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

TY - JOUR

T1 - Identification of a BACH1 lung cancer signature

T2 - A novel tool for understanding BACH1 biology and identifying new inhibitors

AU - Klenja Skudrinja, Donika

AU - Ali, Kevin X.

AU - Walker, David

AU - Higgins, Maureen

AU - Patel, Angana AH

AU - Raj, Dorota

AU - Creelman, Anna

AU - McDowall, Charlotte

AU - Taylor, Conor

AU - Wenta, Tomasz

AU - Larsson, Erik

AU - Wiel, Clotilde

AU - Sayin, Volkan I.

AU - de la Vega, Laureano

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/9

Y1 - 2025/9

N2 - 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.

AB - 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.

KW - Gene signature

KW - Lung cancer

KW - Metastasis

KW - BACH1

UR - https://www.scopus.com/pages/publications/105011610563

U2 - 10.1016/j.redox.2025.103789

DO - 10.1016/j.redox.2025.103789

M3 - Article

C2 - 40716152

SN - 2213-2317

VL - 85

JO - Redox Biology

JF - Redox Biology

M1 - 103789

ER -