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Background: The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood. Methods: High‐throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK‐8 assays were used to assess the function of hsa_circ_0057105 in RCC cells. The clinical relevance of hsa_circ_0057105 was evaluated in a cohort of RCC patients. The hsa_circ_0057105 regulatory axis was defined using RNA pull‐down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa_circ_0057105 was validated using animal experiments. Results: Single‐sample gene set enrichment analysis and correlation analysis of RNA‐seq data showed that hsa_circ_0057105 was potentially oncogenic and may serve to regulate epithelial‐mesenchymal transition (EMT) activation in RCC. Hsa_circ_0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa_circ_0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa_circ_0057105 was shown to inhibit the expression of miR‐577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa_circ_0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa_circ_0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo. Conclusions: In RCC, hsa_circ_0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR‐577, acting like a 'double‐edged sword'. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. Method: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan–Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. Results: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. Conclusion: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility. [ABSTRACT FROM AUTHOR]

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN‐γ‐induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain‐binding protein 1‐like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN‐γ/JAK1/STAT1/PD‐L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell‐mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD‐L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient‐derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy. [ABSTRACT FROM AUTHOR]

G. Representative images (left) and quantification (right) data of Transwell migration/invasion assay of 786-O cells circNTNG1 overexpression salvage experiment. Reference 1 Liang Y, Cen J, Huang Y. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. [Extracted from the article]