A Graphene Oxide-Doped CuMOF Nanoplatform Enhances Chemodynamic Therapy and Suppresses CYP2J2-Mediated Linoleic Acid Metabolism in Castration-Resistant Prostate Cancer

Guoqiang Qin,1,2 Xin Luo,1,2 Ge Zou,1,2 Qishan Mo,2,3 Weide Zhong41Department of Urology, the Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Cancer Institute of Panyu District, the Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Nursing, the Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Urology Key Laboratory of Guangdong Province, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Weide Zhong, Urology Key Laboratory of Guangdong Province, Guangzhou First People’s Hospital, Guangzhou Medical University, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong, People’s Republic of China, Tel +86-13808888068, Email zhongwd2009@live.cnPurpose: Castration-resistant prostate cancer (CRPC) responds poorly to current therapies. A tumor microenvironment-responsive nanoplatform was developed to couple chemodynamic therapy with modulation of oncogenic lipid metabolism.Methods: A graphene oxide-doped copper-based metal–organic framework (GO-CuMOF) was prepared by ultrasonicating solvothermally synthesized CuMOF with graphene oxide, and was characterized physicochemically. Its generation of hydroxyl radicals (•OH) was confirmed by a methylene blue degradation assay. Antitumor activity was evaluated in DU145 and PC3 cells and in a PC3 xenograft model. Untargeted metabolomic and proteomic profiling was integrated with data from The Cancer Genome Atlas prostate adenocarcinoma cohort, and the candidate targets were validated by enzyme-linked immunosorbent assay (ELISA), reverse transcription quantitative PCR, and Western blotting.Results: In the presence of glutathione (GSH), GO-CuMOF released Cu⁺, depleting GSH and generating •OH. It raised intracellular reactive oxygen species (ROS), induced apoptosis, and suppressed CRPC cell proliferation and xenograft growth without reducing body weight or causing overt organ toxicity. Multi-omics profiling showed CYP2J2 downregulation, with accumulation of its substrate linoleate and reduction of 9(10)- and 12(13)-epoxyoctadecenoic acid (EpOME), the latter confirmed by ELISA. CYP2J2 was the most consistently associated candidate across proteomic and public-cohort evidence.Conclusion: GO-CuMOF exerts concurrent chemodynamic ROS generation and CYP2J2-associated changes in linoleic acid metabolism. The CYP2J2–EpOME axis represents a candidate metabolism-directed vulnerability for CRPC that warrants functional and clinical validation.Keywords: castration-resistant prostate cancer, chemodynamic therapy, copper metal–organic framework, CYP2J2, graphene oxide, linoleic acid metabolism