In summary, our findings highlight the important role of Nrf2 inhibition against HER2-positive tumors in cancer therapy; especially, brusatol as a novel Nrf2 inhibitor was capable of sensitizing HER2-positive cancer cells to trastuzumab in vitro and in vivo, suggesting a great potential of brusatol as an adjuvant drug in combination with trastuzumab in treating HER2-positive cancers. This evidence concerns the gene NFE2L2 and cancer.