Prostate cancer is the most diagnosed cancer type and the second leading cause of death in men globally. The pathogenesis of prostate cancer mainly relies on the androgen signaling axis. Therefore, androgen deprivation therapy is the primary treatment for prostate cancer. Nevertheless, the disease progression proceeds, followed by castration resistance and androgen independence. Aberrant androgen signaling activity intertwined with the hyperactivated PI3K-Akt signaling pathway has important oncogenic consequences for castration resistance mechanisms. PTEN, a negative regulator of the PI3K/Akt pathway, is one of the most altered tumor suppressor genes in prostate cancer. PTEN loss occurs in the initial stages of prostate cancer and the frequency of its alteration increases in metastatic and castration-resistant prostate cancer. PTEN has both lipid and protein phosphatase activity, with the former antagonizing the PI3K-Akt pathway by converting membrane-associated PIP3 to PIP2. PTEN loss may cause metabolic rewiring in metastatic prostate cancer cells and the associated metabolic vulnerabilities may be tackled for the disease therapy. To understand the impact of PTEN loss in metastatic prostate cancer cells, we created a dox-inducible system in PTEN-null metastatic and castration-naïve LNCaP cells to re-express WT-PTEN and various PTEN functional mutants, and we employed targeted metastatic prostate cancer. Our multidirectional omics studies suggest that the acquisition of resistance to castration depends on the deregulation of the sphingolipid metabolism in metastatic prostate cancer cells. Furthermore, we showed that PTEN re-expression in metastatic and castration-naïve LNCaP cells attenuated sphingosine kinase levels, which might switch the sphingolipid metabolism towards increased sphingomyelin biosynthesis and ceramide phosphorylation. Moreover, we showed decreased PI3K/Akt pathway activity when we inhibited sphingosine kinase with opaganib in LNCaP cells. Our results also showed a significant upregulation in sphingolipid metabolism in castration-resistant C4-2 cells compared to castration-naïve LNCaP. We treated these cells with several sphingolipid metabolism inhibitors and discovered that castration-resistant prostate cancer cells were more sensitive to opaganib or ARN14988, but not to fingolimod, than castration-naïve prostate cancer cells. These findings suggest that sphingolipid metabolism might be a promising target for the treatment of metastatic and castration-resistant prostate cancer. Understanding changes in sphingolipid metabolism may be critical for developing rational combinatorial targeting strategies for prostate cancer in the long run.