Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc‐accumulating, citrate‐producing cells to citrate‐oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)‐mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer. In this study, we demonstrate that ACO2 expression positively correlates with prostate cancer malignancy and drug resistance. In addition, we found that p53 decreases SIRT3 expression and zinc increases the production of hydroxyl radicals, which lead to an increase in reactive oxygen species (ROS). Furthermore, accumulated ROS causes a decrease in ACO2 activity, which leads to mitochondrial dysfunction and results in apoptosis. Thus, ACO2 can be a target for remodeling metabolism by sensing changes in ROS of prostate cancer cells, and targeting ACO2 through zinc and p53 to change the metabolic pattern of malignant cells can provide a new therapeutic strategy for prostate cancer.