A strong connection exists between iron metabolism homeostasis and ferroptosis. Within cells, hydrogen peroxide (H₂O₂) and iron ions (Fe²⁺) react through the Fenton reaction under acidic conditions, generating hydroxyl radicals (OH^-), which are among the most destructive oxidants in reactive oxygen species (ROS) (27). These highly reactive ROS can initiate a series of oxidative reactions, including lipid peroxidation, DNA damage, and protein oxidation, ultimately leading to cell death (28). In the plasma, iron enters cells as Fe³⁺, bound to transferrin and its receptor (TF/TFRC), and is subsequently reduced to Fe²⁺ by the action of STEAP3 metalloreductase (29). Excess Fe²⁺ is expelled from cells via solute carrier family 40 member 1 (SLC40A1) and is oxidized back to Fe³⁺ during this process (30). Iron ions (Fe²⁺/Fe³⁺), as primary inducers of ferroptosis, can promote ROS generation through both enzymatic and non-enzymatic reactions (31). Studies have demonstrated that iron chelators can reduce free iron levels, inhibit lipid peroxidation, and thus suppress ferroptosis (32). Consequently, the regulation of iron uptake, utilization, storage, and efflux in cells and tissues can significantly influence susceptibility to ferroptosis (33).

The glutathione-GPX4 axis in amino acid metabolism plays a crucial role in maintaining cellular homeostasis. System Xc-, composed of the light chain SLC7A11 and the heavy chain SLC3A2, mediates the reverse transport of intracellular glutamate and extracellular cystine at a 1:1 ratio. In this process, cystine is reduced to cysteine, which is a vital precursor for the synthesis of GSH (25). GSH serves as a non-enzymatic antioxidant within cells, essential for protecting against oxidative stress damage. The glutathione peroxidase family (GPX) consists of a group of antioxidant enzymes widely distributed in mammals, primarily comprising eight members, namely GPX1 through GPX8 (34). A common characteristic of these enzymes is their ability to catalyze the conversion of organic hydroperoxides (ROOH) or H₂O₂ into water and corresponding alcohols, thereby effectively eliminating intracellular reactive oxygen species (ROS) or lipid peroxides and safeguarding cells from oxidative stress damage (34, 35). Although all members of the GPX family contribute to the anti-oxidative stress process, GPX4 plays an irreplaceable role in ferroptosis, a specific form of cell death. GPX4 utilizes GSH as a reducing agent to directly act on lipid hydroperoxides present in the cell membrane, transforming them into innocuous alcohols, thereby inhibiting lipid peroxidation and preserving the integrity of the cell membrane (36). Consequently, the glutathione-GPX4 axis represents a critical antioxidant defense system in the body. Classical ferroptosis inducers, such as Erastin and Ras-selective lethal small molecule 3 (RSL3), specifically target System Xc- and GPX4, respectively, to exert their effects (37–39). Erastin binds to SLC7A11, blocking its transport function, which leads to impaired cystine transport and reduced GSH production. This results in the accumulation of lipid peroxides, inducing ferroptosis (40). RSL3 forms a covalent bond with GPX4, rendering it inactive, disrupting the cellular redox balance, promoting lipid peroxidation, and inducing ferroptosis (41).

Furthermore, lipid metabolism is intricately linked to ferroptosis. Lipid peroxidation predominantly occurs in membrane phospholipids that are rich in polyunsaturated fatty acids (PUFAs) (42, 43). Specific PUFAs, particularly those found in phosphatidylethanolamine (PE) and phosphatidylcholine (PC), serve as principal targets in ferroptosis (7, 43). ROS or lipoxygenases (LOXs) oxidize non-toxic PUFAs (PL-PUFAs) into toxic lipid peroxides (PL-PUFA-OOH), thereby inducing ferroptosis (32). Key enzymes in the lipid metabolism pathway, such as ACSL4 and LPCAT3, play a crucial role in regulating cellular lipid composition and sensitivity to ferroptosis (42, 44, 45). ACSL4 catalyzes the condensation of free PUFA with coenzyme A (CoA) to form derivatives, which are subsequently esterified into membrane phospholipids by LPCAT3. This process facilitates the onset of ferroptosis (46, 47). Therefore, supplementing PL-PUFA or inhibiting enzymes such as ACSL4 and LPCAT3 can modulate cellular sensitivity to ferroptosis (48–50).

Moreover, recent studies have identified several parallel pathways involved in ferroptosis. FSP1 is a novel ferroptosis resistance gene that operates under conditions of GPX4 deficiency or RSL3 inhibition. It is recruited to the plasma membrane through N-myristoylation, functioning as an NAD(P)H-dependent reductase that converts coenzyme Q10 to ubiquinol-10, thereby preventing the accumulation of lipid peroxides (51). The FSP1-CoQ10-NAD(P)H pathway acts as an independent parallel system that collaborates with GPX4 and glutathione to inhibit phospholipid peroxidation and ferroptosis (52). Conversely, DHODH, an enzyme that catalyzes the conversion of dihydroorotic acid to orotic acid, operates parallel to mitochondrial GPX4, inhibiting ferroptosis of the mitochondrial inner membrane by reducing ubiquinone (CoQ) to panalcohol (CoQH) (53). Recent studies have demonstrated that the PRR11-DHODH axis plays a crucial role in regulating ferroptosis in tumor cells. Miao et al. reported that PRR11 maintains the stability of DHODH by inhibiting its polyubiquitination-mediated degradation, thereby driving ferroptosis and drug resistance in glioblastoma (54). Additionally, genome-wide activation screening has identified a group of genes that can counteract ferroptosis, including GCH1 and its metabolites BH4/BH2 (55). GCH1-expressing cells synthesize BH4/BH2 through lipid remodeling to prevent phospholipid depletion and inhibit ferroptosis, a mechanism that operates independently of the GPX4/glutathione system (55). In conclusion, the regulatory mechanisms of ferroptosis remain to be fully elucidated, and their potential impacts on pathophysiological processes, particularly in urologic malignancies, warrant further investigation.

In the complex pathophysiological mechanisms underlying urinary system cancers, the interplay between miRNAs and ferroptosis has increasingly emerged as a focal point of scientific investigation. MiRNAs, a class of short, non-coding RNAs, play a significant role in regulating cellular physiological and pathological processes through the precise modulation of target gene expression (146). Ferroptosis, an emerging mode of cell death, is characterized by the regulation of intracellular iron metabolism and lipid peroxidation; its role in cancer has been progressively elucidated. In the context of urinary system cancers, the relationship between miRNAs and ferroptosis is particularly noteworthy. Studies have demonstrated that several miRNAs act as key regulators of ferroptosis-related genes, thereby influencing the survival and proliferation of cancer cells by modulating the ferroptosis process. For example, Huang et al. identified that miR-217, derived from bladder cancer (BC) tissue exosomes, plays a crucial role in inhibiting ferroptosis in BC. Functionally, the introduction of miR-217 into cells resulted in a reduction of malondialdehyde (MDA), lactate dehydrogenase (LDH), and Fe²⁺ levels, while simultaneously increasing the level of superoxide dismutase (SOD), thus significantly inhibiting both ferroptosis and apoptosis (147). This finding elucidates the potential mechanisms by which miRNAs regulate ferroptosis in urinary system tumors.

Further exploration reveals that the mechanistic role of the miRNA-ferroptosis axis in urinary system tumors operates at multiple levels. On one hand, miRNAs can directly target crucial genes in the ferroptosis pathway, such as ferritin heavy chain 1 (FTH1) and solute carrier family 40 member 1 (SLC40A1), which are essential for maintaining intracellular redox balance and iron homeostasis (148, 149). The significant role of NRF2 and its target genes in preventing ferroptosis positions this pathway as a promising target for cancer treatment. The NRF2/FTH1 axis is critical for maintaining cellular iron metabolism balance (150). In prostate cancer, miR-29a-5p modulates ferroptosis by influencing the levels and accumulation of intracellular Fe²⁺ and MDA via the NRF2/FTH1 axis (148). Knocking down or inhibiting miR-29a-5p can activate ferroptosis, thereby suppressing the proliferation of PC cells both in vitro and in vivo, providing new insights for subsequent cancer treatment (148). Similarly, miR-4735-3p impedes the growth of clear ccRCC cells by binding to the 3’-UTR of SLC40A1 and downregulating its expression, which resultsing in iron overload and ferroptosis (149). Conversely, miRNAs can mediate interactions between tumor cells and macrophages, thereby indirectly regulating ferroptosis (151). Xiao et al. found that tumor-associated macrophages secrete taurine to inhibit ferroptosis by activating the LXRα/SCD1 axis in PC. Mechanistically, LXRα promotes ferroptosis through its downstream target, stearoyl-CoA desaturase 1 (SCD1), which is recognized as a ferroptosis suppressor gene; its overexpression inhibits ferroptosis. Concurrently, LXRα can upregulate the expression of miR-181a-5p and the RNA-binding protein FUS, promoting the enrichment of miR-181a-5p in tumor-derived exosomes. These miR-181a-5p-enriched exosomes can subsequently modulate macrophage M2 polarization and upregulate the expression of the taurine transporter gene TauT by targeting the Hippo-YAP pathway. This process increases taurine secretion and further inhibits ferroptosis in PC. In summary, the study by Xiao et al. demonstrates that miR-181a-5p can shuttle from tumor cells to macrophages, enhancing taurine secretion as a feedback mechanism and thereby facilitating crosstalk between macrophages and tumor cells (151). This finding provides a novel perspective on the role of miRNAs in mediating interactions between tumor cells and immune cells.

The miRNA-ferroptosis axis demonstrates significant potential in the treatment of urinary system tumors. Acquired chemotherapy resistance frequently occurs in advanced tumors, complicating treatment efforts. Since ferroptosis acts as a tumor suppressor in cancer development, its activation may represent an effective anticancer strategy (152). Research has shown that cancer-associated fibroblast (CAF)-derived exosomes can impede ROS accumulation in prostate cancer cells and reduce mitochondrial damage, thereby inhibiting iron-induced ferroptosis in these cells and promoting acquired chemotherapy resistance (153). Zhao et al. found that miR-432-5p within CAF-derived exosomes inhibits the ferroptosis process by targeting CHAC1 expression, thereby enhancing the resistance of prostate cancer cells to docetaxel. Notably, the knockdown of miR-432-5p expression in CAFs significantly increases tumor sensitivity to chemotherapy (153). Consequently, a comprehensive investigation of the miR-432-5p/CHAC1 axis may provide a promising strategy to counteract acquired chemotherapy resistance in advanced tumors. Moreover, certain anti-tumor compounds have been shown to impact the miRNA-ferroptosis axis. Icariin II (ICS II), an active flavonoid derived from the traditional Chinese medicine Epimedium, exhibits anti-tumor activity across various cancers (154, 155). Yu et al. demonstrated that ICS II inhibits the proliferation, migration, and invasion of RCC cells (156). Functionally, ICS II promotes the accumulation of Fe²⁺, MDA, and ROS in RCC cells while reducing glutathione (GSH) levels, thereby inducing ferroptosis. Mechanistically, ICS II downregulates GPX4 expression through miR-324-3p, and this pathway operates independently of p53. Consequently, ICS II may serve as a promising therapeutic agent for RCC by inducing ferroptosis in RCC cells via its action on the miR-324-3p/GPX4 axis (156). Further research has indicated that the combined application of icariin (ICA) and curcumin produces a synergistic effect in inducing apoptosis and ferroptosis, significantly inhibiting the viability and proliferation of PC cells (157). Both compounds affect lipid metabolism in PC by modulating the miR-7/mTOR/SREBP1 pathway, thereby influencing autophagy and ferroptosis (157).

In the progression of urinary system tumors, miRNAs modulate ferroptosis by targeting ferroptosis-related genes, thereby influencing tumor cell proliferation, invasion, and immune modulation ( Figure 2 ). The aforementioned studies have identified promising avenues for the development of novel ferroptosis-regulating targets, including the miRNA-217, miR-29a-5p/NRF2/FTH1 axis, miR-4735-3p/SLC40A1 axis, and the miR-181a-5p/Hippo-YAP signaling pathway. These targets have the potential to impede the progression of urinary system tumors. In the realm of cancer therapy, precise control of ferroptosis through pathways such as miR-432-5p/CHAC1, miR-324-3p/GPX4, and miR-7/mTOR/SREBP1 presents a promising strategy to enhance the efficacy of drug treatments. This approach not only supports ongoing research into therapeutic interventions but also lays the groundwork for the development of innovative anticancer therapies. Consequently, there is an urgent need to further explore the crucial role of the miRNA-ferroptosis axis in urinary system cancers, as it may enrich our understanding of tumorigenesis and unlock the potential to transform cancer treatment, ultimately enhancing patient outcomes.

Given the ability of long non-coding RNAs (lncRNAs) to regulate gene expression at multiple levels—including chromatin remodeling, transcription, translation, and post-translational regulation—the lncRNA-ferroptosis axis in urinary system cancers has been the subject of extensive research (103). Primarily, lncRNAs regulate ferroptosis in urinary system tumors through gene transcription. For instance, the high expression of lncRNA-LUCAT1 significantly inhibits ferroptosis in bladder cancer (BC) (158). Cao et al. reported that LUCAT1 binds to the m6A reader IGF2BP1 to form a LUCAT1-IGF2BP1 complex, which stabilizes STAT3 mRNA and inhibits the expression of ferroptosis-related genes, including down-regulation of COX2, ACSL4, and NOX1, as well as up-regulation of SLC7A11 and GPX4. This mechanism promotes the migration and invasion of BC cells (158). Additionally, lncRNA MAFG-AS1 also inhibits ferroptosis in bladder cancer by modulating iron metabolism-related proteins (159). Further investigations have shown that high expression of MAFG-AS1 correlates with poor prognosis in bladder cancer patients, while those with low expression exhibit greater sensitivity to adjuvant chemotherapy involving cisplatin and gemcitabine. In conclusion, this study highlights the critical role of the MAFG-AS1/UCHL5/PCBP2/FPN1 axis in cisplatin resistance in bladder cancer, suggesting that inhibition of MAFG-AS1 may promote ferroptosis and enhance cellular sensitivity to cisplatin treatment (159). Second, lncRNA functions as a ceRNA that regulates ferroptosis in urinary system cancers (160–162). LncRNA can exert a “sponge effect” on miRNA, thereby promoting the upregulation of related target gene expression. An illustrative example is lncRNA RP11-89 in BC, which upregulates the expression of PROM2 by sponging miR-129-5p, consequently activating iron output and inhibiting ferroptosis in BC. This finding elucidates the novel role of RP11-89 as an oncogene and suggests the potential for treating BC by modulating the miR-129-5p/PROM2 axis (160). Similarly, lncRNA OIP5-AS1 and SLC16A1-AS1 regulate ferroptosis through the miR-128-3p/SLC7A11 and miR-143-3p/SLC7A11 signaling axes in prostate cancer and kidney cancer, respectively, further confirming the extensive role of lncRNA in regulating ferroptosis in urinary system cancers (161, 162).

As research on urinary system cancers deepens, an expanding body of evidence indicates that ncRNAs, particularly ferroptosis-associated lncRNAs (FRLs), play a significant role in the occurrence, development, and prognosis of these malignancies. Bioinformatics analyses further underscore the considerable potential of FRLs as prognostic markers for urological cancers.

In 2021, Xing et al. first identified that three FRLs—DUXAP8, LUCAT1, and LINC02609—were significantly associated with the overall survival (OS) of renal clear cell carcinoma (163). The risk assessment model developed using these FRLs can accurately predict ccRCC prognosis and offers novel approaches for cancer prognosis screening. This finding not only enhances our understanding of ccRCC prognosis but also provides a critical foundation for the development of personalized treatment options. In a subsequent study, Lai et al. integrated data from the TCGA and FerrDb databases, screening a total of 433 FRLs. They conducted univariate Cox regression, Lasso regression, and multivariate Cox regression analyses, identifying eight FALs (LINC00460, AC124854.1, AC084876.1, IGFL2-AS1, LINC00551, AC083967.1, AC073487.1, and LINC02446) as prognostic features of ccRCC (164). They developed a risk assessment model, FLPS, using these eight FALs. This model not only demonstrates independent predictive value for ccRCC but also elucidates how lncRNAs involved in FLPS influence the progression and survival outcomes of ccRCC. Furthermore, they found that FLPS was closely related to immune infiltration, suggesting the potential therapeutic value of immune checkpoint inhibitors for high-risk ccRCC patients. This discovery provides a new strategy and direction for immunotherapy in ccRCC (164). In renal papillary cell carcinoma (KIRP), Wu et al.’s study also revealed the potential of FRLs as biomarkers (165). They identified a specific group of FRLs associated with both the occurrence and progression of KIRP. CASC19, AC090197.1, AC099850.3, AL033397.2, LINC00462, and B3GALT1-AS1 were significantly upregulated in high-risk groups, suggesting their potential role as oncogenic factors. Conversely, LNCTAM34A and AC024022.1 were significantly upregulated in the low-risk group, indicating their potential function as tumor suppressor factors in KIRP. The differential expression patterns of these FRLs in high-risk and low-risk groups imply that they may serve as either tumor-promoting or tumor-suppressing factors. These findings provide a crucial reference for the early diagnosis, prognosis evaluation, and treatment selection of KIRP.

Studies have demonstrated that a variety of functional RNA molecules (FRLs) serve as prognostic markers not only in renal cell carcinoma but also in prostate and bladder cancers (166–168). FRLs influence tumor cell proliferation and apoptosis directly, while also modulating immune cell infiltration and function by regulating the tumor immune microenvironment. This dual role contributes significantly to tumor development and progression. Therefore, the critical importance of FRLs in urinary system cancers must be acknowledged. Identifying FRLs associated with urinary system tumors and developing a prognostic risk assessment model based on these FRLs will facilitate more accurate prognosis predictions and enable the creation of personalized treatment and monitoring plans. This approach not only enhances the relevance and effectiveness of cancer treatment but also improves patients’ quality of life and extends their survival.

The aforementioned studies have illuminated two critical aspects of the lncRNA-ferroptosis axis in urinary system tumors. Firstly, lncRNAs significantly influence tumor progression and treatment response by modulating ferroptosis. Specifically, lncRNAs such as LUCAT1, MAFG-AS1, RP11-89, OIP5-AS1, and SLC16A1-AS1 exert their effects by regulating ferroptosis-related genes, thereby impacting the development and management of urinary system cancers. Notably, the role of lncRNAs as miRNA sponges adds an additional layer of complexity to this regulatory network, underscoring the necessity for a comprehensive understanding of their interactions. Elucidating the precise mechanisms by which these lncRNA-mediated ferroptotic processes contribute to tumorigenesis is essential for enhancing our understanding of cancer development. Secondly, FRLs identified through bioinformatic methods underscore their strong association with patient prognosis. With an anticipated continuous increase in the identification of FRLs, the establishment of more accurate and sensitive prognostic models based on these biomarkers represents a significant advancement for urinary system cancers.

Similar to lncRNAs, circRNAs can regulate the expression of downstream genes by acting as miRNA sponges, thereby influencing the process of ferroptosis in tumors. Although relatively few studies have focused on circRNAs in urinary system cancers, existing research has highlighted their significant potential in this area. Cen et al. demonstrated that circRNA (Has-circ-0057105) functions as a sponge for miR-577 in renal cell carcinoma, modulating the expression of the COL1A1 and VDAC2 genes at both mRNA and protein levels (169). VDAC2 is a nuclear-encoded mitochondrial protein involved in ferroptosis, responsible for regulating the exchange of ions and metabolites between the cytosol and mitochondria (170). Notably, Overexpression of VDAC2 is closely associated with sensitivity to ferroptosis (40, 170). VDAC2 overexpression did not directly induce ferroptosis in their experiments, nor did it influence cell proliferation or levels of intercellular iron, MDA, and GSH. However, when the ferroptosis inducer Erastin was administered to RCC cells, a more pronounced ferroptosis effect was observed in the VDAC2 overexpression group, characterized by iron accumulation, MDA overproduction, and GSH depletion (169). In summary, this study illustrates that Hsa-circ-0057105 regulates ferroptosis sensitivity in RCC through the miR-577/VDAC2 axis, providing a novel target for RCC treatment. Additionally, circRNAs can bind to functional proteins, influence downstream signaling pathways, and regulate ferroptosis. Wang et al. elucidated the mechanism by which circST6GALNAC6 regulates ferroptosis in BC (171). CircST6GALNAC6 interacts with HSBP1, inhibiting its phosphorylation at serine-15, and thereby activating the P38/MAPK signaling pathway to promote ferroptosis (171). Recently, a novel circRNA, circPKN2, has been identified as significantly down-regulated in bladder cancer and closely associated with patient prognosis (172). Subsequent studies have demonstrated that circPKN2 promotes the ubiquitination of SCD1 and inhibits the WNT pathway by recruiting STUB1 in bladder cancer, thereby enhancing ferroptosis in BC cells and inhibiting tumor growth and metastasis (172).

Therefore, the circRNA-ferroptosis axis plays a crucial role in the development of urinary system cancers ( Figure 2 ). A detailed investigation into the specific mechanisms of these circRNAs in ferroptosis may pave the way for novel therapeutic strategies in the treatment of urinary system cancers.