BTB and CNC homolog 1 (BACH1) is a master transcriptional regulator of the cellular oxidative stress response and pro-metastatic oncogene. Post-translational stability of BACH1 is tightly regulated by distinct F-box ubiquitin ligases, including SCFFBXO22and SCFFBXL17. However, the molecular details have been elusive. Here, we reveal a structural switch in FBXO22 that controls the recognition of a three-dimensional degron in the BACH1 BTB domain, thus explaining its specificity for dimeric BACH1. We describe how cancer-associated mutations in FBXO22 modulate binding and ubiquitylation of BACH1. Further, we reveal that cancer-related mutations or cysteine-modifications destabilize the BTB domain and redirect BACH1 to FBXL17, where it is recognized as a monomer. This explains how complementary ligases post-translationally regulate BACH1 depending on the state of its BTB domain. Our findings provide mechanistic insights into the regulation of the oxidative stress response and may spur therapeutic strategies to targeting oxidative stress-related disorders and metastatic cancers.