Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with a poorer prognosis compared to its HPV-positive counterpart; however, the underlying regulatory molecular mechanisms driving its progression remain poorly understood. In this study, we identify BTB Domain and CNC Homolog 1 (BACH1) as a critical oncogenic regulator that is upregulated in HPV-negative HNSCC. We demonstrate that BACH1 promotes tumor progression by enhancing the proliferation and inhibiting apoptosis of cancer cells. Mechanistically, BACH1 is associated with the SWI/SNF chromatin remodeling complex and transcriptionally activates downstream target genes, including IL1B , thereby inducing a transcriptional reprogramming that promotes proliferation and resists apoptosis. Notably, BACH1-driven upregulation of interleukin-1β (IL-1β) establishes a positive feedback loop that sustains oncogenic signaling. Pharmacological disruption of this axis using the IL-1 receptor antagonist Anakinra significantly attenuates tumor growth in vitro and in vivo. Clinically, co-upregulation of BACH1, BRG1, and IL-1β is correlated with reduced overall survival in patients with HPV-negative HNSCC. Collectively, our findings characterize the BACH1–IL-1β signaling axis as a prognostic biomarker and highlight IL-1R blockade as a promising therapeutic strategy for the treatment of HPV-negative HNSCC.
Zhang et al. (Mon,) studied this question.