Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11/xCT.

Bladder cancer (BLCA) is a prevalent cancer with high case-fatality rates and a substantial economic burden worldwide. Understanding its molecular underpinnings to guide clinical management is crucial. Ferroptosis, a recently described non-apoptotic form of cell death, is initiated by the lethal accumulation of iron-dependent lipid peroxidation products. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in BLCA remain unclear. Re-analysis of single-cell RNA data reveals a decrease in high-ferroptosis cancer cells as BLCA advances. USP52/PAN2 is identified as a key regulator of ferroptosis in BLCA through an unbiased siRNA screen targeting 96 deubiquitylases (DUBs). Functionally, USP52 depletion impedes glutathione (GSH) synthesis by promoting xCT protein degradation, increasing lipid peroxidation and ferroptosis susceptibility, thus suppressing BLCA progression. Mechanistically, USP52 interacts with xCT and enzymatically cleaves the K48-conjugated ubiquitin chains at K4 and K12, enhancing its protein stability. Clinical BLCA samples demonstrate a positive correlation between USP52 and xCT expression, with high USP52 levels associated with aggressive disease progression and poor prognosis. In vivo, USP52 depletion combined with ferroptosis triggers imidazole ketone Erastin (IKE) synergistically restrains BLCA progression by inducing ferroptosis. These findings elucidate the role of the USP52-xCT axis in BLCA and highlight the therapeutic potential of targeting USP52 and ferroptosis inducers in BLCA.

Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics.

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.

Causal association of smoking, blood lipids, and bladder cancer: Insights from a multivariable and mediation mendelian randomization investigation.

We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.

Blood metabolites mediate the impact of lifestyle factors on the risk of urolithiasis: a multivariate, mediation Mendelian randomization study.

Urolithiasis is closely linked to lifestyle factors. However, the causal relationship and underlying mechanisms remain unclear. This study aims to investigate the relationship between lifestyle factors and the onset of urolithiasis and explore potential blood metabolite mediators and their role in mediating this relationship. In this study, we selected single nucleotide polymorphisms (SNPs) as instrumental variables if they exhibited significant associations with our exposures in genome-wide association studies (GWAS) (p < 5.0 × 10-8). Summary data for urolithiasis came from the FinnGen database, including 8597 cases and 333,128 controls. We employed multiple MR analysis methods to assess causal links between genetically predicted lifestyle factors and urolithiasis, as well as the mediating role of blood metabolites. A series of sensitivity and pleiotropy analyses were also conducted. Our results show that cigarettes smoked per day (odds ratio [OR] = 1.159, 95% confidence interval [CI] = 1.004-1.338, p = 0.044) and alcohol intake frequency (OR = 1.286, 95% CI = 1.056-1.565, p = 0.012) were positively associated with increased risk of urolithiasis, while tea intake (OR = 0.473, 95% CI = 0.299-0.784, p = 0.001) was positively associated with reduced risk of urolithiasis. Mediation analysis identifies blood metabolites capable of mediating the causal relationship between cigarettes smoked per day, tea intake and urolithiasis. We have come to the conclusion that blood metabolites serve as potential causal mediators of urolithiasis, underscoring the importance of early lifestyle interventions and metabolite monitoring in the prevention of urolithiasis.

Propensity score-matched analysis for ileal conduit and orthotopic neobladder intracorporeally accomplished following laparoscopic radical cystectomy.

PURPOSE: To compare perioperative results of intracorporeal ileal conduit (ICIC) and intracorporeal orthotopic neobladder (ICONB) following laparoscopic radical cystectomy. MATERIALS AND METHODS: A total of 51 ICIC patients and 32 ICONB patients were included. Propensity score matching was performed based on: age, body mass index, gender, age-adjusted Charlson comorbidity index, history of neoadjuvant chemotherapy, history of abdominal surgery, history of smoking and enhanced recovery protocols. Primary outcomes were length of stay and 30-day complications. Secondary outcomes were operative time and estimated blood loss. RESULTS: ICONB was more likely to be performed in younger patients (P < 0.001). Other baseline characteristics in the 2 groups were similar (P > 0.05). ICIC showed shorter length of stay (11 days vs. 14 days, P = 0.031) and faster pelvic drainage tube removal (6 days vs. 9 days, P = 0.014). Operative time, estimated blood loss, 30-day complications were similar in the 2 groups (P > 0.05). However, postoperative fever was significantly lower in ICIC group (19.6% vs. 62.5%, P < 0.001). After propensity score matching, ICIC still showed shorter length of stay (10 days vs. 15 days, P = 0.002) and less postoperative fever (15% vs. 65%, P = 0.003). In multivariable analysis, ICONB was independently associated with length of stay≥14 days and postoperative fever both before and after propensity score matching (P < 0.05). CONCLUSIONS: In our research, ICONB was more likely to be performed in younger patients. ICIC and ICONB showed no difference on 30-day complications, operative time and estimated blood loss. ICIC group showed shorter length of stay, faster pelvic drainage tube removal and less postoperative fever.

Impact of preoperative body mass index on perioperative outcomes is optimized by enhanced recovery protocols in laparoscopic radical cystectomy with intracorporeal urinary diversion.

BACKGROUND: We aimed to examine whether body mass index (BMI) had an impact on clinical outcomes of laparoscopic radical cystectomy with intracorporeal urinary diversion. Furthermore, we analyzed the optimization of enhanced recovery protocols (ERPs) on the impact of BMI on clinical outcomes. METHODS: By searching our database, data of 83 consecutive patients were retrospectively collected, including 37 patients with a BMI <24 kg/m2 (group A) and 46 patients with a BMI ≥24 kg/m2 (group B). The baseline and peri-operative variables of the two groups were compared. Subgroup analysis was conducted for ERPs (11 patients in group A1, 18 patients in group B1) and conventional recovery protocols (CRPs; 26 patients in group A2, 28 patients in group B2). The primary outcomes were 30-day overall complication rate and ΔALBmin (reduction proportion of minimum albumin). The secondary outcomes were operative time and length of stay. RESULTS: The baseline variables were similar between the two groups (P>0.05). The 30-day overall complication rate, operative time, and length of stay were similar between the two groups (P>0.05). But post-operative nausea and vomiting (PONV) was higher in group A than in group B (32.4% vs. 8.7%, P=0.014). Group A was associated with lower serum albumin level pre-operatively and on post-operative days 1-3. ΔALBmin was higher in group A than in group B (33.08%±9.88% vs. 27.92%±8.52%, P<0.05). In the subgroup analysis, the CRPs group presented similar results, with group A2 showing higher PONV rate, lower albumin level pre- and post-operatively, and higher level of reduction proportion (P<0.05). For the ERPs group, the PONV rate, pre-operative albumin level, and reduction proportion were similar between group A1 and B1 (P>0.05). Multivariable analysis showed that PONV and CRPs were independently associated with ΔALBmin ≥34% (P<0.05). CONCLUSIONS: BMI had no impact on the 30-day overall complication rate, operative time, and length of stay of patients who underwent laparoscopic radical cystectomy with intracorporeal urinary diversion. BMI <24 kg/m2 was associated with higher PONV rate and more albumin loss, both of which could be optimized by ERPs.

Modified ileal conduit intracorporeally accomplished following laparoscopic radical cystectomy with enhanced recovery protocols: experience with 48 cases.

BACKGROUND: This study introduces the results of laparoscopic radical cystectomy with modified intracorporeal ileal conduit (mICIC), which was accompanied by enhanced recovery after surgery (ERAS) protocols. METHODS: From March 2014 to June 2020, 48 patients underwent mICIC. Patients were divided into ERAS (n=17) and non-ERAS groups (n=31). Baseline and perioperative variables were analyzed. The primary outcome was 90-day complications. Secondary outcomes were operative time, length of stay, two-year overall survival, cancer-specific survival, and disease-free survival. RESULTS: Forty-eight patients underwent intracorporeal ileal conduit with no transition to open surgery. Twenty-five patients (52.1%) experienced at least one complication, including 22 minor cases (45.8%) and three major cases (6.2%). The median operative time, urinary diversion time, estimated blood loss, and length of stay were 320 min, 135 min, 200 mL, and 10.5 days, respectively. The median time to flatus and normal diet were two days and three days, respectively. A comparison between ERAS and non-ERAS groups indicated that ERAS implementation was associated with less complications (29.4% vs. 64.5%, P=0.018), faster time to flatus (2 vs. 3 days, P=0.016) and liquid diet (2 vs. 4 days, P<0.001). The results of hydronephrosis and compromised renal function showed no difference between the preoperative period and six months after surgery. The mean follow-up time was 25.4 months, and the two-year overall survival, cancer-specific survival, and disease-free survival rates were 61.3%, 73.2%, and 58.4%, respectively. CONCLUSIONS: The complication rate and operative time of the mICIC were acceptable. Clinical outcomes can be optimized with ERAS pathway.