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Ye Wang,1,* Qi-Wei Yang,1,2,* Qing Yang,2,* Tie Zhou,1 Min-Feng Shi,1,3 Chen-Xia Sun,4 Xiu-Xia Gao,4 Yan-Qiong Cheng,1 Xin-Gang Cui,2 Ying-Hao Sun1 1Department of Urology, Changhai Hospital, 2Department of Urology, The Third Affiliated Hospital, 3Reproductive Center, Changhai Hospital, Second Military Medical University, Shanghai, 4The Reproductive Center, Institute for Nutritional Sciences, Shanghai Institute for Biological Science, Chinese Academy of Science, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: Disordered copper metabolism plays a critical role in the development of various cancers. As a nanomedicine containing copper, cuprous oxide nanoparticles (CONPs) exert ideal antitumor pharmacological effects in vitro and in vivo. Prostate cancer is a frequently diagnosed male malignancy prone to relapse, and castration resistance is the main reason for endocrine therapy failure. However, whether CONPs have the potential to treat castration-resistant prostate cancer is still unknown. Here, using the castration-resistant PC-3 human prostate cancer cell line as a model, we report that CONPs can selectively induce apoptosis and inhibit the proliferation of cancer cells in vitro and in vivo without affecting normal prostate epithelial cells. CONPs can also attenuate the stemness of cancer cells and inhibit the Wnt signaling pathway, both of which highlight the great potential of CONPs as a new clinical castration-resistant prostate cancer therapy. Keywords: cuprous oxide nanoparticle, prostate cancer, CRPC, nanomedicine, Wnt signaling pathway