Fatty acid metabolism is a critical part of lipid metabolism. The altered metabolic activity of fatty acids can contribute to the malignant properties of cancer cells (17). Some fatty acids are produced by adipose tissue lipolysis or triglyceride breakdown in circulating chymotrypsin and lipoproteins. These exogenous fatty acids are the preferred source of adenosine 5'-triphosphate production, membrane biosynthesis, energy storage and the production of a wide range of signaling molecules in the majority of non-tumor cells (Fig. 1) (18).

Adipose-derived fatty acids are also strongly linked to cancer, and when adipocytes are located near tumor lesions, their secretory products can influence disease progression, as observed in ovarian and breast cancers (19,20). The prostate is surrounded by PPAT, which provides a high concentration of fatty acids and alters the prostate tumor microenvironment (TME) (11). Lipoproteins in the TME can also be taken up by cancer cells, providing them with cholesterol and fatty acids (21). In PCa cells, fatty acid uptake increases and serves as a direct raw material for substance production. CD36 has been described as a carrier that mediates fatty acid transport. It has been shown that CD36 knockdown in cancer-susceptible PTEN^−/− mice reduces fatty acid uptake and the lipid abundance of oncogenic signals, thereby inhibiting tumor progression (22). These data suggest that the inhibition of fatty acid uptake may be a promising therapeutic approach for the treatment of PCa.

The de novo production of fatty acids is another key source of fatty acids. Beginning with citrate, ATP citrate lyase (ACLY) catalyzes the production of acetyl-CoA, which is then converted to malonyl-CoA by acetyl-CoA carboxylase (ACC) in the ab initio synthesis process (23). Fatty acid synthase (FASN) transforms malonyl-CoA into the 16-carbon fatty acid, palmitate. Stearoyl-CoA desaturase (SCD) then transforms palmitate into monounsaturated fatty acids. These monounsaturated fatty acids are then converted into polyunsaturated fatty acids by the action of enzymes, such as the elongation of very-long-chain fatty acid protein (ELOVL), which results in triacylglycerols (Fig. 1) (23).

ACLY is the first rate-limiting enzyme in the ab initio fatty acid synthesis pathway, catalyzing the synthesis of acetyl-CoA from citric acid. ACLY overexpression has been linked to a number of types of cancer, including lung cancer, cervical cancer, prostate cancer and osteosarcoma (24). A recent study found that androgen receptor (AR) transcript levels correlated with ACLY expression, and that inhibiting ACLY activity increased castration-resistant PCa (CRPC) cell sensitivity to AR antagonists via the ACLY/AMPK/AR axis. ACLY and AR inhibition reduced tumor cell proliferation and induced apoptosis (25). The reduced ACLY expression in PCa cells can increase caspase-3/7 intracellular levels, increase the proportion of early and late apoptotic cells, and inhibit PCa cell proliferation (26). ACLY inhibition can effectively enhance CRPC sensitivity to androgen deprivation therapy (ADT) and is expected to be a novel target for CRPC therapy.

The rate-limiting enzyme of FASN is ACC, which catalyzes the conversion of acetyl-CoA to malonyl-CoA. ACC has two isoforms: ACC1 (ACCα) and ACC2 (ACCβ) (27). The ACACA gene encodes ACC1, while the ACACB gene encodes ACC2. ACC1 and ACACA have been linked to the development and progression of numerous types of cancers, including breast (28), ovarian (29), liver (30) and colon cancer (31). The ACACA gene is upregulated in PCa tissues, and silencing the ACACA gene can inhibit PCa cell proliferation and induce apoptosis (32). The expression of the ACACA gene is associated with the local infiltration of tumor cells, lymph node metastasis and distant metastasis, and its expression level is positively associated with the Gleason score of PCa (33).

In the fatty acid ab initio synthesis pathway, FASN catalyzes the conversion of malonyl-CoA to 16-carbon fatty acid palmitate. In physiologically active human malignancies, FASN is frequently overexpressed, while it is barely detectable in healthy individuals. FASN controls tumor growth and body weight and is linked to PCa incidence and prostate cancer-specific mortality (34). Dysregulated lipid metabolism is a hallmark of PCa development and progression. FASN levels increase with the Gleason score of PCa tissue and can be used as a biomarker (35).

FASN expression is regulated by the transcription factor, AR (36), and in the presence of AR, FASN can function as an oncogene for PCa, inhibiting apoptosis and exerting oncogenic effects (37). An enhanced FASN activity is closely linked to multiple oncogenic mechanisms, such as endoplasmic reticulum function and anti-genotoxic damage (38), the activation of the PI3K/AKT/mTORC1 pathway and the palmitoylation of oncogenes (e.g., Kras and Wnt-1) (39). FASN and AR-FL are found in 87% of human CRPC metastases. FASN/AR-V7 double-positive metastases have been found in 77% of patients treated with enzalutamide and/or abiraterone (40). Inhibiting FASN activity can result in cell cycle arrest and/or apoptosis, which can be used to inhibit PCa cell growth (38). Orlistat, a FASN inhibitor commonly used to treat obesity, has also been shown to have antitumor properties in breast cancer, in situ oral squamous cell carcinoma of the tongue and PCa (41-43).

SCD is a key enzyme for the synthesis of monounsaturated fatty acids. Human PCa has a higher ratio of monounsaturated to saturated fatty acids than normal prostate tissue, and SCD is highly expressed in PCa. SCD promotes the proliferation of AR-positive LNCaP cells, increases dihydrotestosterone (DHT)-induced AR transcriptional activity and increases prostate-specific antigen (PSA) and kallikrein-related peptidase 2 expression, and the inhibition of SCD attenuates the progression of PCa (44,45). A previous study discovered that inhibiting SCD activity with sterculic oil reduced LNCaP and PC3 cell viability, blocked the G2 cell cycle, decreased cell proliferation and promoted apoptosis (46). Furthermore, SCD1 is a transcriptional target of sterol regulatory element binding protein (SREBP)1 that mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids, rendering PI3K/AKT/mTOR pathway-mutant PCa cells ferroptosis-resistant (47). SREBP1 is a central transcription factor regulating lipid metabolism, and SREBPs are discussed in more detail below.

Members of the ELOVL protein family are involved in the production of polyunsaturated fatty acids, which are critical components of cell membranes and are involved in the composition of the cytoskeleton, the regulation of cell membrane fluidity, signaling between the cell membrane and the cytoplasm, and the regulation of ferroptosis. ELOVL is also linked to ferroptosis regulation and plays a key role in tumorigenesis, development and drug resistance (48-50).

ELOVL7 is required for the synthesis of saturated very long-chain fatty acids and their derivatives, and its level is negatively associated with the survival of patients with PCa. ELOVL7 is promising as a novel molecular target for the treatment or prevention of PCa (51).

Compared to normal tissues, PCa tissues have higher levels of ELOVL2. A high expression of ELOVL2 indicates a better prognosis for patients with PCa, while ELOVL2 expression is adversely associated with the Gleason score. Low levels of ELOVL2 expression stimulate the growth of subcutaneous xenografts, colony formation, migration, invasion and PCa by downregulating inositol polyphosphate-4-phosphatase type II B to activate the PI3K/AKT signaling pathway. EVOVL2 may thus be a predictive biomarker and treatment target for PCa (52).

ELOVL5 is the main ELOVL expressed in primary and metastatic PCa, and the level of ELOVL5 in PCa is higher than that in non-malignant prostate tissue. When ELOVL5 is not present, mitochondrial function is disrupted, and oxidative stress is induced, inhibiting PCa cell proliferation and metastasis (15). When ELOVL5 is overexpressed, PCa cells exhibit an increased resistance to enzalutamide treatment, whereas ELOVL5 downregulation renderes PCa cells more responsive to enzalutamide treatment. The lipid raft/mTOR/AKT pathway is responsible for this effect, which has significant therapeutic implications for CRPC (53).

SREBP overexpression is associated with aggressive pathological features of human PCa (36). The set of genes activated by SREBP transcription factors is significantly upregulated in PML and PTEN double-null PCa (54). SREBPs are spliced into two biologically active products, SREBP-1 and SREBP-2 (55).

SREBP-1 is a master transcription factor that controls lipid metabolism. By binding to the FASN promoter region and either directly or indirectly activating FASN transcription, SREBP-1 can also participate in the transcriptional regulation of AR and fatty acid synthesis. This in turn can promote PCa growth, migration, invasion and depot resistance (36,56) and is positively associated with the clinical Gleason classification of human PCa (56). SREBP-1/FASN inhibition reduces fatty acid levels and lipid droplet accumulation in PCa cells (57). In healthy cells, there are two proteins SREBP-1, SREBP-1a and SREBP-1c, the latter of which is involved in controlling the ab initio production of endogenous fatty acids (55). SREBP-1 is transcriptionally regulated by microRNA-21 in vitro in cultured cells and mouse models (58) and can increase the production of reactive oxygen species, and NADPH oxidase 5 expression induces oxidative stress in PCa cells (56).

SREBP2 controls cholesterol production in healthy cells, and studies have shown that PTEN/p53-deficient cancers depend on cholesterol metabolism. Through the activation of SREBP2, PTEN/p53 deficiency transcriptionally elevates squalene epoxidase/monooxygenase (SQLE), and SQLE boosts cholesterol production and encourages tumor cell proliferation and survival (59).

In terms of medicine, the inhibition of SREBP is a possible novel strategy for the treatment of PCa. The SREBP pathway and AR signaling network can be targeted and blocked in vitro and in vivo by lipoinhibitors, new SREBP inhibitors, to decrease tumor development and distant metastasis with anti-prostate cancer action (36,54). In addition, drugs targeting the SREBP-2 pathway, such as tocotrienols, which can lower cholesterol levels, are also potential treatment options for PCa (60).

FABPs are multifunctional proteins that regulate fatty acid uptake, transport, signal transduction and intracellular lipid droplet formation (61) and regulate metabolic and inflammatory pathways that have been closely linked to obesity, metabolic diseases, cardiac dysfunction and cancer (62).

All five FABP genes, FABP4, FABP5, FABP12, FABP9 and FABP8, located on chromosome 8q21.13, are linked to PCa, and patients with high Gleason scores have higher levels of all five FABP mRNAs. Chromosome 8q21 is the most often amplified area in metastatic PCa (63,64).

FABP4 promotes the activation of PPARγ (65), and FABP5 promotes the activation of PPARγ and PPARβ/δ (66,67). Both PPARγ and PPARβ/δ are key regulators of lipid metabolism and energy homeostasis (68,69), and PPARγ is also a fatty acid-activated nuclear receptor and a driver of PCa metastasis (70). FABP4 can be secreted by adipocytes, is present in the circulation (71), and can promote the progression and metastasis of PCa (72). FABP4 is also an independent predictor of a high-grade Gleason score and prostate needle biopsy (PNB), and it is anticipated to be a novel biomarker for PNB optimization (73).

The promotion of PCa metastasis by FASN is largely dependent on the expression of vitamin A and FABP5 in vivo (74). By enhancing FA oxidation, the tricarboxylic acid cycle and oxidative phosphorylation, FABP5 deficiency may rewire metabolic pathways and increase ATP production by activating the PPAR signaling pathway (75). Vascular endothelial growth factor (VEGF) expression is controlled by androgens in androgen-dependent PCa cells; however, when PCa cells are no longer androgen-dependent, this route is replaced by the FABP5/PPAR/VEGF signaling pathway. Angiogenesis is another key element in the evolution of PCa (76). In the absence of FABP5, VEGF levels and microvessel density are reduced (77), PCa cells are less proliferative and invasive in vitro, and tumor growth and metastasis are decreased in vivo (78).

Through ab initio synthesis and improved fatty acid intake in the microenvironment, FABP12 upregulates FASN expression and promotes intracellular lipid buildup and PCa translocation (66). FABP12 also boosts the oxidative phosphorylation of fatty acid derivatives in the mitochondria, initiates epithelial-mesenchymal transition in PCa cells, and increases cell viability and invasiveness. FABP12-expressing cells treated with a carnitine palmitoyl transferase 1 (CPT1) inhibitor can prevent cell migration and mitochondrial β-oxidation mediated by FABP12 (79).

In terms of other FABPs, FABP1 and FABP2 levels are higher in PCa cells than in normal prostate cells, while FABP3 expression is lower (66).

HOX genes are a group of highly conserved genes that control cell and tissue differentiation, morphogenesis, and homeostasis during development. A number of human tumors have an aberrant HOX gene expression (80,81). Different HOX genes are linked to the development of various prostate lobes, seminal vesicles and epididymis (80). HOXA10 is required for prostate development and can affect PCa progression by regulating fatty acid metabolism (82).

Human PCa frequently exhibits an abnormal HOXA10 expression, and HOXA10 levels are inversely associated with PCa cell differentiation, the Gleason score and clinical stage (83). It has been established that HOXA10 plays a crucial role in regulating AR signaling and adipogenesis. HOXA10 can bind AR to form a protein complex that inhibits AR from entering the FASN gene promoter, hence suppressing FASN gene transcription and preventing the progression of PCa to CRPC. By contrast, the downregulation of HOXA10 activates the FASN gene through AR signaling, promoting adipogenesis and the progression of PCa (82).

The synthesis of cholesterol in the human body is very complex, and cells use acetyl-CoA as a raw material for ab initio synthesis, going through a total of ~30 steps, which can be broadly divided into four stages: The production of β-hydroxy-β-methylglutaryl-CoA, the production of mevalonate, the production of squalene and the production of cholesterol. Acetyl-CoA undergoes a series of stages consisting of β-hydroxy-β-methylglutaryl-CoA reductase, 2,3-oxidosqualene cyclase, squalene synthetase, SQLE, lanosterol synthase and farnesyl-diphosphate synthase-mediated enzymatic reactions (100,101), resulting in the synthesis of cholesterol (Fig. 2).