Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats

Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by hepatotoxicity associated with oxidative stress and inflammatory signaling. This study aimed to investigate the potential protective effects of melatonin and agomelatine on DOX-induced hepatic injury using scintigraphic, biochemical, and molecular parameters. Methods: Twenty-eight rats were randomly divided into four groups: Control, DOX, DOX + Melatonin, and DOX + Agomelatine. Melatonin and agomelatine were administered as a one-week pretreatment, and DOX was injected during the experimental period (total dose: 18 mg/kg). Hepatic injury was evaluated using 99mTc-PYP scintigraphic imaging, serum liver enzymes (AST, ALT, and LDH), oxidative stress markers (MDA, GSH, Nrf2, and SIRT1), and inflammatory cytokines (TNF-α, IL-6, and IL-10). Results: DOX administration significantly increased hepatic 99mTc-PYP uptake, as well as serum AST, ALT, and LDH levels, indicating hepatocellular necrosis and membrane damage. DOX also increased MDA, TNF-α, and IL-6 levels while reducing GSH, Nrf2, SIRT1, and IL-10, demonstrating pronounced oxidative stress and inflammatory activation. Treatment with melatonin or agomelatine significantly reduced tracer uptake and liver enzyme levels compared with the DOX group. Both treatments improved antioxidant status by decreasing MDA and restoring GSH, Nrf2, and SIRT1 levels, while simultaneously attenuating inflammatory cytokine responses through reduction in TNF-α and IL-6 and partial restoration of IL-10. Conclusions: Melatonin and agomelatine attenuated DOX-induced hepatotoxicity by reducing oxidative stress, modulating inflammatory responses, and restoring hepatic SIRT1 and Nrf2 levels. These findings suggest that melatonergic interventions may represent promising protective strategies against doxorubicin-induced liver injury.