Our finding reveals that NRF2-responsive HO-1 contributes to DPP-4i–induced oncogenic NRF2 activation via a positive-feedback NRF2-HO-1 loop, not only providing novel mechanism insights into the oncogenic NRF2 in BC metastasis, but also offering new strategies to inhibit the dark side of oncogenic NRF2 activation by targeting its downstream target HO-1. This evidence concerns the gene HMOX1 and breast cancer.