Fluvastatin suppresses breast cancer initiation and progression via targeting CYP4Z1

Breast cancer ranks highest globally in terms of both incidence and mortality rates among female malignancies. Elucidating the molecular mechanisms driving breast cancer initiation and progression, as well as identifying novel therapeutic agents, remains a critical unmet medical need. This study aimed to identify FDA-approved CYP4Z1 inhibitors with anti-breast cancer activity through a drug repurposing strategy, thereby providing preclinical evidence for potential clinical adjuvant therapies. Fluvastatin was identified as a concentration-dependent CYP4Z1 inhibitor through molecular docking and site-directed mutagenesis studies, binding to critical residues Lys109, Pro444, and Arg450 in the enzyme's active site. Functional studies demonstrated that Fluvastatin significantly attenuated cancer stem cell properties, migratory/invasive capacities, and epithelial-mesenchymal transition in breast cancer cell lines. In vivo experiments revealed that fluvastatin suppressed primary tumor growth and lung metastasis in xenograft models, while delaying mammary tumorigenesis in PyMT-MMTV-CYP4Z1 transgenic mice. Notably, this effect was less pronounced in PyMT-MMTV wild-type controls. This study establishes Fluvastatin as a novel CYP4Z1-targeted therapeutic candidate for breast cancer, providing preclinical validation for its potential use in combination therapies.