Background: Hepatotoxicity and immune changes are the major side effects induced by chemotherapy, which is largely due to high levels of reactive oxygen species (ROS). Methotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, has been reported to induce hyperlipidemia, oxidant stress, and immune dysfunction. Current studies have identified the promise of natural antioxidants and nanomaterials for these protective strategies. Peel of Citrus sinensis (CS) is abundant in flavonoids and phenol which exhibit potent antioxidant and hepatoprotective effects whereas gold nanoparticles (AuNPs) demonstrate immunomodulatory and cytoprotective activities.

Methods: 36 male Wistar rats were randomly assigned into six groups (n = 6): control, MTX (10 mg/kg), MTX together with C. sinensis peel extract (at doses of 75, 150 and 250 mg/kg) and MTX combined with AuNPs(0.3–0.6 mg/kg). Serum lipid profiles (TC, TG), oxidative stress biomarkers (MDA, LPO), antioxidant enzyme activities [glutathione peroxidase expression (GPx)] and immune parameters [white blood cell count, lymphocyte percentage and IL-6] were determined over a period of 14 days. Analysis of data was performed using one-way ANOVA followed by Tukey's test, where p < 0.05.

Results: MDA, LPO, TC, TG and IL-6 levels were significantly increased while the GPx activity and total WBCs count/lymphocyte percentage was lowered by MTX administration. The changes were markedly reversed by pretreatment with C. sinensis peel extract and AuNPs in a dose-dependent manner. Both therapies also attenuated oxidative stress, alleviated lipid metabolism disorder, improved antioxidant system and immune status. The most interesting was that even 10% ofn AuNP at the higher doses showed to be about somewhat better than peel extract.