YAP Expression Confers Therapeutic Vulnerability to Cuproptosis in Breast Cancer Cells by Regulating Copper Homeostasis

Copper metabolism plays a complex role in tumor growth and cancer progression and thus holds potential as a therapeutic target. However, reliable diagnostic markers and therapeutic tools for successfully predicting personalized treatment outcomes with copper inhibition remain elusive. In this study, it is discovered that Yes-associated protein (YAP) expression conferred susceptibility toward cuproptosis. Molecular analyses revealed that YAP inhibition significantly abolished cuproptotic characteristics. Interestingly, YAP inhibition does not affect protein lipoylation but disrupts copper homeostasis. Mechanistically, YAP regulates antioxidant-1 (ATOX1), a copper chaperone, and overexpression of ATOX1 restored cuproptotic sensitivity in YAP-silenced cells. To advance copper-targeting therapy, it is identified that melatonin inhibited YAP signaling and attenuated the expression of copper metabolism-related genes. Furthermore, a copper-based functional nanomaterial, EsMP@Fu is developed, which incorporates melatonin and the cuproptosis inducer elesclomol complex with copper ions (Cu(II)) (Es:Cu). This formulation facilitates cuproptotic cytotoxicity via fucoidan-decorated nanocarrier to enhance the targeted delivery toward tumor cells. In vivo study demonstrated that EsMP@Fu significantly suppressed tumor growth by 60%, with more pronounced effects on distant metastasis and the induction of antitumor immunity. Collectively, the findings demonstrate that YAP overexpression confers sensitivity and therapeutic vulnerability to cuproptosis induction, presenting a promising strategy for precision medicine through tailored copper-based therapy.