Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression.

Introduction
Prostate cancer (PCa) is the most common urological cancer, with an estimated 300,000 new cases diagnosed annually in the United States.[1] Morbidity is also high in Eastern countries, including China. The overall mortality rate of PCa is approximately 4.8%.[2]
Most PCa patients are initially diagnosed with localized disease. These early-stage, low-grade cases, in which the disease has not spread beyond the prostate, are often cured through active surveillance, surgery, or radiotherapy, with a 10-year survival rate exceeding 90%. For recurrent, advanced, and metastatic PCa, androgen deprivation therapy (ADT), which inhibits androgen production or blocks androgen receptor (AR) function, is the gold-standard treatment.[3,4] While ADT significantly delays disease progression, nearly all patients eventually develop castration resistance, which is termed castration-resistant prostate cancer (CRPC).[5]
Because second-generation antiandrogen drugs have a limited duration of efficacy in treating CRPC, innovative therapeutic strategies are needed. Understanding the molecular basis of disease progression and exploring treatment strategies beyond AR inhibition are crucial to prevent disease progression or effectively treat CRPC.
Cellular energy dysregulation is a hallmark of cancer. Metabolic reprogramming increases the energy and biomass taken in by tumor cells to satisfy the cells’ requirements for rapid cellular proliferation and treatment resistance.[6] Research on targeting the vulnerability of metabolic characteristics may reveal direct and efficient methods for cancer treatment.[7,8]
PCa is a type of cancer with a highly active metabolism. Metabolites, such as glucose, lipids, and amino acids, exhibit unique metabolic patterns in PCa. Notably, the reprogramming of these metabolic pathways is critical in driving disease progression and therapeutic resistance.[9,10] In this review, we discuss the latest findings concerning the changes in the metabolism of major nutrients, specifically focusing on how these changes contribute to driving the progression of primary PCa to CRPC. We emphasize the critical roles of glutamine and its metabolic network in advanced PCa, providing a metabolic foundation for the development of diagnostic and therapeutic strategies.

Glucose Metabolism

Glycolysis and the Warburg effect
Glucose is the primary energy source for most cells. After being transported into cells, some glucose undergoes glycolysis to generate lactate and a small amount of ATP and nicotinamide adenine dinucleotide (reduced form) (NADH); however, most glucose enters the tricarboxylic acid (TCA) cycle and ultimately undergoes oxidative phosphorylation (OXPHOS) to produce energy [Figure 1]. Compared with normal cells, cancer cells exhibit distinct energy metabolism characteristics. One of these well-known phenomena is the Warburg effect, in which cancer cells primarily use glycolysis to produce lactate from glucose even in the presence of oxygen. Although various hypotheses have been proposed, the underlying reasons for the predominance of the metabolism of glucose to lactate remain unclear. One possible explanation is that when the cellular demand for nicotinamide adenine dinucleotide (oxidized form) surpasses that for ATP, leading to NADH saturation within the mitochondria, tumor cells may sustain aerobic glycolysis even under oxygen-rich conditions.[11,12] Notably, increased aerobic glycolysis in some cancer cells does not result in substantially decreased mitochondrial OXPHOS activity.[6,13] Recent studies have shown that glycolysis and mitochondrial OXPHOS are not mutually exclusive.[14] Notably, in some cancers, glycolysis and OXPHOS are positively correlated. These new findings enable us to revisit the Warburg effect.
Glucose metabolism changes as PCa progresses. In early-stage PCa, tumor cells are highly dependent on glycolysis. Several key factors may account for this dependence.
First, the expression of lactate dehydrogenase (LDH) and the ratio of two LDH isoforms, LDHA and LDHB, change significantly. These isoforms play complementary roles in tumor metabolism: LDHA preferentially converts pyruvate to lactate, which is subsequently exported out of the cell, whereas LDHB oxidizes lactate to pyruvate.[15,16] LDHA is tightly regulated at both the transcriptional and posttranslational levels. For example, in PCa, c-Myc can reactivate the LDHA promoter to directly increase LDHA expression. In addition, fibroblast growth factor receptor 1 (FGFR1) mediates the phosphorylation of LDHA,[17,18] stabilizing phosphorylated LDHA while reducing the transcriptional level of LDHB. Consequently, lactate accumulates, which acidifies the TME, suppresses immune cell function, and aids tumors in evading immune surveillance. The exchange of lactate between tumor cells and the stroma helps maintain the bioenergetic demands of PCa cells, partially explaining the “metabolic paradox” of the Warburg effect: Despite the lower ATP production efficiency in cancer cells, substantial energy is still needed for tumor growth and metastasis. The role of lactate is discussed in detail later in this chapter.
Second, tumor cells not only rely on glucose but also use fructose as an alternative energy source. During this phase, the expression of glucose transporter 1 (GLUT-1) is low, whereas the expression of fructose transporters such as GLUT-5 is significantly increased.[19] Increased fructose uptake subsequently increases the expression of key enzymes, such as hexokinase 2 (HK2) and LDHA, which drive the increase in glycolysis.[17] HK2 is a rate-limiting enzyme that plays a crucial role in glycolysis by catalyzing the conversion of glucose to glucose-6-phosphate.[20] Beyond this metabolic function, recent studies have revealed a second role of HK2 in regulating cellular energy metabolism, particularly during environmental stress responses and metabolic remodeling. Research indicates that glucose deprivation increases the interaction between HK2 and mammalian target of rapamycin complex 1 (mTORC1), thereby suppressing mTORC1 activity and inducing autophagy.[21,22] Therapeutically, BKIDC-1553, a selective inhibitor targeting HK2, has achieved treatment outcomes comparable to those of enzalutamide in preclinical advanced PCa xenograft models.[23]
Finally, although lactate produced during glycolysis is often considered a “waste product”, lactate actually performs multiple functions in tumor cells, including promoting tumor invasiveness, altering the TME, and acidifying the surrounding environment to suppress immune responses, thereby assisting tumors in evading immune surveillance. Inhibition of monocarboxylate transporter 1 (MCT1), a transporter that facilitates the movement of molecules with carboxylate groups, such as lactate, across biological membranes, has been demonstrated to diminish the metastatic ability of melanoma.[24,25] Increased levels of serum LDH are commonly observed in patients with high-risk PCa; these increased levels are linked to a greater likelihood of mortality and disease progression in patients with metastatic PCa.[26] In support of these observations, clinical research using hyperpolarized 13C-pyruvate imaging has revealed a direct relationship between the Gleason score of PCa and the rate at which pyruvate is converted to lactate. Notably, the expression of monocarboxylate transporter 4 (MCT4), which plays a key role in exporting lactate from cells, is increased in both primary and metastatic tumor tissues.[27] These findings suggest that the production and intracellular utilization of lactate are crucial processes in tumorigenesis. However, further research is required to better understand the complex, specific mechanisms of lactate in tumorigenesis, metastasis, and drug resistance.
When PCa progresses to CRPC, glycolytic activity is substantially increased. Glucose is preferentially released through the aerobic catabolism pathway. The expression of glucose transporter 1 (GLUT1), MCT1, HK2, LDH, and pyruvate dehydrogenase kinase 1 (PDK1) is markedly increased in CRPC.[28] For example, GLUT1 has been identified as an important prognostic indicator for tumor recurrence and survival since the expression of GLUT1 is closely related to tumor grade. In CRPC, the reactivation of AR signaling increases GLUT1 expression, subsequently increasing intracellular glucose concentrations and enhancing the activity of the glycolytic pathway. In advanced PCa, a common genetic event is the loss of ataxia telangiectasia mutated (ATM), a serine/threonine kinase involved in DNA damage repair, which increases the dependence on aerobic glycolysis in CRPC.[29] Our group demonstrated that inhibiting LDHA increases the therapeutic efficacy of the PARP inhibitor olaparib in ATM-deficient CRPC tumors.[30] Similarly, the activity of MCT4 is upregulated in neuroendocrine prostate cancer (NEPC), a lethal variant of CRPC. In NEPC cell lines, inhibiting MCT4 expression strongly reduces cell proliferation by downregulating the expression of glycolytic genes and glycolytic activity.[27,31] Additional evidence supporting the enhancement of glycolysis in advanced PCa is the fact that NEPC is frequently detected with 18F-fluorodeoxyglucose (FDG) imaging, whereas primary acinar adenocarcinoma often evades detection with this method.[32] Moreover, studies have demonstrated that lactate concentrations are markedly increased in samples of advanced PCa caused by phosphatase and tensin homolog (PTEN) loss. Activation of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway is a critical contributor to prostate tumorigenesis induced by PTEN deficiency, increasing the stimulation of aerobic glycolysis.[33,34]
Notably, although aerobic glycolysis is highly active in CRPC, TCA cycle and mitochondrial OXPHOS activity are still high. Our group integrated single-cell RNA sequencing and bulk RNA sequencing data, which revealed that the activities of glycolysis and mitochondrial function are concordantly increased in CRPC. Glutamine is largely involved in this metabolic crosstalk, which is discussed later in this review.

TCA cycle and oxidative phosphorylation
The TCA cycle, also known as the citric acid cycle or Krebs cycle, is a series of chemical reactions within the mitochondria that are central to energy production and the synthesis of metabolic intermediates. Studies have demonstrated that the rate of the TCA cycle varies among tumor types and may be influenced by genetic mutations or metabolic reprogramming. Altered processes include the reductive carboxylation reactions observed in various cancers and the exogenous utilization of citrate by mitochondria to regenerate oxaloacetate, thereby restarting the TCA cycle.[35,36] These metabolic modifications are closely associated with the energy metabolism of tumor cells, highlighting the intricate relationship between TCA cycle dynamics and cancer cell bioenergetics.
One of the metabolic characteristics of normal prostate epithelial cells is abnormally high citrate production, which restricts the TCA cycle. The accumulation of citrate is largely attributed to increased levels of zinc (Zn2+), which inhibit the catalytic function of m-aconitase, which is responsible for converting citrate into isocitrate.[37,38] Notably, two major cellular components of the normal prostatic epithelium, basal and luminal cells, use different citrate sources.[39] Generally, basal cells generate citrate primarily from pyruvate dehydrogenase, whereas luminal cells rely more on pyruvate carboxylase for citrate production.[39] Studies have reported a significant increase in the activity of pyruvate carboxylase in PCa. Therefore, PCa cells, particularly luminal cells, may rely on this pathway to sustain their metabolic demands and rapid proliferation. The metabolism of pyruvate, aspartate, glutamine, and branched-chain amino acids (BCAAs) could supply essential metabolites for the disrupted TCA cycle in PCa.[40] This metabolic reprogramming not only supports cellular energy production but also may influence the adaptability and drug resistance of cancer cells.
As discussed above, the activity of the TCA cycle is high in PCa. This increase is likely caused by AR-induced metabolic reprogramming, which leads to downregulation of the expression of the hZIP1 zinc transporter, reducing mitochondrial zinc levels, which in turn activates m-aconitase and restores the TCA cycle.[39] This shift favors reliance on the OXPHOS pathway for ATP production. Therefore, fluorodeoxyglucose positron emission tomography (FDG-PET) is ineffective for identifying early-stage PCa, and clinical diagnosis commonly relies on plasma prostate-specific antigen (PSA) measurements or PSMA-PET imaging.[41,42]
The TCA cycle can be effectively targeted by blocking the transport of mitochondrial substrates. Inhibitors of complex I (CI) in the electron transport chain, such as metformin and rotenone, have been demonstrated to suppress the proliferation of various cancer cell lines, including PCa lines.[43,44] Research indicates that metformin exerts multiple antitumor effects through both AMPK-dependent and AMPK-independent pathways.[45] These effects include alteration of the IGF-1 signaling pathway, inhibition of the AR or mTOR pathways, and suppression of lipogenesis. Consistent with these findings, studies have shown that metformin treatment significantly reduces mortality in PCa patients. The rotenone derivative deguelin has demonstrated antitumor activity in preclinical mouse models of PCa, particularly in models with combined Pten and Trp53 deletions.[46] Therefore, CI inhibitors are likely to be more effective for PCa patients with PTEN loss.

Pentose Phosphate Pathway (PPP)
PPP is an essential supplier of NADPH and precursors for nucleotide synthesis, contributing to the regulation of redox balance in tumor cells.[47] Glucose-6-phosphate dehydrogenase (G6PD) is a critical rate-limiting enzyme in the PPP that catalyzes the conversion of glucose-6-phosphate to 6-phosphogluconate and generates NADPH. NADPH is an essential reducing agent in cells and is involved in antioxidant defense, fatty acid synthesis, and nucleotide synthesis. In cancer cells, G6PD activity is frequently high to meet the increased demand for NADPH and the activity of biosynthetic precursors.[48]
The PPP may be particularly important in the progression of prostate tumors, operating through an AR/sterol regulatory element-binding protein (SREBP)/6-phosphogluconate dehydrogenase (6PGD)-dependent mechanism. A key enzyme associated with the PPP, 6PGD helps mitigate oxidative stress and is involved in a unique feedback mechanism with the AR signaling pathway.[49,50] This discovery provides new therapeutic insights for the combined targeting of AR and the PPP in PCa. However, whether the PPP plays a significant role in PCa by generating nucleotide precursors or maintaining NADPH pools to support lipid synthesis and redox homeostasis remains unexplored. These findings highlight the intricate metabolic dependencies in PCa and underscore the potential of targeting metabolic pathways in combination with traditional therapies to improve treatment outcomes.
Genetic or pharmacological inhibition of 6PGD using specific inhibitors, such as physcion and S3, has demonstrated significant anticancer effects in CRPC disease models and patient-derived xenograft experiments.[51] This effect is partially attributed to an increase in oxidative stress. In addition, 6PGD is closely associated with two key tumor suppression mechanisms. First, increased AMPK activity represses cancer cell proliferation through AMP accumulation. Second, AR ubiquitination results in degradation of the AR protein and decreases AR activity.[52] Compared with monotherapy, a combination of pharmacological treatments targeting both mechanisms is more effective at inhibiting PCa cell growth, suggesting a positive feedback relationship between AR and 6PGD. These findings indicate that the PPP and its key enzyme 6PGD could be valuable targets for cancer treatments and combination therapies.

Glutamine Metabolism

Overview of glutamine metabolism
Glutamine is the most abundant amino acid in the human circulation and the second most prevalent extracellular nutrient after glucose.[53,54] Glutamine can be synthesized endogenously or obtained exogenously. The uptake of glutamine from the extracellular environment is mediated by transporters in the solute carrier (SLC) family. To date, 14 SLC transporters capable of transporting extracellular glutamine into cells have been identified, among which SLC1A5/ASCT2 is the primary transporter; the expression of this transporter is upregulated in various cancers, specifically in PCa patients who relapse after ADT.[55,56]
As described above, the TCA cycle function is maintained in PCa, primarily because glutamine is a metabolite of anaplerosis. Glutamine-derived α-ketoglutarate (α-KG) enters the TCA cycle, generating succinate and subsequently oxaloacetate.[57] This process, along with the conversion of glutamine to α-KG, is collectively known as glutaminolysis, a critical metabolic pathway in most cancer cells.
In addition to the role of glutamine as an additional substrate in the TCA cycle, the two nitrogen atoms in glutamine are crucial nitrogen donors that are involved in the synthesis of various nitrogen-containing biomolecules. During glutamine deamination, which produces glutamate and α-KG, the amino groups are released from the carbon backbone to be used for the synthesis of nucleotides, other nonessential amino acids, and NAD+ cofactors.[58,59]
Moreover, in addition to its metabolic functions, glutamine is also associated with signaling regulation and epigenetic modification. For example, glutamine can directly or indirectly activate the transcription factor signal transducer and activator of transcription 3 (STAT3), thereby promoting the proliferation of cancer cells.[59] Increased leucine uptake (mainly associated with glutamine export) can also influence mTOR activation and autophagy.
In conclusion, glutamine is a multifunctional metabolite that plays important roles in not only PCa metabolism but also cellular and molecular regulation.

Glutamine metabolism in CRPC
Although the role of glutamine in early-stage PCa is relatively small, glutamine is a critical energy and nutrient source for CRPC cells. As mentioned above, since glucose is diverted from the mitochondria to increase glycolytic activity, mitochondrial function is primarily dependent on the glutamine supply. The carbon skeleton of glutamine, an easily accessible nutrient, can enter the TCA cycle after undergoing several deamination reactions. Glutaminase 1 (GLS1) catalyzes the first step of glutamine metabolism.[60] In early hormone-sensitive PCa, the KGA isoform of GLS1, which has relatively weak enzymatic activity, predominates in glutamine metabolism. As the disease progresses to CRPC, GLS1 shifts from the KGA isoform to the more active GAC isoform, increasing the resistance of advanced PCa cells to hormonal therapy and the reliance on glutamine to drive the TCA cycle.[61] This isoform shift is the molecular basis for the recovered ability of tumor cells to use glutamine and the escape of these cells from hormonal therapy.
Glutamine nitrogen metabolism is another pathway that highlights the importance of glutamine in CRPC. Our group has demonstrated that while tumor cells extensively use the carbon components of glutamine, the nitrogen produced by glutamine deamination is not merely a byproduct. The purine and pyrimidine pathways are enriched in CRPC at a comparable level to that of mitochondrial function, as revealed by sequencing data.[61] Experimental results have shown that glutamine is an essential component of nucleotide synthesis, particularly for pyrimidine production.[61] Notably, the metabolism of carbon and nitrogen from glutamine is closely connected in CRPC, with a feedback mechanism between these two metabolic pathways, where the inhibition of one pathway induces activation of the other pathway as a compensation mechanism.
Therapeutically, GLS1 is an ideal target in CRPC tumors. The molecular inhibitor CB-839, which has shown low toxicity and high specificity after multiple optimizations, has a substantial inhibitory effect, particularly in CRPC, in which the splice variant GAC predominates.[62] However, in cellular experiments, long-term inhibition of GLS1 in CRPC gradually resulted in a decrease in the tumor suppression effects of CB-839 over time. This decline likely occurs because treatment increases the activity of the glutamine nitrogen pathway to enable tumor cells to escape GLS1-mediated inhibition of glutamine carbon metabolism. Carbamoyl-phosphate synthetase 2 (CAD) is the rate-limiting enzyme for the glutamine nitrogen pathway.[63,64] A combined therapeutic strategy including both CB-839 and CAD inhibitors was developed that maximally inhibits tumor cell utilization of glutamine; this combination is more effective at suppressing tumor growth than the single therapies alone. In addition, in PTEN-deficient PC-3 and C4-2MDVR cells, CAD upregulation is mediated through the PI3K-AKT-mTOR-S6K signaling axis, further increasing glutamine nitrogen metabolism.[65] Therefore, considering PTEN status is particularly important when using GLS1 inhibition as a therapeutic strategy. Studies have shown that in PTEN-deficient PCa cells, the adaptability of glutamine metabolism is increased, which may lead to a gradual reduction in treatment efficacy.
In addition to its role as an important energy source and nitrogen donor supporting the metabolic demands of cells, the nitrogen in glutamine participates in the synthesis of glutathione (GSH). GSH helps maintain the intracellular redox balance by alleviating the oxidative damage caused by reactive oxygen species (ROS).[66] Recent studies have shown that tumor cells exhibit strong antioxidant capabilities through the adjustment of metabolic changes. One study indicated that polyamine metabolism plays a crucial role in regulating the synthesis of GSH by glutamine.[67] Targeting polyamine metabolism and simultaneously inhibiting glutamine transport (e.g., the ASCT2 inhibitor V-9302), glutamine catabolism (e.g., the GLS1 inhibitor CB-839), or GSH synthesis (e.g., the glutamate-cysteine ligase inhibitor BSO) effectively triggers oxidative stress-induced damage in cancer cells, thereby inhibiting tumor proliferation.[68] Although this strategy has not yet been validated in PCa cells, these findings highlight the high sensitivity of tumor cells to oxidative stress. This sensitivity arises from the redox reactions occurring during polyamine metabolism; these reactions generate ROS, promoting the conversion of glutamine to GSH. Therefore, although polyamines do not directly promote GSH synthesis from glutamine, this process highlights the heightened vulnerability of tumor cells to oxidative stress.

Lipid Metabolism
Reprogramming of lipid metabolism is an early and critical event in prostate tumorigenesis and PCa progression, influencing key processes such as lipid synthesis, storage, and oxidation.[69,70] Numerous epidemiological and experimental studies have shown a close association between obesity and the risk of aggressive PCa.[71] Hormonal therapies often result in increased levels of total cholesterol, triglycerides, and high-density lipoproteins (HDLs), indicating that changes in lipid metabolism may be closely associated with PCa development.[72] The increase in lipid metabolism is driven mainly by the AR signaling pathway. AR not only regulates the expression of enzymes involved in fatty acid synthesis and oxidation to satisfy the energy and biosynthetic needs of cancer cells but also influences lipid uptake and storage, as well as the metabolism of cholesterol and phospholipids.
Cancer cells maintain their rapid proliferation by increasing the synthesis of fatty acids and other lipid components. This increased lipogenesis is often mediated by the activation of critical enzymes, including ATP citrate lyase (ACLY) and acetyl-coenzyme A (CoA) carboxylase, which are regulated by oncogenic signaling pathways such as the PI3K-Akt-mTOR axis and MYC.[73,74] Using a genetically engineered mouse model with deletion of prostate-specific phosphatase and PTEN, studies have shown that the loss of promyelocytic leukemia protein (PML) could promote tumor metastasis by facilitating the synthesis of new lipids.[75,76]

De novo lipogenesis
The de novo lipogenesis (DNL) pathway plays a critical role in both the early and late stages of PCa. This pathway is closely linked to the synthesis of fatty acids from nonlipid precursors.[77] Acetyl-CoA is the primary substrate for fatty acid production and is converted into malonyl-CoA by acetyl-CoA carboxylase. Malonyl-CoA is then transformed into fatty acids through the action of fatty acid synthase (FASN). FASN, a central enzyme in the DNL pathway, is strongly implicated in the progression of PCa.[78,79] FASN expression is upregulated in PCa tissues and is closely correlated with both the Gleason score and clinical stage. Moreover, FASN inhibitors, such as IPI-9119, have been shown to effectively suppress tumor growth, particularly in CRPC models that do not respond to conventional hormonal therapy.[80] In addition, the expression of SREBP, a key transcription factor in lipid synthesis, is upregulated during PCa progression. This upregulation partially depends on AR signaling and activates the expression of enzymes associated with DNL, including FASN.[81,82]
Since AR controls genes associated with DNL, DNL is downregulated during ADT. However, in CRPC, the expression of continuously active AR splice variants increases the expression of genes involved in DNL, including FASN, reactivating the DNL pathway.[80,83] Increased levels of FASN and other lipogenic enzymes in CRPC highlight the role of these enzymes in driving tumor growth and progression.[84] Beyond its function in DNL, FASN, along with other steroidogenic enzymes, is involved in the intratumoral synthesis of androgens, such as the transformation of cholesterol or other steroid precursors into testosterone. This localized testosterone production activates AR target genes and promotes the survival of tumor cells.[85,86]
Various therapeutic strategies targeting the DNL pathway in PCa have been developed. Preclinical studies suggest that the use of SREBP inhibitors, such as fatostatin, may be a promising strategy for inhibiting PCa growth and inducing apoptosis.[87] Fatostatin exerts its effects by blocking the function of SREBP cleavage-activating protein (SCAP), a key regulatory factor in lipid metabolism responsible for transporting SREBP from the endoplasmic reticulum to the Golgi apparatus, where SREBP is cleaved to activate the transcription of genes associated with cholesterol and fatty acid synthesis.[88] By inhibiting SCAP, fatostatin prevents the transport of SREBP, suppressing lipid synthesis. In addition, two FASN inhibitors, difluoromethylornithine (DFMO) and C75, have been developed for use in PCa treatment. DFMO indirectly lowers FASN mRNA levels by inhibiting 5α-reductase, whereas C75 directly binds to FASN, blocking fatty acid synthesis.[89,90]
Although multiple approaches targeting fat synthesis have been used, determining accurate tumor biomarkers for lipogenesis and the underlying mechanisms remains a significant challenge. Identifying patients most likely to benefit from DNL-targeted therapies is crucial; therefore, researchers are exploring new targets in the DNL pathway for therapeutic purposes. A recent large-scale analysis identified fatty acid elongation as another important metabolic process in PCa. Among the genes involved in this process, the fatty acid elongase ELOVL5 is upregulated in PCa, which is correlated with tumor invasiveness and negatively impacts the survival of PCa patients.[91,92] Moreover, the polyunsaturated fatty acids (PUFAs) generated by ELOVL5 are associated with the resistance of neuroendocrine differentiation to enzalutamide and activate the AKT–mTOR pathway.[91]

Lipolysis and fatty acid oxidation
Lipolysis is the process of converting stored fats or triglycerides into glycerol and fatty acids. In PCa, lipolysis is upregulated, and the fatty acids produced serve as an energy source and as components of cellular structures.[93] However, lipolysis is a complex process that requires maintaining a balance between fatty acid catabolism and the production of ATP and NADPH. The expression of adipose triglyceride lipase (ATGL) is associated with poor prognosis in CRPC patients. Inhibition of ATGL has been shown to suppress PCa cell growth and induce a metabolic shift toward glycolysis.[94] In NEPC, the level of monoglyceride lipase (MAGL) is increased, promoting malignant transformation through the endogenous cannabinoid and fatty acid pathways.[93]
Fatty acid oxidation (FAO) is the metabolic process through which fatty acids are oxidized to produce energy, and this process is altered in PCa.[95] The expression of CPT1, the enzyme responsible for transporting medium- and long-chain fatty acids into the mitochondria for oxidation, is upregulated in PCa, potentially increasing the metabolic adaptability and proliferative capacity of tumor cells.[96,97] In addition, FAO plays crucial roles in CRPC, including modulating AR activity, supporting tumor cell growth, and promoting resistance to ADT.[98] FAO inhibitors, such as Platin-L, can restore tumor cell sensitivity to ADT and cisplatin by inhibiting FAO.[99]

Cholesterol metabolism
PCa cells often display increased de novo cholesterol biosynthesis, synthesizing cholesterol from simple precursor molecules, such as acetyl-CoA, rather than using exogenous cholesterol.[100,101] The expression of cholesterol biosynthesis enzymes, such as HMG-CoA reductase (HMGCR), is regulated by AR signaling.[102] In PCa, this metabolic pathway has several biological implications. First, cholesterol is a vital precursor for the synthesis of steroid hormones, including androgens, which contribute to AR activation in tumor cells after castration therapy.[103,104] Second, cholesterol is a major component of lipid rafts, which are specialized microdomains within cell membranes that play a role in signaling processes.[105] Changes in cholesterol levels can influence the dynamics of lipid rafts and affect signaling pathways associated with PCa progression.
Given the importance of cholesterol metabolism in cancer, several therapeutic strategies involving cholesterol metabolism have been proposed for PCa treatment. Statins, cholesterol-lowering drugs widely used by millions of patients, can inhibit HMGCR and have potential anticancer activity.[106] At high doses, statins have been shown to significantly reduce the invasiveness of PCa.[107] However, at low doses (comparable to therapeutic blood concentrations), statins may exert contradictory effects on tumor cells both in vitro and in vivo.[107] The exact mechanisms and pharmacological activities of statins remain to be further explored.
Cholesterol metabolism is particularly important when androgen synthesis or signaling is targeted in PCa. The inhibition of squalene epoxidase (SQLE), a key enzyme involved in cholesterol biosynthesis, has been identified as a promising therapeutic intervention for CRPC.[108,109] In CRPC, PTEN/TP53 loss activates SQLE via SREBP2.[110] Targeting SQLE with terbinafine has effectively inhibited tumor growth in mouse xenograft models. In addition, in clinical studies, terbinafine has been administered to four patients with advanced PCa, with PSA levels decreasing in three patients.[109] Similarly, using the drug FR194738 to block SQLE has been shown to slow the growth of PC3 cells both in vitro and in xenograft models.[108]
Finally, during ADT, the TME can support androgen synthesis by replenishing cholesterol. In this context, macrophages are cholesterol sources for PCa cells, thereby promoting CRPC development.[111]

Metabolic Alterations Involved in the Tumor Microenvironment
PCa tumors undergo significant metabolic changes throughout cancer progression; these changes are driven not only by intrinsic alterations in tumor cells but also by interactions with the TME. To cope with challenges such as nutrient deprivation, tumor cells must adapt to changes in the microenvironment. The characteristics of microenvironment reprogramming include the accumulation of extracellular matrix caused by the recruitment of stromal cells (including immune cell infiltration), expansion of cancer-associated fibroblasts (CAFs), lactate buildup, and lipid accumulation.
Research has shown that myeloid-derived suppressor cells (MDSCs) play a crucial role in the prognosis of PCa patients. MDSCs are a group of immune-suppressive cells that inhibit normal immune responses, thereby facilitating tumor evasion of immune surveillance. Studies indicate that in PCa, the level of the polymorphonuclear (PMN)-MDSC (CD33+ HLA–DR– CD14– CD15+) subtype is increased, whereas that of the M-MDSC (CD33+ HLA– DR+ CD14+ CD15–) subtype is decreased. Increased PMN-MDSC levels are typically associated with worse survival rates in patients with metastatic castration-resistant prostate cancer (mCRPC), suggesting that PMN-MDSCs are promising prognostic biomarkers and potential therapeutic targets.[112]
CAFs are also important components of metabolic regulation in PCa. CAFs play a central role in metabolic reprogramming through metabolic crosstalk with PCa epithelial cells. Studies have shown that lactate released by CAFs modifies the NAD+/NADH balance in PCa cells, resulting in the SIRT1-mediated activation of PGC-1α.[113] This activation increases mitochondrial biogenesis and function, thus promoting tumor growth. Proteomics analysis revealed substantial upregulation of amino acid metabolism pathways, especially those involved in glutamine metabolism, in LNCaP cells cocultured with CAFs. Glutamine deprivation assays revealed that LNCaP cells were resistant to glutamine depletion in the absence of CAFs, but their proliferation was significantly reduced when they were cocultured with CAFs, indicating that CAFs increase the dependence of hormone-sensitive PCa on glutamine through metabolic reprogramming.[114,115] Furthermore, the effectiveness of GLS1 inhibition using CB-839 was reduced in the presence of CAFs, suggesting that CAFs may provide glutamine or its metabolic derivatives through alternative pathways.[116] In addition, CAFs synthesize and supply glutamine to adjacent cancer cells. Specifically, RAS-driven macropinocytosis and the subsequent degradation of albumin in stromal fibroblasts greatly increase glutamine production, thereby supporting the growth of neighboring PCa epithelial cells.[117] This process helps alleviate the metabolic crisis faced by cancer cells due to glutamine deficiency. In other cancers, such as breast and pancreatic cancers, CAFs have been reported to support tumor metabolism by secreting glutamine and pyruvate directly or via exosomes.[118] Although the exact mechanism of CAF-mediated metabolic reprogramming in PCa remains largely unexplored, pathways involving GLS1 regulation and glutamine uptake are worthy of further investigation. If CAFs can compensate for the exogenous glutamine supply, targeting glutamine metabolism alone may have limited efficacy, suggesting the need for combination therapies that inhibit the metabolic support function of CAFs.
Tumor cells also compete with immune cells for energy by altering their metabolic pathways, thereby promoting tumor growth and immune escape. Hypoxic conditions are a common feature of the PCa TME and promote the activation of hypoxia-inducible factor 1α (HIF-1α). HIF-1α increases glucose consumption by regulating the PI3K/Akt/mTOR signaling pathway and the expression of glucose transporters such as GLUT-1, providing the necessary energy for tumor cells and causing TME acidification.[119,120] Lactate, a metabolic byproduct produced by tumor cells, accumulates through lactate transporters (such as MCTs), further acidifying the TME and suppressing immune cell functions.[121] Lactate alters the metabolism of immune cells, particularly by increasing glucose consumption in Treg cells, thereby increasing their immunosuppressive activity and promoting tumor growth.[122,123] Furthermore, PCa is an immunologically low-response tumor, and the hypoxic and metabolic abnormalities in its TME further inhibit immune cell function. This immunosuppressive environment creates favorable conditions for tumor escape and growth. Therefore, interventions targeting TME metabolism, such as lactate metabolism modulation, may offer new strategies for immune therapy.
In PCa stromal cells, lipid metabolism is also crucial. Changes in lipid metabolism, especially fatty acid metabolism (FAM), can impact tumor growth and treatment outcomes by modulating the TME.[124] Previous studies have shown that CD8+ T cells are unable to metabolize accumulated intercellular long-chain fatty acids or store them in lipid droplets, resulting in significant lipotoxicity and subsequent T-cell exhaustion, facilitating immune escape by tumor cells.[125] Moreover, cholesterol biosynthesis is increased in advanced PCa and is associated with poor prognosis.[126] Statins, effective inhibitors of cholesterol biosynthesis, are currently being tested in several clinical trials for PCa treatment (NCT04026230, NCT01561482, NCT01478828, and NCT04094519). A recent study evaluated the combination of atorvastatin with ADT (NCT04026230). Therefore, systematic research into the correlation between FAM and the TME in PCa is essential.

Summary and Future Directions
Reprogramming metabolic pathways, such as the glucose, amino acid, and lipid metabolism pathways, plays a critical role in cancer biology, particularly in PCa. A variety of clinical trials of treatments based on metabolic targets are ongoing to determine whether the efficacy of these treatments outweighs that of traditional hormonal therapy [Figure 2]. While AR-targeted therapies are commonly used clinically, tumor cells may develop mechanisms to bypass these therapies due to the interplay between different signaling pathways, such as crosstalk between AR and the AKT pathway. As a result, single-agent therapies often fail because of resistance. In contrast, targeting metabolic pathways offers a potential therapeutic alternative that exploits the metabolic vulnerabilities of tumor cells. However, despite progress in metabolic research, our understanding of the metabolic pathways involved in different stages of PCa development remains insufficient. Therefore, intensifying research efforts and advancing the development of metabolism-related drugs are crucial to improve treatment outcomes and effectively prevent tumor progression.

Funding
This work was supported by grants from the National Natural Science Foundation of China (Nos. 82272886 and 82200484), the Research Fund of the Anhui Institute of Translational Medicine (No. 2022zhyx-C37), the Natural Science Foundation of Anhui Education Department (Nos. 2022AH030118 and 2023AH030115), and the Youth Cultivation Foundation of Anhui Education Department (No. YQZD2024008).

Conflicts of interest
None.