Prostate cancer is a leading cause of cancer-related deaths worldwide, and its progression is significantly influenced by metabolic adaptations. The androgen receptor (AR) plays a central role in prostate biology, regulating genes involved in growth, maintenance, and differentiation. AR signaling reprograms cellular metabolism, particularly in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and one-carbon metabolism (1C metabolism). These metabolic changes support tumor growth, survival, and metastasis. Key metabolic pathways in prostate cancer include: 1. **Glycolysis and the Warburg Effect**: Cancer cells exhibit increased glycolysis, generating lactate even in the presence of oxygen. This process is driven by AR signaling and is associated with aerobic glycolysis. Inhibiting lactate transporters like MCT4 has shown promise in reducing glycolysis and lactic acid secretion. 2. **TCA Cycle and OXPHOS**: Despite the Warburg effect, the TCA cycle and OXPHOS remain active in metastatic prostate cancer. Targeting these pathways with inhibitors like BKIDC-1553 and metformin has shown potential in inhibiting cancer growth. 3. **1C Metabolism**: The folate and methionine cycles are crucial for DNA synthesis, methylation, and polyamine biosynthesis. AR signaling regulates enzymes involved in these cycles, influencing tumor progression and epigenetic changes. 4. **Lipid Metabolism**: Prostate cancer cells upregulate lipogenic pathways, enhancing fatty acid synthesis and oxidation. Targeting these pathways with inhibitors like SREBP and FASN has shown promise in preclinical studies. 5. **Tumor Cell-Extrinsic Metabolic Influences**: The tumor microenvironment (TME) also plays a significant role. Glucose metabolism in the TME creates acidic conditions, affecting immune activity. Lipid metabolism in stromal cells influences immune responses and tumor growth. One-carbon metabolism in the TME can impact T cell function and immune checkpoint inhibitors. 6. **Diet and Obesity**: High-fat diets and obesity contribute to prostate cancer progression through mechanisms such as insulin resistance and chronic inflammation. Caloric restriction and dietary interventions may offer therapeutic benefits. Despite extensive research, there are still gaps in understanding the metabolic dependencies of prostate cancer at different stages, and further studies are needed to identify actionable metabolic pathways for treatment.Prostate cancer is a leading cause of cancer-related deaths worldwide, and its progression is significantly influenced by metabolic adaptations. The androgen receptor (AR) plays a central role in prostate biology, regulating genes involved in growth, maintenance, and differentiation. AR signaling reprograms cellular metabolism, particularly in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and one-carbon metabolism (1C metabolism). These metabolic changes support tumor growth, survival, and metastasis. Key metabolic pathways in prostate cancer include: 1. **Glycolysis and the Warburg Effect**: Cancer cells exhibit increased glycolysis, generating lactate even in the presence of oxygen. This process is driven by AR signaling and is associated with aerobic glycolysis. Inhibiting lactate transporters like MCT4 has shown promise in reducing glycolysis and lactic acid secretion. 2. **TCA Cycle and OXPHOS**: Despite the Warburg effect, the TCA cycle and OXPHOS remain active in metastatic prostate cancer. Targeting these pathways with inhibitors like BKIDC-1553 and metformin has shown potential in inhibiting cancer growth. 3. **1C Metabolism**: The folate and methionine cycles are crucial for DNA synthesis, methylation, and polyamine biosynthesis. AR signaling regulates enzymes involved in these cycles, influencing tumor progression and epigenetic changes. 4. **Lipid Metabolism**: Prostate cancer cells upregulate lipogenic pathways, enhancing fatty acid synthesis and oxidation. Targeting these pathways with inhibitors like SREBP and FASN has shown promise in preclinical studies. 5. **Tumor Cell-Extrinsic Metabolic Influences**: The tumor microenvironment (TME) also plays a significant role. Glucose metabolism in the TME creates acidic conditions, affecting immune activity. Lipid metabolism in stromal cells influences immune responses and tumor growth. One-carbon metabolism in the TME can impact T cell function and immune checkpoint inhibitors. 6. **Diet and Obesity**: High-fat diets and obesity contribute to prostate cancer progression through mechanisms such as insulin resistance and chronic inflammation. Caloric restriction and dietary interventions may offer therapeutic benefits. Despite extensive research, there are still gaps in understanding the metabolic dependencies of prostate cancer at different stages, and further studies are needed to identify actionable metabolic pathways for treatment.