treatment efficacy while reducing unwanted effects. The current investigation examined the hepatoprotective efficacy of ellagic acid and its selenium-based nano formulation as an antioxidant strategy against cyclophosphamide-induced hepatic damage. Male albino rats received oral treatments of ellagic acid (30 mg/kg) or ellagic acid–selenium nanoparticles (3 mg/kg) three times weekly on alternate days, followed by cyclophosphamide (40 mg/kg, intraperitoneally) once weekly for five weeks. Animals were euthanized at the first day of the sixth week. Bi-omarkers of oxidative stress, antioxidant defense enzymes, autophagic signaling molecules, CYP2B6 expression, and histological and ultrastructural changes were systematically assessed. Sub chronic exposure to cyclophosphamide led to significant biochemical disruption, dysregulation of autophagy pathways, modified expression of drug-metabolizing enzymes, and extensive liver structural damage. Intervention with ellagic acid and its selenium nano formulation markedly reinstated redox equilibrium, normalized autophagic responses, and maintained hepatic architecture. The nano formula-tion demonstrated similar protective effects at a tenfold lowered dosage, highlighting its promise as a dose-efficient treatment. This study emphasizes the translational significance of phytochemical-based nanomedicine in alleviating chemotherapy induced hepatotoxicity and advocates for the advancement of nano-enabled dietary adjuvants as novel instruments in cancer treatment.

Cyclophosphamide, Ellagic acid, Ellagic Acid-selenium Nanoparticles