Signal abnormalities in human cells usually cause unexpected consequences for individual health.We focus on these kinds of events involved in JAK-STAT signal pathway, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases.By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we screened a natural products library which contained purified compounds originally isolated from medicinal herbs.One compound, named Brevilin A, exhibited significant STAT3 signal inhibition in screening cell system.Further investigations revealed that Brevilin A inhibited STAT3 signal specifically and had preferential cell growth inhibition on STAT3 dependent cells.Cytokines induced phosphorylation of STAT3, and following STAT3 regulated gene transcriptions were blocked in the present of Brevilin A.By evaluating other members in the Brevilin A mediated STAT3 inhibition, we found Brevilin A attenuated the upstream JAKs activity.The JAKs tyrosine kinase domain JH1 induced phosphorylation of STAT3 and other substrates were dramatically reduced by treatment of Brevilin A.The roles of Brevilin A targeting on JAKs activity indicates that Brevilin A may not only used as a STAT3 inhibitor but also one compound blocking other JAK-STAT hyperactivation.Thus, these findings provided a strong impetus for the development of selective STAT3 inhibitors and therapeutic anti-tumor drugs in order to improve survival in patients with pTyr-STAT3 overexpressing tumors.