Ziyin Zhang, Jingwen Xu, Kai Zang, Yingshuang Zhang, Zhihao Liu, Yuxuan Song, Shaoya He, Yundong He
FOXA1 and the androgen receptor (AR) are essential for prostate cancer cell survival. Although current targeted therapies against AR are widely used, they frequently lead to drug resistance, partly due to alterations in FOXA1. Minocycline, a commonly prescribed antibiotic, has demonstrated anticancer properties; however, its functional impact on FOXA1 and AR signaling remains unclear. In this study, we investigated whether minocycline suppresses tumor growth by targeting FOXA1 and its mutants while simultaneously inhibiting AR signaling, employing bioinformatics analyses, cellular assays (Western blot, qPCR, ChIP), and in vivo xenograft models. Our results show that minocycline binds directly to FOXA1 and markedly inhibits downstream oncogenic signaling mediated by the FOXA1-AR axis, thereby reducing proliferation and tumor growth. Importantly, in the presence of prevalent FOXA1 mutations (M253K and H247Y), minocycline retains potent inhibitory activity against metastatic prostate cancer driven by these FOXA1 mutants. Collectively, these findings identify minocycline as a novel agent that targets FOXA1 (including its mutants) and suppresses AR signaling, highlighting its potential for therapeutic repurposing and offering a clinically translatable strategy to overcome resistance in prostate cancer.