Melatonin and cerium oxide nanoparticles additively mitigate capecitabine-induced hepatotoxicity via targeting oxidative stress, apoptosis, and ERK signaling

BACKGROUND: Capecitabine (CAP), a chemotherapy prodrug, is associated with a significant dose-limiting hepatotoxicity. This study evaluated the protective efficacy of melatonin (MEL) and cerium oxide nanoparticles (CeO₂ NPs) against CAP-induced toxicity. METHODS: Fifty male Wistar rats were divided into five groups: control, CAP-only (500 mg/kg/week), CAP + MEL (10 mg/kg/day), CAP + CeO₂ NPs (30 mg/kg/day), and a combination therapy group (CAP + MEL + CeO₂ NPs). After a six-week treatment period, assessments included alanine and aspartate transaminases (ALT, AST); hepatic oxidative stress markers [glutathione peroxidase-1 (GPx-1), superoxide dismutase (SOD), and malondialdehyde (MDA)]; apoptotic markers [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) mRNA, cleaved caspase-3 (c-caspase-3), and protein 53 (p53)]; pro-survival signaling [extracellular signal-regulated kinase (ERK1/2)]; and histopathological evaluation of liver tissue. RESULTS: CAP administration induced significant liver damage, characterized by elevated ALT and AST, depletion of GPx-1 and SOD, increased MDA, and activation of the mitochondrial apoptotic pathway, indicated by an elevated BAX/Bcl-2 ratio and increased levels of p53 and c-caspase-3. This was accompanied by suppression of ERK1/2 signaling and severe histopathological alterations. Both MEL and CeO₂ NPs, significantly attenuated these deleterious effects. The combination therapy demonstrated a comparatively superior effect, resulting in a near-complete normalization of all measured parameters, including oxidative stress, apoptosis, ERK1/2 activity, and liver histoarchitecture. CONCLUSION: Melatonin and CeO₂ NPs provide hepatoprotection via distinct yet complementary mechanisms. Their combined administration presents a superior strategy to mitigate CAP-induced liver injury by concurrently counteracting oxidative stress, inhibiting apoptosis, and enhancing pro-survival signaling.