Sesamin is lignans mainly found in sesame seeds and oil. Previous studies have demonstrated that sesamin has potent pharmacological activities including anti-inflammatory, antioxidative, and cholesterol-and lipid-lowering. Detailed studies performed with sesamin revealed that it possesses anti-proliferative and pro-apoptotic properties that could potentially be used to kill tumors. Nevertheless T cell-mediated disorders usually occur when over-activated T cells are proliferative and less apoptotic, however, it is unknown whether sesamin suppresses T cell activation with underlying mechanism related to proliferation and apoptosis. In the present study, we evaluate whether sesamin upregulates apoptosis on activated T cells and improves T cell-mediated disease. First of all, we confirmed that sesamin suppresses IL-2 production and CD69 expression from activated T cells by quantitative PCR, ELISA and flow cytometry. In silico analysis showed that Myeloid cell leukemia 1 (MCL-1) is predicted to physically interact with sesamin in T cells. According to the in silico prediction, pulldown assay using sepharose4B beads and western blot results showed that treatment with sesamin physically binds to MCL-1 in T cells and regulates S56 phosphorylation level of MCL-1 which represents activity of MCL-1 in activated T cells. Moreover, inhibition of MCL-1 activity by sesamin blocked heterodimer interaction between MCL-1 and BAK in activated T cells by co-immunoprecipitation assay. These results led sesamin to selectively induce cell death pathway only in activated T cells. Oral administration of sesamin alleviated the symptoms of dinitrochlorobenzene (DNCB)/mite extract-induced AD, including ear thickness, mRNA levels of pro-atopic cytokines on the ear lesions of sesamin-treated AD mice. Therefore, these results suggest that sesamin has a therapeutic potential for treating T-cell mediated disease through modulating MCL-1 activity on activated T cells. This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2021R1I1A1A01059119). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.