Yangonin is one of the six major kavalactones found in Piper methysticum .Yangonin potently inhibits NF-κB activation through suppression of the transcriptional activity of the RelA/p65 subunit of NF-κB. Yangonin significantly inhibits the induced expression of the NF-κB-reporter gene. However, Yangonin does not interfere with TNF-α-induced inhibitor of κBα (IκBα) degradation, p65 nuclear translocation, and DNA-binding activity of NF-κB. Yangonin inhibits not only the induced NF-κB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Yangonin does not inhibit TNF-α-induced activation of p38, but it significantly impairs activation of ERK 1/2 and stress-activated protein kinase/JNK.