Lipopolysaccharide (LPS)-stimulated macrophages produce large amounts of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). This is an important mechanism in macrophage-induced septic shock and inflammation. In the present study, we tested a synthetic propenone compound, 1-furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) for its ability to inhibit the production of tumor necrosis factor-α (TNF-α) and an inducible enzyme, iNOS, in the LPS-stimulated murine macrophage-like cell line, RAW264.7. FPP-3 consistently inhibited nitric oxide (NO) and TNF-α production in a dose dependent manner, with IC₅₀ values of 10.0 and 13.1 μM, respectively. Western blotting probed with specific anti-iNOS antibodies showed that the decrease in quantity of the NO product was accompanied by a decrease in the iNOS protein level. In cells transiently transfected with nuclear factor (NF)-κB promoter-luciferase reporter construct, this compound clearly inhibited the LPS-stimulated NF-κB activation. Moreover, this compound inhibited IκB-α degradation in a concentration and time-dependent manner. These results indicate that FPP-3 inhibits NO production via inhibition of degradation of IκB-α through NF-κB activation.