Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA-binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin–proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish proinflammatory enhancers and thereby regulate NF-κB–mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and proinflammatory enhancer assembly that endows FH-deficient tumors with epigenetic vulnerabilities. Significance: CHD6 links FH deficiency to aberrant NF-κB activity in renal cell carcinoma, highlighting an epigenetic vulnerability for this rare tumor subtype.

Introduction: The objective of this study is to investigate the predictive ability of abdominal fat features derived from computed tomography (CT) to predict early recurrence within a year following the initial transurethral resection of bladder tumor (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). A predictive model is constructed in combination with clinical factors to aid in the evaluation of the risk of early recurrence among patients with NMIBC after initial TURBT. Methods: This retrospective study enrolled 325 NMIBC patients from three centers. Machine learning–based visceral adipose tissue (VAT) radiomics models (VAT-RM) and subcutaneous adipose tissue (SAT) radiomics models (SAT-RM) were constructed to identify patients with early recurrence. A combined model integrating VAT-RM and clinical factors was established. The predictive performance of each variable and model was analyzed using the area under the receiver operating characteristic curve (AUC). The net benefit of each variable and model was presented through decision curve analysis (DCA). The calibration was evaluated utilizing the Hosmer–Lemeshow test. Findings: The VAT-RM demonstrated satisfactory performance in the training cohort (AUC = 0.853; 95% CI: 0.768–0.937), test cohort 1 (AUC = 0.823; 95% CI: 0.730–0.916), and test cohort 2 (AUC = 0.808; 95% CI: 0.681–0.935). Across all cohorts, the AUC values of the VAT-RM were higher than those of the SAT-RM ( P < 0.001). The DCA curves further confirmed that the clinical net profit of the VAT-RM was superior to that of the SAT-RM. In multivariate logistic regression analysis, the VAT-RM emerged as the most significant independent predictor [odds ratio (OR) = 0.295; 95% CI: 0.141–0.508; P < 0.001]. The fusion model exhibited excellent AUC values of 0.938, 0.909, and 0.905 across three cohorts. The fusion model surpassed the traditional risk assessment frameworks in both predictive efficacy and clinical net benefit. Interpretation: VAT serves as a crucial factor in early postoperative recurrence in NMIBC patients. The VAT-RM can accurately identify high-risk patients with early postoperative recurrence, offering significant advantages over SAT-RM. The new predictive model constructed by integrating the VAT-RM and clinical factors exhibits excellent predictive performance, clinical net benefits, and calibration accuracy.

Chronic kidney disease (CKD) is a globally prevalent chronic condition characterized by progressive renal function decline, imposing significant economic and psychological burdens on patients. Metabolic syndrome (MetS), characterized by obesity, hypertension, hyperglycemia, and dyslipidemia, is a significant risk factor for CKD. A strong epidemiological association exists between CKD and MetS. This study explores the genetic connections between MetS-related diseases and CKD, focusing on identifying shared risk loci, key tissues, and underlying genetic mechanisms. We performed a cross-trait pleiotropy analysis using summary-level GWAS data from ten MetS-related diseases and CKD obtained from the IEU database to detect shared pleiotropic loci and genes. Functional annotation and tissue-specific analyses were conducted to reveal potential associations between CKD and MetS. Additionally, we used metabolite colocalization methods to explore the metabolic perspective of these diseases' associations. Finally, Mendelian randomization (MR) was employed for further association analysis. The study identified shared genetic mechanisms between mental disorders and prostatitis, revealing 1,437 pleiotropic loci at genome-wide significance. Forty-four dominant risk SNP loci were annotated, with 11 loci confirmed through causal colocalization analysis. Further gene-level analysis identified eight unique pleiotropic genes, including APOC1, APOE, BICC1, and PDILT. Pathway analysis identified the significant involvement of the Metabolism of Fat-Soluble Vitamins, Positive Regulation of Plasma Membrane-Bounded Cell Projection Assembly, and Positive Regulation of RNA Metabolic Process pathways in these diseases. Tissue enrichment analyses at the SNP and gene levels indicated that pleiotropic mechanisms play crucial roles in the Adipose Visceral Omentum, Brain Cerebellum, and Testis. Ultimately, phenotypic-level metabolite colocalization analysis revealed a metabolic intermediary mechanism linking MetS-related diseases and CKD. This study uncovers the complex genetic interactions between CKD and MetS-related diseases, identifying shared genetic loci and biological pathways, providing novel insights for future therapeutic strategies.

Radiopharmaceutical therapy (RPT) is a pivotal modality in cancer treatment, with its efficacy substantially modulated by the tumor microenvironment (TME). The TME regulates RPT penetration and influences therapeutic outcomes. Concurrently, RPT actively reconfigures the TME by enhancing immune activation and partially reversing immunosuppression. Specifically, RPT induces tumor cell senescence and immunogenic cell death, and catalyzes immune activation. RPT diminishes immunosuppressive elements, including regulatory T cells and tumor-associated macrophages, and augments populations of CD8⁺ T cells and natural killer cells, thereby fostering a more immunostimulatory TME. Additionally, RPT modulates critical cytokines and upregulates immune checkpoint molecules, bolstering anti-tumor immunity. Nevertheless, pathological features like hypoxia and extracellular matrix stiffness within the TME can hinder RPT biodistribution and therapeutic efficacy. Strategically targeting the TME through approaches, such as fibroblast depletion, hypoxia mitigation, metabolic reprogramming, nerve-immune-cancer interactions, or nanocarrier drug delivery, can amplify RPT effectiveness. Combination immunotherapies that integrate RPT with immune checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells, or cancer vaccines have demonstrated enhanced anti-tumor responses and survival advantages in malignancies such as prostate cancer and neuroendocrine tumors. Given the complexity and heterogeneity of the TME, emerging strategies, including radiation-responsive nanocarriers, CAR-T cells engineered to secrete radiosensitizers, senolytic therapies, and artificial intelligence-driven multimodal data integration, are promising in addressing the challenges and refining precision cancer therapy. In summary, the TME serves as a critical bridge between RPT and immunotherapy; elucidating the interplay among these three elements is essential for advancing combination strategies.

Background Bladder cancer (BCa) represents the fourth most prevalent malignancy worldwide, characterized by unfavorable clinical outcomes. The functional significance and molecular mechanisms underlying circular RNAs in BCa pathogenesis require further investigation. This study reveals that circBARD1 suppresses histone lactylation-driven tumor progression by modulating ENO1 protein stability in bladder cancer. Methods Functional characterization of circBARD1 was performed through gain-of-function experiments in T24 and TCCSUP cell lines. RNA immunoprecipitation (RIP) and immunoprecipitation assays were employed to investigate circBARD1-ENO1 interactions. CUT&Tag and chromatin immunoprecipitation (ChIP) assays were conducted to examine H3K18 lactylation-mediated transcriptional regulation of CCNA2. Results CircBARD1 expression was significantly downregulated in bladder cancer tissues. Ectopic expression of circBARD1 inhibited malignant proliferation and migration capacities in BCa cell lines. Furthermore, circBARD1 demonstrated negative regulation of glycolytic flux and intracellular lactate accumulation. Mechanistic studies revealed that circBARD1 physically interacts with ENO1 protein, facilitating its ubiquitination-mediated proteasomal degradation mediated by FBXW7. This circBARD1/ENO1 regulatory axis attenuates tumor progression through suppression of H3K18 lactylation and subsequent downregulation of CCNA2 transcription. Conclusions Our findings establish that circBARD1 functions as a tumor suppressor in bladder cancer by promoting ENO1 ubiquitination and degradation, thereby inhibiting histone lactylation-mediated oncogenesis. This study provides new insights into therapeutic targets for clinical management of bladder cancer.