Melamine (ML) is a common environmental contaminant, commonly used in food fraud,
representing a serious health hazard and jeopardizing human and animal health. Recently, nootkatone
(NK), a naturally occurring sesquiterpenoid, has garnered considerable attention due to its
potential therapeutic advantages. We investigated the potential mechanisms underlying the protective
effects of NK against ML-induced liver injury in rats. Five groups were utilized: control,
ML, NK10, ML-NK5, and ML-NK10. ML induced substantial hepatotoxicity, including considerable
alterations in biochemical parameters and histology. The oxidative distress triggered by ML increased
the generation of malondialdehyde (MDA) and nitric oxide (NO) and decreased levels of reduced
glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities. In addition, decreased
expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased nuclear factor kappa
beta (NF-B) expression levels were observed in hepatocytes, which indicated the occurrence of
inflammatory changes following ML exposure. These alterations were alleviated by NK supplementation
in a dose-dependent manner. The data revealed that the favorable effects of NK were
attributed, at least in part, to its antioxidant and anti-inflammatory properties. Moreover, our results
were supported by molecular docking studies that revealed a good fit and interactions between NK