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The nuclear factorκB (NFκB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis.In our search for NFκB inhibitors from natural resources, we identified 4′ ,6dihydroxy4methoxyisoaurone (ISOA) as an inhibitor of NFκB activation from the seeds of Trichosanthes kirilowii.However, the mechanism by which ISOA inhibits NFκB activation is not fully understood.In the present study, we demonstrated the effect of ISOA on NFκB activation in TNFαstimulated HeLa cells.This compound suppressed NFκB activation through the inhibition of IκB kinase (IKK) activation.ISOA also has an influence on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptorassociated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1).Consequently, ISOA blocked the phosphorylation and degradationof the inhibitor of NFκB alpha (IκBα), and subsequent phosphorylation and nuclear translocation of p65.The suppression of NFκB activation by ISOA led to the downregulation of target genes involved in inflammation, proliferation, angiogenesis and invasion, as well as potentiation of TNFαinduced apoptosis at least in part through activation of caspase8.Taken together, this study extends our understanding on the mechanisms underlying the antiinflammatory and anticancer activities of ISOA.Our findings provide new insight into the molecular mechanisms and a potential application of ISOA for inflammatory diseases as well as certain cancers associated with abnormal NFκB activation.