Crucial Contribution of <scp>BACH1</scp> to Bladder Cancer Progression via Upregulating Epithelial‐Mesenchymal Transition Pathway

Bladder cancer (BC) is a prevalent urological malignancy, with muscle-invasive subtypes exhibiting a particularly poor prognosis despite recent therapeutic advances. Established risk factors such as smoking contribute to carcinogenesis through the generation of reactive oxygen species, which trigger oxidative stress responses (OSRs). Broad-complex-Tramtrack-Bric a brac and Cap'n' collar homology 1 (BACH1), a key transcription factor regulating OSRs, has been implicated in epithelial-mesenchymal transition (EMT) and metastasis in several malignancies. This study aimed to clarify the role of BACH1 in BC progression and metastasis. Clinical analyses revealed that BACH1-positive expression was correlated with aggressive tumor features, including advanced pathological stage, high tumor grade, and poor prognosis. In vitro experiments demonstrated that BACH1 knockdown suppressed, while overexpression enhanced, the invasive, migratory, and proliferative activities. RNA sequencing indicated significant enrichment of EMT-related and cytokine-driven immune pathways following BACH1 knockdown. Furthermore, in vivo mouse allograft experiments showed that Bach1 knockout cells exhibited reduced tumor growth and fewer lung metastases, accompanied by altered expression of EMT markers and modulation of cytokine-driven immune signaling. Collectively, these findings suggest that BACH1 plays a crucial role in BC progression and metastasis, at least in part, through two complementary mechanisms, EMT activation and immune microenvironment modulation via cytokine signaling.