Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells.However,the molecular mechanisms need to be elucidated.Here,we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1,H460/MX20 and H460,MCF-7/ADR and MCF-7 cells.Furthermore,SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation.Importantly,JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD,which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway.To investigate the mechanisms of upregulation of c-Jun protein by SAD,the mRNA expression level and degradation of c-Jun were examined.We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation.Taken together,these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.