Metabolic Reprogramming: A New Frontier in Prostate Cancer Treatment

A research team led by Professor Lingfan Xu and Master Hekang Ding from the First Affiliated Hospital of Anhui Medical University has conducted a systematic review concerning metabolic reprogramming in prostate cancer (PCa) progression and therapeutic strategies. This comprehensive review addresses the progression of PCa to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT), and proposes novel targeted therapeutic approaches. The significant findings were published online on May 26, 2025, and were officially featured in the Chinese Medical Journal on December 5, 2025.

Glucose Metabolism in Prostate Cancer

In the early stages of prostate cancer, tumor cells demonstrate an increased reliance on glycolysis. Studies have revealed alterations in lactate dehydrogenase (LDH) expression, specifically an upregulation of LDHA, which results in lactate accumulation. This accumulation of lactate acidifies the tumor microenvironment, impairs immune cell function, and consequently promotes tumor immune evasion.

As the disease progresses to the CRPC stage, glucose metabolic activity is further enhanced. Key enzymes such as glucose transporter 1 (GLUT1) and LDHA are significantly upregulated to reinforce glycolysis, thereby supporting the rapid proliferation of tumor cells.

Glutamine Metabolism in Prostate Cancer

"After ADT, prostate cancer cells shift their energy source from glucose to glutamine, making glutamine metabolism particularly crucial in CRPC."
— Professor Lingfan Xu

Glutamine plays a vital role in CRPC, becoming a critical energy source post-ADT. It is catalyzed by glutaminase 1 (GLS1) to produce glutamate, which subsequently enters the tricarboxylic acid (TCA) cycle, supplying both energy and carbon skeletons. Furthermore, glutamine's nitrogen atoms are essential for the synthesis of vital biomolecules, including nucleotides, non-essential amino acids, and nicotinamide adenine dinucleotide (NAD+).

Research indicates a significant shift in GLS1 isoform in CRPC, transitioning from the less active kidney-type glutaminase A (KGA) to the highly active glutaminase C (GAC). This shift allows tumor cells to utilize glutamine with greater efficiency.

Glutamine nitrogen metabolism also holds critical importance in CRPC, contributing to nucleotide synthesis and establishing a feedback mechanism with glutamine carbon metabolism. Therefore, a combined inhibition strategy targeting GLS1 and key enzymes in glutamine nitrogen metabolism (such as carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase [CAD]) may offer a more effective therapeutic pathway.

Lipid Metabolism in Prostate Cancer

Lipid metabolism is another pivotal player in both the initiation and progression of prostate cancer. Tumor cells upregulate lipid synthesis, storage, and oxidation processes to meet the substantial energy and biosynthetic demands imposed by rapid proliferation.

In CRPC, the enhanced lipid metabolism is primarily regulated by the androgen receptor (AR) signaling pathway. This pathway modulates the expression of enzymes involved in fatty acid synthesis and oxidation, while also influencing cholesterol and phospholipid metabolism. Studies have shown that fatty acid synthase (FASN) is upregulated in prostate cancer tissues and correlates with tumor Gleason score and clinical stage. Inhibitors of FASN have demonstrated promising antitumor efficacy in CRPC models, particularly against tumors that exhibit resistance to conventional hormonal therapy.

Therapeutic Implications

"Metabolic reprogramming is critical for prostate cancer progression and treatment resistance."
— Professor Lingfan Xu

Professor Xu concluded that metabolic reprogramming is fundamentally critical for the progression of prostate cancer and its resistance to treatment. Novel therapeutic strategies specifically targeting glucose, glutamine, and lipid metabolism have already shown antitumor effects in CRPC. These findings offer promising new possibilities to overcome current therapeutic bottlenecks and advance treatment options for patients.