Cisplatin-based chemotherapy is the standard first-line treatment for bladder cancer, but its efficacy is limited by drug resistance. Immune checkpoint blockades have emerged as promising therapeutic options; however, their benefits are restricted by the immunosuppressive tumor microenvironment and low response rates. Overcoming both platinum resistance and immune evasion remains a major therapeutic challenge. In this study, we developed NP2, a redox-responsive amphiphilic selenium-containing polymer that encapsulates a platinum(IV) prodrug. NP2 disassembles in response to intracellular glutathione (GSH), releasing active cisplatin to induce DNA damage and apoptosis. Concurrently, diselenide bonds deplete GSH, disturbing the GSH antioxidant system, while selenium residues suppress thioredoxin (Trx) reductase, blocking the Trx system. This dual inhibition prevents cisplatin inactivation, enhances chemotherapy efficacy, and elevates the level of reactive oxygen species (ROS). Therefore, the increased ROS induces immunogenic cell death, promotes dendritic cell maturation, and activates adaptive immunity, thereby converting "immune-cold" tumors into "immune-hot" tumors. Further, NP2 suppressed tumor growth, remodeled the immune microenvironment, and upregulated programmed death-ligand 1 (PD-L1) expression in vivo. In combination with the PD-1 monoclonal antibody (αPD-1), NP2 achieved synergistic effects, inhibiting primary tumors and preventing distant progression. NP2 thus represents dual-action nanoparticles that overcome platinum resistance and enhance immunotherapy for bladder cancer.

BACKGROUND:Prostate cancer is one of the common malignant tumors in men. Recent studies have reported that non-invasive liquid biopsy is of great significance in tumor diagnosis. We hope to find relevant detection genes to establish a diagnostic and prognostic model for prostate cancer. METHODS:This study was based on the RNA expression data of prostate cancer patients from the The Cancer Genome Atlas (TCGA) database and the data of exosome-related genes from the GeneCards website. Key exosome-related differential genes were identified through cluster modeling, univariate and multivariate regression analyses. The roles of these genes in the occurrence and prognosis of prostate cancer were assessed using ROC curves and survival analysis. Validation was performed using prostate cancer patient data from the Gene Expression Omnibus (GEO) database. RESULTS:Firstly, we obtained 117 exosome-related differential genes (ERDEGs) from the RNA expression data of prostate cancer patients in the TCGA database. Next, through Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, univariate Cox regression analysis, and multivariate Cox regression analysis of the ERDEGs, we obtained three genes that were significantly associated with prognosis (AQP2, H4C2, ZNF114) and calculated the risk score accordingly. Patients were divided into high-risk and low-risk groups based on this score, with significant differences in overall survival between the groups. At the same time, we conducted an immunological infiltration analysis on prostate cancer patients and Weighted correlation network analysis (WGCNA) on the ERDEGs. Finally, we used the GEO database (GSE69223, GSE229904) for verification and found that AQP2 and ZNF114 had good predictive value for the occurrence of prostate cancer. CONCLUSION:Exosome-related genes such as AQP2 and ZNF114 exhibit good performance as non-invasive biomarkers in predicting the status and prognosis of prostate cancer to avoid the issues of high invasiveness associated with invasive examinations.

Hepatocellular carcinoma (HCC) is the most common and fatal form of liver cancer and has been associated with the transient receptor potential channel (TRPC) family. However, the exact mechanism underlying this connection remains elusive. In this study, we aimed to investigate the role of TRPCs in HCC using bioinformatics methods. We employed bioinformatics methods to screen and determine the biomarkers (cytochrome P450 family 2 subfamily C member [CYP2C9], kinesin family member 20A [KIF20A], secreted phosphoprotein 1 [SPP1], and TMF-regulated nuclear protein 1 [TRNP1]) for the risk score of HCC patients. To further verify our findings, we conducted western blotting to determine the expression levels of these biomarkers in HCC and normal samples. Functional characterization of the corresponding genes was conducted through wound healing, cell counting kit-8, and transwell invasion assays using cell lines with gene knockdown or overexpression. Notably, there were significant differences in the levels of 13 types of immune cells between the two risk groups, such as activated dendritic cells and activated CD4+ T cells. Western blotting indicated that KIF20A, SPP1, and TRNP1 were upregulated in HCC, which is consistent with the differential analysis. In the TRNP1 overexpression group, the cell migration distance, cell viability, and cell invasion ability were enhanced. In conclusion, this study identified four biomarkers, namely CYP2C9, KIF20A, SPP1, and TRNP1, and established a risk model for HCC. Our findings can pave the way for improving the diagnosis and treatment options for HCC using TRPC-related biomarkers.

Background and objective:Benign prostatic hyperplasia (BPH) is a major cause of lower urinary tract symptoms (LUTS) in men aged ≥50 yr. Xialiqi capsules are a traditional Chinese medicine mainly used for the treatment of moderate BPH-related LUTS. Methods:We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of Xialiqi treatment for 8 wk in a cohort of 395 patients. Changes in BPH-related LUTS were assessed in terms of the International Prostate Symptom Score (IPSS). Irritative and obstructive IPSS subscores and secondary efficacy indicators, including quality of life (QoL) and International Index of Erectile Function (IIEF-5) scores, were also assessed. Safety and tolerability were assessed in terms of adverse events (AEs) and serious AE. Key findings and limitations:At the final time point of 8 wk, the least-squares treatment difference in IPSS between the Xialiqi and placebo groups was -2.33 (95% confidence interval -3.01 to -1.64). Analysis of covariance results suggested that there was no significant difference between the groups in terms of interactions of subgroups or between parameter subgroups. Results for secondary efficacy measures, including Chronic Prostatitis Symptom Index and QoL scores, revealed greater improvement with Xialiqi than with placebo. Safety results show that Xialiqi was well tolerated and AEs were mild. Limitations include the lack of long-term follow-up. Conclusions and clinical implications:Xialiqi was associated with an improvement in LUTS over an 8-wk period among men with moderate BPH symptoms. Patient summary:We looked at the safety and efficacy of Xialiqi capsules for the treatment of benign enlargement of the prostate gland in a large Chinese population. We found that Xialiqi provides an early improvement in urinary symptoms and prostate enlargement in men with moderate symptoms relating to an enlarged prostate.

Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer.

Sonodynamic therapy, a treatment modality recently widely used, is capable of disrupting the tumor microenvironment by inducing immunogenic cell death (ICD) and enhancing antitumor immunity during immunotherapy. Erdafitinib, an inhibitor of the fibroblast growth factor receptor, has demonstrated potential benefits for treating bladder cancer. However, Erdafitinib shows effectiveness in only a small number of patients, and the majority of patients responding positively to the medication have "immune-cold" tumors. To increase the therapeutic efficacy of Erdafitinib, we have herein developed a biodegradable pseudoconjugate polymer (PSP) with sonodynamic capabilities. Erdafitinib could be efficiently encapsulated in nanoparticles (NP-PE) prepared through the self-assembly of PSP with an oxidation-sensitive polymer (P1). Under ultrasound conditions, NP-PE effectively induced cytotoxicity by producing reactive oxygen species and further triggering ICD. Compared with Erdafitinib, NP-PE inhibited the expression of FGFR3 to a higher extent. In animal models with bladder cancer, NP-PE inhibited tumor growth, stimulated antitumor immunity, and synergized with antiprogrammed cell death-ligand 1 (aPD-L1), offering a novel approach for the treatment of bladder cancer.

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer.

Cuproptosis, a newly identified programmed cell death form, is characterized by excessive copper accumulation in cells, resulting in mitochondria damage and toxic protein stress, ultimately causing cell death. Given the considerable therapeutic promise of copper toxicity in cancer treatment, copper-based nanomaterials that induce copper death have attracted interest as a promising approach for tumor therapy. This review comprehensively introduces the mechanisms of cuproptosis and the associated regulatory genes, including both positive and negative regulatory regulators, and systematically summarizes the application of various nanoparticles in inducing cuproptosis, ranging from inorganic copper compounds to delivery systems. These nanoparticles offer significant advantages, such as improving copper absorption, extending the duration of effectiveness, enhancing the precision of copper release, increasing biocompatibility, and serving as enhancers in combination therapy. In conclusion, the authors present a detailed overview and insights into the current research directions of nanoplatforms that facilitate copper-induced cancer treatment, establishing a foundation for the future development of effective nanomedicines that induce cuproptosis and offering new possibilities and treatment strategies for tumor therapy.

The tumor microenvironment (TME) drives therapeutic resistance through immunosuppression, stromal remodeling, and metabolic reprogramming, which pose a major challenge in solid tumor treatment. While surgery remains a cornerstone for tumor eradication, perioperative inflammatory responses and ischemia-reperfusion injuries may exacerbate TME deterioration. However, surgery also offers a strategic opportunity for TME modulation. This narrative review analyzes TME components and resistance mechanisms, proposing a multi-stage intervention framework: preoperative TME reshaping, intraoperative precision resection with local therapy, and postoperative dynamic monitoring. We further explore a multidisciplinary whole-course management model, integrating cutting-edge technologies such as radiomics and single-cell sequencing. By bridging basic research with clinical translation, this review aims to guide surgeons in transitioning from tumor resection to TME precision regulation, with a focus on perioperative multi-stage interventions.

BACKGROUND:Circulating metabolites have been found to play an important role in the development of renal cancer, however, the specific pathways and mechanisms of their influence are still largely unknown. We aimed to investigate the role of metabolites in kidney cancer development and to explain the development of kidney cancer from a genetic perspective. METHOD:We explored the role of plasma metabolites and urinary metabolites in kidney cancer using two-sample mendelian randomization (MR) separately and validated it using multiple databases; in addition, we performed rigorous tests of pleiotropy and heterogeneity to ensure that the results were robust. Next, we explored the role of common modifiable risk factors in kidney cancer and identified the specific mechanisms by which risk factors affect kidney cancer by joint analysis of TCGA and GEO databases. RESULTS:Through MR analysis, we identified six plasma metabolites and one urinary metabolite that play a major role in kidney cancer, confirmed the effects of BMI and type 1 diabetes mellitus on kidney cancer, and constructed the BMI-plasma metabolite-kidney cancer causality networks through mediated MR. In addition, we found that SLPI could significantly affect the prognosis of kidney cancer through multiple databases' joint analyses, and through multiple methods explored the pathways of SLPI's influence on kidney cancer. CONCLUSIONS:In a word, this study shows that BMI can significantly increase the risk of kidney cancer, while the plasma metabolites 4-guanidinobutanoate may partially mitigate this risk, and that SLPI promotes tumorigenesis in obesity-related renal cancer by regulating protease activity.

Neutrophil extracellular traps (NETs) represent a novel form of inflammatory cell death within neutrophils. Emerging research indicates that NETs promote cancer progression and metastasis in various ways. This study aims to provide prognostic NETs characteristics and therapeutic targets for patients with renal cell carcinoma (RCC). NMF analysis was conducted on 89 NET-related genes in the training cohort. Subsequently, WGCNA networks were utilized to study the subtype feature genes. Six machine learning algorithms were assessed for model training, and the optimal model was selected based on 1-year, 3-year, and 5-year AUC values. A NETs signature was then constructed to predict overall survival in RCC patients. Furthermore, multi-omics validation was performed based on NETs signature. Finally, stable knockout key gene RCC cell lines were established to verify the biological function of KCNN4 both in vitro and in vivo. This study highlights the emerging hot topic of NETs in RCC. We provide a prognostic NETs signature and identify multiple roles of KCNN4 in RCC. This work contributes to risk stratification and the identification of new therapeutic targets for RCC patients.

BACKGROUND:At present, biopsy is essential for the diagnosis of prostate cancer (PCa) before radical prostatectomy (RP). However, with the development of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) and multiparametric magnetic resonance imaging (mpMRI), it might be feasible to avoid biopsy before RP. Herein, we aimed to explore the feasibility of avoiding biopsy before RP in patients highly suspected of having PCa after assessment of PSMA PET/CT and mpMRI. METHODS:Between December 2017 and April 2022, 56 patients with maximum standardized uptake value (SUVmax) of ≥4 and Prostate Imaging Reporting and Data System (PI-RADS) ≥4 lesions who received RP without preoperative biopsy were enrolled from two tertiary hospitals. The consistency between clinical and pathological diagnoses was evaluated. Preoperative characteristics were compared among patients with different pathological types, T stages, International Society of Urological Pathology (ISUP) grades, and European Association of Urology (EAU) risk groups. RESULTS:Fifty-five (98%) patients were confirmed with PCa by pathology, including 49 (89%) with clinically significant prostate cancer (csPCa, defined as ISUP grade ≥2 malignancy). One patient was diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN). CsPCa patients, compared with clinically insignificant prostate cancer (cisPCa) and HGPIN patients, were associated with a higher level of prostate-specific antigen (22.9 ng/mL vs . 10.0 ng/mL, P = 0.032), a lower median prostate volume (32.2 mL vs . 65.0 mL, P = 0.001), and a higher median SUVmax (13.3 vs . 5.6, P <0.001). CONCLUSIONS:It might be feasible to avoid biopsy before RP for patients with a high probability of PCa based on PSMA PET/CT and mpMRI. However, the diagnostic efficacy of csPCa with PI-RADS ≥4 and SUVmax of ≥4 is inadequate for performing a procedure such as RP. Further prospective multicenter studies with larger sample sizes are necessary to confirm our perspectives and establish predictive models with PSMA PET/CT and mpMRI.

Abstract Background Prostate cancer is one of the most common cancers in men with notable interpatient heterogeneity. Implications of the immune microenvironment in predicting the biochemical recurrence-free survival (BCRFS) after radical prostatectomy and the efficacy of systemic therapies in prostate cancer remain ambiguous. Methods The tumor immune contexture score (TICS) involving eight immune contexture-related signatures was developed using seven cohorts of 1120 patients treated with radical prostatectomy (training: GSE46602, GSE54460, GSE70769, and GSE94767; validation: GSE70768, DKFZ2018, and TCGA). The association between the TICS and treatment efficacy was investigated in GSE111177 (androgen deprivation therapy [ADT]) and EGAS00001004050 (ipilimumab). Results A high TICS was associated with prolonged BCRFS after radical prostatectomy in the training (HR = 0.32, 95% CI 0.24–0.45, P < 0.001) and the validation cohorts (HR = 0.45, 95% CI 0.32–0.62, P < 0.001). The TICS showed stable prognostic power independent of tumor stage, surgical margin, pre-treatment prostatic specific antigen (PSA), and Gleason score (multivariable HR = 0.50, 95% CI 0.39–0.63, P < 0.001). Adding the TICS into the prognostic model constructed using clinicopathological features significantly improved its 1/2/3/4/5-year area under curve (P < 0.05). A low TICS was associated with high homologous recombination deficiency scores, abnormally activated pathways concerning DNA replication, cell cycle, steroid hormone biosynthesis, and drug metabolism, and fewer tumor-infiltrating immune cells (P < 0.05). The patients with a high TICS had favorable BCRFS with ADT (HR = 0.25, 95% CI 0.06–0.99, P = 0.034) or ipilimumab monotherapy (HR = 0.23, 95% CI 0.06–0.81, P = 0.012). Conclusions Our study delineates the associations of tumor immune contexture with molecular features, recurrence after radical prostatectomy, and the efficacy of ADT and immunotherapy. The TICS may improve the existing risk stratification systems and serve as a patient-selection tool for ADT and immunotherapy in prostate cancer.

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existing Cu ionophores are small molecules with a short blood half-life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)-sensitive polymer (PHPM) is designed, which is used to co-encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA-Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti-programmed cell death protein ligand-1 antibody (αPD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD-L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

Glutathione S-transferase (GST), which is a key enzyme in the conjugation reaction of glutathione (GSH), is overexpressed in cancer cells, leading to cisplatin deactivation and ultimately drug resistance. In addition, many tumors are immune "cold tumors," limiting the application of immune checkpoint inhibitors. Herein, a reactive oxygen species (ROS)-responsive polyphotosensitizer-based nanoparticle (NP2) with Michael addition acceptors inhibiting GST activity and cisplatin deactivation is designed. Under the 808 nm light irradiation, on the one hand, the Michael addition acceptor in NP2 can react with GST and inhibit its activity, thereby decreasing the GSH conjugation and reducing the GSH-mediated deactivation of cisplatin and improving its chemotherapeutic effect. On the other hand, NP2+L induces more ROS production in prostate tumor cells, which can further induce type II immunogenic cell death (ICD) and stimulate a stronger antitumor immune response. It is found that NP2 under the 808 nm light irradiation (NP2+L) can increase PD-L1 expression on the surface of prostate cancer cells. Subsequently, NP2+L combined with PD-L1 treatment is found to simultaneously enhance the efficacies of chemotherapy and photodynamic immunotherapy in prostate tumors, providing a new paradigm for the clinical multimodal treatment of tumors.

Background and objectivesProstate specific antigen (PSA) is currently the most commonly used biomarker for prostate cancer diagnosis. However, when PSA is in the gray area of 4-10 ng/ml, the diagnostic specificity of prostate cancer is extremely low, leading to overdiagnosis in many clinically false-positive patients. This study was trying to discover and evaluate a novel urine biomarker long non-coding RNA (lncRNA546) to improve the diagnostic accuracy of prostate cancer in PSA gray-zone.MethodsA cohort study including consecutive 440 participants with suspected prostate cancer was retrospectively conducted in multi-urology centers. LncRNA546 scores were calculated with quantitative real-time polymerase chain reaction. The area under the receiver operating characteristic curve (AUROC), decision curve analysis (DCA) and a biopsy-specific nomogram were utilized to evaluate the potential for clinical application. Logistic regression model was constructed to confirm the predictive power of lncRNA546.ResultsLncRNA546 scores were sufficient to discriminate positive and negative biopsies. ROC analysis showed a higher AUC for lncRNA546 scores than prostate cancer antigen 3 (PCA3) scores (0.78 vs. 0.66, p<0.01) in the overall cohort. More importantly, the AUC of lncRNA546 (0.80) was significantly higher than the AUCs of total PSA (0.57, p=0.02), percentage of free PSA (%fPSA) (0.64, p=0.04) and PCA3 (0.63, p<0.01) in the PSA 4-10 ng/ml cohort. A base model constructed by multiple logistic regression analysis plus lncRNA546 scores improved the predictive accuracy (PA) from 79.8% to 86.3% and improved AUC results from 0.862 to 0.915. DCA showed that the base model plus lncRNA546 displayed greater net benefit at threshold probabilities beyond 15% in the PSA 4-10 ng/ml cohort.ConclusionLncRNA546 is a promising novel biomarker for the early detection of prostate cancer, especially in the PSA 4-10 ng/ml cohort.

OBJECTIVE:To study the therapeutic effect of lycopene combined with quercetin and curcumin on chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) in rats and its underlying mechanism.METHODS:Thirty-three 6-week-old SD male rats were randomly divided into six groups: normal control (n = 3), CP/CPPS model control (n = 6), quercetin (n= 6), curcumin (n = 6), lycopene (n = 6) and combination therapy (n = 6). CP/CPPS was induced by injection of complete Freund's adjuvant into the ventral lobe of the prostate in the latter five groups of rats. After modeling, the rats in the normal and CP/CPPS model control groups were given corn oil by gavage, and those in the latter four groups treated intragastrically with quercetin at 50 mg/kg/d, curcumin at 50 mg/kg/d, lycopene at 10 mg/kg/d, and quercetin + curcumin + lycopene, respectively, once daily for a course of 4 weeks. Then, cardiac blood and prostate tissue samples were collected from the rats for measurement of related indexes.RESULTS:Histopathological changes in the model rats were basically consistent with the characteristics of CP/CPPS. The expressions of the inflammatory factors IL-1β, IL-2, IL-6, TNFα, MCP1 and MIP-1α in the prostate tissue were all dramatically decreased in the quercetin, curcumin, lycopene and combination therapy groups compared with those in the normal controls (P < 0.01), even lower in the combination therapy group than in the quercetin, curcumin and lycopene groups (P < 0.05). The activities of the oxides CAT, GSH-PX and T-SOD were significantly increased and that of MDA decreased in the four treatment groups (P < 0.05), even more significantly in the combination therapy group than in the other three (P < 0.01). The phosphorylation of MAPKs was inhibited, the activation of NF-kB blocked and the transcriptional activity of Nrf2 enhanced in the four treatment groups (P < 0.05), even more significantly in the combination therapy group (P < 0.01). Conclusions: Lycopene combined with quercetin and curcumin is more effective than any of the three drugs used alone in the treatment of CP/CPPS, which may be associated with its alleviation of inflammatory response and oxidative stress by interaction between the NF-κB, MAPKs and Nrf2 signaling pathways.?

An increasing number of studies have shown that circRNAs are closely related to the carcinogenesis and development of prostate cancer (PCa). However, little is known about the effect of the biological functions of circRNAs on the enzalutamide resistance of PCa. Through bioinformatic analysis and experiments, we investigated the expression pattern of circRNAs in enzalutamide-resistant PCa cells. Quantitative real-time PCR was used to detect the expression of circRAB3IP, and plasmids that knock down or overexpress circRAB3IP were used to evaluate its effect on the enzalutamide sensitivity of PCa cells. Mechanistically, we explored the potential regulatory effects of eIF4A3 and LEF1 on the biogenesis of circRAB3IP. Our in vivo and in vitro data indicated that increased expression of circRAB3IP was found in enzalutamide-resistant PCa, and knockdown of circRAB3IP significantly enhanced enzalutamide sensitivity in PCa cells. However, upregulation of circRAB3IP resulted in the opposite effects. Further mechanistic research demonstrated that circRAB3IP could regulate the expression of serum and glucocorticoid-regulated kinase 1 (SGK1) by serving as a sponge that directly targets miR-133a-3p/miR-133b. Then, we showed that circRAB3IP partially exerted its biological functions via SGK1 signaling. Furthermore, we discovered that eIF4A3 and LEF1 might increase circRAB3IP expression in PCa.