Urologic malignancies, encompassing cancers of the kidney, bladder, and prostate, represent approximately 25 % of all cancer cases. Recent advances have enhanced our understanding of PVT1's crucial functions. Long noncoding RNAs influence both the onset and development of cancer, as well as epigenetic alterations. Recent findings have focused on PVT1's mechanism of action across several malignancies, particularly urologic cancers. Understanding the various functions of PVT1 linked to cancer is necessary for the development of cancer detection and treatment when PVT1 is dysregulated. Furthermore, recent advancements in genomic and epigenetic research have elucidated the complex regulatory networks that control PVT1 expression. Comprehending the intricate role of PVT1 Understanding the complex function of PVT1 in urologic cancers has substantial clinical implications. Here, we summarize some of the most recent findings about the carcinogenic effects of PVT1 signaling pathways and the possible treatment strategies for urological malignancies that target these pathways.

Carbonic anhydrase-9 (CA9) is highly expressed in clear cell renal cell carcinoma (ccRCC) cells despite no expression in normal kidney tissues. Thus, CA9 has been proposed as a theranostic target for radioligand therapy (RLT). However, ccRCC tends to be radioresistant and may not effectively respond to RLT. Alternatively, CA9 can be targeted for near-infrared photoimmunotherapy (NIR-PIT) of ccRCC. Here, we sought to test NIR-PIT using CA9 in a preclinical model of ccRCC to determine its potential as a therapeutic strategy. Tissue microarray analysis showed that membrane CA9 was expressed in the majority of ccRCC cases. In vitro, CA9-targeted NIR-PIT induced cell membrane damage and cell killing in all CA9-expressing ccRCC cell lines specifically, UOK154, UOK220, and UOK122. In vivo, CA9-targeted NIR-PIT significantly inhibited tumor growth and prolonged survival in UOK154 and UOK220 subcutaneous xenograft models. Notably, 70%-80% of mice achieved complete remission after a single treatment of NIR-PIT. Additionally, remaining tumors after the first NIR-PIT persistently expressed CA9, suggesting that remaining tumors can be treated with repeated NIR-PIT. Furthermore, CA9-targeted NIR-PIT induced significant cytoplasmic damages on ccRCC cells in UOK154 orthotopic xenograft models. In conclusion, CA9-targeted NIR-PIT, which allow for safe and repeated application on the same lesion, is a promising treatment for ccRCC, especially in the management of multiple primary ccRCC (e.g., von Hippel-Lindau syndrome) and oligometastatic ccRCC.

Recent advances in immunotherapy and targeted therapy have resulted in survival rates as high as 90% at 1 year in metastatic renal cell carcinoma patients; however, sustained response and ultimate cure is rarely achieved with systemic therapy alone (complete response rates remain <5%), and progression of disease at distant sites is common. Pulmonary metastasectomy is recommended as a component of multimodal management in patients with favorable-risk or intermediate-risk classification and can be associated with excellent survival if complete resection is obtained.

Renal cell carcinoma (RCC) has traditionally been considered to be radioresistant. Response rates are believed to be improved by a high dose of stereotactic body radiotherapy (SBRT). A retrospective analysis was conducted of patients treated with SBRT for metastatic disease from RCC.

We reviewed records from 20 patients who underwent SBRT for a total of 30 RCC metastases from 2015 to 2020. Patients were included who had a confirmed primary RCC and radiographic evidence of metastasis, either synchronous or metachronous. The most common SBRT fractionation was 30 Gy in 3 fractions.

Median age was 60 years (range, 40-77 years) and 60% were male. After a median follow-up of 18 months (range, 3-36 months), overall survival was estimated to be 85% and 70%, at 1 and 2 years, respectively, and local control at 2 years was 83.33%. Only 5 patients had documented progression of disease, all of whom received biologically effective dose inferior to 100 Gy, and no patients treated with a higher biologically effective dose had disease, which progressed. The most common acute toxicity was grade 1 fatigue (20%). No grade 3 or higher acute toxicity occurred.

Treatment with SBRT in patients with RCC metastases yielded a high local control rate, promising survival rate, and low toxicity.

Ubiquitin-specific protease 35 (USP35) has gained attention as a regulator in cancer progression. However, its specific role in kidney clear cell carcinoma (KIRC) remains unclear.

USP35 expression in KIRC tumor and normal tissues was evaluated using TCGA data. Correlations between USP35 expression, clinical parameters, and survival outcomes were examined. Functional enrichment analyses were performed to explore the pathways associated with USP35 expression. Immune-related analyses were conducted to assess the effect of USP35 on immune cell recruitment and neoantigen presentation. Drug sensitivity analyses were used to identify potential therapeutic agents targeting USP35.

USP35 was significantly overexpressed in KIRC tumor tissues compared to normal tissues, and its high expression correlated with advanced disease stages and poor survival outcomes. Gene set enrichment analysis revealed that high USP35 expression was associated with oncogenic pathways, including glycerophospholipid and linoleic acid metabolism, while low expression linked to nitrogen and purine metabolism. USP35 also modulated immune responses, affecting immune cell recruitment and neoantigen presentation, suggesting a role in immune evasion. Drug sensitivity analysis showed that high USP35 expression correlated with increased sensitivity to paclitaxel, bosutinib, and lapatinib. In vitro knockdown of USP35 significantly reduced KIRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), further supporting its role in tumor progression.

USP35 is overexpressed in KIRC and associated with poor prognosis, likely promoting tumor progression through oncogenic pathways and immune modulation. Its correlation with drug sensitivity positions USP35 as a potential therapeutic target, warranting further investigation into its mechanistic functions and therapeutic applications.

Chromophobe renal cell carcinoma is a rare entity with an excellent prognosis compared with clear renal cell carcinoma and is characterized by distinct molecular and genetic specificity. The presence of a sarcomatoid component is an uncommon phenomenon, which indicates a high risk of metastasis and a poor prognosis. We present the case of a 44-year-old patient with chromophobe renal cell carcinoma with a sarcomatoid component. Therapeutic management presents a significant challenge given the absence of standards of care for this rare entity. The current treatments are based on vascular endothelial growth factor tyrosine kinase inhibitors, mammalian target of rapamycin pathway inhibitors, and immune checkpoint inhibitors. Close monitoring based on clinical, biological, and radiological examinations is necessary for rapid and appropriate interventions. Moreover, this histological variant represents a major clinical challenge, not only because of its aggressive behavior but also due to the absence of specific clinical manifestations and its frequent incidental discovery at an advanced stage, further complicating early diagnosis and management.

Kidney and renal pelvic cancer are a significant cause of cancer-related deaths, with the most common malignant kidney tumor being renal cell carcinoma (RCC). Chromophobe renal cell carcinoma is a rarer form of RCC that poses significant challenges to accurate diagnosis, as it shares many histologic features with Oncocytoma, a benign renal tumor. Biopsies for histopathological and immunohistochemical analysis have limitations in distinguishing chromophobe RCC from Oncocytoma. Syndromic cases may also have tumors with overlapping features. Techniques such as infrared (IR) spectroscopic imaging have shown promise as an alternative approach to tissue diagnostics. In this study, we propose a deep-learning-based framework for automating classification in kidney tumor tissue microarrays (TMAs) using an IR dataset. Feature selection algorithms reduce data dimensionality, followed by a deep learning classification approach. A classification accuracy of 91.3% was observed for validation data, even with the use of 13.6% of all wavelengths, thereby reducing training time by 21% compared to using the entire spectrum. Through the integration of scalable deep learning models coupled with feature selection, we have developed a classification pipeline with high predictive power, which could be integrated into a high-throughput real-time IR imaging system. This would create an advanced diagnostic tool for the detection and classification of renal tumors, namely chromophobe RCC and Oncocytoma. This may impact patient outcomes and treatment strategies.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

It has been confirmed that the expression of miR-501-3p is closely related to the behavior of several cancers. This study aimed to elucidate the effects of miR-501-3p/SPC24 axis on the behavior of renal cancer cells and to identify its prognostic value in renal cancer. First, the expression of miR-501-3p in the renal cell carcinoma (RCC) cell line was detected using real-time quantitative polymerase chain reaction (RT-qPCR). Second, cell function identification experiments were performed, including CCK-8, scratch, transwell invasion, and flow cytometry assays. Several databases were applied to explore the possible mechanism of miR-501-3p tumor suppressor effect in RCC. To explore the value of miR-501-3p/SPC24 axis in predicting renal cancer patient overall survival (OS), GEPIA (http://gepia.cancer-pku.cn/index.html) was used. Finally, western blot was performed to detect the expression level of SPC24 in renal cancer cells predicted by bioinformatics analysis. Dual-Luciferase Reporter Assay was used to verify if SPC24 is a target of mir-501-3p. MiR-501-3p was found to be down-regulated in cancer cells and tissues and to play a role in suppressing tumor cell proliferation, cell viability, cell migration, and cell invasion, while promoting apoptosis. We also found that high expression levels of SPC24 were associated with shorter OS time in patients diagnosed with renal cell carcinoma. In addition, the results of TCGA data analysis and western blot showed that the tumor suppressor effect of miR-501-3p may be achieved by targeting SPC24. The MiR-501-3p/SPC24 axis affects cell proliferation, migration, invasion, apoptosis, and prognosis in renal cell carcinoma.

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO-based treatment in ccRCC.

Three-dimensional (3D) in vitro models enable us to understand cell behavior that is a better reflection of what occurs in vivo than 2D in vitro models. As a result, developing 3D models for extracellular matrix (ECM) has been growing exponentially. Most of the efforts for these 3D models are geared toward understanding cancer cells. An intricate network of cells that engages with cancer cells and can kill them are the immune cells, particularly cytotoxic T lymphocytes (CTLs). However, limited reports are available for 3D ECM mimics to understand CTL dynamics. Currently, we lack ECM mimetic hydrogels for immune cells, with sufficient control over variables, such as stiffness, to fully understand CTL dynamics in vitro. Here, we developed PEG-based hydrogels as ECM mimics for CTLs. The ECM mimics are targeted to mimic the stiffness of soft tissues where CTLs reside, migrate, and deliver their function. To understand cell-material interaction, we determined the porosity, biocompatibility, and stiffness of the ECM mimics. The ECM mimics have median pore sizes of 10.7 and 13.3 μm, close to the average nucleus size of CTLs (~8.6 μm), and good biocompatibility to facilitate cell migration. The stiffness of the ECM mimics corresponds to biologically relevant microenvironments such as lungs and kidneys. Using time-lapse fluorescence microscopy, 3D cell migration was imaged and measured. CTLs migrated faster in softer ECM mimic with larger pores, consistent with previous studies in collagen (the gold standard ECM mimic for CTLs). The work herein demonstrates that the PEG-based ECM mimic can serve as an in vitro tool to elucidate the cell dynamics of CTLs. Thus, this study opens possibilities to study the mechanics of CTLs in well-defined ECM mimic conditions in vitro.

The advent of immune checkpoint inhibitors (ICIs) has transformed the management of advanced and high-risk renal cell carcinoma (RCC). In the adjuvant setting, ICIs, such as pembrolizumab, aim to reduce the risk of recurrence following potentially curative nephrectomy. However, this therapeutic approach introduces unique challenges, particularly related to immune-related adverse events (irAEs). The sarcoidosis-like reaction is a particularly rare immune-related adverse event that can be a diagnostic challenge because of its broad clinical symptoms and potential to mimic metastasis. We present a case of a 50-year-old patient who developed mediastinal and hilar lymphadenopathy during adjuvant pembrolizumab therapy following nephrectomy for stage III RCC, which was initially suspected to be metastatic renal cell carcinoma. Endobronchial ultrasound (EBUS) biopsy revealed non-caseating granulomas without malignancy, leading to a diagnosis of pembrolizumab-induced sarcoidosis-like reaction (SLR). The patient was treated with corticosteroids due to progressive fatigue, leading to a complete resolution of his constitutive symptoms and mediastinal lymphadenopathy. This study highlights diagnostic and therapeutic challenges, the importance of distinguishing irAEs from cancer progression, and strategies to avoid cognitive bias in clinical decision making.

Over the past decade, the realm of immunotherapy-based combination therapy has witnessed rapid growth for renal cell carcinoma (RCC), however, success has been constrained thus far. This limitation primarily stems from the absence of biomarkers essential for identifying patients likely to derive benefits from such treatments.

In this study, the immunotherapy-based combination associated score (IBCS) was established using single-sample gene set enrichment analysis (ssGSEA) based on the genes identified in the key modules extracted by weighted correlation network analysis (WGCNA) in the IMmotion151 dataset, a randomized, global phase III trial.

High IBCS patients showed better responses to immunotherapy-based combinations and had longer progression-free survival (PFS). Further transcriptomic analysis revealed that IBCS was negatively correlated to TIDE score, identifying a subset of RCC patients characterized by enrichment of T-effector and moderate cell-cycle/angiogenesis gene expression. Our analysis of hub genes unveiled a novel molecule that could potentially serve as a target antigen in RCC. Validation through multiplex immunofluorescence assays on tissue microarrays (TMAs) containing 180 samples confirmed the pivotal role of this hub gene in immunoregulation. Furthermore, we developed an independent risk score model, which is significant for prognostic evaluation and patient stratification. Notably, we devised a forecasting nomogram using this risk score model, surpassing the IMDC score (a widely accepted risk score for predicting survival in patients undergoing VEGF-targeted therapy) in prognostic accuracy for patients treated with immunotherapy-based combinations.

This study has collectively developed an immunotherapy-based combination associated score, pinpointed effective biomarkers for prognostic and responsiveness of kidney cancer patients to immunotherapy-based combinations, and delved into their potential biological mechanisms, offering promising targets for further exploration.

Prevalent urological cancers, including kidney, prostate, bladder, and testicular cancers, contribute significantly to global cancer incidence and mortality. Metabolomics, focusing on small-molecule intermediates, has emerged as a tool to understand cancer etiology. Given the knowledge gap in this field, we employ a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between genetically determined metabolites (GDMs) and the susceptibility to four common urological cancers.

The study employs genome-wide association studies (GWAS) data from European populations, featuring the most extensive case count available for both blood metabolites and four prevalent urological cancers. Preliminary and secondary MR analyses were separately conducted, employing inverse variance weighted (IVW) as the primary method. Multiple statistical analyses, including the MR-Steiger test, Cochran's Q test, leave-one-out analysis, MR-Egger intercept analysis, and MR-PRESSO analysis, were executed to ensure robustness. Additionally, a meta-analysis was carried out to consolidate findings. The weighted median (WM) method was utilized for a relatively lenient correction (PWM < 0.05).

After rigorous genetic variation filtering, 645 out of 1,400 metabolites were included in both preliminary and secondary MR analyses. Preliminary MR analysis identified 96 potential causal associations between 94 distinct metabolites and four urological cancers. Secondary analysis based on Finnish outcome data revealed 93 potential causal associations. Cross-database meta-analysis identified 68 blood metabolites associated with four urological cancers. Notably, 31 metabolites remained significant after using WM for correction, with additional 37 suggestive causal relationships. Reverse MR analysis revealed a significant causal association between genetically predicted prostate cancer and elevated 4-hydroxychlorothalonil levels (IVW, combined OR: 1.039, 95% CI 1.014-1.064, p = 0.002; WM, combined OR: 1.052, 95% CI 1.010-1.095, p = 0.014).

This comprehensive MR study provides insights into the causal relationships between blood metabolites and urological cancers, revealing potential biomarkers and therapeutic targets, thereby addressing gaps in understanding and laying the foundation for targeted interventions in urological cancer research and treatment.

Renal Cell Carcinoma (RCC) stands as a formidable challenge within the field of oncology, despite considerable research endeavors. The advanced stages of this malignancy present formidable barriers to effective treatment and management.

This review aims to explore the potential of exosomes in addressing the diagnostic and therapeutic challenges associated with RCC. Specifically, it investigates the role of exosomes as biomarkers and therapeutic vehicles in the context of RCC management.

For this review article, a comprehensive literature search was conducted using databases such as PubMed, employing relevant keywords to identify research articles pertinent to the objectives of the review. Initially, 200 articles were identified, which underwent screening to remove duplicates and assess relevance based on titles and abstracts, followed by a detailed examination of full texts. From the selected articles, relevant data were extracted and synthesized to address the review's objectives. The conclusions were drawn based on a thorough analysis of the findings. The quality was ensured through independent review and resolution of discrepancies among multiple reviewers.

Exosomes demonstrate potential as diagnostic tools for early detection, prognosis, and treatment monitoring in RCC. Their ability to deliver various therapeutic agents, such as small interfering RNAs, lncRNAs, chemotherapeutic drugs, and immune-stimulating agents, allows for a personalized approach to RCC management. By leveraging exosome-based technologies, precision and efficacy in treatment strategies can be significantly enhanced.

Despite the promising advancements enabled by exosomes in the management of RCC, further research is necessary to refine exosome-based technologies and validate their efficacy, safety, and long-term benefits through rigorous clinical trials. Embracing exosomes as integral components of RCC diagnosis and treatment represents a significant step towards improving patient outcomes and addressing the persistent challenges posed by this malignancy in the field of oncology.

Kidney renal clear cell carcinoma (KIRC) is a cancer that is closely associated with epigenetic alterations, and histone modifiers (HMs) are closely related to epigenetic regulation. Therefore, this study aimed to comprehensively explore the function and prognostic value of HMs-based signature in KIRC. HMs were first obtained from top journal. Then, the mRNA expression profiles and clinical information in KIRC samples were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Cox regression analysis and least absolute shrinkage and selection operator (Lasso) analysis were implemented to find prognosis-related HMs and construct a risk model related to the prognosis in KIRC. Kaplan-Meier analysis was used to determine prognostic differences between high- and low-risk groups. Immune infiltration and drug sensitivity analysis were also performed between high- and low-risk groups. Eventually, 8 HMs were successfully identified for the construction of a risk model in KIRC. The results of the correlation analysis between risk signature and the prognosis showed HMs-based signature has good prognostic value in KIRC. Results of immune analysis of risk models showed there were significant differences in the level of immune cell infiltration and expression of immune checkpoints between high- and low-risk groups. The results of the drug sensitivity analysis showed that the high-risk group was more sensitive to several chemotherapeutic agents such as Sunitinib, Tipifarnib, Nilotinib and Bosutinib than the low-risk group. In conclusion, we successfully constructed HMs-based prognostic signature that can predict the prognosis of KIRC.

With increasing detection of small renal masses and accumulating evidence that nephron sparing surgery (NSS) could achieve oncological equivalence and functional superiority compared with radical nephrectomy (RN), NSS has become first-line therapy for some patients with localized renal masses.

This study aims to review the publications in the kidney neoplasm and NSS field, exploring the research hotspots.

Kidney neoplasm and NSS related publications before July 3th 2023 were obtained from the Web of Science Core Collection database. We then used bibliometric analysis to conduct performance analysis, citation analysis and co-citation network of publications, together with keyword co-occurrence analysis.

Seven thousand five hundred and sixty-four documents were finally retrieved, and the annual publications increased exponentially. The most productive authors were "KAOUK JH" and "GILL IS", while USA, and 12 American affiliations such as CLEVELAND CLINIC FOUNDATION and MAYO CLINIC were far leading in this field. Journal of Urology and European Urology were journals with the highest citations and h-index.

Through literature reviewing plus co-occurrence and clustering analysis, the therapeutic effects of partial nephrectomy (PN) versus RN on patients with localized renal cell carcinoma, different operative approaches of PN, and conservative NSS methods were deemed as the most focused topics.

Three aspects were the most important hotspots in this field. Firstly, how to provide the optimal management choices for different patients. Secondly, therapeutic effects of different management options and surgical techniques needed more prospective and randomized studies. Finally, more novel technologies and surgical techniques were required.

Increasing evidence suggests that circular RNA (circRNA) plays a regulatory role in the progression of renal cell carcinoma (RCC). However, the precise function and underlying mechanism of circSCNN1A in RCC progression still remain unclear.

The expression levels of circSCNN1A, microRNA-590-5p (miR-590-5p), claudin 8 (CLDN8), cyclin D1, matrix metalloprotein 2 (MMP2), MMP9, E-cadherin, N-cadherin and vimentin were detected by a quantitative real-time polymerase chain reaction and Western blotting analysis. Immunohistochemistry assay was performed to analyze the positive expression rate of CLDN8. Cell proliferation was investigated by cell colony formation, 5-Ethynyl-2'-deoxyuridine and DNA content quantitation assays. Cell migration and invasion were assessed by wound-healing and transwell invasion assays. Interactions among circSCNN1A, miR-590-5p and CLDN8 were identified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft mouse model assay was conducted to verify the effect of circSCNN1A on tumor formation in vivo.

CircSCNN1A and CLDN8 expression were significantly downregulated, while miR-590-5p was upregulated in both RCC tissues and cells. CircSCNN1A overexpression inhibited RCC cell proliferation, migration and invasion, accompanied by decreases of cyclin D1, MMP2, MMP9, N-cadherin and vimentin expression and an increase of E-cadherin expression. CircSCNN1A acted as a miR-590-5p sponge and regulated RCC cell processes by binding to miR-590-5p. CLDN8, a target gene of miR-590-5p, was involved in the regulation of the biological behaviors of RCC cells by miR-590-5p. In addition, circSCNN1A induced CLDN8 production by interacting with miR-590-5p. Further, circSCNN1A suppressed tumor formation in vivo.

CircSCNN1A inhibited RCC cell proliferation, migration and invasion by regulating the miR-590-5p/CLDN8 pathway.

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine.

While recent studies have demonstrated several genetic alterations are associated with pathogenesis of RCC, the significance of cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) in tumorigenesis of RCC is less clear. We investigate the distribution of CDKN2A and CDKN2B mutations in patients with RCC and analyze the impact of CDKN2A and CDKN2B mutations on RCC.

A pathological examination was conducted using thirty fresh renal tissue samples with renal masses that had undergone partial or radical nephrectomy. Multiplex ligation-dependent probe amplification (MLPA) was used to detect genetic aberrations of CDKN2A and CDKN2B in genomic DNA isolated from samples. Subsequently, CDKN2A and CDKN2B mutations were confirmed using chromosomal microarray technique.

Twenty-one patients were diagnosed with RCC, eight with benign diseases, including angiomyolipoma (AML) and oncocytoma, and one with mucinous adenocarcinoma of renal pelvis. Two of twenty-one patients (9.5 %) with clear-cell RCC were positive for CDKN2A and CDKN2B gene deletions. Interestingly, patients with CDKN2A and CDKN2B mutations were associated with sarcomatoid patterns of RCC (2 out of 4, 50 %). In contrast, no CDKN2A or CDKN2B deletions were detected in samples from benign renal tumors, papillary RCC, or other kidney cancers.

This study demonstrated the potential use of CDKN2A and CDKN2B as biomarkers for the prognostic and molecular classification of renal cancer. CDKN2A and CDKN2B mutations may be associated with RCC development and sarcomatoid changes. Further research is needed to understand the underlying molecular mechanisms of CDKN2A and CDKN2B in the pathogenesis of RCC.

We aimed to assess the prognostic importance of perinephric fat features in images of patients with non-metastatic renal cell carcinoma (RCC) undergoing surgery.

We enrolled RCC patients who underwent surgical treatment between 2011 and 2019. Two characteristics, including perinephric fat thickness and perinephric fat stranding, were evaluated using preoperative computed tomography or magnetic resonance images. The association between perinephric fat characteristics and disease progression was examined by Kaplan-Meier survival analysis and Cox regression model.

In a multivariate Cox proportional hazards model adjusting for tumor stage, intratumoral necrosis, and neutrophil-to-lymphocyte ratio, we found that patients in the thin perinephric fat group (<1 cm) had a poorer progression-free survival (PFS) compared to the thick perinephric fat group (≥1 cm) (HR 2.8; 95% CI 1.175-6.674, p = 0.02). Additionally, the fat stranding group had a poorer PFS than the non-stranding group (HR 3.852; 95% CI 1.082-13.704, p = 0.037). The non-stranding with thick perinephric fat group exhibits the highest cumulative PFS while the stranding with thin perinephric fat group has the lowest cumulative PFS. In receiver operating characteristic curve analysis, combing these two perinephric fat characteristics with tumor stage can achieve a better discriminatory power than tumor stage alone.

Our study indicates that the evaluation of image-based perinephric fat features is a simple, straightforward, reproducible tool for predicting RCC prognosis and may assist in preoperative risk stratification.

Kidney renal clear cell carcinoma (KIRC), one of the most prevalent form of kidney carcinoma, is highly aggressive cancer known for significant immune infiltration and high mortality rates. The absence of sensitivity to traditional therapy has spurred the search for new treatments. Protein Tyrosine Kinase 6 (PTK6) is implicated in promoting cancer growth, spread, and metastasis. Our review of The Cancer Genome Atlas database revealed PTK6 overexpression in KIRC, though its specific role in this cancer type was unclear. We investigated PTK6's cancer-promoting roles in KIRC using the database and confirmed our findings with patient-derived tissues. Our analysis showed that elevated PTK6 expression is linked to worse outcomes and higher levels of immune infiltration. It also correlates positively with neo-antigens (NEO) and DNA ploidy changes in KIRC. This research delves into PTK6's role in KIRC development, suggesting PTK6 as a possible biomarker for prognosis and treatment in KIRC.

Glycosphingolipids (GSLs), mainly located in the cell membrane, play various roles in cancer cell function. GSLs have potential as renal cell carcinoma (RCC) biomarkers; however, their analysis in body fluids is challenging because of the complexity of numerous glycans and ceramides. Therefore, we applied wide-targeted lipidomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with selected reaction monitoring (SRM) based on theoretical mass to perform a comprehensive measurement of GSLs and evaluate their potency as urinary biomarkers. In semi-quantitative lipidomics, 240 SRM transitions were set based on the reported/speculated structures. We verified the feasibility of measuring GSLs in cells and medium and found that disialosyl globopentaosylceramide (DSGb5 (d18:1/16:0)) increased GSL in the ACHN medium. LC-MS/MS analysis of urine samples from clear cell RCC (ccRCC) patients and healthy controls showed a significant increase in the peak intensity of urinary DSGb5 (d18:1/16:0) in the ccRCC group compared with that in the control group. Receiver operating characteristic analysis indicated that urinary DSGb5 could serve as a sensitive and specific marker for RCC screening, with an AUC of 0.89. This study demonstrated the possibility of urinary screening using DSGb5 (d18:1/16:0). In conclusion, urinary DSGb5 (d18:1/16:0) was a potential biomarker for cancer screening, which could contribute to the treatment of RCC patients.

Air pollution, tobacco smoke, and red meat are associated with renal cell cancer (RCC) risk in the United States and Western Europe; however, the chemicals that form DNA adducts and initiate RCC are mainly unknown. Aristolochia herbaceous plants are used for medicinal purposes in Asia and worldwide. They are a significant risk factor for upper tract urothelial carcinoma (UTUC) and RCC to a lesser extent. The aristolochic acid (AA) 8-methoxy-6-nitrophenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-I), a component of Aristolochia herbs, contributes to UTUC in Asian cohorts and in Croatia, where AA-I exposure occurs from ingesting contaminated wheat flour. The DNA adduct of AA-I, 7-(2'-deoxyadenosin-N6-yl)-aristolactam I, is often detected in patients with UTUC, and its characteristic A:T-to-T:A mutational signature occurs in oncogenes and tumor suppressor genes in AA-associated UTUC. Identifying DNA adducts in the renal parenchyma and pelvis caused by other chemicals is crucial to gaining insights into unknown RCC and UTUC etiologies. We employed untargeted screening with wide-selected ion monitoring tandem mass spectrometry (wide-SIM/MS2) with nanoflow liquid chromatography/Orbitrap mass spectrometry to detect DNA adducts formed in rat kidneys and liver from a mixture of 13 environmental, tobacco, and dietary carcinogens that may contribute to RCC. Twenty DNA adducts were detected. DNA adducts of 3-nitrobenzanthrone (3-NBA), an atmospheric pollutant, and AA-I were the most abundant. The nitrophenanthrene moieties of 3-NBA and AA-I undergo reduction to their N-hydroxy intermediates to form 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) adducts. We also discovered a 2'-deoxycytidine AA-I adduct and dA and dG adducts of 10-methoxy-6-nitro-phenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-III), an AA-I isomer and minor component of the herbal extract assayed, signifying AA-III is a potent kidney DNA-damaging agent. The roles of AA-III, other nitrophenanthrenes, and nitroarenes in renal DNA damage and human RCC warrant further study. Wide-SIM/MS2 is a powerful scanning technology in DNA adduct discovery and cancer etiology characterization.

The implementation of primary tumor resection (PTR) in the treatment of kidney cancer patients (KC) with bone metastases (BM) has been controversial. This study aims to construct the first tool that can accurately predict the likelihood of PTR benefit in KC patients with BM (KCBM) and select the optimal surgical candidates. This study acquired data on all patients diagnosed with KCBM during 2010-2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was utilized to achieve balanced matching of PTR and non-PTR groups to eliminate selection bias and confounding factors. The median overall survival (OS) of the non-PTR group was used as the threshold to categorize the PTR group into PTR-beneficial and PTR-Nonbeneficial subgroups. Kaplan-Meier (K-M) survival analysis was used for comparison of survival differences and median OS between groups. Risk factors associated with PTR-beneficial were identified using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC), area under the curve (AUC), calibration curves, and decision curve analysis (DCA) were used to validate the predictive performance and clinical utility of the nomogram. Ultimately, 1963 KCBM patients meeting screening criteria were recruited. Of these, 962 patients received PTR and the remaining 1061 patients did not receive PTR. After 1:1 PSM, there were 308 patients in both PTR and non-PTR groups. The K-M survival analysis results showed noteworthy survival disparities between PTR and non-PTR groups, both before and after PSM (p < 0.001). In the logistic regression results of the PTR group, histological type, T/N stage and lung metastasis were shown to be independent risk factors associated with PTR-beneficial. The web-based nomogram allows clinicians to enter risk variables directly and quickly obtain PTR beneficial probabilities. The validation results showed the excellent predictive performance and clinical utility of the nomograms for accurate screening of optimal surgical candidates for KCBM. This study constructed an easy-to-use nomogram based on conventional clinicopathologic variables to accurately select the optimal surgical candidates for KCBM patients.

Clear-cell renal cell carcinoma frequently metastasizes to the pancreas (PMRCC). The management of such metastases remains controversial due to their frequent multifocality and indolent evolution.

This study describes the surgical management of these lesions and their long-term oncological outcomes. The study included patients who underwent pancreatic resection of PMRCC at Bordeaux University Hospital between June 2005 and March 2022. Morbidity and mortality were assessed at 90 days. Overall survival (OS) and disease-free (DFS) survival were assessed at 5 years.

Forty-two patients underwent pancreatic resection for PMRCC, including 18 (42.8 %) total pancreatectomies. The median time from nephrectomy to the diagnosis of PMRCC was 121 (range: 6-400) months. Lesions were multiple in 19/42 (45.2 %) patients. Ten (23.8 %) patients suffered a severe complication (Dindo-Clavien classification ≥ IIIA by D90), including one patient who died postoperatively. The median follow-up was 76 months. The R0 rate was 100 %. The OS and DFS rates were 92.8 % and 29.6 %, respectively, at 5 years.

Pancreatic resection for PMRCC provides long-term oncological control despite a high recurrence rate.

Kidney renal clear cell cancer (KIRC) is a type of urological cancer that occurs worldwide. Core fucosylation (CF), as the most common post-translational modification, is involved in the tumorigenesis.

The alterations of CF-related genes were summarized in pan-cancer. The "ConsensusClusterPlus" package was utilized to identify two CF-related KIRC subtypes. The "ssgsea" function was chosen to estimate the CF score, signaling pathways and cell deaths. Multiple algorithms were applied to assess immune responses. The "oncoPredict" was utilized to estimate the drug sensitivity. The IHC and subgroup analysis was performed to reveal the molecular features of FUT8. Single-cell RNA sequencing (scRNA-seq) data were scrutinized to evaluate the CF state.

In pan-cancer, there was a noticeable alteration in the expression of CF-related genes. In KIRC, two CF-related subtypes (i.e., C1, C2) were obtained. In comparison to C2, C1 exhibited a higher CF score and correlated with poorer overall survival. Additionally, the TME of C2 demonstrated increased activity in neutrophils, macrophages, myeloid dendritic cells, and B cells, alongside a higher presence of silent mast cells, NK cells, and endothelial cells. Compared to normal samples, higher expression of FUT8 is observed in KIRC. The mutation of SETD2 was more frequent in low-FUT8 samples while the mutation of DNAH9 was more frequent in high-FUT8 samples. scRNA-seq analyses revealed that the CF score was predominantly higher in endothelial cells and fibroblast cells.

Two CF-related subtypes with distinct prognosis and TME were identified in KIRC. FUT8 exhibited elevated expression in KIRC samples.

Renal cell carcinoma (RCC) is an uncommon malignancy whose incidence has been increasing over the past few decades, posing treatment challenges for elderly or infirm patients who are not surgical candidates. Stereotactic ablative radiotherapy (SABR) has emerged as a promising non-invasive treatment modality for RCC. The high dose-per-fraction used in SABR overcomes some of the mechanisms of radioresistance that has hindered the effective treatment of RCC with conventional radiotherapy. For primary RCC, local control rates for SABR exceed 90%, with typically minimal grade 3 or higher toxicities, offering a viable alternative for inoperable patients and those not eligible for or unable to tolerate radiofrequency or cryotherapy ablation. SABR can also be used in patients with a solitary kidney as a strategy for renal preservation to avoid need for dialysis. Given its excellent local control rates, low toxicity and preservation of renal function, SABR offers an attractive alternative to more invasive modalities for treatment of localized RCC.

A major subtype of renal cancer is clear cell renal cell carcinoma (ccRCC). Krüppel-like factor 3 (KLF3) dysfunction is also revealed leading to poor prognosis in multiple cancer types. However, dysregulation and molecular dynamics of KLF3 underlying ccRCC progression still remains elusive. Here KLF3 gene and protein expressions in ccRCC were explored using data cohorts from The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and verified them in our patient cohort. Correlations of KLF3 expression with clinicopathological features, epigenetic modification, and immune microenvironment characteristics were further investigated. KLF3 was significantly down-regulated expressed in ccRCC tissues compared to adjacent normal controls. Adverse pathological parameters and poor prognosis were associated with lower expression of KLF3. Mechanically, KLF3 regulation was mainly attributed to CpG island methylation. KLF3-high expression subgroup was significantly enriched in cell signaling pathways most associated with EMT markers, angiogenesis, inflammatory response, apoptosis, TGF-β, degradation of ECM, G2M checkpoint, and PI3K-AKT-mTOR. Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions.

Kidney transplant patients have a higher risk of renal cell carcinoma (RCC) compared to non-transplanted end-stage kidney disease (ESKD) patients. This increased risk has largely been associated with the use of immunosuppression; however, recent genetic research highlights the significance of tissue specificity in cancer driver genes. The implication of tissue specificity becomes more obscure when addressing transplant patients, as two distinct metabolic environments are present within one individual. The oncogenic potential of donor renal tissue is largely unknown but assumed to pose minimal risk to the kidney transplant recipient (KTR). Our review challenges this notion by examining how donor and recipient microenvironments impact a transplant recipient's associated risk of renal cell carcinoma. In doing so, we attempt to encapsulate how ESKD-RCC and KTR-RCC differ in their incidence, pathogenesis, outcome, and approach to management.

Cadherins (calcium-dependent adhesion proteins) are important in cellular adhesion and may play a role in the development and progression of renal cell carcinoma (RCC). This study investigated changes in cadherin 3 (CDH3; P-cadherin) mRNA expression, DNA methylation, and protein expression in RCC and compared the results with the histopathological and clinical characteristics of patients. The possible contribution of CDH3 to tumor cell invasiveness was tested in a functional assay using siRNA-based suppression of CDH3 expression and subsequent real-time impedance analysis using a Matrigel invasion model. Our analyses revealed a tumor-specific loss of CDH3 mRNA expression, CDH3 DNA hypermethylation, and loss of distal tubular and collecting duct CDH3 protein expression in RCC. A relatively higher methylation level in tumors was associated with a loss of cell differentiation and higher clinical stage. siRNA-induced suppression of CDH3 expression modulated the invasion characteristics of tumor cells in the impedance-based real-time cellular analysis. Our results indicate that loss of CDH3 expression is common in RCC and may contribute to the pathogenesis of a subset of RCC. Further studies to reveal the mechanisms of loss of expression and its effects on the invasive behavior of renal tumor cells are required.

Purpose: The purpose of this study was to examine the pharmacokinetics (PK), bioequivalence and safety of generic sunitinib and its original product Sutent® in healthy Chinese subjects through a phase-I clinical trial. Methods: The study selected two groups of 24 healthy Chinese subjects in a 1:1 ratio through random allocation. Each participant received either 12.5 mg of sunitinib or Sutent® per cycle. A total of 15 different time points were employed for blood sample collection during each cycle. Furthermore, a comprehensive assessment of the drugs' safety was consistently maintained throughout the trial. Results: The average adjusted geometric mean ratios (GMR) (90% CI) for the primary PK parameters Cmax, AUC0-t and AUC0-∞ were 97.04% (93.06%-101.19%), 98.45% (93.27%-103.91%) and 98.22% (93.15%-103.56%), respectively. The adjusted GMRs for essential pharmacokinetic (PK) parameters all met the requirements for bioequivalence, with values within the acceptable range of 80%-125%. In addition, the two drugs showed comparable results for the other PK parameters. These results indicate that the two drugs were bioequivalent. Furthermore, both drugs showed well safety. Conclusion: The research results proved that the PK and safety profiles of sunitinib in healthy Chinese subjects were comparable to those of Sutent®. These results advocate the clinical application of generic sunitinib as a potential alternative to original product Sutent® in the treatment of certain medical conditions.

ELABELA (ELA), also known as Toddler or Apela, is a novel endogenous ligand of the angiotensin receptor AT1-related receptor protein (APJ). ELA is highly expressed in human embryonic, cardiac, and renal tissues and involves various biological functions, such as embryonic development, blood circulation regulation, and maintaining body fluid homeostasis. ELA is also closely related to the occurrence and development of acute kidney injury, hypertensive kidney damage, diabetic nephropathy, renal tumors, and other diseases. Understanding the physiological role of ELA and its mechanism of action in kidney-related diseases would provide new targets and directions for the clinical treatment of kidney diseases.

The definition of oligometastasis is still controversial. Cytoreductive nephrectomy and metastasectomy are important approaches in selected patients with oligometastasis for improving survival. We aimed to present our laparoscopic metastasectomy experience in a rare case of contralateral adrenal metastasis in an oligometastatic kidney tumor.

A 52-year-old male patient was admitted to our clinic with the diagnosis of an incidental right renal mass. On contrast-enhanced abdominal CT revealed a mass reaching approximately 8 cm in diameter in the right kidney located in the middle pole. On contrast-enhanced thorax, CT showed a metastatic lesion in the left main bronchus bifurcation. The patient underwent an open radical nephrectomy with the diagnosis of an oligometastatic right renal mass. His pathology was reported as clear cell renal cell carcinoma (ccRCC). The patient was referred to the medical oncology clinic for immunotherapy. The metastatic lesion in the lung completely regressed in the follow-up of the patient who was started on Chek point inhibitors. However, he was referred to our clinic after an incidental metachronous mass was detected in the contralateral left adrenal in FDG PET/CT (SUVmax: 6.7) in 1st year. Dynamic contrast-enhanced MRI was performed to reevaluate and for mass characterization, and a 4 cm mass was observed in the left contralateral adrenal. Laparoscopic metastasectomy was performed for the left adrenal mass. No recurrence or adrenal insufficiency developed in the 6-month follow-up after discharge.

Transperitoneal adrenalectomy is a minimally invasive method that can be safely performed in metastatic adrenal masses. Although contralateral adrenal metastasis is rare in ccRCC, it should be kept in mind that adrenal metastasis may develop in the late period in patients with a history of renal cancer.

Over the past two decades, significant progress has been made in the treatment of clear cell renal cell carcinoma (ccRCC), with a shift towards adopting new treatment approaches ranging from monotherapy to triple-combination therapy. This progress has been spearheaded by fundamental technological advancements that have allowed a deeper understanding of the various biological components of this cancer. In particular, the rapid commercialization of transcriptomics technologies, such as single-cell RNA-sequencing (scRNA-seq) methodologies, has played a crucial role in accelerating this understanding. Through precise measurements facilitated by these technologies, the research community has successfully identified and characterized diverse tumor, immune, and stromal cell populations, uncovering their interactions and pathways involved in disease progression. In localized ccRCC, patients have shown impressive response rates to treatment. However, despite the emerging findings and new knowledge provided in the field, there are still patients that do not respond to treatment, especially in advanced disease stages. One of the key challenges lies in the limited study of ccRCC metastases compared to localized cases. This knowledge gap may contribute to the relatively low survival rates and response rates observed in patients with metastatic ccRCC. To bridge this gap, we here delve into recent research utilizing scRNA-seq technologies in both primary and metastatic ccRCC. The goal of this review is to shed light on the current state of knowledge in the field, present existing treatment options, and emphasize the crucial steps needed to improve survival rates, particularly in cases of metastatic ccRCC.

To assess the safety and efficacy of sorafenib and sunitinib as first-line treatments for metastatic renal cell carcinoma (mRCC), to provide evidence-based support for clinical decision-making regarding rational drug use.

Until May 10, 2023, a comprehensive search was conducted across PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang databases to identify clinical studies comparing sorafenib with sunitinib as first-line treatment for mRCC. The literature was screened, data extracted, and quality evaluated independently by 2 researchers. Meta-analysis was conducted using Revman5.4 software.

A total of 3741 patients were enrolled in 20 studies. The meta-analysis results indicated that there were no significant differences in the 2- and 5-year progression-free survival (PFS) and overall survival (OS) rates between the sorafenib and sunitinib groups (P > .05). The disease control rate (DCR) was comparable between the 2 groups (P > .05), while the objective response rate (ORR) was higher in the sunitinib group (P = .03). However, subgroup analysis revealed no significant differences in ORR, DCR, 2- and 5-year PFS, and OS rates between sorafenib and sunitinib among both Asian populations as well as European and American populations (P > .05). In terms of drug-related adverse events, the incidence of grade ≥ 3 hypertension, leukopenia, neutropenia, thrombocytopenia, anemia, nausea and vomiting were significantly lower in the sorafenib group compared to the sunitinib group (P < .05).

In the first-line treatment of mRCC, sorafenib exhibits comparable efficacy to sunitinib but with lower toxicity.

Nivolumab is a monoclonal antibody that binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. High response rates have been achieved with its use in the treatment of metastatic renal cell carcinoma (mRCC). We aimed to determine a relationship between 18-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) performed before nivolumab treatment and treatment-related survival.

Between 2014 and 2021, 32 patients who received nivolumab and had pre-treatment 18F-FDG-PET/CT evaluation were included in this retrospective study. The total SUVmax (sum of SUVmax) of all tumoral foci and the lesion with the highest SUVmax value were recorded. The relationship of these values with progression-free survival (PFS) and overall survival (OS) was evaluated.

The median highest SUVmax and sum of SUVmax values were found as 14.4 and 41.4, respectively. PFS and OS were longer in the group with a sum of SUVmax value below 41.4 compared to the group with a higher group (OS, median 9.52 vs. 4.2 months [P=0.018]; PFS, median 9.6 vs. 3 months [P=0.003], respectively). In the group with the highest SUVmax value below 14.4, PFS was evaluated as statistically significant compared to the higher group (PFS, median 16.74 vs. 3.3 months [P=0.004]), while OS was not found to be statistically significant (OS, median 25.45 vs. 16.74 months (P=0.110)).

Our study showed that there might be a relationship between SUVmax values and PFS and OS. The SUVmax values before nivolumab treatment can be used to predict prognosis and survival in mRCC patients.

The ubiquitin-proteasome system governs a wide spectrum of cellular events and offers therapeutic opportunities for pharmacological intervention in cancer treatment. Renal clear cell carcinoma represents the predominant histological subtype and accounts for the majority of cancer death related to kidney malignancies. Through a systematic survey in the association of human ubiquitin-specific proteases with patient prognosis of renal clear cell carcinoma and subsequent phenotypic validation, we uncovered the tumor-promoting role of USP35. Biochemical characterizations confirmed the stabilizing effects of USP35 towards multiple members of the IAP family in an enzymatic activity-dependent manner. USP35 silencing led to reduced expression levels of IAP proteins, which were accompanied with increased cellular apoptosis. Further transcriptomic analysis revealed that USP35 knockdown affected the expression levels of NRF2 downstream transcripts, which were conferred by compromised NRF2 abundance. USP35 functions to maintain NRF2 levels by catalyzing its deubiquitylation and thus antagonizing degradation. NRF2 reduction imposed by USP35 silencing rendered renal clear cell carcinoma cells increased sensitivity to ferroptosis induction. Finally, induced USP35 knockdown markedly attenuated xenograft formation of renal clear cell carcinoma in nude mice. Hence, our findings reveal a number of USP35 substrates and uncover the protecting roles of USP35 against both apoptosis and ferroptosis in renal clear cell carcinoma.