bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–12–14
47 papers selected by
Grigor Varuzhanyan, UCLA
  1. CircPPFIA2 drives prostate cancer progression and enzalutamide resistance by sponging miR-646 and miR-1200 to upregulate ETS1.
  2. SENP5 acts as a downstream target of androgen receptor and contributes to prostate cancer growth.
  3. Targeting tumor microenvironment-derived NRG1-HER2/3 signaling with zenocutuzumab restores sensitivity to AR inhibition in PTEN wild-type prostate cancer.
  4. High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.
  5. ZBTB7B modulates the androgen receptor as an upstream regulator via colocalization and direct binding in LNCaP prostate cancer cells.
  6. Multi-omics characterization of metabolic and immune interactions in prostate cancer.
  7. Reprogramming prostate cancer through the microbiome.
  8. SBFI Inhibitors Reprogram Transcriptomic Landscape of Prostate Cancer Cells Leading to Cell Death.
  9. The Histone Methyltransferase KMT2D is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration Resistant Prostate Cancer.
  10. A novel peptide explicitly induces prostate cancer cell death by destabilizing AR and inhibiting AR-mediated transcription.
  11. Optimised dissociation and multimodal profiling of prostate cancer stroma reveal fibromuscular cell heterogeneity with clinical correlates.
  12. Urine metabolic analysis as a non-invasive method to predict biochemical recurrence in prostate cancer.
  13. Deciphering Resistance: Beyond the Androgen Paradigm; Report From the 2025 Coffey-Holden Prostate Cancer Academy Meeting.
  14. OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer.
  15. Extracellular Vesicles Released From Prostate Cancer Cells Confer Pro-Tumor Properties to Adipocytes by Stimulating Lipolysis.
  16. SNRPA upregulation promotes mitochondrial function and drives CRPC aggressiveness.
  17. Emerging Therapeutic Approaches to Engage the Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.
  18. BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.
  19. Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer.
  20. High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.
  21. Chronic IL-1 Exposure Attenuates RELA- and STAT3-Dependent Synergistic Cytokine Signaling in Prostate Cancer Cell Lines.
  22. Gut microbiota as a multifaceted modulator of prostate cancer: Mechanistic insights, therapeutic opportunities and clinical challenges (Review).
  23. Investigating the synergistic cytotoxicity and apoptosis-inducing effects of eugenol derivatives in combination with docetaxel on PC3 human prostate cancer cells.
  24. Exploration between caffeine intake, physical activity, and prostate cancer using data from the large-scale NHANES survey: A cross-sectional study.
  25. APOBEC3B-driven mutations negatively regulated by P53 promote tumor progression and immunosuppressive microenvironment in prostate cancer.
  26. Association between serum uric acid and prostate cancer risk: The modifying role of CTGF genotype.
  27. ATHENA: A deep learning-based AI for functional prediction of genomic mutations and synergistic vulnerabilities in prostate cancer.
  28. Modulating Prostate Cancer Therapy Through the Gut Microbiome: A Comprehensive Review.
  29. IP-SNPs-seq links noncoding risk alleles to lineage transcription factor programs in prostate cancer.
  30. Serum metabolites with diagnostic potential in prostate cancer and the inhibitory effects of alpha-Tocomonoenol on prostate cancer cells.
  31. Characterising the effect of circulating sphingolipids on metastatic prostate cancer cells.
  32. Identification of programmed cell death associated key genes in benign prostatic hyperplasia and prostate cancer development by integrated bioinformatics analysis and machine learning.
  33. Hypoxia and cribriform growth in prostate cancer - establishing a link via MRI.
  34. Precision Risk Stratification in Prostate Cancer: Unveiling MRI-Based Habitat-Driven Radiomics Model for Enhanced Treatment Guidance.
  35. Association between lifetime co-use of classic psychedelics and cannabis and prostate cancer diagnosis among US adults 50 years and older.
  36. Molecular subtypes of metastatic prostate cancer: from pathophysiology to diagnosis.
  37. Immune profiling identifies the contribution of extracellular vesicles to immune modulation and progression in prostate cancer.
  38. Exosomal non-coding RNAs: orchestrators of intercellular crosstalk in the prostate cancer tumor microenvironment.
  39. A U-shaped association between blood selenium levels and prostate cancer: findings of a case-control study among Nigerian men.
  40. Prostate Cancer: Artificial Intelligence Advancements in Diagnosis and Early Detection.
  41. Development and In Vitro Evaluation of [64Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer.
  42. The Clinical Relevance of Tumor Biomarkers in Prostate Cancer-A Review.
  43. Influence of Diabetes Mellitus on Metabolic and Hormonal Interactions Promoting Aggressive Prostate Cancer.
  44. Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance.
  45. Safety and efficacy of darolutamide in combination with androgen-deprivation therapy for prostate cancer: a systematic review and meta-analysis.
  46. Shining the PSMA spotlight on peritoneal metastases in prostate cancer.
  47. Proteome-wide association study of prostate cancer risk across populations.
  1. Cell Death Discov. 2025 Dec 08.
    CircPPFIA2 drives prostate cancer progression and enzalutamide resistance by sponging miR-646 and miR-1200 to upregulate ETS1.
    Yiyou Mao, Qu Leng, Jun Wu, Wenbin Chen, Chunxi Lin, Zhihai Deng, Qiang Shen, Jun Zou, Zining Long, Yiyuan Zhan, Shilong Cheng, Zhongjie Chen, Rui Zhou, Jiaxing Wang, Hangyang Peng, Yangbai Lu, Yilan Huang, Chenglu Li, Aihua Cai, Jingyan Xu, Hongxing Huang, Dongmei Jiang, Xiangming Mao, Daojun Lv.
      Prostate cancer (PCa) represents a leading cause of cancer-related morbidity in men worldwide, necessitating deeper insights into its molecular drivers. Circular RNAs (circRNAs) are increasingly recognized as key regulatory molecules in carcinogenesis; however, their functional significance in PCa pathogenesis and treatment resistance remains incompletely defined. Here, we identify circPPFIA2 as a novel clinically relevant oncogenic circRNA with dual roles in PCa progression and therapeutic resistance. CircPPFIA2 is markedly upregulated in PCa clinical specimens and cell lines. Through gain- and loss-of-function experiments in both cell-based and animal models, we established that circPPFIA2 drives oncogenic phenotypes by enhancing tumor cell proliferation, migratory capacity, and resistance to enzalutamide therapy. Mechanistic investigations revealed that circPPFIA2 functions as a competitive endogenous RNA (ceRNA), simultaneously sequestering tumor-suppressive miR-646 and miR-1200. This miRNA sponge activity facilitates post-transcriptional upregulation of ETS1, a critical effector of androgen receptor signaling and treatment resistance. This molecular interplay establishes the circPPFIA2/miR-646/miR-1200/ETS1 axis as a central driver of PCa progression and therapy resistance. To functionally validate this finding, we employed lipid nanoparticle (LNP)-mediated co-delivery of si-circPPFIA2 and enzalutamide, which effectively restored drug sensitivity and inhibited tumor growth in resistant PCa models. Our findings highlight circPPFIA2 as both a prognostic biomarker and a promising therapeutic target for advanced PCa, providing a rationale for developing circRNA-directed therapies to overcome treatment resistance.
    DOI:  https://doi.org/10.1038/s41420-025-02904-z
  2. Oncol Lett. 2026 Feb;31(2): 51
    SENP5 acts as a downstream target of androgen receptor and contributes to prostate cancer growth.
    Ximin Chen, Xubo Gong, Jingcheng Zhang, Weiwei Liu.
      The androgen receptor (AR) signaling pathway plays an important role in prostate cancer (PCa) progression. In the present study, a significant co-expression was found between SENPs and AR. In addition, SENP5 was obviously negatively correlated with overall survival and disease-free survival in patients with PCa. Moreover, SENP5 silencing markedly inhibited the proliferation of PCa cells. Chromatin immunoprecipitation quantitative PCR assays further confirmed that AR could transcriptionally activate SENP5 expression. In summary, the present results suggested that SENP5 acts as a downstream target of AR and contributes to PCa growth, the underlying molecular mechanism of which needs further investigation.
    Keywords:  SENP5; androgen receptor; prognosis; prostate cancer
    DOI:  https://doi.org/10.3892/ol.2025.15404
  3. Mol Cancer Ther. 2025 Dec 11.
    Targeting tumor microenvironment-derived NRG1-HER2/3 signaling with zenocutuzumab restores sensitivity to AR inhibition in PTEN wild-type prostate cancer.
    Brian M Shinder, Young Sun Lee, Ninghui Mao, Nazifa Salsabeel, Zeda Zhang, Harmanpreet Kaur, Xiaoping Chen, Qing Chang, Elisa de Stanchina, Anuradha Gopalan, Charles L Sawyers, Brett S Carver.
      Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAFs) promotes antiandrogen resistance through HER3-AKT signaling. Here, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. Immunohistochemical analysis of radical prostatectomy specimens from prostate cancer patients treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells, and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, zenocutuzumab did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment (TME)-derived NRG1 impacts responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN-wildtype prostate cancers.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0505
  4. Cancer Lett. 2025 Dec 09. pii: S0304-3835(25)00776-1. [Epub ahead of print] 218204
    High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.
    Yupeng Guan, Fei Cao, Yusheng Luo, Jun Li, Peng Wu, Junfu Zhang, Wenhan Qiu, Shaohong Lai, Hanqi Lei, Jun Pang.
      High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation.. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.
    Keywords:  chemoresistance; high-fat diet; matrix stiffness; mitochondria-endoplasmic reticulum contacts; piezo1
    DOI:  https://doi.org/10.1016/j.canlet.2025.218204
  5. Transl Cancer Res. 2025 Nov 30. 14(11): 7598-7610
    ZBTB7B modulates the androgen receptor as an upstream regulator via colocalization and direct binding in LNCaP prostate cancer cells.
    Eunji Im, Su-Yeon Park, Deok-Yong Sim, Ah Reum Cho, Bum Ju Kil, Bonglee Kim, Bum-Sang Shim, Sung-Hoon Kim.
       Background: Though ZBTB7B is overexpressed in breast and prostate cancers and dysregulates CD8 T cell response, there is no report on the close relationship between ZBTB7B and androgen receptor (AR) yet. This study aimed to investigate the molecular interaction between ZBTB7B and AR and to determine its role in prostate cancer progression.
    Methods: Prostate cancer cell lines (AR-dependent LNCaP and AR-independent DU145) were subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and cell cycle analysis. Protein-protein interaction was examined using immunoprecipitation and immunofluorescence. Protein stability was assessed by cycloheximide chase and ubiquitination assays. RNA interference was employed to deplete ZBTB7B or AR, and tissue expression patterns were analyzed by The Cancer Genome Atlas (TCGA) and human tissue microarray.
    Results: ZBTB7B was overexpressed in prostate cancer cells and tissues with poor prognosis by human tissue microarray and TCGA analysis. However, ZBTB7B depletion suppressed viability, the number of colonies and increased G1 arrest in AR dependent LNCaP cells, but not in AR independent DU145 cells. Interestingly, ZBTB7B depletion suppressed the expression of AR and prostate specific antigen (PSA) in LNCaP cells, while AR depletion did not affect ZBTB7B. Furthermore, AR inhibitor finasteride and AR activator dihydrotestosterone (DHT) did not affect ZBTB7B. However, ZBTB7B was colocalized with AR by immunofluorescence and was bound to AR by immunoprecipitation. Consistently, ZBTB7B depletion attenuated the nuclear translocation and stability of AR through its degradation and also promoted AR degradation by ubiquitination assay. Notably, N-terminal domain (NTD) of AR is requisite for binding with ZBTB7B in HEK293 cells, not AR-DNA-binding domain (DBD) or AR-ligand-binding domain (LBD) in HEK293 cells.
    Conclusions: Overall, these findings provide a novel insight that ZBTB7B promotes prostate cancer progression as a potent oncogene via colocalization and binding with AR.
    Keywords:  N-terminal domain of the androgen receptor (AR-NTD); ZBTB7B; androgen receptor (AR); dihydrotestosterone (DHT); finasteride; prostate cancer
    DOI:  https://doi.org/10.21037/tcr-2025-1365
  6. Transl Androl Urol. 2025 Nov 30. 14(11): 3729-3744
    Multi-omics characterization of metabolic and immune interactions in prostate cancer.
    Yong-Qiang Fu, Feng-Xia Wang, Jin-Feng Wu.
       Background: Prostate cancer (PCa) is a common malignancy among men, marked by pronounced clinical and molecular heterogeneity. Metabolic reprogramming and immune evasion are recognized as critical factors in PCa progression; however, the underlying regulatory mechanisms remain insufficiently characterized. This study aimed to elucidate the interaction between metabolic reprogramming and the immune microenvironment in PCa through a multi-omics approach, and to identify key metabolic biomarkers with prognostic significance.
    Methods: A multi-omics analytical framework was used, integrating single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) data from publicly available datasets. Following quality control and clustering using Seurat and Signac, cell types were annotated. Key metabolic genes were identified through combined gene activity and chromatin accessibility analyses. Immune cell infiltration was estimated using Cell Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), and functional pathway enrichment was assessed using gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). Furthermore, using The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) cohort, a prognostic nomogram was constructed by integrating ENO1 and CKB expression with clinical parameters [age, pathological tumor stage (T stage), node stage (N stage)] via multivariate Cox regression. Gene expression differences across N stages (N0 vs. N1) were assessed using the Wilcoxon rank-sum test.
    Results: Six distinct cell subtypes were delineated, along with enrichment of key metabolic pathways, particularly glycolysis and oxidative phosphorylation associated with tumor progression. The metabolic regulators ENO1 and CKB demonstrated significant involvement in both metabolic reprogramming and modulation of the immune microenvironment. Their expression levels were positively correlated with the infiltration of immune cells, including CD8+ T lymphocytes and macrophages. The prognostic nomogram demonstrated that CKB contributed substantially to the total points, indicating strong prognostic relevance. Stratified analysis revealed ENO1 was significantly upregulated in N1 tumors (P<0.01), while CKB was higher in N0 tumors (P<0.05).
    Conclusions: ENO1 and CKB serve as clinically meaningful markers-ENO1 indicating metastatic potential and CKB predicting overall prognosis-while also representing promising therapeutic targets. These findings bridge molecular metabolism-immune crosstalk with clinical outcomes, offering novel perspectives for integrating metabolic intervention and immunotherapy in PCa management.
    Keywords:  Immune microenvironment; metabolic genes; multi-omics analysis; prostate cancer (PCa); single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq)
    DOI:  https://doi.org/10.21037/tau-2025-502
  7. Front Med (Lausanne). 2025 ;12 1690498
    Reprogramming prostate cancer through the microbiome.
    Jhommara Bautista, Walter D Cardona-Maya, Kelly Gancino-Guevara, Andrés López-Cortés.
      Prostate cancer (PCa) is a major global public health challenge, driven by a multifactorial interplay of genetic, epigenetic, hormonal and environmental determinants. In recent years, the human microbiome has emerged as a critical and previously underappreciated contributor to PCa initiation, progression, and therapeutic response. Emerging high-resolution multi-omics studies have demonstrated that microbial communities across the gut, urinary tract and prostate form a functional axis that shapes immune surveillance, hormonal metabolism, inflammatory tone and epigenetic regulation. Dysbiosis in these compartments promotes chronic inflammation, modulates androgen receptor signaling, and produces bioactive metabolites, including short-chain fatty acids, that activate oncogenic IGF-1/MAPK/PI3K and NF-κB/JAK/STAT pathways. Cross-compartmental trafficking of bacterial taxa and metabolites reinforces tumor-promoting circuits, while specific commensals such as Akkermansia muciniphila enhance antitumor immunity and improve responses to androgen deprivation therapy. Importantly, microbiota-derived factors also modulate microRNA (miRNAs) expression and epigenetic signatures, thereby affecting tumor plasticity and resistance to therapy. These mechanistic insights have catalyzed interest in microbiome-based therapeutic approaches, including probiotics, prebiotics, fecal microbiota transplantation, dietary modulation and bacteriophage therapy, which hold promise for restoring eubiosis and enhancing treatment efficacy. Nevertheless, clinical translation remains limited by inter-individual variability and the need for well-designed, longitudinal studies integrating shotgun metagenomics, metabolomics and host-microbe interactomics. Overall, the prostate, urinary and gut microbiomes represent interconnected targets that may inform precision diagnostics and novel therapeutic strategies in PCa.
    Keywords:  dysbiosis; fecal microbiota transplantation; microbiome-based therapeutic approaches; probiotics; prostate cancer
    DOI:  https://doi.org/10.3389/fmed.2025.1690498
  8. Cancers (Basel). 2025 Nov 21. pii: 3723. [Epub ahead of print]17(23):
    SBFI Inhibitors Reprogram Transcriptomic Landscape of Prostate Cancer Cells Leading to Cell Death.
    Shubhra Rajput, Joseph F LaComb, Chris Gordon, Hehe Wang, Manisha Sarder, Martin Kaczocha, Iwao Ojima, Agnieszka B Bialkowska.
       BACKGROUND: Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men in the United States. Fatty acid-binding protein 5 (FABP5), a member of a class of intracellular lipid transporters, promotes PCa progression via enhanced lipid metabolism and trafficking of lipid ligands. Previous work from our group has demonstrated that small-molecule FABP5 inhibitors based on the truxillic-acid monoester scaffold reduce PCa growth.
    METHODS: Here, we assessed the effect of third-generation FABP5 inhibitors on the PCa cell cycle, proliferation, apoptosis, signaling pathway activity, and transcriptomic landscape.
    RESULTS: We demonstrate that the third-generation FABP5 inhibitor SBFI-1143 significantly inhibits the viability of PCa cells by arresting them at the G0/G1 and G2/M phases of the cell cycle, inducing apoptosis, and promoting cell death. Strikingly, SBFI-1143 efficiently inhibited the growth of PCa spheroids compared to its predecessor, SBFI-103. RNA-seq and Gene Set Enrichment Analysis demonstrated that SBFI-1143 more effectively suppressed pathways involved in cell cycle progression, cell cycle division, and chromosome organization while upregulating genes associated with endoplasmic reticulum stress, responses to incorrectly folded proteins, and regulating apoptosis, compared to SBFI-103. Notably, SBFI-1143 treatment downregulated genes associated with the subpopulation of PCa cells characterized by a lineage plasticity-related signature, related to trans-differentiation, recurrence, and poor cancer prognosis.
    CONCLUSIONS: Our findings demonstrate that SBFI-1143 significantly alters the transcriptomic landscape of prostate cancer and may serve as a potentially effective therapeutic option for this disease.
    Keywords:  FABP5; metastatic castration-resistant prostate cancer; prostate cancer
    DOI:  https://doi.org/10.3390/cancers17233723
  9. Cancer Res. 2025 Dec 11.
    The Histone Methyltransferase KMT2D is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration Resistant Prostate Cancer.
    Srushti Kittane, Erik Ladewig, Taibo Li, Jillian R Love, Ryan Blawski, Yangzhenyu Gao, Amaia Arruabarrena-Aristorena, Peihua Zhao, Susan L Dalrymple, Huayang Liu, Xinyu Guo, Mirna Sallaku, Nachiket Kelkar, Liliana Garcia-Martinez, Javier Carmona Sanz, Wanlu Chen, Candice Stoudmann, Laura Baldino, Milad Razavi-Mohseni, Ingrid Kalemi, Michael A Beer, Pau Castel, W Nathaniel Brennen, Maurizio Scaltriti, Lluis Morey, Emiliano Cocco, Hongkai Ji, Ho Man Chan, Alexis Battle, Christina S Leslie, Wouter R Karthaus, Eneda Toska.
      Castration-resistant prostate cancer (CRPC) is largely dependent on the androgen receptor (AR) for growth and often exhibits hyperactive PI3K signaling, most frequently due to PTEN loss. Therapeutic pressure from anti-AR therapies can induce trans-differentiation toward an AR-independent phenotype. Recently, different subtypes of AR-independent CRPC have been redefined, with the stem cell-like (SCL) subtype emerging as one of the most prevalent. Elucidation of the epigenetic mechanisms controlling the maintenance of these distinct CRPC cell states could pave the way for effective combinatorial therapies for CRPC. In this study, we identified a key role for the histone methyltransferase KMT2D in establishing the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) that are essential for the AR transcriptional output in AR-dependent CRPC cell lines, patient derived organoids, and patient samples. Unexpectedly, KMT2D maintained the identity of the AR-low CRPC-SCL subtype and controlled activity of AP-1 TFs such as FOSL1, which acts as a master regulator of this subtype. Single cell transcriptomics and chromatin assays underscored the role of KMT2D in sustaining a mixed lineage cell state via AP-1 and FOXA1. The combined suppression of PI3K/AKT and KMT2D reduced cell proliferation in prostate cancer cells and patient-derived organoids in both CRPC-AR and CRPC-SCL subtypes. Altogether, these results unveil KMT2D as a major mediator of the epigenetic landscape in subtype-specific CRPC, contributing to tumor growth and therapeutic response.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2053
  10. Biochem Pharmacol. 2025 Dec 08. pii: S0006-2952(25)00881-0. [Epub ahead of print] 117616
    A novel peptide explicitly induces prostate cancer cell death by destabilizing AR and inhibiting AR-mediated transcription.
    Akanksha Agarwal, Aishani Patnaik, Ekta Gupta, Bharti Jaiswal, Ashish Gupta.
      Current treatment strategies for prostate cancer primarily focuses on regulating androgen receptor (AR) activity, either through androgen deprivation or the use of anti-androgen therapies. While these approaches are initially effective, many patients eventually develop resistance, resulting in the emergence of castration-resistant prostate cancer (CRPC). This transition not only complicates disease management but also leads to persistent side effects, underscoring the urgent need for alternative therapeutic strategies that directly target AR or disrupt its interactions with co-regulatory proteins. Given the deregulated expression and altered subcellular localization of TIP60, a key AR coregulator in prostate cancer, we hypothesized that interfering with the AR-TIP60 interaction could mitigate aberrant AR signaling. To investigate this, we selectively expressed the C-terminal region of TIP60 containing the nuclear receptor box (NRB) motif as a short peptide in prostate cancer cells and demonstrated that this peptide effectively disrupts the AR-TIP60 interaction and exerts broad suppressive effects on AR signaling. Importantly, the peptide selectively induces cell death in AR-positive prostate cancer cells. Mechanistic studies revealed that the peptide impairs AR signaling by inhibiting dihydrotestosterone (DHT)-mediated AR chromatin binding and promoting AR degradation via the proteasome pathway. Furthermore, in silico analyses suggest that the peptide directly binds to AR's N-terminal domain, leading to its structural destabilization. Collectively, these results identify a novel AR-targeting peptide with multifaceted inhibitory effects, offering a promising therapeutic avenue for AR-positive prostate cancers, particularly in treatment-resistant cases. The peptide holds potential for development as a standalone therapy or in combination with existing chemotherapeutic agents.
    Keywords:  Androgen receptor; Nuclear receptor box motif; Prostate cancer; TIP60
    DOI:  https://doi.org/10.1016/j.bcp.2025.117616
  11. Front Cell Dev Biol. 2025 ;13 1653780
    Optimised dissociation and multimodal profiling of prostate cancer stroma reveal fibromuscular cell heterogeneity with clinical correlates.
    Elisabeth Damisch, Elena Brunner, Lukas Nommensen, Lucy Neumann, Georgios Fotakis, Zlatko Trajanoski, Sieghart Sopper, Georg Schäfer, Martin Puhr, Isabel Heidegger, Marianna Kruithof-de Julio, Natalie Sampson.
       Background: Dynamic remodelling of the tumour microenvironment (TME) plays a central role in prostate cancer (PCa) progression, immune evasion and therapy resistance. However, the co-existence of both tumour-promoting and tumour-restraining stromal elements necessitates extensive characterisation of the TME for effective targeting. Fibromuscular cell heterogeneity in PCa remains poorly characterised, in part due to challenges in isolating cells embedded within the desmoplastic stroma. This study therefore aimed to better characterise fibroblast and smooth muscle cell (SMC) populations as the major tissue-resident stromal cell subtypes within the PCa TME.
    Methods: A PCa single-cell RNA sequencing (scRNA-seq) dataset was re-analysed to define fibromuscular subtypes. Due to low fibroblast yields, an optimised tissue dissociation protocol was developed and benchmarked against two commercial kits via flow cytometry, immunostaining of clinical specimens and ex vivo culture. Dimensionality reduction and clustering were applied to the CD31- stromal fraction using a multiparameter surface marker panel. Annotation of the resulting clusters based on their surface marker profile was supported by integrating scRNA-seq and immuno-histological findings.
    Results: The optimised protocol yielded over twice the viable cells/mg tissue compared to two commercial kits, preserved surface marker integrity, enhanced successful cultivation of mesenchymal cells and recovered diverse stromal subpopulations from benign and malignant samples. Dimensionality reduction and clustering of flow cytometry counts identified 11 distinct CD31- stromal populations. Integration with transcriptomic data and immunofluorescence of clinical specimens identified spatially- and prognostically-distinct fibroblast subtypes, including inflammatory and myofibroblastic cancer-associated fibroblasts, pericytes linked to poor prognosis and a novel SMC subset associated with stromal activation.
    Conclusion: This study presents a robust workflow for improved isolation and characterisation of fibromuscular stromal cells in PCa. The multimodal approach enabled refined characterisation of phenotypically distinct and clinically-relevant stromal subpopulations within their spatial context providing a foundation for future TME-targeted therapies.
    Keywords:  cancer-associated fibroblast; prostate cancer; single cell RNA sequencing; smooth muscle cell; tissue dissociation; tumour microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1653780
  12. Transl Androl Urol. 2025 Nov 30. 14(11): 3708-3717
    Urine metabolic analysis as a non-invasive method to predict biochemical recurrence in prostate cancer.
    Jorge Panach-Navarrete, Vannina González-Marrachelli, José Manuel Morales-Tatay, Francisco García-Morata, María Ángeles Sales-Maicas, Daniel Monleón-Salvado, José María Martínez-Jabaloyas.
       Background: Metabolomics has proven to be a useful science for obtaining biomarkers in prostate cancer. In this work, urine samples were analyzed by nuclear magnetic resonance (NMR) spectroscopy to identify potential urinary biomarkers associated with biochemical recurrence in prostate cancer.
    Methods: Urine samples were obtained from patients undergoing transrectal prostate biopsy after prostate massage. Patients were classified as with or without biochemical recurrence after having received prostate cancer treatment. All spectra were acquired using a Bruker Avance III DRX 600 spectrometer. Univariate and multivariate analysis were performed with metabolites and clinical variables to predict tumor presence.
    Results: Data were collected from 70 patients treated for prostate cancer, 16 of whom developed biochemical recurrence within 5 years following treatment, with an average time to diagnosed recurrence of 25.68±15.39 months. After establishing a predictive model with the 25 most influential metabolites in Partial Least Squares Discriminant Analysis (PLS-DA analysis), a predictive model of biochemical recurrence was obtained with an area under the curve of 0.95, a sensitivity of 80%, specificity of 98%, positive predictive value (PPV) of 92% and a negative predictive value (NPV) of 96%. Metabolites derived from amino acid metabolism and glycolysis featured most predominantly in this model.
    Conclusions: The metabolic profile in urine can be used to construct a model with good discrimination for predicting the development of biochemical recurrence. The molecules highlighted herein frequently belong to amino acid metabolism and glycolysis.
    Keywords:  Metabolomics; biochemical recurrence; biomarkers; prostate cancer
    DOI:  https://doi.org/10.21037/tau-2025-592
  13. Prostate. 2025 Dec 07.
    Deciphering Resistance: Beyond the Androgen Paradigm; Report From the 2025 Coffey-Holden Prostate Cancer Academy Meeting.
    Tanya Stoyanova, Saul J Priceman, Ashley E Ross, Phuoc T Tran, Rana R McKay, Kenneth J Pienta, Howard R Soule, Andrea K Miyahira.
       INTRODUCTION: The 12th Annual 2025 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Deciphering Resistance: Beyond the Androgen Paradigm," was held at the University of California, Los Angeles (UCLA), Luskin Conference Center, in Los Angeles, CA, from June 19 to 22, 2025.
    METHODS: The CHPCA Meeting is a discussion-focused conference held annually by the Prostate Cancer Foundation (PCF), for in-depth academic analysis of emerging research with the greatest potential to drive new understandings and treatments for prostate cancer. The 2025 CHPCA Meeting included attendance by 79 academic investigators and 39 talks over 8 sessions.
    RESULTS: The session topics included: drug discovery in academia, non-apoptotic cell death mechanisms, understanding and overcoming treatment resistance, chromosomal instability (CIN) as a driver of metastasis and treatment resistance, targeting metastatic sites, immunotherapy sensitizers, and optimizing therapy delivery and biomedical engineering.
    DISCUSSION: This meeting report summarizes the presentations from the 2025 CHPCA Meeting. We hope that disseminating this information will directly contribute to novel research efforts and improved treatment strategies for patients with prostate cancer.
    Keywords:  biomarkers; cancer disparities; cancer metabolism; theranostics; therapeutics; tumor biology
    DOI:  https://doi.org/10.1002/pros.70102
  14. Cell Death Dis. 2025 Dec 07.
    OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer.
    Linghui Liang, Zhiyi Shen, Yuwei Zhang, Yifei Cheng, Bing Yao, Ninghan Feng, Ruizhe Zhao.
      Neuroendocrine differentiation (NED) plays a critical role in endocrine therapy resistance and dismal outcomes among prostate cancer (PCa) patients. The emergence of treatment-induced neuroendocrine prostate cancers (t-NEPCs) with the utilization of second-generation androgen receptor (AR) pathway inhibitors (ARPIs) poses a significant challenge, as the molecular underpinnings remain elusive. Here, our investigation unveils a close correlation between heightened levels of opioid receptor membrane protein OPRK1 and treatment-induced NED (t-NED), alongside an adverse prognosis in PCa cohorts. Our findings illuminate that AR represses OPRK1 transcription by binding to its promoter, a regulation amenable to reversal via ARPI administration. Further exploration reveals that OPRK1 stimulation triggers autophagic degradation of REST upon up-regulation and interaction with SLC9A3R1, thereby instigating NED. In essence, OPRK1 experiences negative control by AR and emerges as a pivotal instigator of t-NED. Combining JTC-801 with CQ successfully impedes NEPC progression by impacting the OPRK1/SLC9A3R1/autophagy/REST axis. Our study accentuates OPRK1 as a novel therapeutic target for PCa management and furnishes profound insights into the pathogenesis of t-NEPC.
    DOI:  https://doi.org/10.1038/s41419-025-08279-4
  15. Biofactors. 2025 Nov-Dec;51(6):51(6): e70067
    Extracellular Vesicles Released From Prostate Cancer Cells Confer Pro-Tumor Properties to Adipocytes by Stimulating Lipolysis.
    Gaia Giannitti, Kinga Kamińska, Sara Marchesi, Riccardo Garavaglia, Ivan Preosto, Małgorzata Grzesiak, Fabrizio Fontana.
      There is consistent evidence of an association between obesity and the risk of prostate cancer (PCa). A crosstalk between PCa and adipocytes has been highlighted; however, the role of extracellular vesicles (EVs) in this communication still needs to be elucidated. Herein, we demonstrated that PCa EVs can trigger lipolysis in 3T3-L1 adipose cells, by downregulating G0/G1 switch protein 2 (G0S2), inducing adipose triglyceride lipase (ATGL) expression and activating the cyclic AMP (cAMP)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) signaling pathway. Interestingly, we showed that the free fatty acids (FFAs) released from the EV-treated adipocytes could increase PCa cell proliferation and clonogenic ability. Moreover, they promoted tumor cell migration and invasion, while parallelly reducing the induction of anoikis. Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype.
    Keywords:  Akt; adipocytes; extracellular vesicles; free fatty acids; lipolysis; prostate cancer
    DOI:  https://doi.org/10.1002/biof.70067
  16. Cell Death Dis. 2025 Dec 07.
    SNRPA upregulation promotes mitochondrial function and drives CRPC aggressiveness.
    Xiao-Long Liu, Lu Jin, Yong-Qiang Yang, Mei-Hua Lu, Bo-Xin Xue.
      Identifying novel molecular targets for castration-resistant prostate cancer (CRPC) is crucial. This study examines the expression and functional role of small nuclear ribonucleoprotein polypeptide A (SNRPA), a core component of the U1 snRNP complex, in CRPC. Bioinformatics analyses indicate a positive correlation between SNRPA overexpression and the aggressiveness of prostate cancer, with high levels linked to poor outcomes. Single-cell RNA data further shows increased SNRPA expression in prostate cancer cells. Expression of SNRPA is also elevated in both locally-treated CRPC tissues and various CRPC cells. Knockdown via shRNA or knockout using CRISPR/Cas9 significantly reduced cellular proliferation, migration, and invasion in CRPC cells, while inducing apoptosis. SNRPA depletion decreased complex I activity, ATP production, and mitochondrial membrane potential, increased reactive oxygen species levels, and downregulated NDUFB8/NDUFS9 expression. In contrast, SNRPA overexpression enhanced the aggressive phenotype of CRPC cells, boosting mitochondrial complex I activity and ATP generation, while upregulating NDUFB8/NDUFS9. In vivo studies using xenograft models further validated the therapeutic potential of targeting SNRPA. SNRPA knockdown significantly inhibited CRPC xenograft growth, reduced ATP levels, and altered redox balance, as evidenced by decreased glutathione/glutathione disulfide ratio and increased lipid peroxidation. These effects were accompanied by decreased proliferation, increased apoptosis and downregulated NDUFB8/NDUFS9. Our findings collectively suggest that SNRPA plays a crucial role in driving CRPC progression and represents a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-025-08302-8
  17. Cancers (Basel). 2025 Nov 25. pii: 3755. [Epub ahead of print]17(23):
    Emerging Therapeutic Approaches to Engage the Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.
    Isla Henry, Rebecca Foreman, Lakshana Balachandran, Ethan Mortimer, Mohammad Asim.
      Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, with disease progression frequently occurring despite the use of potent androgen receptor (AR)-targeted therapies. As AR signalling continues to drive tumour growth in this setting, new therapeutic strategies are being developed to disrupt the AR axis through both direct and indirect mechanisms. This review highlights a selection of promising agents in preclinical or clinical development that represent the next generation of therapies targeting AR signalling. Direct approaches include novel agents that degrade the AR or target domains beyond the conventional ligand-binding domain, aiming to overcome resistance to existing anti-androgens. Indirect strategies are designed to interfere with AR function by modulating AR-associated transcriptional co-regulators, chromatin accessibility, and other regulatory proteins, such as splicing factors, that are critical for sustaining AR-driven gene expression in prostate cancer. Together, these therapies form the basis of emerging strategies to more effectively suppress AR activity in CRPC. This review discusses AR-activating mechanisms, the mechanisms of action of these agents, their clinical development status, and their potential to reshape future treatment paradigms in CRPC.
    Keywords:  DNA-binding domain (DBD); N-terminal domain (NTD); androgen receptor (AR); androgen receptor splice variants (AR-Vs); castration-resistant prostate cancer (CRPC); full-length androgen receptor (AR-FL); ligand-binding domain (LBD); metastatic castration-resistant prostate cancer (mCRPC); prostate cancer (PCa)
    DOI:  https://doi.org/10.3390/cancers17233755
  18. Nat Commun. 2025 Dec 11.
    BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.
    Hee-Young Jeon, Sudeep Khadka, Majid Pornour, Hyunju Ryu, Hegang Chen, Arif Hussain, Hung-Ming Lam, Eva Corey, Htoo Zarni Oo, Martin Gleave, Xiaofang Che, Christopher Barbieri, Jianfei Qi.
      BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of several malignancies, but its role in prostate cancer (PCa) remains unclear. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily enhances the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF increases AR binding at promoters, enhancers and super-enhancers. ATAC-seq further demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, in part through SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR co-bound regions are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We further show that BPTF forms a protein complex with AR and FOXA1, in which FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. Importantly, BPTF interacts with AR through its bromodomain, and a BPTF bromodomain inhibitor disrupts this interaction, impairs AR signaling and suppresses PCa cell growth. In summary, our findings establish BPTF as a critical regulator of AR activity by promoting chromatin accessibility and stabilizing the AR-FOXA1 complex, highlighting BPTF as a potential therapeutic target in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-025-67329-9
  19. J Nat Med. 2025 Dec 10.
    Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer.
    Kamil Piska, Michał Zubek, Adam Bucki, Maria Świtalska, Paulina Koczurkiewicz-Adamczyk, Benedykt Władyka, Marcin Kołaczkowski, Elżbieta Pękala.
      Castration-resistant prostate cancer (CRPC) continues to represent a critical therapeutic hurdle owing to its resistance to both androgen deprivation and next-generation antiandrogens like abiraterone (ABI). One of the key mechanisms underlying this resistance involves overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme contributing to intratumoral androgen biosynthesis. In this study, casticin (CAS), a flavonoid derived from Vitex agnus-castus, was identified as a potent inhibitor of AKR1C3. CAS showed potent inhibitory activity in enzymatic assays (IC₅₀ = 5.99 µM), significantly suppressed AKR1C3-mediated coumberone metabolism in 22Rv1 prostate cancer cells, and showed greater cytotoxicity in AKR1C3-expressing 22Rv1 cells relative to AKR1C3-deficient LNCaP cells. CAS significantly enhanced ABI's cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31-0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. CAS enhanced apoptosis in ABI-treated 22Rv1 cells, as well as combination showed only a limited effect against normal epithelial PNT-2 cell line. Docking and molecular dynamics simulations indicated a stable CAS-AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.
    Keywords:  17β-hydroxysteroid dehydrogenase type 5; Ethnopharmacology; Prostate cancer; Steroids; Vitexicarpin
    DOI:  https://doi.org/10.1007/s11418-025-01974-8
  20. iScience. 2025 Dec 19. 28(12): 113996
    High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.
    Peng Wu, Sicheng Wang, Zanmin Hu, Haoyan Zhang, Yuqing Lin, Zizhao Li, Jiahong Wu, Yani Chen, Yujie Chen, Yuandong Xu, Jun Li, Yupeng Guan.
      Chemoresistance remains a major obstacle in prostate cancer therapy. This study demonstrates that high extracellular matrix stiffness promotes chemoresistance by disrupting mitochondrial-nuclear communication. Culturing prostate cancer cells on polyacrylamide hydrogels of varying stiffness revealed that a high-stiffness environment promotes mitochondrial fusion and enhances function. Mechanistic investigations revealed that high matrix stiffness activates YAP, leading to dysregulation of the Hippo signaling pathway, which subsequently upregulates the expression of OPA1 and induces mitochondrial fusion. This fusion triggers a reprogramming of glutamine metabolism. The resulting metabolite, α-ketoglutarate, activated DNA demethylases TET1 and TET3, causing epigenetic modifications of YAP target genes and further exacerbating Hippo pathway dysregulation. Together, this establishes a YAP-OPA1-TET1/3-mediated positive feedback loop between the nucleus and mitochondria that drives drug resistance. Crucially, targeting OPA1 disrupted this loop and reversed stiffness-induced chemoresistance. These findings reveal a novel mitochondrial-nuclear communication, offering new insights for overcoming chemoresistance in prostate cancer.
    Keywords:  bioinformatics; biological sciences; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113996
  21. Cancers (Basel). 2025 Nov 26. pii: 3778. [Epub ahead of print]17(23):
    Chronic IL-1 Exposure Attenuates RELA- and STAT3-Dependent Synergistic Cytokine Signaling in Prostate Cancer Cell Lines.
    Stephanie Akemi Yamauchi, Haley Dahl-Wilkie, Mohamed Hussien Mohamed Zaky, Vivian Liu, Adora Onuogu, Ahmed Abdi, Shreya Billa, Rahael Javaid, Sheza Siddiqui, Chisom Mbah, Olaoluwapo Bankole, Sarah Wells, Sydney Greene, Rafah Falah, Nikki Ayanna Delk.
       BACKGROUND/OBJECTIVES: The milieu of inflammatory cytokines present in the prostate cancer (PCa) tumor microenvironment exerts various effects on cancer progression. Chronic exposure to the inflammatory cytokine interleukin-1 (IL-1) has been shown to impact signaling via the RELA/NF-kB pathway; however, the effects of chronic inflammation on the integration of different inflammatory signaling pathways, such as the interleukin-6 (IL-6)/STAT3 axis, requires further exploration.
    METHODS: We generated in vitro subline models by exposing the C4-2 and LNCaP PCa cell lines to either IL-1α or IL-1β for several months. We then treated the resulting sublines with acute IL-1 alone, IL-6 alone, or IL-1/IL-6 in combination and assessed for sensitivity to cytokine signaling. We observed changes in proliferation and quantified using Ki-67 immunostaining. Cell proliferation was assessed after siRNA silencing RELA or STAT3.
    RESULTS: IL-1/IL-6 signaling in combination enhanced the signaling effects of either cytokine alone, particularly cytostasis. While the chronic IL-1 sublines maintained sensitivity to acute IL-6 signaling, they lost sensitivity to acute IL-1 signaling and did not show the enhanced IL-1/IL-6 cytostatic response. Inhibition of RELA and STAT3 rescued cytostasis after IL-1/IL-6 treatment in parental PCa cell lines, but only STAT3 inhibition rescued proliferation in the chronic IL-1 sublines.
    CONCLUSIONS: Our work shows that IL-1/RELA and IL-6/STAT3 work in parallel to synergistically induce cytostasis. However, chronic IL-1 exposure selects for cells that attenuate IL-1/RELA signaling, subsequently attenuating IL-1/IL-6 synergy.
    Keywords:  cell proliferation; cytokine; inflammation; prostate cancer
    DOI:  https://doi.org/10.3390/cancers17233778
  22. Mol Med Rep. 2026 Feb;pii: 65. [Epub ahead of print]33(2):
    Gut microbiota as a multifaceted modulator of prostate cancer: Mechanistic insights, therapeutic opportunities and clinical challenges (Review).
    Zhenming Hao, Yongqiang Xie, Ru Zhang, Hui Sang, Luxi Li, Yulin Liu, Jinbo Hu, Jijun Wang, Keqiang Chai, Qiang Zhao.
      Prostate cancer (PCa) ranks among the most prevalent malignancies among men worldwide, emphasizing the need for innovative therapeutic strategies. Studies have suggested that the gut microbiota may markedly influence PCa pathogenesis through mechanisms such as immunomodulation and metabolic regulation. The present review systematically examined the composition and diversity of the gut microbiota, highlighted clinical evidence linking microbial dysbiosis to PCa risk and examined discrepancies in existing research. Additionally, it explored the therapeutic potential of microbiota modulation, through the use of probiotics and dietary interventions, in enhancing treatment responses. Despite emerging insights, challenges persist, including methodological variations and patient heterogeneity. The present review highlighted the need for further research to elucidate the role of the gut microbiota and support the development of personalized approaches for PCa management. The novelty of this work lay in its comprehensive synthesis of current evidence on the role of the gut microbiota in PCa, identification of gaps in existing research and proposal of future directions to advance our understanding of this emerging field.
    Keywords:  dysbiosis androgen biosynthesis; resistance; gut microbiota; prostate cancer; therapeutic target
    DOI:  https://doi.org/10.3892/mmr.2025.13775
  23. Med Oncol. 2025 Dec 11. 43(1): 41
    Investigating the synergistic cytotoxicity and apoptosis-inducing effects of eugenol derivatives in combination with docetaxel on PC3 human prostate cancer cells.
    Ghazaleh Behrouzian Fard, Hamid Sadeghian, Fatemeh B Rassouli, Fatemeh Valinezhad Sani.
      Prostate cancer is one of the most common cancers among men in developed countries. Research indicates that conventional chemotherapy is often accompanied by drug resistance and significant side effects. One promising strategy to overcome these challenges is to increase tumor cell sensitivity to chemotherapy by utilizing non-toxic natural compounds. This study, for the first time, evaluates the synergistic effects of new synthesized eugenol derivatives combined with docetaxel on PC3 human prostate cancer cells. Cell viability and apoptosis induction in PC3 cells were assessed after treatment with synthetic eugenol derivatives alone or in combination with docetaxel, using the Alamar Blue assay and flow cytometry with FITC/Annexin V-PI, respectively. Additionally, the effects of monotherapy and combination therapy on the expression of genes involved in the apoptosis process, including BAX and BCL-2, were analyzed using quantitative real-time PCR (qRT-PCR). The findings demonstrated that synthetic eugenol derivatives significantly reduced cell viability and induced apoptosis in PC3 cells in a dose-dependent manner. Furthermore, the inhibitory effect of docetaxel on PC3 cell survival was enhanced when combined with eugenol derivatives. This combination treatment enhanced apoptosis in the cells, as indicated by upregulation of the pro-apoptotic gene BAX and downregulation of the anti-apoptotic gene BCL-2. This study demonstrated that synthetic eugenol derivatives potentiated the effects of docetaxel in prostate cancer cells. Further research is necessary to elucidate the underlying mechanisms and to better understand its clinical advantages in prostate cancer therapy.
    Keywords:  Combination therapy; Docetaxel; Eugenol derivatives; Prostate cancer
    DOI:  https://doi.org/10.1007/s12032-025-03174-6
  24. Medicine (Baltimore). 2025 Dec 05. 104(49): e44281
    Exploration between caffeine intake, physical activity, and prostate cancer using data from the large-scale NHANES survey: A cross-sectional study.
    Qiaomei Liu, Siying Xu.
      This study aimed to explore the association between caffeine intake, physical activity (PA), and prostate cancer, machine learning algorithms to build predictive models of prostate cancer. A total of 1789 subjects from the National Health and Nutrition Examination Survey 2009 to 2018 waves were enrolled in this study. Multivariable-adjusted logistic regression was applied to evaluate the association. Then, we conducted 4 machine learning models, including extreme gradient boosting, AdaBoost, Catboos, and Boost tree to predict the occurrence of prostate cancer. In the fully adjusted model, compared to those reporting little caffeine consumption, those who reported large intake had a multivariate adjusted odd ratio (OR) with 95% confidence interval (CI) of 1.25 (2.21-15.52). Participants with large PA were more likely to develop prostate cancer (OR = 1.68, 95% CI: 1.47-3.80), whereas a significant inverse association between medium PA and prostate cancer was observed (OR = 0.66, 95% CI: 0.48-0.81). Extreme gradient boosting, Catboost, and Boost tree all have good prediction effects, with an AUC of up to 0.90 (95% CI: 0.87-0.93). No significant association was observed between small to medium caffeine intake and prostate cancer, large caffeine intake and PA was associated with increased prostate cancer. Moderate PA has the potential to favorably influence prostate cancer.
    Keywords:  caffeine intake; machine learning; physical activity; prediction; prostate cancer
    DOI:  https://doi.org/10.1097/MD.0000000000044281
  25. Mol Cell Biochem. 2025 Dec 12.
    APOBEC3B-driven mutations negatively regulated by P53 promote tumor progression and immunosuppressive microenvironment in prostate cancer.
    Yan Guo, Haodi Yu, Xiang Li, Lina Liu, Jing He, Xin Wang, Hui Zhang, Qingyu Zhang, Jing Fu, Ruixue Gu, Hehe Li, Dengfei Xu, Qinglin Liu, Shun-Dong Cang.
      APOBEC3B (A3B), a key cytosine deaminase, plays a multifaceted role in the malignant progression of various cancers. However, the precise role of A3B in prostate cancer (PCa) remains largely elusive. This study aimed to investigate the functional significance of A3B in PCa and evaluate its potential as a therapeutic target. We first demonstrated that A3B is significant upregulated in PCa tissues and positively correlated with higher Gleason scores, poorer prognostic outcomes, and an increased frequency of cytosine deamination-induced mutagenesis. Functional enrichment analysis further revealed that A3B is closely associated with biological processes such as "cell cycle regulation" and "epithelial-mesenchymal transition (EMT)." To validate the biological role of A3B in PCa cells, we conducted a series of in vitro assays, including CCK-8, EdU, colony formation, and transwell migration/invasion. Notably, A3B knockdown suppressed the proliferation of PC-3 cells and reduced their migratory and invasive capabilities by modulating EMT. Conversely, A3B overexpression enhanced these effects in 22RV1 cells. In vivo tumor xenograft experiments further supported our findings, confirming that A3B promotes the growth of PCa cells in mice. Mechanistically, p53 was identified as a suppressor of A3B expression, thereby alleviating genomic instability. Additionally, a combination of multiplex immunofluorescence (mfIHC) and qRT-PCR analyses validated that elevated A3B expression correlates with increased infiltration of immunosuppressive cells, including regulatory T cells (Tregs), CD8 + PD-1 + T cells, and CD163 + macrophages. This infiltration may be mediated by cytokines and chemokines. Collectively, these findings suggest that A3B holds potential as a novel prognostic biomarker and immunotherapeutic target for PCa.
    Keywords:  APOBEC3B; Immune microenvironment; P53; Prostate cancer; Tumor progression
    DOI:  https://doi.org/10.1007/s11010-025-05442-5
  26. J Clin Transl Res. 2025 Oct 29. 11(5): 96-105
    Association between serum uric acid and prostate cancer risk: The modifying role of CTGF genotype.
    Randi Chen, Timothy A Donlon, Richard C Allsopp, Brian J Morris, Bradley J Willcox, Kamal H Masaki.
       Background: The role of uric acid in prostate cancer risk remains uncertain, with evidence suggesting both carcinogenic and protective effects. Genetic factors may be key modifiers of this association.
    Objective: This study aimed to determine whether the relationship between uric acid and prostate cancer risk differs by the rs9399005 genotype of connective tissue growth factor (CTGF).
    Methods: We examined 6,259 Japanese-American men in Hawaii, cancer-free at baseline (1965-1968, ages 45-68), who were followed for incident prostate cancer until 1999. Hyperuricemia was defined as serum uric acid ≥7.0 mg/dL. CTGF genotypes were classified as common allele homozygotes (CC) or minor allele carriers (T). Cox proportional hazards models estimated hazard ratios (HRs), adjusting for age and potential confounders.
    Results: During a median follow-up of 29.7 years, 285 prostate cancer cases were identified. A significant interaction between CTGF and hyperuricemia was observed. Among men with the CTGF-T genotype, hyperuricemia was not associated with risk (HR = 0.77, 95% confidence interval [CI]: 0.51-1.17). In contrast, among CTGF-CC homozygotes, hyperuricemia was linked to a higher risk (HR = 1.91, 95% CI: 1.21-2.99). Men with both the CTGF-CC genotype and hyperuricemia had a higher risk (HR = 1.72, 95% CI: 1.17-2.54) compared with all other subjects.
    Conclusion: The association between uric acid and prostate cancer varied by CTGF genotype. Hyperuricemia increased risk among CTGF-CC homozygotes, whereas a nonsignificant protective effect was seen among T allele carriers.
    Relevance to patients: Monitoring and lowering serum uric acid may help reduce prostate cancer risk in men with the CTGF-CC genotype.
    Keywords:  CTGF; Connective tissue growth factor; Gene-environment interaction; Hyperuricemia; Prostate cancer; Uric acid
    DOI:  https://doi.org/10.36922/jctr025260029
  27. bioRxiv. 2025 Nov 29. pii: 2025.11.26.690813. [Epub ahead of print]
    ATHENA: A deep learning-based AI for functional prediction of genomic mutations and synergistic vulnerabilities in prostate cancer.
    Siyuan Cheng, Xiao Jin, Jiaying Qian, Yuyin Jiang, Isaac Yi Kim, Su Deng, Ping Mu.
      Identifying functional mutations that drive therapy resistance remains a major challenge in prostate cancer. Large-scale sequencing often produces extensive lists of mutations but provides limited insight into which alterations are functionally relevant. To overcome this gap, we developed ATHENA (Attention-based Therapeutic Network Analyzer), a deep learning-based AI framework that predicts the functional impact of genomic mutations and reveals their synergistic vulnerabilities. Integrated with our RNA/DNA-informed variant discovery pipeline OncoVar , ATHENA models nonlinear dependencies among mutations to distinguish driver events from passenger variants. Trained on large multi-cohort datasets and interpreted using SHAP analysis, ATHENA not only stratifies patients by clinical outcomes but also predicts which specific mutations alter tumor behavior and therapy response, enabling direct validation through base editing experiments. Applied to prostate cancer progression models, the OncoVar-ATHENA framework identified stage-specific driver signatures across castration-resistant, AR-variant-driven, and metastatic disease, and uncovered cooperative interactions such as SYVN1-STC2 that promote tumor proliferation. By moving beyond simple mutation identification, ATHENA enables functional prediction of genomic interactions. This approach accelerates the discovery of actionable targets and provides a foundation for rational design of next-generation combination therapies in advanced prostate cancer.
    DOI:  https://doi.org/10.1101/2025.11.26.690813
  28. Cancers (Basel). 2025 Nov 29. pii: 3842. [Epub ahead of print]17(23):
    Modulating Prostate Cancer Therapy Through the Gut Microbiome: A Comprehensive Review.
    Mohammed A Magashi Ali, Sarki A Abdulkadir.
      Background/Objectives: There is growing interest in the gut microbiome's role in cancer, particularly its influence on prostate cancer therapy. This review explores how the gut microbiota modulates treatment outcomes and how prostate cancer therapies affect microbial composition. Methods: A semi-systematic PubMed search was performed for English-language articles published between 2010 and 2025 using relevant keywords related to prostate cancer therapy and the gut microbiome. Both original research and reviews were included, with additional studies identified through citation tracking. Results: The literature reveals a dynamic, bidirectional relationship between the gut microbiome and prostate cancer therapies. Gut microbes can modulate treatment efficacy and toxicity through immune regulation, metabolic activity, and the production of bioactive compounds such as short-chain fatty acids and tryptophan derivatives. These interactions influence responses to androgen deprivation therapy, chemotherapy, radiotherapy, and immunotherapy. In parallel, prostate cancer treatments induce notable shifts in gut microbial composition, reducing diversity, increasing intestinal permeability, and promoting dysbiosis. These changes may impair therapeutic outcomes. Specific microbial taxa, including Akkermansia muciniphila, Faecalibacterium, and Bacteroides, have been linked to both therapeutic response and microbiome alterations. Conclusions: The reciprocal influence between gut microbes and prostate cancer therapies presents a compelling avenue for therapeutic innovation. However, current knowledge is largely derived from preclinical or cross-cancer studies, highlighting a major evidence gap in prostate-specific research. Bridging this gap through well-designed translational studies could inform clinical strategies that harness microbiome modulation to enhance treatment efficacy, reduce toxicity, and personalize prostate cancer therapy.
    Keywords:  dysbiosis; gut microbiome; prostate cancer
    DOI:  https://doi.org/10.3390/cancers17233842
  29. Cell Mol Life Sci. 2025 Dec 08. 82(1): 438
    IP-SNPs-seq links noncoding risk alleles to lineage transcription factor programs in prostate cancer.
    Wenjie Xu, Qixiang Zhang, Lijuan Qiao, Zixi Wang, Tian Wang, Dandan Dong, Qin Zhang, Liang Wang, Gong-Hong Wei, Peng Zhang.
      Most prostate cancer risk variants reside in noncoding DNA, but connecting germline alleles to lineage transcription factor (TF) programs has been challenging. We developed immunoprecipitation-coupled SNPs-seq (IP-SNPs-seq), enabling high-throughput, allele-specific, TF-resolved interrogation of candidate regulatory variants. Screening 903 prostate cancer-associated SNPs with androgen receptor (AR) immunoprecipitation, we identified multiple alleles with biased AR binding and convergent evidence from eQTL and ChIP-seq datasets. Among these, rs7600820 emerged as a functional enhancer variant: the risk G allele conferred stronger reporter activity, heightened AR responsiveness to dihydrotestosterone, and increased ODC1 expression; chromatin profiling and Hi-C revealed an active enhancer loop to the ODC1 promoter. ODC1 was consistently upregulated in primary and metastatic tumors across independent cohorts, associated with adverse clinicopathologic features, and required for prostate cancer cell proliferation. Gene-set enrichment analyses linked high ODC1 expression to MYC target signatures, positioning ODC1 as a clinically relevant, AR-regulated oncogenic node that integrates germline risk with core prostate cancer circuitry. IP-SNPs-seq thus provides a scalable route from association to mechanism, broadly applicable to diverse TFs and diseases, and nominates the AR-rs7600820-ODC1 axis as a potential biomarker and therapeutic vulnerability in androgen-driven prostate cancer.
    Keywords:  Chromatin looping; EQTL; GWAS noncoding variants; IP-SNPs-seq; ODC1; Prostate cancer; Transcription factor
    DOI:  https://doi.org/10.1007/s00018-025-05964-7
  30. Front Oncol. 2025 ;15 1691767
    Serum metabolites with diagnostic potential in prostate cancer and the inhibitory effects of alpha-Tocomonoenol on prostate cancer cells.
    Yang Shen, Bo Liu, Yuhua Zhou, Jing Lv, Xiang Zhang, Chun Yang, Yuwei Zhang, Ninghan Feng.
       Introduction: Prostate cancer is the most common malignant disease of the male urinary system, seriously endangering men's health. Currently, early detection of prostate cancer mainly relies on prostate-specific antigen (PSA) screening; however, PSA is characterized by high sensitivity but low specificity. Patients with PSA levels in the gray zone (4-10ng/ml) are at risk of excessive medical interventions, highlighting the great significance of exploring new diagnostic indicators for prostate cancer.
    Methods: A total of 60 subjects were enrolled in this study, including 30 prostate cancer patients and 30 benign prostatic hyperplasia patients. Non-targeted metabolomics analysis was performed on the subjects, and the profiling results were statistically analyzed. A diagnostic model was constructed using stepwise regression, and experimental verification was conducted on alpha-Tocomonoenol, one of the key differential metabolites. Additionally, the effect of alpha-Tocomonoenol on cell proliferation was evaluated in LNCaP, 22Rv1, and RWPE-1 cells.
    Results: Six differential metabolites between the prostate cancer group and the benign prostatic hyperplasia group were used to construct a diagnostic model, which showed a high area under the curve (AUC = 0.9433). Experimental verification revealed that alpha-Tocomonoenol inhibited the proliferation of LNCaP and 22Rv1 cells by binding to androgen receptors, while it had no significant effect on the proliferation of RWPE-1 cells.
    Discussion: This study demonstrates that serum metabolites have the potential to serve as diagnostic biomarkers for the early detection of prostate cancer. Furthermore, alpha-Tocomonoenol might exert an anti-proliferative effect on prostate cancer cells through binding to androgen receptors, providing new insights into the development of novel diagnostic tools and therapeutic strategies for prostate cancer.
    Keywords:  PSA gray zone; alpha-tocomonoenol; early detection; prostate cancer; serum metabolites
    DOI:  https://doi.org/10.3389/fonc.2025.1691767
  31. EBioMedicine. 2025 Dec 08. pii: S2352-3964(25)00502-X. [Epub ahead of print]123 106058
    Characterising the effect of circulating sphingolipids on metastatic prostate cancer cells.
    Neil Portman, Blossom Mak, Nicole Yeung, Hui-Ming Lin, Rachel M N Kim, Rhiannon Mellor, Luke Ardolino, Diana Gutierrez, Martina Raneri, Tahlia Scheinberg, David J Handelsman, Tania Moujaber, Peter J Meikle, Kevin Huynh, Anthony M Joshua, Andrew J Hoy, Lisa Butler, Lisa G Horvath.
       BACKGROUND: Prostate cancer (PC) is a leading cause of cancer-related deaths in men, with advanced cases exhibiting resistance to androgen deprivation therapy. Dysregulated lipid metabolism has emerged as a hallmark of aggressive PC. This study investigates the biological underpinnings of a circulating three-lipid signature (3LS) previously validated as a prognostic biomarker in patients with metastatic castration-resistant prostate cancer (mCRPC).
    METHODS: Using plasma samples from 16 mCRPC patients (8 positive and 8 negative for the 3LS), we assessed the impact of 3LS-positive plasma on three prostate cancer cell lines representative of disease progression. We investigated changes in cell viability and intracellular lipid metabolism associated with plasma from the two patient cohorts.
    FINDINGS: Exposure to 3LS-positive plasma improved cell viability across AR-positive (LNCaP, C4-2B) and AR-negative (PC3) cell lines compared to exposure to 3LS-negative plasma. Lipidomic profiling revealed elevated sphingolipids and glycosphingolipids in 3LS-positive plasma-treated cells, accompanied by metabolic shifts characterised by increased monounsaturated and reduced polyunsaturated fatty acid levels. Inhibition of sphingosine kinase 1 abrogated the 3LS-positive plasma-treatment phenotype consistent with ceramide/sphingosine 1 phosphate (S1P) signalling being the mechanism of action.
    INTERPRETATION: These findings suggest that the circulating 3LS is not just a prognostic biomarker, but an actionable signature reflecting changes in PC biology. The plasma lipid milieu identified by the 3LS drives a pro-survival phenotype by modifying lipid metabolism and upregulating ceramide/S1P signalling. The study provides the biological rationale to target ceramide-S1P signalling in patients, who are 3LS-positive.
    FUNDING: National Health and Medical Research Council of Australia Investigator grants (1196225; 2009965; 1197190); Cancer Institute New South Wales Translational Program Grant (TPG172146); Victorian Government Operational Infrastructure Support Program; Australian Government Research Training Program; University of Sydney merit award.
    Keywords:  Biomarker; Lipid; Prostate cancer; Sphingolipid
    DOI:  https://doi.org/10.1016/j.ebiom.2025.106058
  32. Transl Androl Urol. 2025 Nov 30. 14(11): 3696-3707
    Identification of programmed cell death associated key genes in benign prostatic hyperplasia and prostate cancer development by integrated bioinformatics analysis and machine learning.
    Jie Chen, Bo Chen, Yin Ning, Biao Ran, Liangren Liu, Dehong Cao.
       Background: Up to now, the underlying molecular mechanisms of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remain unclear. This study aimed to identify programmed cell death (PCD) associated genes in BPH and PCa development by integrated bioinformatics analysis and machine learning using publicly available genomic datasets.
    Methods: The GSE119195 and GSE55597 datasets were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were obtained using the Limma package for differential expression analysis. The intersection of core genes was filtered using four machine learning methods [least absolute shrinkage and selection operator (LASSO) regression, eXtreme gradient boosting (XGBoost), random forest, and Boruta].
    Results: We identified 159 key genes from the intersection of two DEGs. Fifteen hub genes were obtained by intersecting 159 DEGs with PCD genes. Two hub genes [bone morphogenetic protein 5 (BMP5) and cytochrome p450 family 1 subfamily b member 1 (CYP1B1)] were ultimately chosen after further reducing the dimension of 15 hub genes using four machine learning techniques. The nomogram's findings showed that BMP5 and CYP1B1 together were a reliable indicator of the risk factors of PCa and BPH. Furthermore, the risk score in the GSE55597 dataset displayed an area under the curve (AUC) value of 0.988. Moreover, the risk score in the GSE119195 dataset displayed an AUC value of 1. In addition, PCa patients' prognosis was significantly correlated with CYP1B1, Gleason score, and tumor (T) in the tumor-node-metastasis (TNM) stage.
    Conclusions: We established a prediction model with a high predictive ability in the analyzed datasets. As a bioinformatics analysis, our study indicated that there are possible DEGs in the prostate, such as BMP5 and CYP1B1, which might provide further insight for the pathogenesis of BPH and PCa. However, these findings warrant further validation in prospective, real-world clinical studies.
    Keywords:  Benign prostatic hyperplasia (BPH); bioinformatics analysis; machine learning; nomogram; programmed cell death (PCD)
    DOI:  https://doi.org/10.21037/tau-2025-527
  33. BMC Med Imaging. 2025 Dec 09.
    Hypoxia and cribriform growth in prostate cancer - establishing a link via MRI.
    Mar Fernandez Salamanca, Petra J van Houdt, Tord Hompland, Malgorzata Deręgowska-Cylke, Pim J van Leeuwen, Henk G van der Poel, Elise Bekers, Marcos A S Guimaraes, Heidi Lyng, Uulke A van der Heide, Ivo G Schoots.
       BACKGROUND: Prostate Cancer (PCa) is a heterogeneous disease, where hypoxia and cribriform growth have been established as adverse prognostic features. Hypoxia refers to a condition of limited oxygen concentration within the tumor microenvironment, associated with enhanced tumor aggressiveness, resistance to therapy, and poor clinical outcome. Likewise, cribriform growth has also been related to poor prognosis, though the biologic basis remains unclear. Recent pathological studies suggest that there is an association between cribriform growth and tumor hypoxia, but evidence from PCa patient studies are scarce. To fill this knowledge gap, this study aims to investigate the association between hypoxia measured by MR imaging and cribriform growth identified in whole-mount histological specimens.
    METHODS: A retrospective cohort of 291 patients with biopsy-confirmed PCa who underwent radical prostatectomy and pre-operative MRI was analyzed. Tumors were graded according to the 2019 ISUP classification, and cribriform growth presence and length were assessed on whole-mount histology. The oxygen consumption and supply based model using apparent diffusion coefficient and fractional blood volume was applied to estimate hypoxia level (HL) and hypoxia fraction (HFDWI). Differences in HL and HFDWI across Gleason patterns and between cribriform growth-positive and -negative tumors were assessed. Furthermore, a linear regression model was used to evaluate the association between cribriform growth and hypoxia after adjusting for confounders.
    RESULTS: Cribriform growth-positive tumors exhibited significantly higher HFDWI values compared to cribriform growth-negative tumors (p < 0.001). Within individual cancer Grade Groups (GG), cribriform growth length was significantly associated with increased HFDWI in pGG 3 tumors. HLmedian values were highest in Gleason Pattern 3 (GP3) regions and lowest in cribriform growth (GP4Crib+) regions, with significant differences observed between GP3 vs. non-cribriform growth GP4 regions (p < 0.001) and GP3 vs. GP4Crib+ (p < 0.001), consistent with more hypoxia in GP4Crib+. Multivariable regression confirmed cribriform growth presence as an independent predictor of increased hypoxia fraction, even after adjusting for tumor volume and GG.
    CONCLUSIONS: This study shows an association between cribriform growth and tumor hypoxia using an MRI-based biomarker. These findings provide further biological insights into the aggressive nature of cribriform growth architecture and highlight the potential clinical utility of non-invasive hypoxia quantification for risk stratification in prostate cancer management.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Cribriform growth; Hypoxia; Hypoxia biomarker; Prostate cancer
    DOI:  https://doi.org/10.1186/s12880-025-02084-3
  34. J Imaging Inform Med. 2025 Dec 09.
    Precision Risk Stratification in Prostate Cancer: Unveiling MRI-Based Habitat-Driven Radiomics Model for Enhanced Treatment Guidance.
    Yang Qiu, Huan Liu, Xin Shu, Yunfan Liu, Xiaofeng Qiao, Xiaojing He.
      The objectives of this study are to identify tumor subregions and develop a habitat-driven, MRI-based predictive radiomics model for risk stratification and further assess the spatial heterogeneity within prostate cancer (PCa). This retrospective study included 344 patients with histologically confirmed PCa who underwent preoperative MRI. Patients were categorized into low-to-intermediate and high-risk groups according to the EAU-EANM-ESTRO-ESUR-SIOG guidelines. Intensity clustering of T2-weighted imaging (T2WI) and dynamic contrast-enhanced MR images were applied to partition the whole gland and tumor into multiple habitat subregions. Predictive models based on subregional and conventional radiomic features were established using logistic regression, and their performances were assessed through receiver operating characteristic curve analysis. Further analysis explored the correlation between the features of tumor subregions and risk-related clinical-pathological parameters, as well as the spatial heterogeneity in tumor subregions. The tumor subregion model outperformed the whole-gland model. Specifically, the tumor subregion 3 model derived from the T2WI (HD_T2W_TR3) demonstrated superior efficacy in the validation set, achieving an AUC of 0.84 (95% confidence interval 0.766-0.923). Habitat-radiomic features were strongly correlated with prostate-specific antigen and T-stage. Our research results emphasize the potential benefits of a habitat-driven model for risk stratification prediction of PCa. These findings provide valuable information in identifying high-risk tumor subregions.
    Keywords:  Habitat imaging; Magnetic resonance imaging; Prostate cancer; Risk stratification; Tumor subregion
    DOI:  https://doi.org/10.1007/s10278-025-01782-2
  35. Sci Rep. 2025 Dec 08.
    Association between lifetime co-use of classic psychedelics and cannabis and prostate cancer diagnosis among US adults 50 years and older.
    Amrit Baral, Yue Pan, WayWay M Hlaing, Albert Garcia-Romeu, Paulo S Pinheiro, Denise C Vidot.
      Prostate cancer is the second leading cause of cancer-related deaths among U.S. men. While cannabis and classic psychedelics gain attention for symptom management in oncology, their associations with prostate cancer remain unexplored. This study evaluates associations between lifetime classic psychedelic and cannabis use with prostate cancer diagnoses among older U.S. adults using 2015-2019 National Survey on Drug Use and Health (NSDUH) data. A nationally representative sample of 19,460 males (weighted N = 50,842,517) aged ≥ 50 years was included in the analysis. Participants were categorized as: cannabis-only users, classic psychedelic-only users, co-users, and non-users. The primary outcome was self-report of physician-diagnosed prostate cancer. Multivariable logistic regression models estimated the adjusted odds ratios (AORs) for lifetime use and prostate cancer, adjusting for socio-demographic, behavioral, and clinical covariates, and analyses further stratified by age. Among participants, 3.9% reported prostate cancer. Exclusive classic psychedelic use was associated with increased odds of prostate cancer (AOR: 2.62, 95% CI: 1.31-5.22, p < 0.01) versus non-users. Among those ≥ 65, classic psychedelic-only use was also associated with higher odds (AOR: 3.60, 95% CI: 1.71-7.55, p < 0.01) of prostate cancer than non-users. Classic psychedelic-only users had higher odds of prostate cancer versus co-users (AOR: 4.58, 95% CI: 1.89-11.1, p < 0.01). This study identified a novel association between classic psychedelic use and prostate cancer in older adults. Future research should explore reasons for use, potential biological mechanisms, and consider longitudinal studies to clarify causality.
    Keywords:  Cannabis; Classic psychedelic; Co-use; NSDUH; Older adults; Prostate cancer
    DOI:  https://doi.org/10.1038/s41598-025-30172-5
  36. Histopathology. 2026 Jan;88(1): 24-39
    Molecular subtypes of metastatic prostate cancer: from pathophysiology to diagnosis.
    Jeanne M Dsouza, Erolcan Sayar, Michael T Schweizer, Stephanie Harmon, Colm Morrissey, Himisha Beltran, Peter S Nelson, Liang Cheng, Chien-Kuang Cornelia Ding, Michael C Haffner.
      Metastatic prostate cancer (mPC) is characterized by molecular and phenotypic heterogeneity. With increasing guideline-driven use of metastatic biopsies, more mPC specimens are being evaluated in surgical pathology. However, unlike localized prostate cancer, no standardized framework currently exists to guide the diagnostic workup of metastatic biopsies or reliably determine phenotypic subtypes. While many mPCs retain conventional acinar features, a growing subset exhibits phenotypic plasticity - including loss of prostate epithelial identity and emergence of neuroendocrine or other divergent lineages. This phenotypic diversity often occurs in castration-resistant prostate cancer as a mechanism of resistance to chronic androgen receptor pathway inhibition and is characterized by genomic alterations and epigenetic reprogramming. This review outlines the histologic and molecular spectrum of mPC and proposes a practical, pathology-informed diagnostic approach integrating morphologic assessment and immunohistochemistry. Adoption of a standardized diagnostic framework and multidisciplinary integration will be useful for employing precision oncology in advanced mPC.
    Keywords:  heterogeneity; metastasis; molecular subtype; prostate cancer
    DOI:  https://doi.org/10.1111/his.70033
  37. Sci Rep. 2025 Dec 10.
    Immune profiling identifies the contribution of extracellular vesicles to immune modulation and progression in prostate cancer.
    Giovanni Pecoraro, Ginevra Sarnacchiaro, Giovanni Smaldone, Andrea Soricelli, Jessie Santoro.
      Prostate cancer is the fourth leading cause of death in men worldwide. Currently, the gold standard for PCa diagnosis remains the Prostate-Specific Antigen (PSA); therefore, there is a growing demand for novel diagnostic approaches for early prediction of aggressive types of prostate cancer. The complexity of tumors is further enhanced by the presence of extracellular vesicles (EVs). These membrane-enclosed spherical particles are directly derived from their parent cells with their information (mRNAs, non-coding RNAs, and proteins) and play a critical role in intercellular communication. However, the role of PCa EVs in the crosstalk between cancer cells and resident cells in the microenvironment is still under investigation. Different prostate cancer cell lines were cultured for 48 h in medium supplemented with FBS exo-free medium. Next, secreted EVs were separated using differential ultracentrifugation, and further EVs characterization was performed by nanoparticle tracking analysis, immunoblotting, and scanning electron microscopy. The effect of prostate cancer EVs on the immune cell population was analyzed after staining PBMCs using flow cytometry. Additionally, cytokines released into the conditioned media were evaluated using an ELISA assay. We illustrated how EVs from prostate cancer cells of different background variously affected immune cells and modulated the expression of several cytokines after 24 h of treatment. We observed that the number of rare monocytes, CD14 + CD16 + , was significantly reduced in PBMCs treated with PC-3 and DU 145 EVs compared with LNCaP EVs. Furthermore, CD4 + and CD8 + activated cells were significantly more responsive when PBMCs were treated with PC-3 EVs compared to LNCaP EVs. Subsequently, pro- and anti-inflammatory cytokines were found to be more abundant in samples treated with PC-3 and DU 145 EVs. This suggests a potential role of EVs in prostate cancer progression and immune system evasion. Our study provides preliminary evidence that prostate cancer EVs exert distinct immunomodulatory effects, depending on their cellular origin. Ultimately, the differences observed between PC-3 EVs, DU 145 EVs and LNCaP EVs highlight the potential use of immune cell markers as reliable indicators of disease progression and as a non-invasive tool to complement prostate cancer risk stratification strategies.
    Keywords:  Early diagnosis; Extracellular vesicles; Immune cells; Microenvironment; Prostate cancer
    DOI:  https://doi.org/10.1038/s41598-025-31838-w
  38. Front Immunol. 2025 ;16 1644861
    Exosomal non-coding RNAs: orchestrators of intercellular crosstalk in the prostate cancer tumor microenvironment.
    Huanglin Duan, Baisheng Xu, Peiyue Luo, Tao Chen, Jun Zou.
      Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men worldwide, primarily due to its propensity for therapy resistance and metastasis. Emerging evidence underscores that exosomes, nanoscale extracellular vesicles, act as critical mediators of intercellular communication within the tumor microenvironment (TME), particularly via the non-coding RNAs (ncRNAs) they transport. These molecules include microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs). Exosomal ncRNAs drive tumor progression, immune evasion, and therapy resistance by reprogramming neighboring stromal cells, immune cells, and malignant cells. This review systematically examines the multifaceted roles of exosomal ncRNAs in remodeling the prostate cancer tumor microenvironment, focusing on their communication between tumor cells, tumor-stromal cells (including immune cells), and within the pre-metastatic niche preceding bone metastasis. We emphasize their mechanisms of action and clinical relevance. These findings position exosomal ncRNAs as central drivers of prostate cancer progression, revealing novel diagnostic and therapeutic opportunities. Future research must address challenges in standardizing exosome isolation techniques, resolving spatiotemporal heterogeneity, and advancing clinical translation to fully realize the potential of exosome-based strategies in precision oncology.
    Keywords:  exosomes; immune microenvironment; non-coding RNA; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1644861
  39. Sci Rep. 2025 Dec 12.
    A U-shaped association between blood selenium levels and prostate cancer: findings of a case-control study among Nigerian men.
    Onyinyechi Bede-Ojimadu, Nwakasi Nnamah, Jude A Onuegbu, Fiorella Barraza, Iain Grant-Weaver, Jideofor Orakwe, Joseph Abiahu, Nkiru Ezeama, Ejeatuluchukwu Obi, Orish Ebere Orisakwe, Jerome Nriagu.
      The ability of selenium to both prevent and induce cancer at varying biological concentrations has been reported in previous studies. We studied the associations between selenium exposure and prostate diseases such as prostate cancer (PCa) and benign prostatic hyperplasia (BPH), and estimated the optimal range of selenium concentrations that may be needed to prevent these diseases among Nigerian men. Blood and urine samples from men with histologically diagnosed PCa (n = 90), BPH (n = 97), and controls (n = 98) were analyzed for trace elements, including selenium. The associations between selenium concentrations and prostate diseases were estimated using logistic regression and restricted cubic splines. Men in the lowest and highest blood selenium tertiles had increased odds of PCa {AOR (95% CI): 2.90 (1.13, 7.46) and 4.42 (1.68, 11.59), respectively}. Compared with the first tertile of blood selenium, men in the highest tertile had significantly higher odds of BPH (AOR: 3.92; 95% CI: 1.68, 9.11). We found that a putative range of blood selenium concentration associated with minimum odds of PCa may lie between 125.55 and 134.86 µg/L. No significant association was observed between urinary selenium levels and PCa. The narrow-ranged U-type relationship between blood selenium concentration and PCa needs to be confirmed in larger longitudinal cohort studies.
    Keywords:  Benign prostatic hyperplasia; Environmental exposure; Nigeria; Prostate cancer; Selenium
    DOI:  https://doi.org/10.1038/s41598-025-32341-y
  40. Clin Oncol (R Coll Radiol). 2025 Nov 24. pii: S0936-6555(25)00239-0. [Epub ahead of print]49 103984
    Prostate Cancer: Artificial Intelligence Advancements in Diagnosis and Early Detection.
    A Shahzad, M Waqar, T Imran, M Faisal.
      
    Keywords:  Artificial intelligence (AI); early detection; microultrasound; multimodal imaging; prostate cancer (PCa)
    DOI:  https://doi.org/10.1016/j.clon.2025.103984
  41. Int J Mol Sci. 2025 Dec 01. pii: 11651. [Epub ahead of print]26(23):
    Development and In Vitro Evaluation of [64Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer.
    Hoda Talebian, Samia Ait-Mohand, Prenitha Mercy Ignatius Arokia Doss, Léon Sanche, Brigitte Guérin.
      Prostate cancer (PCa), particularly in its metastatic form, remains a major clinical challenge due to limited diagnostic and therapeutic options. To address this, we developed a novel radiotheranostic agent, [64Cu]Cu-NOTA-TP-PSMA, by conjugating a prostate-specific membrane antigen (PSMA) ligand to a 64Cu-radiolabeled terpyridine-platinum (TP) compound previously shown to exert selective cytotoxicity against cancer cells. In this study, the biological performance of [64Cu]Cu-NOTA-TP-PSMA was compared with the monomeric analogs [64Cu]Cu-NOTA-PSMA and [64Cu]Cu-NOTA-TP through in vitro studies in PSMA-positive LNCaP prostate cancer cells and non-malignant HEK-293 cells. [64Cu]Cu-NOTA-TP-PSMA showed high stability, PSMA binding affinity and exhibited substantially enhanced uptake, internalization, retention, and nuclear localization in LNCaP cells relative to the monomers, whereas uptake and nuclear accumulation in HEK-293 cells were negligible. Cytotoxicity assays further demonstrated potent and selective activity in LNCaP cells, with EC50 values in the low nanomolar range, and minimal toxicity in HEK-293 cells. Collectively, these results identify [64Cu]Cu-NOTA-TP-PSMA as a promising radiotheranostic agent, warranting further in vivo evaluation for prostate cancer imaging and targeted radiotherapy.
    Keywords:  PSMA; copper-64; in vitro validation; prostate cancer; radiotheranostic agent; terpyridine-platinum
    DOI:  https://doi.org/10.3390/ijms262311651
  42. Cancers (Basel). 2025 Nov 23. pii: 3742. [Epub ahead of print]17(23):
    The Clinical Relevance of Tumor Biomarkers in Prostate Cancer-A Review.
    Zuzanna Majewska, Monika Zajkowska, Sara Pączek, Adam Rafał Nowiński, Weronika Sokólska, Mariusz Gryko, Karolina Orywal.
      Prostate cancer is one of the most common malignancies in men worldwide. Therefore, there is an urgent need to develop accurate, accessible biomarkers for diagnosis, prognosis, and therapy monitoring. Tumor markers, which can be measured in blood, urine, or tissue, provide valuable information regarding tumor presence, progression, and response to treatment. This review provides a comprehensive overview of routinely used diagnostic and emerging biomarkers for prostate cancer, based on a systematic MEDLINE/PubMed search. Key biomarkers analyzed include PSA and its derivatives, PCA3, and TMPRSS2-ERG, as well as genomic tests such as Prolaris, Decipher, and ConfirmMDx, and liquid biopsy-based tests such as ExoDx Prostate and SelectMDx. This narrative review demonstrates that although PSA remains the mainstay of prostate cancer diagnosis, emerging molecular and genomic biomarkers are enhancing diagnostic specificity, refining risk stratification, and enabling more personalized patient care. The integration of routinely used and novel biomarkers can improve early detection, optimize treatment decisions, and ultimately improve outcomes of prostate cancer patients.
    Keywords:  ConfirmMDx; PCA3; TMPRSS2-ERG; decipher; diagnostic biomarkers; liquid biopsy; prolaris; prostate cancer; prostate-specific antigen
    DOI:  https://doi.org/10.3390/cancers17233742
  43. Cureus. 2025 Nov;17(11): e96338
    Influence of Diabetes Mellitus on Metabolic and Hormonal Interactions Promoting Aggressive Prostate Cancer.
    Afreen Khan, Anu Chandra, Preeti Agarwal, Syed Tasleem Raza, Avneet Gupta, Abbas A Mahdi, Satya N Sankhwar.
      Background and objectives Diabetes mellitus might play a vital role in promoting prostate cancer development, progression, and aggressiveness. The influence of diabetes on prostate cancer outcomes has long been debated. However, the mechanism through which diabetes mediates its effect on prostate cancer development and progression has not been established. This study aimed to study the influence of diabetes mellitus on prostate cancer outcome and aggressiveness. Material and methods This study includes 100 patients newly diagnosed with benign prostatic hyperplasia (BPH) and 200 patients with histologically confirmed prostate adenocarcinoma, of which 100 were diabetic. Descriptive statistics were performed to analyse and summarize the results as mean±standard deviation (SD). Statistically significant differences between two or more groups were determined using ANOVA and the post hoc Tukey test. Chi-square test was performed to compare the distribution of tumor grades and risk categories between patients with prostate cancer with diabetes and without diabetes. Correlation analyses were performed to analyse the association of metabolic and hormonal parameters among themselves and cancer grade. Multiple linear regression analysis was done to analyse the relationship of hormone profile with the risk of prostate cancer in men with and without diabetes. Results Data showed that serum insulin and IGF-1 were significantly elevated in prostate cancer, highest being in prostate cancer with diabetes, and they had a positive association with prostate cancer Gleason score, grade, and high risk. Lipid profile and HbA1c also had a significant association with prostate cancer Gleason score and grade. Men with diabetes and prostate cancer were diagnosed with higher-grade and high-risk cancer than men with prostate cancer but without diabetes. Conclusion This study confirms the influence of diabetes on metabolic and hormonal parameters, particularly serum HbA1c, insulin, IGF1, and prostate-specific antigen, which are positively associated with higher grade and high risk, thus leading to the development and promotion of aggressive cancer in patients with coincidental diabetes.
    Keywords:  benign prostatic hyperplasia; diabetes mellitus; dyslipidemia; gleason score; insulin; insulin-like growth factor; prostate cancer; prostate specific antigen
    DOI:  https://doi.org/10.7759/cureus.96338
  44. J Med Chem. 2025 Dec 08.
    Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance.
    Kai Yuan, Wanqi Wang, Chen Tong, Huanaoyu Yang, Weijiao Chen, Xiao-Yu Zhang, Genbei Wang, Guixia Li, Yuanyuan Chen, Xujie Zhuang, Wenjian Min, Haiping Hao, Yibei Xiao, Xiaohui Ma, Peng Yang.
      Prostate cancer (PCa) is a highly prevalent and aggressive malignancy that poses a serious threat to men's health globally. Current treatments for PCa largely rely on hormone therapy; however, the development of drug resistance significantly diminishes its efficacy, highlighting the urgent need for novel therapeutic agents. Based on our prior work identifying dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) as a promising target in PCa, we developed a novel and potent DYRK2 inhibitor TSL2109, and resolved its cocrystal structure with DYRK2. TSL2109 exhibited high kinase selectivity, favorable pharmacokinetic properties, and potent antitumor activity against PCa. Notably, it effectively suppressed tumor growth in enzalutamide-resistant 22Rv1 xenografts, patient-derived organoids, and patient-derived xenografts. Collectively, these results indicate that TSL2109 is a highly promising anticancer agent with the potential to overcome therapy resistance, thereby addressing an unmet clinical need. Supported by these findings, TSL2109 has been approved for clinical trials in China.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03245
  45. Ann Med Surg (Lond). 2025 Dec;87(12): 8699-8707
    Safety and efficacy of darolutamide in combination with androgen-deprivation therapy for prostate cancer: a systematic review and meta-analysis.
    Allahdad Khan, Haji Abdul Rehman Akhter, Shree Rath, Raza Aslam, Izere Salamon, Muhammad Abdullah Ali, Muhammad Bashir, Mohamed Antar, Fnu Muhibullah.
       Background: Prostate cancer is the second most common cancer in men. Androgen deprivation therapy (ADT) is the standard treatment, but many patients develop resistance, leading to metastatic castration-resistant prostate cancer (CRPC). Darolutamide, an androgen receptor inhibitor, has shown promise in treating prostate cancer, but its combination with ADT remains under-researched. This study evaluated the safety and efficacy of darolutamide with ADT in patients with hormone-sensitive prostate cancer and CRPC compared to ADT plus placebo.
    Methods: We searched electronic databases for randomized controlled trials on darolutamide + ADT in prostate cancer. The primary outcome was overall survival, and secondary outcomes included pain progression, time to subsequent antineoplastic therapy, and adverse events (fatigue, bone fractures, falls, mental disorders, rash, hypertension, and serious events).
    Results: Four studies (N = 3,473) were included. Darolutamide + ADT showed no significant difference in overall survival (HR = 0.71, P = 0.28), but CRPC patients had improved survival (HR = 1.08, P = 0.007). The combination reduced pain progression [risk ratio (RR) = 0.81, P = 0.001] and delayed subsequent therapy (RR = 0.46, P < 0.00001). Risks of bone fractures (RR = 1.52, P = 0.008) and hypertension (RR = 1.28, P = 0.03) were increased. Other adverse events, such as fatigue, rash, mental disorders, falls, and serious adverse events, showed no significant differences compared to ADT plus placebo.
    Conclusion: Darolutamide + ADT improves outcomes for PC patients but presents safety concerns, including bone fractures and hypertension. Further trials are needed for optimal patient selection and long-term management.
    DOI:  https://doi.org/10.1097/MS9.0000000000004029
  46. Eur J Nucl Med Mol Imaging. 2025 Dec 11.
    Shining the PSMA spotlight on peritoneal metastases in prostate cancer.
    Jonathan Kuten, Stephanie Chahwan, Charlie White, Audrey Mauguen, Heiko Schöder, Simone Krebs.
      
    Keywords:   177Lu-PSMA-617; FDG PET/CT; PSMA PET/CT; Peritoneal metastases; Prostate cancer
    DOI:  https://doi.org/10.1007/s00259-025-07703-3
  47. Nat Commun. 2025 Dec 06.
    Proteome-wide association study of prostate cancer risk across populations.
    Hua Zhong, Jingjing Zhu, Shuai Liu, Chong Wu, Liang Wang, Seamus P Whelton, Catherine H Marshall, Michael J Blaha, Peter Durda, Xiuqing Guo, Craig W Johnson, Henry J Lin, Kent D Taylor, Russell P Tracy, Ronit I Yarden, Ani W Manichaikul, Stephen S Rich, Jerome I Rotter, Rajat Deo, Ruth F Dubin, Peter Ganz, Lang Wu.
      There is insufficient understanding of the molecular basis of prostate cancer (PCa) across different populations. We perform a large-scale proteome-wide association study (PWAS) to identify proteins with genetically regulated expression in plasma to be associated with PCa risk across populations. We develop genetic prediction models for expression of 1578, 1993, 1218, and 1390 proteins for African (n = 450), European (n = 758), Asian (n = 289), and Hispanic/Latino (n = 474) males, respectively, and evaluate associations of genetically regulated protein expression with PCa risk in 19,391 PCa cases and 61,608 controls of African population, 122,188 cases and 604,640 controls of European population, 10,809 cases and 95,790 controls of Asian population, and 3931 cases and 26,405 controls of Hispanic/Latino population. We identify three, four, 15, and 73 PCa-associated proteins in African, Hispanic/Latino, Asian, and European populations, respectively, and 83 in trans-population meta-analysis. There are both pan-population and population-specific associations. Our findings provide valuable insights into etiology of PCa.
    DOI:  https://doi.org/10.1038/s41467-025-66250-5
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