Prostate cancer (PCa) is one of the most common malignant tumors among men worldwide. Following androgen deprivation therapy (ADT), the disease often progresses to castration-resistant prostate cancer (CRPC). Despite the advent of next-generation antiandrogen agents, significant bottlenecks remain in the treatment of CRPC. Metabolic reprogramming has risen to prominence as a key area of investigation in cancer research over the past few years. This review systematically summarizes the metabolic characteristics of prostate cancer across different stages and proposes novel targeted therapeutic strategies.
To elucidate the process of metabolic reprogramming in prostate cancer, Professor Lingfan Xu, Master Hekang Ding, and their research team from the First Affiliated Hospital of Anhui Medical University conducted a systematic review on the role of metabolic reprogramming in driving prostate cancer progression and the corresponding therapeutic strategies. The relevant findings were published online on May 26, 2025, and officially featured in Chinese Medical Journal on December 5, 2025.
In the early stages of prostate cancer, tumor cells exhibit a marked increase in glycolytic dependence (Figure 1). Studies have demonstrated that the expression of lactate dehydrogenase (LDH) and the ratio of its two isozymes (LDHA and LDHB) undergo significant alterations in prostate cancer. LDHA preferentially converts pyruvate to lactate, while LDHB oxidizes lactate back to pyruvate. In prostate cancer, upregulated LDHA expression leads to lactate accumulation, which in turn acidifies the tumor microenvironment, impairs immune cell function, and promotes tumor immune evasion. In the CRPC stage, glucose metabolic activity is further enhanced, with key enzymes such as glucose transporter 1 (GLUT1) and LDHA being upregulated to reinforce glycolysis, ensuring tumor cells acquire sufficient energy to support their rapid proliferation.
Glutamine, the most abundant amino acid in the human body, serves as a critical energy source for tumor cells. "After ADT, prostate cancer cells switch their energy source from glucose to glutamine, and glutamine metabolism becomes particularly crucial in CRPC," explained Professor Xu. Glutamine is catalyzed by glutaminase 1 (GLS1) to generate glutamate, which then enters the tricarboxylic acid (TCA) cycle, providing energy and carbon skeletons for tumor cells. Additionally, the nitrogen atoms of glutamine participate in the synthesis of biomolecules such as nucleotides, non-essential amino acids, and nicotinamide adenine dinucleotide (NAD+). Research has found that in CRPC, the isoform of GLS1 shifts from the less active kidney-type glutaminase A (KGA) to the highly active glutaminase C (GAC), enabling tumor cells to utilize glutamine more efficiently and thus evade the inhibitory effects of ADT. Furthermore, glutamine nitrogen metabolism plays a vital role in CRPC: studies indicate that glutamine nitrogen not only participates in nucleotide synthesis but also forms a feedback mechanism with glutamine carbon metabolism—suppressing one pathway activates the other, leading to increased tumor cell dependence on glutamine. Therefore, combined inhibition of GLS1 and key enzymes in glutamine nitrogen metabolism (e.g., carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase [CAD]) may represent a more effective therapeutic strategy.
Lipid metabolism also exerts a pivotal role in the initiation and progression of prostate cancer. Tumor cells enhance lipid synthesis, storage, and oxidation to meet the energy and biosynthetic demands of rapid proliferation. Particularly in CRPC, the upregulation of lipid metabolism is primarily regulated by the androgen receptor (AR) signaling pathway. AR not only modulates the expression of enzymes involved in fatty acid synthesis and oxidation but also influences cholesterol and phospholipid metabolism. Studies have shown that fatty acid synthase (FASN) is upregulated in prostate cancer tissues and is closely associated with tumor Gleason score and clinical stage. FASN inhibitors have demonstrated significant antitumor efficacy in CRPC models, especially against tumors resistant to conventional hormonal therapy.
"Metabolic reprogramming is critical for prostate cancer progression and treatment resistance, and novel therapeutic strategies targeting glucose, glutamine, and lipid metabolism have shown remarkable antitumor effects in CRPC—offering a brand-new possibility to break through the current therapeutic bottlenecks," concluded Professor Xu regarding the core findings of the research on metabolic regulation in prostate cancer.
