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BACKGROUND: Abnormal activity of STAT3 is associated with a number of human malignancies. Hsp90 plays a central role in stabilizing newly synthesized proteins and participates in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis, such as STAT3. Hsp90 interacts with STAT3 and stabilizes Tyr-phosphorylated STAT3. It has been reported that luteolin possesses anticancer activity through degradation of Tyr(705)-phosphorylated STAT3. METHODOLOGY/PRINCIPAL FINDINGS: We found that overexpression of Hsp90 inhibited luteolin-induced degradation of Tyr(705)-phosphorylated STAT3 and luteolin also reduced the levels of some other Hsp90 interacting proteins. Results from co-immunoprecipitation and immunoblot analysis demonstrated that luteolin prevented the association between Hsp90 and STAT3 and induced both Tyr(705)- and Ser(727)-phosphorylated STAT3 degradation through proteasome-dependent pathway. The molecular modeling analysis with CHARMm-Discovery Studio 2.1(DS 2.1) indicated that luteolin could bind to the ATP-binding pocket of Hsp90. SPR technology-based binding assay confirmed the association between luteolin and Hsp90. ATP-sepharose binding assay displayed that luteolin inhibited Hsp90-ATP binding. CONCLUSIONS/SIGNIFICANCE: Luteolin promoted the degradation of Tyr(705)- and Ser(727)-phosphorylated STAT3 through interacting with Hsp90 and induced apoptosis of cancer cells. This study indicated that luteolin may act as a potent HSP90 inhibitor in antitumor strategies.