Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a poor prognosis and limited treatment options. Current clinical management relies primarily on surgical resection and adjuvant chemotherapy, underscoring the urgent need for novel therapeutic strategies. Through systematic pharmacological screening, we reveal that fenticonazole, a widely used imidazole antifungal, functions as a potent suppressor of TNBC cell growth. Mechanistic studies revealed that fenticonazole directly binds to NF-κB p105, impairing its processing into p50. Consequently, the formation of the p50–p65 heterodimer is suppressed, accompanied by enhanced p65 activation and inhibition of NRF2 transcription. These molecular alterations drive the accumulation of mitochondrial reactive oxygen species (ROS), resulting in endoplasmic reticulum (ER) stress and ultimately apoptosis in TNBC cells. Our results not only elucidate a previously unrecognized antitumor mechanism of fenticonazole but also provide a compelling rationale for its drug repurposing as a promising therapeutic option for TNBC.