The fundamental and significant source of energy in the biological system is glucose. In RCC cells, glucose deprivation causes oxidative stress and cellular cytotoxicity (82). Several mechanisms, including glucose absorption, glycolysis, glycogenolysis, gluconeogenesis, lactate reabsorption, and lactate excretion, maintain glucose homeostasis (83) (Fig. 3).

Renal carcinoma cells need more glucose than normal cells to function as an energy source and as a resource for the production of various chemicals (84). Several cancer cell types exhibit upregulated expression levels of glucose transporters (GLUTs), particularly GLUT1, to maintain steady glucose uptake. Therefore, targeting GLUTs using various natural substances, such as flavonoids, is an optimal strategy for RCC treatment. Catechins from green tea exhibit inhibitory action against GLUT1 in RCC (85). Other polyphenols, such as epicatechin gallate (ECG) and EGCG, inhibit GLUT1 by directly binding to the transporter (86), which can change how it recognizes its substrates competitively or non-competitively. The connections of the extracellular side of the transporter with ECG and EGCG can competitively prevent glucose from binding to GLUT1 (87). Studies have demonstrated that quercetin exerts non-competitive inhibition by binding to GLUT1. Kinetic analysis has also demonstrated that flavonoids can decrease the Michaelis constant and maximum velocity values of GLUT1 (87,88). Genistein, an iso-flavonoid compound, exerts a preventive effect against prostate and breast cancer by blocking GLUT1 activity and acting as a competitive inhibitor (89). Due to its potent activities, including antioxidant, chemopreventive and anticancer activities, resveratrol might directly inhibit GLUT1 by non-competitively binding to its internal domains, decreasing uptake of glucose in human leukemia cells (90). Flavonoids, natural substances in plants with anticancer and antioxidant properties, might affect GLUTs in RCC (91,92). Flavonoids may affect how RCC cells utilize glucose, interfering with their energy metabolism and preventing the formation of tumors (24). More research is required to fully comprehend the mechanism and therapeutic implications of flavonoids in the metabolic reprogramming of RCC. Research on the possible therapeutic effect of flavonoids in targeting glucose metabolism in renal cancer is ongoing.

In normal cells, glycolysis converts the majority of glucose to pyruvate. The mitochondria undergo this process to participate in the TCA cycle (83). Through OXPHOS, pyruvate causes the synthesis of ATP. Renal cancer cells use the enzyme lactate dehydrogenase (LDH)A to ferment lactic acid to convert pyruvate into lactate (93). This mechanism produces less energy compared with OXPHOS (94). To compensate for this lower energy yield, renal cancer cells require a higher rate of glucose consumption. A complex web of processes, including glucose absorption, glycolysis, glycogenolysis, gluconeogenesis, glucose reabsorption, and glucose excretion, manages glucose homeostasis, which is influenced by kidney function (83). ccRCC cells exhibit increased glycolysis, suppressed pyruvate dehydrogenase (PDH) flux, and decreased TCA cycle activity compared with other tumor cells. A substantial difference is observed when comparing the rate of glycolysis in ccRCC cells with that in adjacent kidney cells (94). Renal cancer cells have been found to exhibit the conventional Warburg effect, which is characterized by increased cellular expression of all glycolysis-related enzymes (93). Fructose-1,6-bisphosphate, the rate-limiting enzyme, is also recognized as a tumor suppressor in RCC tumors (94). Various biological effects, including antioxidative, antiangiogenic and general antitumor effects, have been attributed to certain phytochemicals (24,47–49). Flavonoids target the modulation of certain glycolysis-related enzyme activities (24); therefore, flavonoids offer a promising therapeutic strategy for cancer-related studies. A common dietary flavonoid, apigenin, inhibits multiple biochemical pathways involved in the formation of tumors and has anticancer properties. Apigenin inhibits glycolysis by regulating pyruvate kinase M2 (PKM2) activity in HCT116 colon cancer cells (95). Inhibition by apigenin can result in the maintenance of a low PKM2/pyruvate kinase 1 ratio (96). Proanthocyanidin B2 influences PKM2 activity in hepatocellular carcinoma (97). The first irreversible stage in glycolysis is the phosphorylation of hexoses, carried out by the enzyme HK (98). Since cancer cells mostly exhibit upregulated expression levels of HK, HK may be a promising molecular target for flavonoid-based treatment (99). Xanthohumol is a flavonoid that affects colon cancer by inhibiting HK2, a crucial enzyme involved in glycolysis (98). In hepatocellular carcinoma, quercetin inhibits Akt/mTOR signaling and decreases the activity of HK2 (99). Both in vitro and in vivo, the synthetic flavonoids Gl-v9 and 10v reduce HK2 expression (100,101). Morin, a flavonoid, may prevent LDH from acting enzymatically in RCC (102). In addition, to efficiently inhibiting the growth and proliferation of several cancer cell lines, quercetin also reduces the levels of enzymes linked to glycolysis, such as LDH and LDHA (103). The flavonoid EGCG decreases the activity of LDH, LDHA and phosphofructokinase in in vitro analysis (86,104,105). Quercetin also downregulates the enzymatic activity of aldolase, GAPDH and α-enolase (106). Overall, researchers are currently studying how flavonoids affect glycolysis in the metabolic reprogramming of RCC. Although the preclinical results are encouraging, more thorough research, including clinical trials, is required to determine whether flavonoids can be used to treat RCC by modulating glycolytic pathways.

Nephrological disorders, such as type 2 diabetes, chronic kidney disease, and kidney damage, can disrupt the TCA cycle by impairing mitochondrial function and reducing levels of key TCA cycle intermediates leading to altered energy metabolism (107,108). The enzyme PDH restores the metabolic flux to the TCA cycle in renal cancer cells, which is often disrupted by downregulation of pathways such as glycolysis, lipid metabolism, and amino acid metabolism (93). These enzymes catalyze the biochemical reactions that generate end products, which either enter the TCA cycle directly or are converted into intermediates that feed into the cycle (94). PDH catalyzes the conversion of pyruvate into acetyl-CoA (109,110). Different flavonoids, such as betulinic acid, can inhibit the activity of PDH in cancer cells, as demonstrated in an in vitro study (111). Typically, RCC cells divert glucose for aerobic glycolysis breakdown from the TCA cycle. Thus, glutamine and fatty acids are needed by kidney cancer cells to power the TCA cycle (111,112). Further study is required to fully establish the direct actions of flavonoids against the TCA cycle in the metabolic reprogramming of RCC. Future research is needed to fully understand how flavonoids affect RCC metabolism, particularly given the complex interactions suggested by their potential influence on mitochondrial function, redox balance, and enzyme activity.

Normal kidney cells filter blood and reabsorb nutrients, which are processes that are heavily dependent on ATP. These cells have high OXPHOS activity, which is supported by the electron transport chain (ETC) (94). In renal cancer cells, decreasing the activity of the TCA cycle also results in diminished ETC activity (94). A study has measured the activity of OXPHOS and the ETC in RCC tissues (93). From the less aggressive to the most aggressive type of RCC, there is an increase in mitochondrial damage. Marked downregulation of OXPHOS complexes, which impairs the overall OXPHOS process, has been observed. This impairment is linked to dysfunction in the ETC, which is responsible for generating the proton gradient required for ATP synthesis (113). Different phytochemicals present in various medicinal plants control the activity of different complexes. Curcumin is a flavonoid that suppresses the activity of ATP synthase (113–116). A study examined the role of metabolic reprogramming in breast cancer, specifically focusing on the targeting of the ATP synthase complex (117). The flavonoid arctigenin also inhibits mitochondrial complexes II and IV, selectively killing only OXPHPOS-dependent pancreatic cancer cells (116). Some flavonoids, including luteolin, myricetin, fisetin, rhammetin, and baicalein, directly inhibit complex I activity by lowering H₂O₂ production in rat heart mitochondria (118). Other flavonoids, such as hispidulin and eupafolin, inhibit complex III by lowering H₂O₂ production (118). Flavonoids may influence mitochondrial processes that could modify cellular energy metabolism, thereby potentially affecting OXPHOS in the metabolic reprogramming of RCC. The therapeutic implications of flavonoids in targeting OXPHOS in RCC require additional investigation, including clinical studies.

Kidney cancer cells, particularly ccRCC cells, exhibit distinct metabolic reprogramming that supports their rapid proliferation and survival under hypoxic conditions. This reprogramming often involves a shift from OXPHOS to glycolysis, even in the presence of oxygen (91). Hypoxia-inducible factor 1 (HIF-1) serves a central role in this metabolic adaptation. HIF-1 is a transcription factor that is stabilized and activated under hypoxic conditions, leading to the upregulation of genes involved in glycolysis, angiogenesis, and cell survival (91,119). Quercetin, resveratrol, and EGCG have been shown to decrease HIF-1α protein levels by promoting its degradation and inhibiting its synthesis (91,120). This effect occurs through the inhibition of the PI3K/Akt/mTOR signaling pathway, which serves a crucial role in the translation and stabilization of HIF-1α (121). Kaempferol influences mitochondrial function and OXPHOS, providing an additional layer of metabolic regulation by activating the AMP-activated protein kinase pathway. This shifts the metabolic balance towards OXPHOS, reducing the reliance on glycolysis and inhibiting cancer cell proliferation (73). Luteolin promotes mitochondrial apoptosis by increasing the production of ROS and disrupting the mitochondrial membrane potential. This leads to the activation of caspase-dependent apoptotic pathways, thereby reducing the survival of cancer cells (122).

Glycolysis is diverted from glucose 6-phosphate (G-6-P) to fructose 6-phosphate by the PPP. In the context of cellular metabolism, this process provides crucial components for nucleotide synthesis. Specifically, it generates five-carbon sugars (ribose and deoxyribose) and reduces equivalents in the form of NADPH. The five-carbon sugars are essential for the backbone structure of nucleotides, which are the building blocks of DNA and RNA. NADPH is a key reducing agent that supplies the necessary electrons for various biochemical reactions, including those involved in the synthesis of nucleotides. This synthesis is vital for cell proliferation and repair, making these components critical for maintaining cellular function and integrity (123). The PPP in renal cancer cells acts as a defense against high levels of oxidative stress. This pathway influences kidney diseases by altering key metabolic processes involved in disease progression. For example, in diabetic kidney disease, the pathway can affect the accumulation of advanced glycation end-products and oxidative stress, which are critical in the development of diabetic nephropathy. By modulating these factors, the pathway may help mitigate inflammation, fibrosis, and oxidative damage associated with kidney injury. In cases of kidney damage, the pathway modulation of oxidative stress and cellular repair mechanisms can impact the extent of tissue damage and repair processes, potentially slowing disease progression and improving renal function (12,93). According to a previous study, RCCs may rewire their metabolism to control glucose flow into the PPP (124). G-6-P enters the PPP pathway, which produces precursors for lipids, nucleotides, and NADPH. These molecules provide cells with the energy and substrates required for the creation of macromolecules, which promotes the growth of tumors (125). Two steps in the PPP are often reprogrammed in cancer. First, the oxidative phase, an irreversible step that involves the enzyme G6PD, which catalyzes the conversion of G6P to 6-phosphoglucose lactone. The step is considered rate-limiting and is crucial for generating NADPH, which is essential for counteracting oxidative stress. Second, the non-oxidative phase, the subsequent step involving the enzyme ribulose-5-phosphate epimerase, which converts ribulose-5-phosphate into xylulose-5-phosphate. This step is important for the generation of nucleotides and amino acids, which are often upregulated in cancer cells to support rapid cell proliferation (126).

Renal cancer cells express glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, at high levels (127). Similar to G6PD, other oxidative branch NADPH-generating enzymes, such as 6-phosphogluconate dehydrogenase (6PGD), regulate PPP flux in renal cancer cells (93). Different phytochemicals, including caffeic acid, ellagic acid and physcion, directly downregulate the activity of G6PD and 6PGD in different types of cancer, including lung cancer, leukemia, and breast cancer (124,125,128). Limited research has been performed on the precise impact of flavonoids on the PPP in the metabolic reprogramming of RCC. Flavonoids may indirectly impact the PPP. The PPP is essential to sustain redox equilibrium and supply the building blocks for nucleotide synthesis (129,130). Although further research is required to understand the precise mechanism and clinical implications, the aforementioned information suggests that flavonoids may impact the course of RCC by modulating the PPP.

One of the most prominent metabolic abnormalities found in cancer cells is defective lipid metabolism, which serves a major role in the development and metastasis of cancer cells (131). Dysregulated lipid de novo synthesis was observed in tumor cells in the 1950s, and this was found to be a critical metabolic state for cancer cells (132). Obesity is frequently linked to RCC, and patients with ccRCC have been found to exhibit greater levels of cholesterol ester accumulation in their kidneys (93). An outline of the metabolic pathways for fatty acids in ccRCC and how flavonoids alter them is shown in Fig. 4. Metabolomics research has revealed that ccRCC cells exhibit higher levels of fatty acyl-carnitines and carnitine than control cells (16). These differences were shown to be closely linked to the clinical features of patients with kidney cancer. Furthermore, RCC cells have a markedly compromised β-oxidation pathway, which may cause a greater accumulation of fatty acyl-carnitines (133). Since the formation of lipid droplets in the cytoplasm produces the characteristic clear cell phenotype, ccRCC is considered to be characterized by these droplets (134). Additionally, the accumulation of lipid droplets around the endoplasmic reticulum (ER) supports the ER integrity in ccRCC cells (135). It has been demonstrated that, compared with normal kidney cells, ccRCC cells exhibit downregulation of fatty acid oxidation enzymes, such as acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl CoA desaturase (SCD) (136). NADPH oxidation is catalyzed by the β-ketoacyl reductase (KR) and enoyl reductase domains of the multifunctional enzyme FAS (93). EGCG can inhibit the enzymatic activity of FAS in vitro by competing with NADPH to bind the KR domain (135,137). Emodin flavonoids can also inhibit FAS activity in breast, liver, prostate, leukemia, and colon cancer (133). SCD1 is the enzyme that is responsible for lipid storage, which is highly expressed in ccRCC and serves an important role in growth and proliferation (138). Flavonoids, such as betulinic acid and platyphylloside, directly inhibit SCD1 in colon cancer (139). Flavonoids reduce the activity of SCD1, which subsequently inhibits RCC growth. FAS is also associated with RCC tumor growth aggressiveness and poor patient survival (140). The activity of FAS can be directly affected by flavonoids such as kaempferol, luteolin, morin, platyphylloside, quercetin, and resveratrol (131,133,135,137,141,142). HIFs are essential for the proliferation of RCC cells (91). Flavonoids such as oroxylin A, resveratrol, methylalpinumisoflavone, and EGCG can also regulate the activity of HIFs, which has been primarily observed in patients with breast cancer (133,143,144). Malonyl CoA is produced by ACC, a rate-limiting enzyme for fatty acid synthesis (145). Soraphen A is a polyketide that inhibits the activity of ACC1, which is upregulated in ccRCC (139). Additionally, quercetin reduces the production of triacylglycerol and fatty acids in rat hepatocytes and inhibits ACC without having any detectable influence on FAS (146). One of the distinctive features of kidney cancer is the reprogramming of the glycerophospholipids and arachidonic acid metabolism (147). The primary constituents of cell membranes are glycerophospholipids, which are also the sources of triacylglycerol, lysophosphatidic acid (LPA), and phosphatidic acid, which are the building blocks of lipid storage. Autotaxin, the enzyme responsible for producing LPA, is highly expressed in the endothelial cells surrounding the tumor, and its activity can be inhibited by several polyphenols (148). Arachidonic acid, a crucial compound in RCC derived from membrane phospholipids, is synthesized through pathways involving inflammatory enzymes such as cyclooxygenase (COX)-1, COX-2, and lipoxygenases (149). Different flavonoids have a potential effect on these inflammatory enzymes and have exhibited inhibitory effects on them. Quercetin, EGCG, and resveratrol have been reported to inhibit the activity of COX-1 and COX-2 in enzymatic assays (82,135,150). Compared with normal kidney cells, RCC cells express more of these enzymes (82). Numerous investigations have demonstrated that elevated COX-2 levels are linked to tumor size, stage, and grade in RCC. These findings imply that COX-2 may be a target in ccRCC (151,152). Sterol regulatory element binding protein-1 (SREBP-1) is a key regulator of lipid metabolism. Specifically, flavonoids may inhibit SREBP-1 activity, thereby reducing the expression of genes involved in lipogenesis and contributing to the reprogramming of metabolic pathways in ccRCC (153). Recognized antioxidants and anti-inflammatory flavonoids may affect important facets of RCC fatty acid metabolism. According to some research, flavonoids may alter lipid metabolism-related enzymes and pathways, which may have an impact on lipid synthesis, storage, and utilization in RCC cells. Targeting fatty acid metabolism with flavonoids offers a promising approach to understanding and creating treatment plans for RCC; however, further research is required to fully evaluate their effectiveness.

In the context of cancer cell metabolic reprogramming, amino acid metabolism is increasingly recognized for its critical role. Amino acids serve not only as substrates for protein synthesis but also act as essential mediators of redox homeostasis and support various biosynthetic pathways that are upregulated in kidney cells (154) (Fig. 5). Their significance is underscored by the rapid proliferation of renal cancer cells, which depend heavily on amino acids as both metabolites and metabolic regulators to promote growth (94). This underscores the potential of targeting amino acid metabolic pathways as a strategy to manage and inhibit cancer cell proliferation effectively in different ways mentioned below (155).

Glutamine is one of the primary nutrients that cancer cells use to preserve their biomass and bioenergetics. Furthermore, it serves as a component in the synthesis of lipids and proteins. In the renal cortex, glutamine is employed to keep the pH of the urinary system stable (156). Compared with that in normal kidney tissues, the use of glutamine in ccRCC is increased, and the GSH/GSH disulfide balance is strictly regulated (156). Increased levels of glutamine are linked to elevated levels of free fatty acids in RCC (93,156). Furthermore, in rapidly proliferating renal cancer cells, one of the predominant metabolic pathways is the reductive carboxylation of glutamine (156). In transgenic mouse models of human RCC, there was an increase in the amounts of glutamate and α-ketoglutarate, alongside upregulation of glutaminase (GLS), which serves a crucial role in glutamine metabolism and supports the metabolic needs of rapidly proliferating cancer cells (156). Based on assessment of the literature, it has been established that HIF expression serves a crucial role in triggering the reductive carboxylation of α-ketoglutarate in RCC cells. Additionally, the reversal of isocitrate dehydrogenase flux to the reductive carboxylation of glutamine to citrate has been predicted (93,156). GSH peroxidase 1 (GPX1) expression is upregulated in ccRCC cells. The activity of GLS and GPX1 can be controlled by the flavonoids present in different medicinal plants (93). Curcumin is a flavonoid that downregulates the activity of GLS in RCC (93). GLS is an important enzyme that converts glutamine into glutamate in the metabolic reprogramming of RCC, which can be directly inhibited by betulinic acid (150,157).

Serine can be obtained through extracellular absorption, with a portion of it derived from glucose metabolism (155). Serine and glycine are two amino acids that are connected during biosynthesis, and function as vital precursors for the formation of proteins, lipids and nucleic acid building blocks, all of which are essential for the growth of cancer (155). Under the catalysis of serine hydroxy methyltransferases, serine, whether synthesized de novo from 3-phosphoglycerate or imported from external sources, can be further converted into glycine (158). Threonine dehydrogenase and glycine C-acetyltransferase may also convert threonine into glycine (159). The creation of macromolecules, including lipids, proteins and nucleic acid, requires methyl groups for one-carbon metabolism, which glycine subsequently supplies (160). Serine is also involved in DNA methylation, an important step for the metabolic reprogramming of cancerous cells (161). Various synthetic drugs are currently in clinical trials targeting different metabolic pathways to reprogram renal cancer cells (159). However, synthetic drugs often come with side effects, which makes natural alternatives an appealing option (40). Plant-derived secondary metabolites, such as flavonoids, including quercetin, apigenin, morin and resveratrol, have shown efficacy in reprogramming cancer cells with potentially fewer side effects (162).

Numerous solid tumor cells quickly succumb to growth media without arginine, which is an important amino acid (163). Additionally, it participates in several crucial cellular metabolic processes, including the urea cycle, the manufacture of nitric oxide, proline and glutamate, as well as nucleotide biosynthesis (16). Arginine can also be depleted by catalytically converting arginine to citrulline using the pegylated version of arginine deaminase (163). In addition to catalyzing the synthesis of argininosuccinate from citrulline and aspartic acid, argininosuccinate synthetase (ASS) is an enzyme that limits the pace at which arginine may be synthesized entirely from the beginning (163). Renal and parenchymal cells, which can recycle citrulline back to arginine, are examples of cells with normal expression levels of ASS1 (16). However, cells lacking ASS1, such as ccRCC cells, are unable to convert citrulline into arginine (16). Other enzymes, such as argininosuccinate lyase, catalyze the conversion of argininosuccinate to arginine and fumaric acid, which in turn connects arginine metabolism to the TCA cycle-generated energy metabolism of glucose (163). According to the literature, certain human malignancies, such as hepatocellular carcinoma and malignant melanoma, lack ASS, making them vulnerable to arginine deprivation treatment since they are unable to synthesize arginine (164). The activity of these enzymes may be influenced by the flavonoids present in different medicinal plants (165). During oncogenesis, cells often become dependent on external supplies of arginine due to the loss or absence of the enzyme ASS1. While ASS1 is normally expressed in proximal tubule cells, it is absent or not significantly expressed in ccRCC (16,163–165). In arginine metabolism, the activity of arginase and nitric oxide synthase serves vital roles in cancer cell proliferation and immune response (165). Researchers have investigated flavonoids such as quercetin and genistein for their potential effects on nitric oxide production, which is intricately linked to arginine metabolism (123,166). The specific impact of flavonoids on RCC and arginine metabolism requires further research.

There are three main downstream pathways of tryptophan. The serotonin, indole acetate and kynurenine pathways are significant in understanding its metabolism (15,94). Indoleamine 2,3-deoxygenase (IDO) catabolizes the majority of tryptophan. Through the kynurenine pathways, it serves as a rate-limiting enzyme in this reaction. Tryptophan levels in ccRCC are lower compared with those in normal kidney cells, indicating higher consumption (167). ccRCC tissues exhibit elevated amounts of quinolinate and kynurenine (168). On the other hand, there is a decrease in the amounts of enzymes that support the kynurenine pathways, such as aldehyde dehydrogenase 2, monoamine oxidase and DOPA decarboxylase, in RCC, which is considered to be related to the serotonin and indole acetate pathways (169). These findings suggest the reduction of tryptophan/kynurenine through IDO enrichment in RCC (170). The approval of PD-1 inhibitors such as nivolumab as second-line treatments for RCC represents an advancement in immunotherapy. These inhibitors work by blocking the PD-1 pathways, which normally help to dampen the immune response and prevent autoimmunity. By inhibiting PD-1, these drugs enhance the activity of cytotoxic T cells against cancer cells, leading to increased tumor cell death. In addition to PD-1 inhibitors, adjuvant therapies that stimulate cytotoxic T-cell activity are employed to further boost the immune response (171). Tryptophan catabolism by IDO and other enzymes can suppress T-cell activity and contribute to immune evasion by tumor (172). These therapies help to optimize the effectiveness of PD-1 inhibitors by promoting a more robust and sustained immune attack on RCC cells (173). The activity of enzymatic pathways can be influenced by flavonoids such as morin, quercetin, EGCG, resveratrol and betulinic acid because tryptophan metabolism is involved in various cellular processes, including immune modulation and the production of metabolites, such as serotonin and kynurenine (174).