Signal transducer and activator of transcription-3 (STAT3) is critical for 
cancer progression by regulating tumor cell survival, proliferation, and 
angiogenesis. Herein, we investigated the regulation of STAT3 activation and the 
therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium 
Genus, in renal cell carcinoma (RCC). Icaritin showed significant anti-tumor 
activity in the human and mouse RCC cell lines, 786-O and Renca, respectively. 
Icaritin inhibited both constitutive and IL-6-induced phospho-STAT3 
(STAT3(Y705)) and reduced the level of STAT3-regulated proteins Bcl-xL, Mcl-1, 
Survivin, and CyclinD1 in a dose-dependent manner. Icaritin also inhibited 
activation of Janus-activated kinase-2 (JAK2), while it showed minimal effects 
on the activation of other key signaling pathways, including AKT and MAPK. 
Expression of the constitutively active form of STAT3 blocked Icaritin-induced 
apoptosis, while siRNA directed against STAT3 potentiated apoptosis. Finally, 
Icaritin significantly blunted RCC tumor growth in vivo, reduced STAT3 
activation, and inhibited Bcl-xL and Cyclin E, as well as VEGF expression in 
tumors, which was associated with reduced tumor angiogenesis. Overall, these 
results suggest that Icaritin strongly inhibits STAT3 activation and is a 
potentially effective therapeutic option for the treatment of renal cell 
carcinoma.