In normal cells, the energy required for cellular metabolism is converted mainly from glycogen and other substances into 6-phosphate-glucose, and then enters the mitochondria via the glycolysis pathway, where it undergoes the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, providing 70% of the energy required for its own metabolism. Glycolysis can only provide a small portion of the energy, which is about 20-30% of the metabolism of normal cells. The Warburg effect describes that how cancer cells tend to absorb glucose and convert it predominantly to lactate, even in the presence of oxygen, and refers to the abnormal glucose metabolism in cancer cells ( Figure 1 ). The Warburg effect assumes that glycolysis is the main energy supply pathway for tumor cells, and that tumor cells rely on glycolysis for energy supply even when sufficient oxygen is available. Studies have shown that tumor cells transport extracellular glucose into the cell via glucose transporters distributed on the cell membrane and catabolize it to generate ATP using glycolytic enzymes such as hexokinase, phosphoglucose isomerase, and the product of the multistep metabolism of pyruvate. In the hypoxic region of the tumor, a large amount of lactate is formed from pyruvate by lactate dehydrogenase. Lactate is released to the outside of the cell through the only carboxyl transporter in the cell membrane and accumulates locally, creating an acidic environment for tumor growth. This microenvironment promotes tumor cell invasion into surrounding tissues (14). At the same time, researchers found that tumor cells in the oxygenated area could take up the lactic acid produced by cells in the hypoxic area and synthesize glucose through gluconeogenesis, which can be used by tumor cells in the hypoxic area to realize energy cycle (14). Lactic acid can also enter the bloodstream, reach the liver via gluconeogenesis, and eventually generate liver glycogen or blood glucose, resulting in a lactic acid cycle (15). In the oxygenated tumor oxygen region, tumor cells also have the same energy me of the TCA cycle as normal cells, i.e, the metabolite pyruvate enters the mitochondria through oxidative decarboxylation to form acetyl-CoA via transporters, and is oxidatively metabolized in the TCA cycle.

Aerobic glycolysis is a unique metabolic mode of tumor cells. The aerobic glucose metabolic pathway is actually a low-productivity metabolic pathway. One molecule of glucose is degraded to pyruvate via the glycolytic pathway, generating 2 molecules of ATP, whereas complete oxidation by oxidative phosphorylation in mitochondria generates 32 to 33 molecules of ATP. Tumor cells require a large amount of energy to proliferate rapidly, but they choose glycolysis, which is less productive. However, there is no obvious defect in the mitochondria of tumor cells. It has been found that mitochondria maintain complete functions in tumor cells, and the tumorigenic function of cancer cell lines in vitro and in vivo is reduced when mitochondrial DNA is specifically knocked down (4, 16).

Why do some tumor cells still prefer the less efficient pathway of glycolysis as their primary energy source, even though mitochondria are so efficient? First, the cytoplasm produces ATP 100 times faster than mitochondria, meaning the yield is low but the rate is high. As long as glucose supply is sufficient, the ATP produced by glycolysis per unit time is higher than that of oxidative phosphorylation (17). Second, the increase in glycolysis leads to the accumulation of metabolic intermediates that can generate the demand for tumor cell proliferation through other reactions. Finally, the massive accumulation of pyruvate during glycolysis generates lactate under the action of lactate dehydrogenase A (LDHA), which is transported outside the cell by monocarboxylic acid transporter 4 (MCT4), creating an acidic environment outside the cell that promotes tumor cell growth, invasion and metastasis.

In addition, tumor cells adapt to different survival conditions by altering their metabolism, a process known as metabolic plasticity. When using chemotherapeutic agents that target the proliferation phase of tumor cells, cancer stem cells (CSCs) can circumvent the killing effects of chemotherapeutic agents by regulating their own metabolic processes to keep them in a “resting state” with low energy metabolism. At the same time, CSCs also promote the metabolism of the pentose phosphate pathway and increase their own antioxidant capacity to adapt to different tumor microenvironments (TMEs) (18). Elgendy et al (19) also demonstrated through intermittent diet and drug administration that tumor cells have metabolic plasticity that can switch between glycolysis and oxidative phosphorylation to adapt to different survival challenges. Adenosine-activated protein kinase (AMPK) and HIF-1 are two important regulators of oxidative phosphorylation and glycolysis. To explain the Warburg effect in tumor metabolism, Sotgia et al (20) proposed that cancer-associated fibroblasts in the vicinity of the tumor are “induced” by cancer cells to switch energy metabolism to aerobic glycolysis and that these interstitial cells are “induced” by cancer cells. Metabolites of fibers can provide metabolic substrates for epithelial cancer cells as an energy source. In this model, interstitial cell glycolysis produces L-lactate and ketone bodies that provide raw materials for mitochondrial metabolism, and their transport to epithelial tumor cells with oxidative properties drives mitochondrial oxidative phosphorylation. This metabolic mode is also referred to as the “reverse Warburg effect” because mesenchymal cells, rather than tumor cells, take over aerobic glycolysis. At the same time, this also shows that tumor and tumor stromal cells belong to the same metabolic symbiosis.

Glutamine is the most abundant non-essential amino acid in human blood under normal conditions and accounts for about 50% of the free amino acids in the human body (21). In stressful situations, the body must supply glutamine to meet the demand, and glutamine is absorbed by the body and classified as a conditional non-essential amino acid. Under normal conditions, glutamine is synthesized and stored primarily in skeletal muscle, and some is also synthesized in adipose tissue, lung and liver, with skeletal muscle having the highest glutamine synthase activity. Glutamine taken up and stored by skeletal muscle is gradually released into the bloodstream and delivered to all parts of the body. The proliferation of lymphocytes and macrophages stimulated by antigens, and the renewal and maintenance of the intestinal mucosa require large amounts of glutamine. Therefore, the intestine and immune cells are important consumption organs for glutamine.

Glutamine metabolism is another characteristic of tumor cells (22) ( Figure 2 ). Glutamate is synthesized from glutamate and ammonia under the catalysis of glutamine synthase (GS). However, in tumor cells or rapidly proliferating cells, the de novo synthesis of glutamine cannot meet the demand of cellular energy metabolism for glutamine, so it is converted to a conditionally essential amino acid. Glutamine enters the cell via the amino acid transporters SLClA5 and SLC7A5/SLC3A2, and is deaminated into glutamate in the mitochondria by glutaminase (GLS). Glutamate is formed under the action of glutamate dehydrogenase (GDH) or amino acid transaminase. Ketoglutarate (KG) is fed back into the TCA cycle and provides energy to cells through oxidative phosphorylation. The study found that tumor cells take up more glutamine and less glucose than immune cells in the TME. At the same time, it was observed that glutamine uptake and metabolism can significantly inhibit glucose metabolism. The specific mechanism is not clear (23), but it indicates that glutamine metabolism is very important for tumor cells. However, in later studies, glutamines was found to be an energy source only in some tumor cells and not in all tumor cells (24).

In recent years, researchers have paid more attention to fatty acid metabolism in tumor cells because fatty acids are not only the main components of membrane formation, but also a source of energy supply and secondary messengers of signal transduction in rapidly proliferating tumor cells (25). In a state of energy stress, fatty acids in mitochondria produce acetyl-CoA through iodine oxidation, accompanied by the production of NADH and FADH, thereby supporting the cell’s biosynthetic pathway and producing ATP. In addition, phosphatidylinositol 3-kinase (PI3K) regulates several important signaling pathways. PI3K-AKT signaling pathway promotes glucose uptake and glycolysis by activating glucose transporter 1 (GLUT1) and hexokinase. PI3K-AKT signaling pathway can also enhance glutamine replenishment and lipid remodeling by activating glutamate pyruvate transaminase (26).

The catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) are the best-known and most studied neurotransmitters, formed from the amino acid tyrosine and released mainly by sympathetic nerves and the adrenal medulla. The interactions between epinephrine and norepinephrine and the alpha (α)- and beta (β)-adrenergic receptors (ARs), which are G-protein-coupled 7-transmembrane receptors widely distributed in most tissues of mammals, mediate their actions. Epinephrine and norepinephrine, serve as stress hormones to respond to external stress or danger to the sympathetic and adrenal nervous systems (57, 58). Norepinephrine, in particular, plays a crucial role as a neurotransmitter in the brain and at the output of the sympathetic nervous system, which includes the network of peripheral nerves that controls the body’s organs. It was reported that there is a gender difference in responses to epinephrine. In men, but not in women, the release of free fatty acids (FFA) from lower body adipose tissue increased in response to epinephrine, whereas in both sexes the release of palmitate increased in the upper body. These results support some in vitro research and suggest that the differences in body fat distribution between males and females may be influenced by catecholamine activity (59). Furthermore, the biological properties of malignant tumors, such as cancer cell proliferation, invasion, metastasis, angiogenesis, resistance to apoptosis, and stromal compartments in the tumor microenvironment, are strongly influenced by epinephrine and norepinephrine (60). Isoproterenol, an α-adrenergic agonist, can imitate the tumor growth and angiogenesis brought on by prolonged stress, while propranolol, an α-adrenergic antagonist, can prevent this (61). Importantly, epinephrine and norepinephrine have been considered to be one of the main regulators in the metabolism of tumor cells. In breast cancer survivors, epinephrine, cortisol, and lactate responses appeared to be attenuated compared with controls, while glucose and responses showed larger magnitude changes. The adrenergic system regulates energy balance in part by promoting thermogenesis and the release of lipids from brown or white adipose tissues (62, 63), and human fat cells are equipped with adrenergic receptors (adrenoceptors) β₁ (ADRB1), β₂ (ADRB2) and β₃ (ADRB3). Beta-adrenergic genes have already been linked to a variety of cancers, including their interactions with environmental or other risk factors (64–67). Adrenoceptor polymorphisms and the dopamine beta-hydroxylase enzyme, which produces norepinephrine, can modify insulin resistance and change glucose signaling (68–71), which may have an impact on the Warburg effect. Norepinephrine can activate the metabolism of endothelial cells to block oxidative phosphorylation and activate an angiogenic switch that promotes the growth of cancer (72, 73). In pancreatic cancer, catecholamines promote neurotrophins to be secret by β-ARs, which in turn raises norepinephrine levels and aids tumor growth (74). Chronic stress-induced epinephrine promotes the development of breast cancer stem-like traits by rewiring the metabolism in a lactate dehydrogenase A (LDHA) dependent manner (75). Catecholamines norepinephrine and epinephrine have been demonstrated to play a role in metabolic reprogramming and epithelial-to-mesenchymal transition in liver and colorectal cancers (76, 77). PCK1 regulates glucose metabolism and neuroendocrine differentiation through the activation of LIF/ZBTB46 signaling in castration-resistant prostate cancer (78). Together, these and other numerous studies provide compelling evidence that epinephrine and norepinephrine play an important role in the metabolism of substances and energy, which promotes the growth and spread of tumors in multiple of cancer types ( Figure 4 ).

Epinephrine (EPI) and norepinephrine (NE) interact with environmentally-regulated factors like obesity, hypertension, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress to promote the Warburg effect by facilitating glucose. These interactions are in addition to the direct interaction of elevated central catecholamine release or peripheral sympathetic-adrenomedullary signaling with epigenetic and genetic risk factors including mutagenesis, and perhaps by increasing insulin resistance. Additionally, it is suggested in this research that many cancer cells produce and release catecholamine molecules to autocrinely activate their own α-ARs and β-ARs. To encourage cancer and metastasis, EPI and NE may potentially interact with oxidative stress, systemic inflammation, and immunological function.

γ-GABA is the adult mammalian brain’s major inhibitory neurotransmitter for CNS. The ionotropic GABA_A and GABA_C receptors as well as the metabotropic GABA_B receptor are three distinct types of GABA (A, B, and C) receptors. Numerous tumor tissues have been found to contain GABA receptors, which control the migration and proliferation of tumor cells (79, 80). The GABAergic system and the growth of tumors appear to be closely associated, according to recent research using human cancer cell lines, animal models, and human tissues. In general, stimulation of GABA receptors slows migration (81) and suppresses tumor cell proliferation (82). These findings imply that the GABAergic system contributes significantly to cell pathology, and it is possible that GABA plays a substantial role in the prognosis of cancer patients. Some cancers has been shown to have higher GABA levels, such as breast cancer (80), ovarian cancer (80), gliomas (83), gastric cancer (84), colon cancer (85), and prostate cancer (86). Typically, GABA inhibits cancer cell growth through the GABA_B receptor, but stimulates cancer cell growth through the GABA_A receptor pathway (87). The GABAergic system and the growth of tumors appear to be closely related, according to recent research using human cancer cell lines, animal models, and human tissues. Recently, it was demonstrated that two independent 13C-labeled substrates, [1,6-13C2] glucose and [2-13C] acetate, which are metabolized in neurons and glia differently, may be used to evaluate the TCA cycle and neurotransmitter cycle fluxes of glutamatergic and GABAergic neurons in vivo separately (88). Using this technique in adult rats under halothane anesthesia, it was found that cortical glutamatergic and GABAergic neurons contribute 80% and 20%, respectively, of neuronal glucose oxidation and neuronal/glial cycling (88). The γ-GABA abnormality is present in many diseases and can be served as potential target. It was reported that abnormalities in Glu/GABA-Gln are present in rat dyskinetic syndrome, and the amino acid neurotransmitter imbalance was improved by “Tiapride,” which also increased the expression of GS and EAAT2 protein, decreased Glu levels, increased γ-GABA levels, and increased γ-GABA levels (89). Additionally, treatment with 10 mM γ-GABA considerably slowed down the loss of malate and titratable acidity and increased the levels of succinate and oxalate. Fruit treated with GABA had higher cytosolic activities of nicotinamide adenine dinucleotide-dependent malate dehydrogenase (cyNAD-MDH) and phosphoenolpyruvate carboxylase (PEPC) than control fruit, whereas administration of 10 mM GABA significantly reduced the loss of malate and titratable acidity and raised the concentrations of succinate and oxalate. GABA-treated fruit had larger cytosolic activities of nicotinamide adenine dinucleotide-dependent malate dehydrogenase (cyNAD-MDH) and phosphoenolpyruvate carboxylase (PEPC) than control fruit, although cyNADP-ME and phosphoenolpyruvate carboxykinase activities were lower. Notably, GABA administration drastically decreased ethylene production while also downregulating the expression of MdACS, MdACO, and MdERF. GABA therapy also boosted the accumulation of GABA and improved the function of the GABA shunt (89). The GABA_A receptor agonist muscimol promotes gastric cancer cell growth by triggering mitogen-activated protein kinases (MAPK). Similar to this, GABA promotes the formation of pancreatic cancer by increasing intracellular Ca²⁺ levels and the MAPK/ERK cascade by overexpressing GABRP, a subunit of GABA_A (90). Contrarily, activation of GABA_B receptors successfully prevents DNA synthesis and cell migration by inhibiting isoproterenol-induced cAMP, p-CREB, cAMP response element-luciferase activity, and ERK1/2 phosphorylation (91). The GABA or GABA_B agonist baclofen has been demonstrated to promote Epidermal growth factor receptor (EGFR) transactivation, which has been connected to the propensity of prostate cancer cells to invade (92). According to these findings, various GABA activation-induced effects on cancer development and migration may vary on the kind of cancer or GABA receptor. Contrary to the mechanism described above, our most recent research showed that the GABA_A receptor subunit promotes the growth of pancreatic cancer by altering KCNN4-mediated Ca²⁺ in a GABA-independent manner (93). Besides, it is intriguing that GABA is present in the tumor microenvironment, which suggests that it may be able to control inflammation by concentrating on immune cells that have invaded the tumor (93). In summary, these advances remind that nutrition has evidently metabolic consequences that may change the incidence and progression of cancer, reinforcing the metabolic cancer model.

In brain tissue, glutamate is widely distributed and has the highest concentration all amino acids. Over the past 50 years, numerous studies have been conducted on the functions of glutamate in the brain, revealing a wealth of information about glutamate. Early research by Krebs indicated that glutamate has an important metabolic function in the brain (94). Waelsch and colleagues made the first observation about the complicated compartmentation of glutamate metabolism in the brain (95). Neurotransmission in both cell types has the highest energetic cost, which increases with cortical activity. Interpretation of functional imaging results is significantly influenced by the contribution of GABAergic neurons and inhibition to cortical energy metabolism (88). Using NAD or NADP as cofactors, glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of glutamate to α-ketoglutarate. GDH is found in primarily in astrocytes in the mammalian brain, where it is likely involved in the metabolism of the transmitter glutamate. Thus, while GTP primarily controls housekeeping GDH, the availability of ADP or L-leucine has a significant impact on GDH activity in neural tissue. GDH specific to neural tissue is likely to be activated under circumstances that promote hydrolysis of ATP to ADP (e.g., during intense glutamatergic transmission), increasing glutamate flux through this pathway (96). In synaptosomes and cultured neurons that do not produce GDH, the rate of oxidative glutamine metabolism was significantly lowered when glucose was restricted. In contrast, the absence of GDH expression had no impact on glutamine metabolism when glucose was present. In brain mitochondria from GDH KO mice, respiration powered by glutamate was significantly lower, and synaptosomes were unable to increase their respiration in response to increased energy demand. The importance of GDH for neurons, especially during times of high energy demand, is highlighted by its role in the metabolism of glutamine and the capacity for respiration. This may be due to the significant allosteric activation of GDH by ADP (97). Using 13C, astroglia plays a role in energy metabolism of human brain. The primary pathway for the neurotransmitter glutamate repletion has been identified, and nuclear magnetic resonance spectroscopy has been used to study astrocytic oxidative metabolism (98). The pathophysiology of hyperammonemia and hepatic encephalopathy appears to be heavily influenced by abnormalities in glutamate metabolism and glutamatergic neurotransmission. The pathogenesis of hepatic encephalopathy and other hyperammonemia conditions involves an abnormality in astroglial glutamate uptake caused by ammonia (99). Additionally, in the absence of ad hoc activity-related metabolic restrictions, the glutamate-glutamine cycle does not control the relative energy requirements of neurons and astrocytes, and as a result, their intake of glucose and the exchange of lactate (100). Glutamate-induced Ca²⁺ loads cause mitochondria to sequester Ca²⁺, which then uncouples respiration and results in metabolic acidosis. The acidification brought on by glutamate is a sign of metabolic stress and may suggest that mitochondria are crucial in the process of glutamate-induced neuronal death (101).

Dopamine served as a minor intermediary in the synthesis of noradrenaline in 1957. Today, it is a significant neurotransmitter in the brain. It was reported that dopamine plays a key role in modulating learning and motivation. Excitatory and inhibitory synaptic transmission are altered by dopamine. While the nature of neuromodulation of inhibitory transmission is still under discussion, it appears that activation of the dopamine 1 (D1) receptor specifically promotes N-methyl-D-aspartic acid receptor (NMDA) but not α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicaci (AMPA) synaptic transmission in the cortex and striatum. Because of their dependence on voltage, NMDA currents are less active when the postsynaptic cell is not firing than they are when it is depolarized. Large networks of pyramidal neurons may be induced to enter bistable states resembling working memory, according to experimental and theoretical data (102). The capacity of the striatum to store dopamine as assessed by L-[¹⁸F]-fluorodopa uptake was normal, but dopamine (D2) receptor binding was decreased in huntington’s disease compared with normal subjects (103). In addition, glutathione is a critical neuroprotectant for midbrain neurons in conditions when energy metabolism is compromised and show that an oxidative challenge occurs during suppression of energy metabolism by malonate (104). Parkinson’s disease (PD) neurons had damaged PI3K/Akt, mTOR, eIF4/p70S6K, and Hif-1 pathways, which are part of a network regulating energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation. The primary hubs of this network, which is important for longevity and may be a target for therapeutic intervention along with the stimulation of mitochondrial biogenesis, are PI3K/Akt and mTOR signaling (105). Recently, a distinct metabolomic profile linked to parkin dysfunction and demonstrate the value of combining metabolomics with an iPSC-derived dopaminergic neuronal model of parkinson’s disease to gain fresh understanding of the pathogenesis of the disease (105). The striatum and prefrontal cortex of the spontaneously hypertensive rat model of attention deficit hyperactivity disorder (ADHD) show impaired energy metabolism and disturbed dopamine and glutamate signaling (106). Several metabolic abnormalities, including insulin resistance, abdominal obesity, dyslipidemia, and hypertension, make up the metabolic syndrome. Its pathogenesis may be influenced by faulty dopamine D2 receptor (D2R) signaling, according to earlier studies. D2R activation simultaneously improves various metabolic traits in obese women (107). The failure of dopamine and glutamate’s connection in controlling energy metabolism results in neuronal death (108). Midbrain dopaminergic cells with Lesch-Nyhan disease have limited developmental potential and impaired energy metabolism (109). Catecholamine toxicity may result from interactions with the mitochondrial electron transport system as well as from the induction of an oxidative stress state, and this was further supported by the fact that ADP was able to reverse the dose-dependent inhibition of NADH dehydrogenase activity caused by dopamine (110).

Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has a variety of effects on the peripheral organs as well as the CNS. In the brain, 5-HT is a neurotransmitter that regulates mood, sleep, behavior, appetite, and other functions (111). Serotonin is also an important regulator of the inputs to the energy balance, including energy intake and energy expenditure. Serotonin in the CNS plays a complex and intricate role in appetite and subsequent nutrient intake (112). Receptor agonists for the treatment of obesity have been approved due to serotonin’s inhibition of appetite (113). The rate-limiting enzyme tryptophan hydroxylase (TPH) transforms the amino acid tryptophan into 5-hydroxtryptophan (5-HTP), which is then converted to 5-HT by aromatic acid decarboxylase. TPH2 is expressed in the CNS and peripheral neuronal tissues, whereas TPH1 is present in peripheral nonneuronal tissues. These two isoforms of TPH were discovered to be expressed in a mutually exclusive pattern in the early 2000s (114). Since 2010, scientists have become more aware of how peripheral serotonin controls systemic energy metabolism. The enterochromaffin cells of the gut produce the majority of the 5-HT present in the body. However, 5-HT is also generated by many metabolic organs and has been shown to have biological effects that are endocrine, paracrine, and autocrine in nature. 5-HT promotes proliferation and mass enlargement of pancreatic β-cells. 5-HT encourages lipogenesis and prevents adaptive thermogenesis in adipose tissues. 5-HT activates hepatic stellate cells and causes lipogenesis and gluconeogenesis in the liver (115). It was reported that dairy cows in late lactation treated with 5-HTP had improved energy metabolism, reduced urinary calcium loss, and increased milk calcium secretion. To ascertain any advantages for post-partum calcium and glucose metabolism, additional research should focus on the effects of increased serotonin during the transition period. Chronic acetyl-l-carnitine administration reduced the conversion of glucose to lactate, elevated energy metabolite levels, and changed the levels of monoamine neurotransmitters in the mouse brain (116). Recent genetic studies suggest that leptin signaling physiological processes, most notably leptin’s control over appetite and the accumulation of bone mass, are primarily involved in the inhibition of serotonin synthesis and released by brainstem neurons (117). Collectively, 5-HT plays an emerging role in regulating metabolism in cancer cells.

Neuropeptide Y (NPY) is one of the most prevalent neuropeptides in the brain, with 36 amino acids (118, 119). In order to regulate hunger and energy balance, agouti-related protein neurons (AgRP) in the CNS emit NPY, which was first identified as a powerful neuropeptide that stimulates appetite (120–122). The central regulatory effects of NPY on circadian rhythm, the cardiovascular system, stress, and anxiety were gradually demonstrated as this peptide’s role in the body’s regulation of these processes became better understood (123). Mammals have five different types of NPY receptors (Y1, Y2, Y4, Y5, and Y6), which are found throughout the CNS (124, 125) and linked to various stages of oncogenesis, allowing NPY to exercise its biological effects. When Y2-R is activated, it appears to encourage angiogenesis, whereas Y1-R appears to be involved in the regulation of cancer cell growth. Furthermore, a thorough investigation of the NPY receptor revealed that it is expressed in peripheral tissues such as adipose tissue, the pancreas, and bone (126, 127). As a result, the peripheral effect of NPY has drawn a lot of attention. For instance, activating the NPY receptor in the pancreas can lower hyperglycemia and β-cell apoptosis (128). Adipocyte proliferation and adipogenesis are promoted by NPY in adipose tissue (127). This suggests that in addition to being secreted in the brain by peripheral tissues, NPY also plays significant regulatory roles in the endocrine system (129, 130). In addition to these conventional functions, neuropeptides have been shown to promote tumor growth (131, 132). Numerous neuropeptides, including SP and NPY (133) have been thoroughly investigated in malignancies. Neuropeptide receptors are often GPCRs, which is a superfamily of receptors. For instance, the neurokinin-1 (NK-1) receptor, which is connected to the Gq family of G proteins, is primarily responsible for the pharmacological activity of SP. Upon activation, the NK-1 receptor produces the second messenger’s inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (134). Through its effects on energy homeostasis, the NPY system has complex and significant implications for the development of cancer. Botox particularly, but not only, suppresses NPY in cancer using in vitro models and tissues from a prior human chemical denervation investigation. NPY nerve quantification is an independent predictor of prostate cancer-specific mortality. Last but not least, radiation-induced apoptosis is reduced when prostate cancer cells are cocultured with dorsal root ganglia/nerves, and NPY-positive nerves are increased in the prostates of patients who failed radiation therapy, suggesting that NPY nerves may be involved in radiation therapy resistance (135). In summary, understanding the role of NPY in whole-body energy balance could provide insight on mechanisms underlying the pathogenesis of cancer.