Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors.

BACH1 is a transcriptional repressor that regulates oxidative stress and inflammatory responses and has emerged as a promising therapeutic target in cancer and other diseases. In lung cancer, BACH1 overexpression is linked to poor prognosis and metastasis, yet a consistent transcriptional signature reflecting its activity has not yet been defined. To address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying a set of direct BACH1 target genes. This novel lung cancer BACH1 signature is highly sensitive and specific to BACH1 perturbation, unaffected by NRF2 modulation, and consistent across a large panel of cancer cell lines. Despite NRF2 binding to the same regions, BACH1-mediated gene repression is dominant over NRF2-driven gene activation, suggesting a previously unappreciated regulatory hierarchy between these two transcription factors. Importantly, this signature correlates with BACH1 basal levels in lung cancer, PDAC and melanoma cells, highlighting its relevance as a surrogate for BACH1 activity. Using this signature, we identified paeoniflorin as a novel FBXO22-dependent BACH1 degrader with anti-invasive activity, and the novel BACH1 target gene HTRA3 as a potential effector of BACH1's pro-migratory effect. In summary, this novel BACH1 signature holds potential as a therapeutically relevant biomarker for identifying lung tumours with elevated BACH1 activity, serves as a powerful platform for discovering anti-invasive BACH1 inhibitors, and provides mechanistic insights into BACH1's role in driving metastasis.