In summary, this study demonstrates that xanthohumol directly attenuates Ets-1 phosphorylation and its interaction with USP9X, contributing to Ets-1 degradation and the inhibition of Ets-1/c-Met axis, thereby inducing apoptosis activation in osimertinib-resistatant NSCLC cells. Here, ETS1 is linked to non-small cell lung carcinoma.