The RNA N⁶-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Purpose: This study aimed to evaluate the clinical significance of a novel systemic immune-inflammation score (SIIS) to predict oncological outcomes in upper urinary tract urothelial carcinoma(UTUC) after radical nephroureterectomy(RNU). Method: The clinical data of 483 patients with nonmetastatic UTUC underwent surgery in our center were analyzed. Five inflammation-related biomarkers were screened in the Lasso-Cox model and then aggregated to generate the SIIS based on the regression coefficients. Overall survival (OS) was assessed using Kaplan-Meier analyses. The Cox proportional hazards regression and random survival forest model were adopted to build the prognostic model. Then we established an effective nomogram for UTUC after RNU based on SIIS. The discrimination and calibration of the nomogram were evaluated using the concordance index (C-index), area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration curves. Decision curve analysis (DCA) was used to assess the net benefits of the nomogram at different threshold probabilities. Result: According to the median value SIIS computed by the lasso Cox model, the high-risk group had worse OS (p<0.0001) than low risk-group. Variables with a minimum depth greater than the depth threshold or negative variable importance were excluded, and the remaining six variables were included in the model. The area under the ROC curve (AUROC) of the Cox and random survival forest models were 0.801 and 0.872 for OS at five years, respectively. Multivariate Cox analysis showed that elevated SIIS was significantly associated with poorer OS (p<0.001). In terms of predicting overall survival, a nomogram that considered the SIIS and clinical prognostic factors performed better than the AJCC staging. Conclusion: The pretreatment levels of SIIS were an independent predictor of prognosis in upper urinary tract urothelial carcinoma after RNU. Therefore, incorporating SIIS into currently available clinical parameters helps predict the long-term survival of UTUC.

Background: Early detection of prostate cancer (PCa) remains a clinical challenge. Plasma proteomics provides a non-invasive tool for identifying individuals at elevated risk prior to symptom onset or PSA elevation. Methods: We quantified 1463 plasma proteins in 23 825 PCa-free men from the UK Biobank (UKB). Participants were split into training and validation sets. Cox regression and Light Gradient Boosting Machine (LightGBM) with forward feature selection were used to identify and rank predictive proteins. Model performance was assessed by area under the receiver operating characteristic curve (AUC) in the validation set, and SHAP values were used to interpret feature contributions. Results: TSPAN1 and GP2 consistently ranked as top predictors across all analyses. In the training set, both proteins remained significantly associated with PCa risk after Bonferroni correction in multivariable Cox models. LightGBM with forward selection further prioritized TSPAN1 and GP2 as key contributors, and SHAP analysis confirmed their dominant importance. In the validation set, a model combining TSPAN1, GP2, and demographic variables achieved an AUC of 0.728 for overall PCa prediction and 0.760 for 5-year risk. Based on Youden Index–derived thresholds, high-expression groups of TSPAN1 and GP2 were associated with hazard ratios of 1.75 and 1.60, respectively. Longitudinal profiling showed that TSPAN1 levels began rising approximately 9 years before diagnosis, while GP2 increased from 6 years prior. Conclusions: TSPAN1 and GP2 are promising long-term predictive biomarkers for PCa. A streamlined proteomics-based model may enable individualized risk stratification and inform earlier, less invasive screening strategies.

Background: Benign prostatic hyperplasia (BPH) is a prevalent condition among older men that significantly reduces quality of life. Despite its global impact, comprehensive estimates of lifetime risk remain limited. This study aims to quantify the lifetime risk of BPH at both global and regional levels using data from the Global Burden of Disease (GBD) 2021. Materials and methods: We estimated the lifetime risk of developing BPH in men aged over 40 using the “adjusted for multiple primaries (AMP)” method, derived from age-specific incidence rates provided by GBD. The analysis included data from 204 countries and regions covering the period from 1990 to 2021, stratified by age, region, and sociodemographic index (SDI). Results: In 2021, the global lifetime risk of BPH from age 40 to death was estimated at 27.29% (95% CI 27.26–27.31), with significant regional and socioeconomic inequalities. Eastern Europe exhibited the highest risk (37.57%), while Central Sub-Saharan Africa had the lowest (13.66%). When stratified by SDI, lifetime risk increased from 19.46% in low SDI regions to 31.51% in high-middle SDI regions but declined to 24.71% in high SDI settings. Across all regions, most cases were observed in individuals aged 50–70. Furthermore, between 1990 and 2021, the global lifetime risk of BPH showed a gradual increase. Projections indicate that this risk will remain stable over the next 30 years, with pronounced regional disparities expected to persist. Conclusions: This study offers a comprehensive assessment of the global lifetime risk of BPH, revealing significant regional variations and age-related trends. These findings underscore the need for targeted prevention and management strategies, particularly for high-risk regions and men aged 50–70, to reduce the global burden of BPH.

Mitosis serine/threonine–protein kinase BUB1 is an anoikis-related gene that may be inversely related to tumor progression due to its role in programmed cell death. We aimed to develop a risk and prognosis prediction model for the BUB1 gene after in vitro validation and find potential targeted drugs for prostate cancer (PCA). The prediction model was established using univariate Cox, multivariate Cox, and LASSO regression. Receiver operating characteristic curves determined the predictive performance, and the GEO database was used for external validation. Patients’ prognoses were compared using Kaplan–Meier analysis. We investigated immune cell infiltration and sensitivity to immunotherapeutic drugs in PCA patients. Cell experiments illustrated the influence of BUB1 on cell invasiveness, viability, and epithelial–mesenchymal transition (EMT). BUB1-based four-gene prediction model divided patients into low- and high-risk group. Patients in the high-risk group had worse overall survival than those in the low-risk group, with significant differences in immune cell infiltration, immune checkpoint expression, and sensitivity to immunotherapeutic drugs. Drug sensitivity illustrated that over ten drugs may be effective for higher risk patients. Knocking down the BUB1 gene in PC3 and C4-2 cell lines reduced PCA cell proliferation and invasion and altered EMT-related protein expression. After external validation, a BUB1-based four-gene prognostic signature, which may represent a subtype of PCA with more aggressive and metastatic characteristics, was shown to accurately predict the prognosis of PCA. In vitro experiments revealed that the BUB1 gene significantly affects the proliferation, invasion, and expression of specific EMT-related proteins in PCA cells.