Schematic representation of the mechanism by which wogonin sensitizes TNFα-induced apoptosis. (A) The backbone of flavonoids. The activities of a flavonoid depend on the number of hydroxyl substitutions in its backbone structure. Wogonin contains 2 free 5,7,-OH groups. (B) The TNFR signaling pathway can either trigger activation of NF-κB crucial for TNFα-mediated immunity, inflammation, and proliferation or leads to programmed cell death. According to a recent model,²  TNFR signaling can be divided into 2 distinct stages that sequentially activate NF-κB and apical caspases. Within a few minutes after binding of TNFα to TNFR (stage 1), a signaling complex (complex I) containing the receptor itself and the adaptor proteins TRADD, TRAF2, and RIP1 but lacking the FAS/APO-1–associated death domain adaptor protein FADD forms and transduces signals that lead to activation of NF-κB and the JNK cascade. At later time points (stage 2), possibly after receptor internalization, RIP1, TRAF2, and TRADD dissociate from the receptor and recruit FADD and caspase-8 to form the second complex (complex II), which signals programmed cell death. Because of the long delay in the second complex assembly, NF-κB, activated at stage 1, has sufficient time to activate a variety of antiapoptotic factors that block the apoptotic pathway. We show that TNFα induces generation of ·O₂^– and shifts the cellular redox potential to a more oxidative state. Wogonin is able to transfer electron free radicals and thereby shift the cellular redox equilibrium to a more reduced state and thereby attenuate NF-κB activity and sensitize TNFα-induced apoptosis.