Prostate cancer (PCa) is one of the most prevalent malignant tumors among men globally, with limited treatment options, especially in cases that progress to castration-resistant prostate cancer (CRPC). Identifying novel molecular targets and effective therapeutic strategies is crucial for improving patient outcomes. In this study, we identified serum and glucocorticoid-regulated kinase 1 (SGK1) as a potential target of the trifluoromethylquinoline derivative TKL007. A series of in vitro assays, including CCK-8, colony formation, Transwell migration and invasion assays, and flow cytometry, were performed to systematically evaluate the anti-tumor effects of TKL007 on the PC3 and LNCaP prostate cancer cell lines. Western blot analysis revealed that TKL007 significantly inhibited the activation of the PI3K/AKT signaling pathway. Further transfection experiments confirmed that SGK1 expression levels regulate the activity of the PI3K/AKT pathway, suggesting that SGK1 may modulate this signaling axis. In vivo xenograft experiments in nude mice demonstrated that TKL007 effectively inhibited tumor growth without causing significant toxicity. Taken together, these results suggest that TKL007 exerts anti-prostate cancer effects by downregulating SGK1 protein levels and inhibiting the PI3K/AKT pathway, providing a new candidate molecule and theoretical foundation for targeted therapy.

Prostate cancer cells of different anatomical locations display remarkable heterogeneity. This poses a challenge to the clinical relevance of pre-clinical models and the efficacy of contemporary therapeutic approaches. Here we develop the snFLARE-seq and mxFRIZNGRND methodologies to directly investigate the transcriptomic and metabolomic landscape of prostate cancer patients utilizing formalin-fixed paraffin-embedded (FFPE) specimens. A retrospective analysis reveals the clinical disparities of prostate cancer from peripheral zone (PZ), transition zone (TZ), and across PZ and TZ. The snFLARE-seq, refined for enhanced single-nucleus sequencing, unveils distinct cell type distributions and signaling pathways between PZ and TZ samples. Hormone therapy substantially affects cancer cells and microenvironment, leading to a polarized feature of epithelial cells and a subverted immune microenvironment. With improvements in metabolite extraction, mxFRIZNGRND reveals unique metabolic features of prostate cancer from different origins. The metabolomic results indicate that PZ cancer cells are in a metabolic-dormant status, which are probably awaken by hormone therapy. Integrative analysis of results from snFLARE-seq, mxFRIZNGRND, and TCGA database uncovers four metabolic pathways and related genes associated with disease aggressiveness. Our work could accelerate investigations on disease heterogeneity and evolution in real-world clinical settings, stimulating patient-specific precision healthcare solutions.

We analysed reimbursement differences for prostate (PC), renal cell (RCC), and urothelial (UC) cancers drugs in Canada, France, England, Wales, Scotland, Spain, Italy, and Portugal, assessing substantial clinical benefit (SCB) and pivotal trials characteristics. This is a retrospective analysis of PC, RCC, and UC drug-indication pairs (2005-2024). Approvals were identified via FDA and EMA. Reimbursement recommendations were reviewed. Primary endpoint was reimbursement rate by SCB, tumour type, and country. Trial characteristics, overall survival (OS), and quality of life (QoL) were analysed. SCB was defined by ESMO-MCBS v1.1. Statistical significance set at p < .05. Fifty-five drug-indication pairs for PC (20), RCC (20), and UC (15) were analysed. Most trials were randomized, open-label, phase 3, and in the metastatic settings. Canada (PC: 85%, RCC: 75%, UC: 53%) and France (PC: 85%; RCC: 75%; UC: 33%) had highest reimbursement rates; while Portugal, lowest (PC: 65%; RCC: 50%; UC: 20%). Among SCB indications, PC reimbursement was highest in Canada, France, and Spain (91%), and lowest in England (64%). For RCC, was highest in Canada, France, and Italy (100%), and lowest in Portugal (57%). For UC, was highest in Canada (100%), and lowest in Wales and England (33%). OS was primary endpoint in 47% trials; QoL was assessed in 25%. OS benefit was observed in 53%; QoL in only 9%. This study reveals marked international variation in genitourinary cancer drug reimbursement, particularly in Europe and for UC-even for indications with SCB. Most trials lacked evidence of OS or QoL benefit.

Exhaustive evidence about the impact of racial disparities in oncological outcomes after a negative prostate biopsy is still lacking. We explored the relationship between race and long-term oncological risk among men with an initial negative prostate biopsy using a contemporary U.S. Non-Hispanic Black (NHB) and Non-Hispanic White (NHW) men who had a negative prostate biopsy at Henry Ford Health between 1995-2023 were included. An Area Deprivation Index (ADI)-score was assigned to each patient based on their residential census-block group. The higher the ADI, the more the area has a socio-economic disadvantage. Competing-risk methods were used to estimate the cumulative incidence of any PCa diagnosis, clinically significant PCa diagnosis, receipt of active treatment, Prostate Cancer Specific Mortality (PCSM) and Other Cause Mortality (OCM) for the entire cohort of patients, after stratification according to race. Fine-Gray regression models tested the impact of race on the aforementioned outcomes. We included 17,446 men, 5,729 (30.3%) of whom were NHB. Within a median follow-up time of 7.8years, the 15-years estimated rates of any PCa diagnosis, clinically significant PCa, active treatment and PCSM were 15.9% vs. 9.5%, 10.7% vs. 6.4%, 10.4% vs. 6.4% and 2.4% vs. 1.3%, for NHB versus NHW patients, respectively (all p-value < 0.0001). At multivariable analysis, NHB men had significantly higher hazard of any PCa (HR:1.90), clinically significant PCa (HR:1.91), active treatment for PCa (HR:1.84) and PCSM (HR:1.89) (all p < 0.001). NHB men, even after an initial negative prostate biopsy, face a higher risk of subsequent any PCa, clinically significant disease, active treatment and PCSM. Overall, these findings underscore the multifaceted impact of racial disparities on PCa prognosis.

To assess 2-year biochemical control, radiological progression, late side effects, and survival outcomes following stereotactic body radiotherapy (SBRT) for localized prostate cancer in a multicenter Spanish cohort. A total of 250 patients with localized prostate cancer treated with SBRT across 12 Spanish centers between January 2020 and December 2023 were analyzed. Biochemical recurrence was defined according to the Phoenix criterion (nadir PSA + 2ng/mL). Late genitourinary (GU), gastrointestinal (GI), and sexual adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Univariate and multivariate analyses were performed to identify factors associated with outcomes. Survival was estimated using the Kaplan-Meier method and the log-rank test (p < 0.05). The median age was 72years (IQR: 65-76), and the median baseline PSA was 6.7ng/mL (5.3-8.7). According to the NCCN classification, 30% of patients were low risk, 67% intermediate (26.8% favorable, 39.6% unfavorable), and 3% high or very high risk. The median prescribed dose was 40Gy in five fractions (36.25-40.0), administered on alternate days. At 2 years, biochemical control was 96.4%, and radiological progression occurred in 2.8% of patients, predominantly nodal. The incidence of grade ≥ 2 late adverse events was 7.6% GU, 1.2% GI, and 14.3% sexual. SBRT for localized prostate cancer offers excellent 2-year biochemical control with low rates of late adverse events, supporting its safety and effectiveness in routine clinical practice for selected patients. A longer follow-up is warranted to fully characterize long-term outcomes.

Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.

N6-methyladenosine (m6A) represents the most abundant internal RNA modification and a key regulator of gene expression. Although individual m6A regulators and sites have been linked to cancer, their transcriptome-wide functional landscape remains undefined. Here we developed an epitranscriptomic screening platform based on targeted m6A deposition to identify functional modifications in prostate and lung cancer models. The unbiased screens uncovered 222 m6A sites that modulate cell proliferation, predominantly in a cell-type-specific manner. Among them, an m6A site within CHD9 emerged as a potent tumor-suppressive modification in prostate cancer. Deposition of m6A at this site increased CHD9 protein abundance, suppressed cell proliferation and attenuated xenograft growth. Mechanistically, m6A at CHD9 enhances translation through YTHDF1 and YTHDF3, promoting CHD9-MYBBP1A interaction in the nucleoplasm, sequestrating MYBBP1A from the nucleolus and activating CDKN1A (p21)-associated tumor-suppressive signaling. Collectively, our study establishes a scalable framework for functional mapping of the m6A epitranscriptome and uncovers a mechanistic link between CHD9 m6A modification and tumor suppression, paving the way for systematic exploration of other RNA modifications in cancer.

To identify second primary malignancies (SPMs) death risk factors in prostate cancer (PCa) survivors and high-risk PCa patients for SPMs. With improved PCa survival, there's a growing need to study second SPMs in PCa survivors. PCa patients from 2004 to 2015 in the surveillance, epidemiology, and end results database were screened for SPM risk. The Fine and Gray competing risk model identified SPM mortality risk factors via univariate and multivariate analyses. A competing risk nomogram predicted 3-, 5-, and 10-year SPM mortality risk, stratifying patients by total scores for risk assessment. Model performance was assessed using the correlation index, receiver operating characteristic curve, calibration curve, and area under the curve. SPM-diagnosed PCa patients (2004-2015) were split into a 7:3 training (n = 31,435) and validation set (n = 13,472). The nomogram included 12 factors: age, chemotherapy, radiation, Gleason score, race, grade, marital status, tumor size, surgical site, surgery/radiation sequence, scope, and stage. C-index values were 0.70 (se: 0.001) and 0.684 (se: 0.002) in training and validation, respectively, indicating high discriminative power. The 3-, 5-, and 10-year area under the curves in training were 0.75 (95% confidence interval (CI): 0.72-0.77), 0.73 (95% CI: 0.72-0.75), and 0.72 (95% CI: 0.7-0.73), and in validation were 0.7 (95% CI: 0.65-0.74), 0.7 (95% CI: 0.67-0.73), and 0.71 (95% CI: 0.69-0.73), respectively, showing good predictive accuracy. The calibration curve confirmed model fit. A competing risk model predicts SPM mortality in PCa survivors, aiding high-risk patient identification and guiding survival-oriented treatment and follow-up strategies.

CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.

Prostate cancer (PC) is the second most common cancer in men. Although many studies have assessed its economic burden, no recent reviews have focused on studies conducted under current clinical guidelines. This study systematically reviews recent cost-of-illness studies evaluating direct and indirect costs associated with PC. A systematic search was conducted using the PICOS framework and a combination of free-text and MeSH terms in PubMed and the Cochrane Library, and only free-text terms in EconLit. The search included articles published between January 2015 and October 2025. Data on total, direct, and indirect costs were extracted and synthesized. All costs were converted to 2025 USD, and quality of studies was assessed with a simplified version of the CHEERS checklist. Ninety-five studies met the inclusion criteria. Direct medical costs for non-metastatic prostate cancer (nmPC) varied widely by disease stage, treatment, and country, ranging from approximately US$1200 to US$280,000 per patient-year, with higher costs observed in advanced stages and in patients experiencing treatment-related adverse events (AEs). Progression to metastatic disease was associated with a marked cost escalation, with annual costs largely driven by systemic therapies and skeletal-related events. Indirect costs ranged from US$666 to US$12,900 per patient-year and accounted for up to 30% of total PC-related costs, primarily due to productivity losses from premature mortality. PC imposes a substantial economic burden on healthcare systems and society, particularly in advanced stages. Policy promoting early detection, risk-adapted treatment, and equitable therapy access may help contain costs. Further research should address the economic impact of emerging diagnostics and minimally invasive interventions.

Prostate cancer (PCa) lesions can be measured on MRI using maximum or biaxial diameters, or as volumes derived by the ellipsoid formula or planimetry. We evaluated the inter- and intra-rater reliability (reliability between different radiologists and the same radiologist during different reading sessions) of lesion size measurements on baseline MRI scans for patients on active surveillance (AS). Twenty patients with low- or intermediate-risk PCa (Gleason score 3 + 3 or 3 + 4) and MRI-visible lesions were selected from AS cohorts at two centres (United Kingdom and Italy). Five radiologists, blinded to clinical outcomes and reports, independently measured the index lesion on abaseline MRI scanin a single readingsession using: (1) maximum diameter; (2) biaxial diameters; (3) ellipsoid volume, and (4) planimetry volume. Measurements were repeated after a 4-week washout period. Strip plots present lesion size measurements for all methods and readers. Bland-Altman plots were used to present intra-rater reliability. Graphical presentation of measurements across the twenty patients enabled examination of variability between methods, readers, and reads. There was considerable variation for all methods, and for a single lesion, size measurements spanned previously accepted definitions of clinically significant and insignificant disease. Inter-rater reliability decreased for larger lesions, with notable radiologist-specific differences, and intra-rater reliability appeared better overall. This study underscores the difficulty of reliably measuring PCa lesions during AS. Intra-rater reliability appeared greater than inter-rater reliability, emphasising that radiologists should remeasure lesions when tracking changes. More work is needed on measuring change in lesion size across serial MRI scans. Question Several methods exist for measuring prostate cancer lesion size on MRI for patients on active surveillance, but it is unclear how reliable these methods are. Findings Lesion size measurements varied widely across methods and readers, often spanning thresholds for clinically significant disease, and intra-rater reliability was generally better than inter-rater reliability. Clinical relevance Variability in lesion size measurements on MRI may lead to inconsistent clinical decisions during active surveillance. Our findings emphasise that regardless of the method used, lesions should be remeasured by the same radiologist when monitoring patients on active surveillance.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne disease with a high mortality rate. While research has focused on high-risk rural populations and healthy individuals in endemic regions, such as Jeju Island, data on patients with underlying chronic diseases remain limited. This study aimed to evaluate the seroprevalence of SFTS virus (SFTSV) in patients with various chronic diseases across the Republic of Korea. Serum samples (N = 2948) collected from 10 regional biobanks between 2009 and 2019 were analyzed using a double-antigen sandwich enzyme-linked immunosorbent assay. The overall seroprevalence was 1.22% (36/2948). Seropositivity was significantly higher in males (1.73%) than in females (0.73%, p = 0.013) and increased with age (p = 0.001), peaking at 2.73% in individuals aged 70–79. Geographically, the highest rates were in Gyeongbuk (3.03%), Jeonnam (2.40%), and Gangwon (1.83%). Multivariable logistic regression showed older age (adjusted odds ratio 1.47 per 10-year increase, 95% confidence interval: 1.12–1.97) as the strongest independent predictor of seropositivity. Patients with hepatobiliary/pancreatic cancer (3.16%) and prostate cancer (2.50%) exhibited higher seroprevalence than those in other disease groups. SFTSV exposure is non-negligible among those with chronic diseases, particularly older males in rural provinces. Public health strategies should specifically address these vulnerable populations.

Clonal hematopoiesis (CH) is a precursor state linked to risk of hematological neoplasms, and may be exacerbated by radiation exposure. We aimed to compare CH prevalence after the new radioligand therapy 177Lu-PSMA-617 versus the alternative standard-of-care cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free DNA and leukocyte DNA underwent deep error-corrected targeted sequencing. CH mutations were called at variant allele frequency (VAF)≥0.25%. Variants detected at progression but undetected at baseline were defined as treatment-emergent CH. 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline-progression samples (median interval 29 versus 27 weeks). Baseline CH was detected in 77% (138/178) of patients, with similar prevalence and gene distribution between arms. Treatment-emergent CH occurred more often after 177Lu-PSMA-617 than cabazitaxel (62% [37/60] vs 40% [19/47]; P=0.03), and 83% (121/146) of all emergent mutations were detected after 177Lu-PSMA-617. The DNA damage response gene PPM1D accounted for 42% (51/121) of 177Lu-PSMA-617-emergent mutations; with odds ratios of 3.2 for any treatment-emergent CH and 5.4 for PPM1D, relative to cabazitaxel. CH clones expanded more frequently and to a greater magnitude with 177Lu-PSMA-617 (proportion expanding, 70.9% vs 29.5%; P=7.5×10-5), and increases in maximal CH VAF correlated with number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P=0.002). 177Lu-PSMA-617 strongly promotes CH, supporting integration of longitudinal monitoring for long-term hematologic sequelae as radioligand therapy is implemented earlier in prostate cancer care.

Wilms' tumor 1-associated protein 1 (WTAP) is an epitranscriptomic regulator with multifaceted roles in cancer biology. Acting beyond its function in the m6A methyltransferase complex, WTAP governs RNA splicing, stability, and translation, influencing oncogenic signaling, immune modulation, and therapy resistance. Recent evidence reveals its dynamic involvement in diverse malignancies, where it can act as both an oncogene and tumor suppressor depending on the cellular context. WTAP promotes tumor progression through epithelial-mesenchymal transition (EMT), metabolic reprogramming, angiogenesis, and immune evasion, and contributes to resistance against chemotherapy and immunotherapy by regulating DNA repair, ferroptosis, and immune checkpoint pathways. However, studies have also demonstrated that WTAP can exert tumor-suppressive effects under specific physiological conditions, such as hepatocyte-specific WTAP loss leading to extracellular-signal regulated kinases (ERK)-driven hepatocarcinogenesis, and WTAP-mediated m6A regulation restraining oncogenic signaling in some prostate cancers. Moreover, by enhancing ferroptosis resistance, WTAP may weaken ferroptosis-driven antitumor immunity and contribute to immune-checkpoint resistance. Understanding these mechanisms offers opportunities for exploiting WTAP as a biomarker and therapeutic target across multiple cancer types. This review explores the multifaceted role of WTAP in cancer, focusing on its mechanisms of action in tumorigenesis, immune modulation, and therapy resistance, and offers insights into potential therapeutic strategies targeting WTAP in cancer treatment.

Tumor suppressor gene (TSG) alterations prognosticate inferior survival in metastatic hormone-sensitive prostate cancer (mHSPC) and may affect response to therapy. We evaluated association of TSG alterations with overall survival (OS) in mHSPC, stratified by initial treatment. We identified veterans with de-novo mHSPC diagnosed from 2017-2023 within the Veterans Health Administration. TSG alterations included loss-of-function alterations in RB1, TP53, and PTEN identified by somatic sequencing through the National Precision Oncology Program. Treatments within 4 months of diagnosis included androgen deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs). Kaplan-Meier and Cox models evaluated relationships between TSG alterations, clinical factors, and OS. Among 1842 veterans who met criteria, 865 had sequencing within six months. TSG alterations were found in 935 veterans, with the most common alterations being TP53 (36.7%), PTEN (23.4%), and RB1 (4.5%). In veterans sequenced within 6 months, RB1, TP53, and PTEN alterations were associated with mortality with a hazard ratio (95% CI) of 2.86 (1.94-4.21) (p < 0.001), 1.64 (1.30-2.05) (p < 0.001), and 1.52 (1.20-1.91) (p < 0.001), respectively. In the same cohort, median OS (95% CI) was 40.7 months (37.5-NR) with no alterations, 34.1 months (30.3-37.3) with one, and 19.7 months (16.5-25.5) with ≥2 TSG alterations. In veterans with ≥1 alteration and sequencing within six months, combination therapy with ARPIs was associated with decreased mortality, aHR (95% CI) of 0.65 (0.48-0.88, p = 0.005). TSG alterations were associated with inferior OS in veterans with mHSPC. In this real-world observational study, ARPI-based combination therapy in veterans with TSG alterations was associated with the longest survival.

Background/Objectives Targeted High-Intensity Focused Ultrasound (HIFU) is an emerging treatment option for localized prostate cancer (PCa), aiming to balance oncological control with functional preservation. However, data on the feasibility and outcomes of salvage robotic-assisted radical prostatectomy (sRARP) after targeted HIFU remain limited. This study aimed to evaluate feasibility, functional and early oncological outcomes of sRARP in this specific setting. Methods Among 112 men treated with targeted HIFU for localized prostate cancer, 15 underwent sRARP between June 2022 and June 2025. The primary outcome was surgical feasibility and safety, assessed by conversion rate, operative time, nerve-sparing approach, lymphadenectomy, positive surgical margins (PSM) at frozen section and final pathology, and intraoperative complications. Secondary outcomes included urinary continence (full or social continence at 1 year), erectile function (with or without phosphodiesterase type 5 inhibitors at 1 year), PSA levels at 45 days and one year after surgery, and postoperative complications. Results All procedures were completed robotically without intraoperative complications or conversions. Bilateral nerve-sparing was performed in 13 patients (87%). PSM were found in three (20%) patients at frozen section and in two patients (13%) at final pathology; one patient (11%) had lymph node metastases. Early complications occurred in three patients (20%), with only one Clavien Dindo grade ≥3 event. At 1-year follow-up, one patient (8%) had PSA &amp;gt;0.2 ng/mL; nine patients (75%) were continent and six (50%) reported preserved erectile function. The median follow-up was 14 months (IQR 10.8–16.5; 95% CI). Conclusions sRARP after targeted HIFU is feasible and safe, with favorable early oncological and functional outcomes. These findings suggest that targeted HIFU may be a viable option in selected patients, without compromising future curative strategies in case of recurrence.

Validation and context-dependent effects of a prostate cancer polygenic risk score in the All of Us Research Program.

Prostate cancer is always regarded as 'we' disease with unavoidable influence within the couples, particularly during the early post-diagnosis period. Thus, this qualitative research is to explore the psychosocial experiences of prostate cancer couples coping within six months of diagnosis in China. The study was conducted through semi-structured interviews between June 2023 and June 2024. All interviews were recorded, transcribed, and analyzed following Braun and Clarke's reflective thematic analysis approach. Fourteen couples were enrolled using purposive sampling with variation in sociodemographic information. The participants' normal lives were disrupted, and couples adopted both individual and joint coping strategies to regain a new sense of balance. The overarching theme "Refine and Regain" was proposed during this process. This emerged from five main themes: "Unrecognized distress and emotional fluctuation," "Lost in frustration," "Interrupted family and social connections," "Striving for survival," and "Growth and adaption." Couples got through physical and emotional difficulties during the anti-cancer treatment, starting from accepting the fact they got the cancer. Some participants showed a progressive adaptation to cancer over time, while others experienced a dynamic, non-linear adjustment process. The findings revealed variations in couples' psychosocial adaptation to prostate cancer, highlighting the need for tailored interventions to enhance mutual coping.

Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀ = 10.30μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but itdirectly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.

Objectives: Transperineal (TP) prostate biopsy is increasingly used because of its lower complication rates compared with the transrectal approach. However, prospective data regarding its effects on erectile and ejaculatory function remain limited. This study prospectively evaluated short-term sexual function outcomes after TP prostate biopsy in sexually active men. Methods: This single-center prospective observational cohort study included men undergoing TP prostate biopsy between 15 April 2025 and 1 September 2025. Indications for biopsy were prostate-specific antigen levels &gt;4 ng/mL, abnormal digital rectal examination findings, or suspicious lesions (PI-RADS ≥ 3) on multiparametric prostate MRI. Sexual function was assessed at baseline and at 1 and 3 months after biopsy using the International Index of Erectile Function (IIEF-5), the Premature Ejaculation Diagnostic Tool (PEDT), and the Male Sexual Health Questionnaire–Ejaculatory Dysfunction Short Form (MSHQ-EjD-SF). Results: Overall, 249 sexually active men were analyzed. No significant changes in erectile or ejaculatory function were observed in the overall cohort at either follow-up point. In contrast, among 132 men diagnosed with prostate cancer, significant declines were observed in IIEF-5, PEDT, and MSHQ-EjD-SF scores at both 1 and 3 months compared to baseline (all p &lt; 0.001). Conclusions: Transperineal prostate biopsy minimally affects sexual function in the general population. However, prostate cancer patients experience notable deterioration in erectile and ejaculatory outcomes, which may be a transient decline, and long-term follow-up is necessary for this subgroup.