Genitourinary cancer (GC) engirds a group of heterogeneous cancers about three major organs kidney (2.3%), bladder (3.2%), and prostate (7.8%). The major histological subtypes of this cancer include renal cell carcinoma, urothelial carcinoma, and prostate cancer (Zarrabi et al., 2019; Sung et al., 2021). Renal cell carcinoma (RCC) is classified as clear cell RCC which is among the 80% diagnosed and the other 20% are nonclear cell RCC (Zarrabi et al., 2019; Riscal et al., 2021). Unfortunately, the tumor proved resistant to anticancer therapies. As a result, RCC has been challenging to treat (De Meerleer et al., 2014; Ross and Jones, 2017; Linehan and Ricketts, 2019).

Urothelial carcinoma is the most prevalent type of urinary bladder cancer. Its tumorgenicity can be presented by 70%–75% of non-muscle-invasive bladder cancer (NMIBC) and 30% of the muscle-invasive bladder (MIBC). MIBC has a high mortality rate compared to NIMBC as it has a limited metastatic disease potential, though it depicts a high recurrence rate (Cheng et al., 2009; Lavallee et al., 2021; Huang et al., 2022).

Prostate cancer (PC) is the most frequent cancer in men. The risk of developing PC is very frequent. The treatment of PC contingents on the stages of the disease, histological grade, and serum prostate-specific antigen level. Radical prostatectomy is regularly used to treat localized PC. However, the recurrence rate (27%–53%) is very high (Hu et al., 2009; Vikramdeo et al., 2023).

The non-coding RNAs (ncRNAs) are less frequently expressed than the protein-coding genes, where their characteristic functional structures are well conserved across evolutionary timescales. It is well-established that ncRNAs function as both tumor enhancers and tumor suppressors in nearly all types of cancer (Mattick and Makunin, 2006; Tantray et al., 2023). Despite these expression patterns, ncRNAs are precisely tuned to specific tissues or cancer types, regulating complex mechanisms (Table 2). Thus, they establish an elaborate network of interactions that contribute to cancer development and progression (Grillone et al., 2020). ncRNAs are divided into long non-coding RNAs, microRNAs, and circularRNAs.

Long non-coding RNAs (lncRNAs) are generally about 200 nucleotides to 100 kilobases. Genomic regions transcribed into certain low-level lncRNAs have fewer exons, known as long intergenic RNAs (lincRNAs) (Ransohoff et al., 2018; Gallo Cantafio et al., 2023). There are over 5,400 to 10,000 lncRNA generated from various DNA elements in the genome. LncRNAs are implicated in the regulation of embryonic stem cell differentiation, as well as being involved in various disease progression (Villegas et al., 2007; Mattick et al., 2023). The lncRNA expression is more specific to cell and tissue type compared to protein-coding genes. The sequence similarity of lncRNA is conserved in secondary structures (Hung et al., 2014; Xu et al., 2021; Mattick et al., 2023). lncRNAs have the potential to form complex three-dimensional structures due to their long length and can contain multiple structural or functional domains. They also have a high number of protein-binding sites for the multimerization of proteins or scaffolding for the assembly of large multimeric proteins (Ma et al., 2013). The secondary or tertiary structures of lncRNAs play an indispensable role in their interactions with proteins and other nucleic acids to regulate gene expression (Shi et al., 2001; Zampetaki et al., 2018). lncRNAs can regulate gene expression, epigenetic modifications, transcription, post-transcriptional activity, and metabolic function. Additionally, LncRNAs indirectly modulate gene expression via RNA-binding protein partners or miRNAs (Olgun et al., 2018; Li et al., 2020).

MicroRNAs (miRNAs) are short ncRNA molecules (∼22 nucleotides) (O’Brien et al., 2018). miRNAs typically interact with the promoter region, 3′ UTR & 5′ UTR region, coding sequence, and gene promoters, to suppress the expression of the target gene (Gu et al., 2009). The miRNAs are capable of activating gene expression by two mechanisms, via inhibiting translation or by degradation of complementary mRNA. miRNAs are transported or exported within the intracellular compartments to regulate cell fate by controlling transcription and translational activity (Peng and Croce, 2016).

Single-stranded, covalently closed circRNAs possess a unique structure with a longer half-life and have recently been involved in various diseases including cancer (Zhou et al., 2020; Raza et al., 2022). Additionally, circRNAs were shown to act as miRNA sponges (Bosson et al., 2014). However, the role of circRNAs in physiological or pathological conditions remains poorly understood.

Deregulated glucose metabolism is a defining characteristic of cancer (Ward and Thompson, 2012; Pavlova and Thompson, 2016). miRNAs can target glucose metabolic enzymes either directly or indirectly through intermediary loops, for instance, miR-34a/c and miR-374a directly target LDH mRNA in pancreatic can (Wang et al., 2015). Interestingly, miR-34a is decreased in bladder cancer. Transfection of miR-miR-34a mimics upregulated expression of PTEN, thereby decreasing cancer cell growth and viability (Hoque et al., 2003; Vinall et al., 2012). Similarly, miR-34a expression is inhibited in prostate cancer tissue (Duan et al., 2015). This evidence suggests the tumor-suppressor role of miR-34a in bladder and prostate cancer. On the contrary, miR-34a is upregulated in chromophobe renal cell carcinoma, where MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 are downregulated. Another miRNA, miR-155 targets C/enhancer-binding protein alpha which is a transcription factor for miR-143 that inhibits hexokinase 2 (Jiang et al., 2012). Cell-free miR-155 expression is correlated with the stage, and grade of bladder cancer and renal cell carcinoma (Aveta et al., 2023). Further, miR-124 regulates genes of both pyruvate kinase M2 (PKM2) and pentose phosphate pathway (PPP) in prostate cancer and bladder cancer (Sun et al., 2012; Qiu et al., 2015; Taniguchi et al., 2015). The miR-124 was found to be significantly lower in renal cell carcinoma tissue compared to the normal tissue. However, the involvement of miR-34a, miR374a, and miR-124 has not been extensively studied in the mitochondrial metabolism of genitourinary cancer.

LncUCA1 activates mTOR, by inducing signal transducer and activator of transcription 3 protein, and inhibiting miR-143, thereby upregulating hexokinase 2 and glycolysis in bladder cancer (Li et al., 2014). Another lncRNA PCGEM1 is shown to be overexpressed in prostate and renal cell carcinoma, suggesting its role as an oncogenic ncRNA. Interestingly, this promotes glucose uptake for aerobic glycolysis and couples it with PPP to facilitate nucleotide and lipid biosynthesis, thereby generating NADPH for redox homeostasis (Hung et al., 2014).

Hu et al. (2017) discovered that the lncCASC8 gene is reduced in high-grade bladder cancer. CASC8 protein binds to the fibroblast growth factor receptor 1 (FGFR1) and abrogates lactate dehydrogenase-A phosphorylation, thereby reducing glycolysis, and inhibiting bladder cancer cell growth. In RCC, the knockdown of the lncFILNC1 gene increases the c-Myc protein level by the FILNC1-AUF1-c-Myc signaling axis under glucose starvation conditions (Xiao et al., 2017). Another, lncRNA, SLC16A1-AS1 was shown to improve glycolysis and mitochondrial respiration by increasing ATP synthesis in bladder cancer. This leads to an increase in the proliferation of bladder cancer by fatty acid -oxidation (Logotheti et al., 2020).

During hypoxia, RCC cells show upregulated expression of miR-210. This study supports that miR-210 upregulation in RCC is predominantly mediated by hypoxia-inducible factor- 1 (Juan et al., 2010; McCormick et al., 2013; Wach et al., 2013). Another study has found that miR-429 decreased RCC cell growth and viability by inhibiting PDCD4, VEGF, c-myc, and AKT pathways (Su et al., 2020). miR-210 was found to be upregulated in the blood serum of bladder cancer patients, and its levels increase with the progression of the disease (Yang et al., 2017). Furthermore, miR-210-3p was shown to regulate bladder cancer growth, invasion, and metastasis by targeting FGFRL1. Similarly, in prostate cancer, overexpression of miR-210-3p was found significantly higher in tumor tissues. In addition, the expression levels of miR-210-3p are correlated with bone metastasis in prostate tissue (Ren et al., 2017).

Glutamine is a key nutrient that fuels cellular metabolism, especially in cancer cells (Figure 3). Glutamine is transformed into glutamate through the action of an enzyme called glutaminase (GLS). There are two types of glutaminase, kidney type (GLS) and liver type (GLS2) (Katt et al., 2017). Two paradigms of GLS modulation have emerged: the first is the concurrent regulation by miR-23a/b and the lncRNA CCAT2, and the second is the allele-specific metabolic reprogramming of glutamine by CCAT2 (Redis et al., 2016). Additionally, miR-23b and miR-23b share the same transcript, with the latter inhibiting GLS translation. Importantly, miR-23b downregulates POX/PRODH in renal cell carcinoma. Findings from the MYC-inducible human Burkitt lymphoma model P493 and PC3 human prostate cancer cells affirm that MYC primarily suppresses POX/PRODH expression by up-regulating miR-23b (Liu et al., 2010; Liu et al., 2012).

Recent studies found that lincRNA-p21 can inhibit bladder cancer proliferation by negatively regulating glutaminase, glutamate, and α-ketoglutarate expression (Benitez et al., 2021; Scholda et al., 2023). Overexpression of glutaminase rescued inhibitory nature of lincRNA-p21 on bladder cancer survival. Additionally, the abundance of lincRNA-p21 and glutaminase dictates the response of bladder cancer cells to BPTES (glutaminase inhibitor) treatment. In bladder cancer tissues the lincRNA-p21 expression is significantly decreased, while glutaminase mRNA level is increased compared to normal tissues (Zhou et al., 2019). It has been observed that in prostate cancer, lincRNA-p21 downregulates and stimulates apoptosis. On the other hand, the malignant prostate tissues showed a reduction in the expression of the downstream genes of p53 (Wang et al., 2017). Moreover, lncRNA-p21 augments the methylation of STAT3 by enhancer of zeste homolog 2 (EZH2), leading to prostate cancer neuroendocrine transdifferentiation (Luo et al., 2019).

LncRNA UCA1 is a critical player in bladder cancer cells. LncUCA1 is significantly expressed in bladder cancer tissues compared to normal tissue. LncUCA1 was shown to reduce ROS production to rescue mitochondrial function by altering glutamine metabolism. LncUCA1 can also upregulate glutaminase levels and increase mRNA expression of both GLS1 and GLS2. miR-16 directly binds to the 3′UTR of GLS2 mRNA to inhibit bladder cancer growth, whereas lncUCA1 was found to interfere with miR-16’s tumor suppressor role in bladder cancer cells. This study indicates that the UCA1-miR-16-GLS2 axis regulates redox state, and glutamine metabolism, contributing to tumorigenesis (Li et al., 2015).

In addition to GLS, other key enzymes involved in TCA cycle are targeted by ncRNAs, such as isocitrate dehydrogenase (IDH) by miR-181a and miR-183, or PDK1 by let-7 (Fedele et al., 2022). LncGAS5 acts as a tumor suppressor by blocking TCA cycle regulation (Sang et al., 2021). Another study found that GAS5 overexpression decreased cell viability through inhibition of enhancer of zest homolog 2 (EZH2) transcription by interacting with E2F4, which resulted in increased expression of miR-101. Treatment with Gambogic acid elevated the level of GAS5 and its knockdown abolished gambogic acid-induced apoptosis in bladder cancer cells (Wang et al., 2018). However, overexpression of GAS5 can inhibit cell proliferation by inhibiting androgen receptor transactivation in castration-resistant prostate cancer cells (CRPC). Interestingly, a feedback loop has been discovered where suppressed androgen receptor downregulates the expression of GAS5, leading to increased transcription activity in CRPC. This study suggests that GAS5 plays a key role in androgen receptor axis activity and CRPC progression (Lv et al., 2021). GAS5 and miR-34a were positively correlated in renal cell carcinoma, however further studies are required to explore the effect of GAS5 on mitochondrial metabolism of renal cell cancer.

Oxidative phosphorylation uses the reduction of oxygen to produce high-energy ATP by the chemiosmotic electron transfer chain (ETC). In tumor cells, the functional electron transport chain is essential for promoting tumor growth by enabling the proliferation of cells through the mitochondrial complex I and III (Nolfi-Donegan et al., 2020; Ojha et al., 2022). A recent study used bioinformatics analysis to screen candidate target genes of miR-195 in bladder cancer, to identify which genes may play a role in regulating mitochondrial function. The analysis found that glutamate dehydrogenase 1 (GLUD1) and ADP- ADP-ribosylation protein (ARL2) were the ideal targets for miR-195 (Li et al., 2017). In bladder tumor cells, miR-195 directly inhibited ARL2 mRNA and protein levels, indicating that miR-195 may function as a tumor suppressor gene (Yu et al., 2018). LncUCA1 acts as a competing endogenous RNA to decrease the expression level of miR-195, resulting in increased ARL2 expression. This study highlights that the UCA1-miR-195-ARL2 signaling axis sustains mitochondrial metabolism in bladder cancer (Li et al., 2017; Newman et al., 2017).

Overexpression of miR-195 has been found to suppress the proliferation, migration, invasion, and apoptosis of a human clear cell renal cell carcinoma cell line, by inhibiting both the MAPK signaling pathways (Sun et al., 2016). Similarly, in prostate cancer, overexpression of miR-195 significantly inhibits cancer growth and epithelial-mesenchymal transition (EMT). This study further indicated that miR-195 inhibitor rescued the effect of 5-azacytidine on cell viability and metastatic potential of prostate cancer cells (Liu et al., 2015).

Conventional radiotherapy can adaptively induce antioxidant enzyme expression, manganese superoxide dismutase, glutathione peroxidase 2, and thioredoxin reductase 2, promoting therapeutic resistance (Liu et al., 2022). The overexpression of miR-17-3p, inhibits these three major antioxidant enzymes, thereby sensitizing prostate cancer cell lines to ionizing radiation. Therein, inhibition of NFκB-mediated protein activation has been shown to improve radiotherapy for aggressive tumors, including advanced prostate cancer (Xu et al., 2010; Xu et al., 2018). A new study has revealed that bladder cancer tissue samples and cells have significantly downregulated circ_0004463, indicating circ_0004463 role as a tumor suppressor. On the contrary, miR-380-3p was found to be upregulated in bladder cancer. It provides bladder cancer cell proliferation by mitochondrial metabolism, suggesting miR-308-3p role as a tumor promoter (Wu et al., 2020b).

LncRNAs play a significant role in reprogramming of cancer lipid metabolism by regulating the expression of multiple signaling pathways during tumor development (Sellitto et al., 2021). LncRNA phospholipid-binding protein annexin A3 (AnxA3) negatively regulates the differentiation of adipose tissue into fat cells. There are two subtypes of AnxA3: 33 kDa and 36 kDa. The expression of 36 kDa AnxA3 is significantly decreased in renal cell carcinoma (ccRCC), while the expression of 33 kDa AnxA3 is increased, resulting overall decrease in AnxA3 expression. When ccRCC cells were exposed to an adipose culture medium, the expression of 36 kDa AnxA3 was found to be low, indicating that AnxA3 plays a negative role in the storage of lipids in ccRCC cells (Gu et al., 2009). Therefore, the impact of AnxA3 on RCC and its underlying mechanisms requires further investigation.

In prostate cancer cell lines, LNCaP and C4-2B, miR-185 and miR-342 regulate lipid and cholesterol production by inhibiting sterol regulatory element-binding proteins (SREBP)-1 and −2. This downregulates fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), inhibiting cell growth, migration, and invasion (Li et al., 2013). The miR-17/92 cluster targets peroxisome proliferator-activated receptor α (PPARA), a key lipid metabolism regulator. Testosterone and 1,25-dihydroxy vitamin D3 downregulate miR-17/92, relieving its inhibitory effect on PPARA, promoting lipid synthesis, and slowing tumor progression (Wang et al., 2013). Furthermore, miR-101 suppresses COX-2 expression, inhibiting cell and tumor growth in prostate cancer (Hao et al., 2011). These findings suggest that targeting abnormal lipid metabolism is a promising therapeutic approach for prostate cancer.

It has been shown by a recent study that certain metabolism-related lncRNA, such as LINC02004, DUXAP8, PWAR6, and AC073335, are abnormally regulated in bladder cancer (Zhang et al., 2019; Cui et al., 2021; Li et al., 2021; Wan et al., 2021; Wu et al., 2021). However, it is important to note that these lncRNA are not known to be involved in the regulation of lipid metabolism.