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Nasopharyngeal carcinoma is a malignant tumor with high incidence in Asia. This study investigated the anti-tumor capacities of lupeol in nasopharyngeal carcinoma. CCK-8 assay was employed to select the suitable concentration and intervention time of lupeol in 5–8 F and CNE1 cells. The anti-cancer impacts of lupeol were evaluated by flow cytometry, ROS generation, western blotting, ELISA, iron assay, lipid peroxidation, mitochondrial membrane potential (MMP), TUNEL, and immunohistochemistry assays. Additionally, levels of AMPK/NF-κB pathway-related proteins were tested by western blotting. Cell viability was notably decreased after administration of lupeol ≧ 20 μM. 20 μM and 40 μM lupeol induced cell apoptosis, enhanced oxidative stress and restrained immune response in nasopharyngeal carcinoma cells to some extent, as evidenced by the elevation of apoptotic rate, Bax and cleaved caspase-3 expression, ROS production and malondialdehyde level, and reduction of levels of Bcl-2, MMP, superoxide dismutase, TNF-α, IL-6 and IL-1β. Also, lupeol promoted the iron secretion and lipid peroxidation, the effects of which were reversed by ferroptosis inhibitor (Fer-1). The inhibitory impacts of lupeol at the doses of 20 μM and 40 μM on glutathione and GPX4 levels were observed. Importantly, lupeol significantly elevated AMPKα phosphorylation, and reduced the levels of p-IκBα and nuclear NF-κB p65. Rescue assay stated that siAMPK could neutralize the above impacts of lupeol. Moreover, lupeol suppressed tumorigenesis of xenografts in nude mice. Lupeol exerted the anti-cancer impacts by inducing oxidative stress, ferroptosis and apoptosis, and suppressing inflammation via the AMPK/NF-κB pathway in nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]