Two anthracyclines, doxorubicin and epirubicin have been widely used alone or in combination with other antitumor reagents in the chemotherapeutic treatment of various malignancies. Although therapeutic efficacy of anthracyclines has been studied extensively, precise cytotoxic mechanism of these drugs is not been completely elucidated. Here we show that epirubicin-induced degradation of transmembrane protein gp130 contributes to antitumor effect of epirubicin. gp130 is degraded by epirubicin in a proteasome- and autophagy-dependent manner. Epirubicin induces activation of p38-MK2 signaling pathway to phosphorylate gp130 at Ser 782, which results in gp130 internalization and degradation by lysosome. Although mutation of Ser 782 to Ala or Cys in gp130 upregulates global epirubicin-induced autophagy, reduced degradation of gp130 accompanied with enhanced Stat3 phosphorylation at tyrosine 705 is observed. We also show that epirubicin-resistant tumor cells express higher level of gp130. Altogether, our results indicate that degradation of gp130 and subsequent reduction of gp130-Stat3 signaling contributes to epirubicin-induced tumor cell death. (C) 2019 Elsevier Inc. All rights reserved.