The complete manuscript title: Exploring the Hepato-Cardiac Axis in Epirubicin Toxicity: The Interplay of Kynurenine Pathway and Antioxidant Intervention with N-Acetylcysteine

Introduction: Epirubicin (EPI) is a widely used chemotherapeutic agent whose clinical use is limited by severe side effects, primarily due to oxidative stress-induced cardiotoxicity exacerbated by impaired hepatic clearance. This study investigated EPI-induced alterations in hepatic kynurenine pathway metabolites and their potential role in cardiotoxicity, as well as the protective effects of N-acetylcysteine (NAC). Methods: Rats received intraperitoneal injections of NAC (50 or 300 mg/kg) followed by EPI (9.6 mg/kg). Hepatic levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, kynureninase, kynurenine 3-monooxygenase, and cleaved caspase-3 were measured by ELISA. The total antioxidant and oxidant status in liver tissue was assessed colorimetrically. Plasma biomarkers, including AST, ALT, CK-MB, and lipids, were analyzed. Results: EPI significantly elevated plasma CK-MB, AST/ALT ratio, LDL, cholesterol, and triglycerides; NAC attenuated these effects. Hepatic kynurenine pathway dysregulation correlated positively with cardiotoxicity markers. Discussion: EPI disrupts hepatic kynurenine metabolism, contributing to cardiotoxicity, while NAC confers partial protection, likely via antioxidant and metabolic modulation mechanisms.