bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–12–07
fifty-four papers selected by
Grigor Varuzhanyan, UCLA
  1. Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer.
  2. Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer.
  3. KDM4A promotes NEPC progression through regulation of MYC expression.
  4. G protein-coupled receptors in prostate cancer: research progress and therapeutic targets.
  5. CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer.
  6. IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.
  7. Triglyceride lipase PNPLA2-independent suppression of c-MYC signaling by the metabolic coactivator ABHD5 in prostate cancer.
  8. Targeting CHD1L suppresses prostate cancer progression via the FOXO3-PUMA axis.
  9. STARD4 suppresses tumorigenesis and attenuates enzalutamide resistance via lipid metabolic reprogramming and AR stabilization in prostate cancer.
  10. Non-canonical functions of UGT2B17 promote castrate-resistant prostate cancer progression.
  11. Anticancer Activity of Annonacin and Its Synergistic Enhancement of Docetaxel Efficacy in Prostate Cancer.
  12. Development of a prognostic model based on immunogenic cell death/ferroptosis-related genes and the study of TREX1 effects on prostate cancer cells.
  13. Ferroptosis modulates invasion and migration in prostate cancer PC-3M subclones.
  14. Megalin (LRP2) Expression Patterns in Prostate Cancer Stem Cells and Metastatic Subtypes: Implications for Tumor Progression and Metabolism.
  15. Monoamine neurotransmitter functionalized poly(amidoamine) dendrimers for targeting of cabazitaxel to human prostate cancer cells.
  16. Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion.
  17. Establishment and Maintenance of Patient-derived Prostate Cancer Organoids: A Detailed Experimental Protocol.
  18. Active-targeting biomimetic nanosystem for prostate cancer enhances radiotherapy efficacy by inducing ferroptosis.
  19. A Metastasis-Competent CAF Subpopulation Defined by MFAP5⁷THY1⁷ Co-expression Drives Prostate Cancer Metastasis via EMT Activation.
  20. Submicron silica particles drives prostate cancer aggressiveness via lipid-metabolic reprogramming.
  21. Targeting androgen receptor signaling to enhance cancer immunotherapy.
  22. PROCA11 early activation fuels prostate cancer neuroendocrine traits by regulating cell survival and migration.
  23. Cytotoxicity and cell cycle changes in prostate cancer cells with differing PSMA expression and p53 status after treatment with PSMA-targeting radioligand [212Pb]Pb-AB001.
  24. Cellular senescence: A novel mechanism of therapeutic resistance in prostate cancer.
  25. Novel causal associations between plasma metabolites and prostate cancer risk revealed by mendelian randomization.
  26. Identification and validation of palmitoylation-related signature genes based on machine learning for prostate cancer.
  27. Overcoming radioresistance in prostate cancer by targeting DNA damage repair.
  28. Associations of specific food sources of dietary fat with prostate cancer incidence and mortality: results from a large prospective cohort.
  29. Androgen receptor splice variant expression and prostate cancer recurrence after salvage therapy.
  30. High-Risk Prostate Cancer in a Patient with Untreated Prolactinoma and Castrate-Level Testosterone Suppression: A Case Report.
  31. Metabolomics in Prostate Cancer: A Minimally Invasive Method Using Urine after Prostatic Massage to Predict Gleason Grade.
  32. ASO Author Reflections: Shifting Age Demographics in Prostate Cancer Surgery: Insights from 17 Years of German Data.
  33. Real-Time Antiproliferative Activity of Carthamus tinctorius L. (Safflower) Against PC3 and C6 Cell Lines: A Correlative Chemical Profile Assessment.
  34. Editorial: New potential biomarkers and cellular strategies for the study of prostate cancer and testicular cancer cells.
  35. Preoperative predictors about lymph node metastasis and biochemical recurrence in high-risk prostate cancer patients: a clinic pathological retrospective study.
  36. Aminated Quinolinequinones With EDG(s) as a Prostate Cancer Inhibitor: Mechanistic Insights and Pharmacokinetic Limitations.
  37. Androgen receptor blockade and its effect on PSMA-localization in prostate cancer: Implications for radioligand therapy.
  38. High-fat diet exacerbates risk of prostate cancer in arecoline-induced prostatic hyperplasia via modulation of periprostatic adipose tissues in rats.
  39. Systematic characterization of cancer-associated SPOP mutants reveals novel and reprogrammable degradative activities.
  40. Unraveling the YAP1-TGFβ1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts.
  41. Emerging biomarkers in prostate cancer diagnosis and treatment: Insights into genetic, RNA and metabolic markers (Review).
  42. Altered expression of nucleotide excision repair genes ERCC2 and ERCC5 in prostate cancer tissues.
  43. Germline DNA Repair and Immune-metabolic Alterations Suggest a Potentially Distinct Form of Early-onset Prostate Cancer in Men of African Descent.
  44. Prostate Cancer: Current Status of Novel Molecular Imaging and Future Prospects.
  45. How small molecules stabilize oligomers of a phase-separating disordered protein.
  46. Multivariable model integrating PHI and mpMRI for detecting csPCa in biopsy-naïve men.
  47. Enhanced Antitumor Efficacy of 225Ac-NM600 Compared to 177Lu-NM600 in Murine Prostate Cancer Models.
  48. Unravelling targeted therapy in prostate cancer: from molecular mechanisms to translational opportunities.
  49. Staging Prostate Cancer with AI: A Comparative Study of Large Language Models and Expert Interpretation on PSMA PET-CT Reports.
  50. Clinically informed intermediate reasoning enables generalizable prostate cancer prognostication through machine learning in limited settings.
  51. Mendelian randomization analysis integrating GWAS and eQTL data identified potential regulatory genes associated with prostate cancer in neural cells.
  52. Updated dose-response meta-analysis of sexual activity and prostate cancer risk.
  53. Comparative analysis of ultrasound-guided magnetic resonance imaging-cognitive fusion transrectal versus transperineal prostate biopsy: a 10-year single-center retrospective analysis.
  54. Prostate cancer diagnostics: the independent and combined roles of SelectMDx and mpMRI.
  1. Int J Urol. 2025 Dec 03.
    Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer.
    Ekrem Basaran, Ceyhan Hacioglu.
       OBJECTIVES: Prostate cancer (PCa) is a leading malignancy among men, with treatment resistance posing significant clinical challenges, especially in advanced, castration-resistant cases. Abiraterone acetate (AA), a CYP17A1 inhibitor, suppresses androgen biosynthesis and is used to manage metastatic disease; however, its complete mechanism of action is not fully understood. This study investigates whether AA modulates androgen receptor (AR) expression via endoplasmic reticulum (ER) stress in PCa.
    METHODS: LNCaP (androgen-sensitive) and 22Rv1 (AR-variant-expressing) PCa cells were treated with AA (0.5-16 μM) for 24-72 h. Cytotoxicity and proliferation were assessed via CCK-8 and BrdU assays. Apoptosis was quantified by caspase-3/7 activation. ER stress markers (PERK, ATF4, CHOP) and AR were evaluated using RT-qPCR, Western blot, and immunofluorescence staining. Pharmacological PERK inhibition (GSK2656157) and activation (CCT020312) validated pathway involvement.
    RESULTS: AA induced concentration/time-dependent cytotoxicity in LNCaP cells (24 h IC₅₀ = 4.8 μM) and 22Rv1 cells (24 h IC₅₀ = 15.2 μM) and proliferation decreased by 54.1% and 7.3% at 4.8 μM, respectively. AA triggered apoptosis in LNCaP cells, increasing caspase-3/7-positive cells to 71.58% vs. 1.73% in controls (p < 0.0001). Mechanistically, AA upregulated PERK, ATF4, and CHOP mRNA/protein (p < 0.0001) while downregulating AR. Immunofluorescence confirmed reciprocal ATF4 nuclear accumulation and AR reduction in AA-treated LNCaP cells. PERK inhibition reversed AA-induced effects, while PERK activation phenocopied AA's AR suppression and cytotoxicity, confirming ER stress mediation via the PERK/ATF4/CHOP axis.
    CONCLUSIONS: AA induces ER stress, leading to transcriptional downregulation of the AR and suppression of PCa cell viability and proliferation. Targeting the PERK pathway may enhance AA efficacy in AR-driven PCa.
    Keywords:  abiraterone acetate; androgen receptor; endoplasmic reticulum (ER) stress; prostate cancer
    DOI:  https://doi.org/10.1111/iju.70304
  2. Cell Death Dis. 2025 Dec 03.
    Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer.
    Zhen Kang, Bin Lin, Zhi-Bin Ke, Qing-Shui Zheng, Xue-Yi Xue, Yong Wei, Ning Xu.
      Prostate cancer (PCa) remains a major therapeutic challenge due to aberrant androgen receptor signaling and a remodeled tumor microenvironment. Disulfidptosis, a recently identified form of cell death characterized by cytoskeletal collapse under conditions of glucose deprivation and elevated SLC7A11 expression, presents a potential novel avenue for intervention. In this study, we integrated TCGA and GEO data and employed machine learning techniques to identify disulfidptosis-related genes in prostate cancer. Functional analyses using SLC7A11-overexpressing and knockout cell lines demonstrated that SLC7A11 promotes cellular proliferation, migration, and invasion, while its overexpression under glucose-starved conditions triggers disulfidptosis, also inducible pharmacologically using the glucose uptake inhibitor BAY-876. Through CUT&Tag, ChIP-seq, and luciferase assays, we identified FOXA1 as a key transcriptional regulator of SLC7A11, driven by a super-enhancer located at chr14:37583488-37589585. CRISPR-Cas9 deletion of this super-enhancer reduced FOXA1 and SLC7A11 expression, thereby protecting cells from disulfidptosis. These findings highlight the critical role of the SE/FOXA1/SLC7A11 regulatory axis in driving both disulfidptosis and tumor progression, suggesting that targeting this pathway, particularly in glucose-deprived tumor environments, may offer promising therapeutic strategies for PCa.
    DOI:  https://doi.org/10.1038/s41419-025-08227-2
  3. Cancer Lett. 2025 Nov 28. pii: S0304-3835(25)00756-6. [Epub ahead of print] 218184
    KDM4A promotes NEPC progression through regulation of MYC expression.
    Celia Sze Ling Mak, Ming Zhu, Jie Fu, Xin Liang, Xiaoxuan Wang, Fei Yuan, Feng Wang, Anh G Hoang, Xingzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jordan Contreras, Thisawin Dang, Cindy Yan, Brandon Figueroa, Mathias Mazzocco, Athena Luo, Bijeta Pradhan, Jiwon Park, Mirrah Bashir, Miao Zhang, Eric Metzger, Roland Schüle, Abhinav K Jain, Ellen Karasik, Daniel Frigo, Barbara A Foster, Min Gyu Lee, Paul Corn, Christopher J Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Zhi Tan, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang.
      Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a promising therapeutic target, as knockdown or knockout of KDM4A suppresses NEPC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we found that KDM4A directly regulates the transcription of the oncogene MYC, which we show is essential for NEPC cell growth through knockdown and inhibitor studies. Importantly, pharmacologic inhibition of KDM4A using QC6352, a potent pan-KDM4 inhibitor, significantly reduced NEPC cell proliferation in vitro and tumor growth in vivo, providing proof-of-concept for therapeutic targeting. Collectively, our findings establish KDM4A as a critical epigenetic driver of NEPC through MYC regulation and demonstrate its therapeutic potential for this lethal disease that currently lacks effective treatments.
    DOI:  https://doi.org/10.1016/j.canlet.2025.218184
  4. Front Cell Dev Biol. 2025 ;13 1709098
    G protein-coupled receptors in prostate cancer: research progress and therapeutic targets.
    Wei Xiong, Bingpeng Zhou, Jian Shi, Dong Ni, Zhiyong Xiong.
      Prostate cancer (PCa) is one of the most common cancers of male genitourinary system, with castration-resistant prostate cancer (CRPC) posing a major therapeutic challenge. G protein-coupled receptors (GPCRs), the largest family of cell surface receptors, are increasingly recognized as critical regulators of tumor progression, metastasis, and therapy resistance. This review summarizes the research progress of orphan receptors, chemokine receptors and hormone-sensitive receptors of GPCRs in PCa. We highlight how these receptors modulate key oncogenic processes such as androgen receptor (AR) signaling, cell proliferation, migration, and immune evasion. Emerging therapeutic strategies targeting GPCRs, including biased ligands and combination therapies, are discussed. This synthesis provides a mechanistic foundation for understanding GPCR functions in PCa and identifies promising directions for future research and drug development.
    Keywords:  G protein-coupled receptors; chemokine receptors; hormone-responsive GPCRs; orphan receptors; prostate cancer
    DOI:  https://doi.org/10.3389/fcell.2025.1709098
  5. bioRxiv. 2025 Nov 19. pii: 2025.11.18.689150. [Epub ahead of print]
    CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer.
    Guoqiang Liu, Shiyu Wang, Loan Duong, Ziyu Zeng, Jing Yang, Yun Zhao, Sharif Rahmy, Shan Feng, Ariana Arce, Linchuan Jia, Jun Wan, Liang Cheng, Xuemin Lu, Xin Lu.
       Purpose: Basal-like (also known as double-negative) prostate cancers are aggressive tumors that lack effective targeted therapies. We aimed to delineate the role of CDH3 (P-cadherin) in basal-like prostate cancer and evaluate CDH3-directed therapeutic strategies.
    Methods: We integrated genetically engineered mouse models (GEMMs) of prostate cancer, bulk and single-cell transcriptomic analyses, and a suite of in vitro and in vivo experiments. CDH3 expression and associated signaling pathways were examined in Pten/Apc double-knockout mouse prostates and human datasets. Functional studies included antibody-drug conjugate (ADC) cytotoxicity assays and the development of chimeric antigen receptor (CAR) T cells targeting CDH3, tested in prostate cancer cell lines and xenograft models.
    Results: Pten/Apc double deletion in prostate GEMMs led to highly aggressive tumors with markedly elevated CDH3 expression and enrichment of non-canonical WNT signaling components. Transcriptomic analyses of patient-derived prostate tumors confirmed that CDH3 is significantly upregulated in basal-like prostate cancer subtypes relative to luminal subtypes. Single-cell RNA sequencing revealed CDH3 expression predominantly in basal epithelial cells. Mechanistically, we found that active YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. Targeting CDH3 with a CDH3-specific ADC induced potent, antigen-dependent killing of CDH3⁺ prostate cancer cells in vitro and significantly suppressed tumor growth in in vivo metastatic prostate cancer models. Likewise, CDH3-targeted CAR T cells specifically recognized and lysed CDH3-expressing prostate tumor cells while sparing CDH3-negative cells, leading to tumor regression and improved survival in mouse models, especially when combined with PD-1 checkpoint blockade.
    Conclusions: CDH3 is a key marker and functional driver of basal-like prostate cancer. Therapeutic strategies leveraging CDH3, including ADCs and CAR T cells, demonstrate strong preclinical efficacy, supporting the development of CDH3-targeted treatments to overcome resistance in aggressive prostate cancer.
    DOI:  https://doi.org/10.1101/2025.11.18.689150
  6. Mol Cancer Ther. 2025 Dec 05.
    IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.
    Amy R Leslie, Shu Ning, Masuda Sharifi, Zachary A Schaaf, James P Maine, Wei Lou, Kristina D Leslie, Chengfei Liu, Hongyu Xu, Alan P Lombard, Hong-Wu Chen, Mamta Parikh, Marc Dall'Era, Allen C Gao.
      Enzalutamide resistance remains a significant challenge in the treatment of advanced prostate cancer. Identifying molecular drivers of enzalutamide resistance is crucial for developing effective therapeutic strategies. In this study, we identify insulin-like growth factor binding protein 3 (IGFBP3) as a key driver of enzalutamide resistance in castration-resistant prostate cancer (CRPC). We demonstrate that IGFBP3 expression is significantly upregulated in enzalutamide-resistant C4-2B MDVR cells compared to parental C4-2B cells. This upregulation was consistently observed across multiple enzalutamide-resistant CRPC models, including LNCaP-derived 42D and 42F cells, as well as long-term enzalutamide-resistant cell lines derived from LNCaP, VCaP, LAPC-4, and CWR-R1 cells. Additionally, Enzalutamide treatment directly induced IGFBP3 expression in sensitive cells. Elevated IGFBP3 expression was also observed in CRPC patient samples post-enzalutamide treatment and was associated with higher Gleason scores and reduced disease-free survival. Mechanistically, IGFBP3 activates the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway, which promotes cell survival and resistance to enzalutamide. IGFBP3 knockdown decreased SphK1 expression, reduced S1P secretion, and enhanced enzalutamide sensitivity, whereas IGFBP3 overexpression induced SphK1 expression and S1P production, conferring enzalutamide resistance. Inhibition of IGFBP3 via siRNA reduced cell viability, induced apoptosis, and re-sensitized resistant models to enzalutamide. Similarly, targeting SphK1 with the inhibitor SKI-II suppressed SphK1 activity, reduced S1P production, enhanced enzalutamide sensitivity, and significantly inhibited resistant tumor growth while enhancing enzalutamide sensitivity. Collectively, these findings highlight IGFBP3-mediated SphK1 signaling as a critical mediator of enzalutamide resistance and suggest that targeting the IGFBP3/SphK1/S1P axis represents a promising therapeutic strategy to overcome resistance in advanced prostate cancer.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0644
  7. J Biol Chem. 2025 Dec 03. pii: S0021-9258(25)02853-4. [Epub ahead of print] 111001
    Triglyceride lipase PNPLA2-independent suppression of c-MYC signaling by the metabolic coactivator ABHD5 in prostate cancer.
    Aaron Lotvola, Guohua Chen, Guoli Zhou, James G Granneman, Jian Wang.
      The MYC oncogene encodes a transcription factor that regulates cell growth, metabolism, and proliferation. Its dysregulation is a hallmark of many cancers, including prostate cancer. Elevated c-MYC expression promotes tumor progression and therapy resistance, yet c-MYC remains a challenging therapeutic target due to its intrinsically disordered structure and lack of enzymatic activity. Identifying upstream regulators of MYC activity may reveal new therapeutic strategies. α/β-Hydrolase domain-containing protein 5 (ABHD5) is best known as a coactivator of the triglyceride lipase PNPLA2, facilitating intracellular lipolysis. However, recent studies have suggested a tumor-suppressive role for ABHD5 in various cancers, including prostate cancer, though the molecular mechanisms remain unclear. Here, we identify ABHD5 as a suppressor of c-MYC-driven transcriptional programs in prostate cancer cells. Transcriptomic profiling in 22Rv1 cells revealed that ABHD5 overexpression downregulates MYC target genes and reduces c-MYC protein levels. In contrast, ABHD5 knockout increased c-MYC protein expression, enhanced cell proliferation, and markedly elevated colony-forming capacity. ABHD5 deficiency also conferred resistance to the pharmacologic c-MYC inhibitor 10058-F4. Notably, PNPLA2 knockout failed to phenocopy these effects, indicating that ABHD5's tumor-suppressive function is independent of its canonical lipolytic role. Furthermore, ABHD5 overexpression continued to suppress c-MYC in PNPLA2-deficient cells, confirming a lipase-independent mechanism. These findings define a previously unrecognized role for ABHD5 as a negative regulator of c-MYC and highlight a novel, noncanonical pathway linking lipid metabolism regulators to oncogene control in prostate cancer.
    Keywords:  ABHD5; PNPLA2; c-MYC; lipid metabolism; tumor suppressor
    DOI:  https://doi.org/10.1016/j.jbc.2025.111001
  8. J Transl Med. 2025 Dec 04.
    Targeting CHD1L suppresses prostate cancer progression via the FOXO3-PUMA axis.
    Pusheng Hui, Yanru Lai, Haiqi Fan, Qinrong Yan, Yue Yang, Zhe Chen, Yu Hou, Youlin Kuang.
       BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies in men worldwide, and advanced or metastatic disease remains a major therapeutic challenge. Chromodomain helicase DNA binding protein 1-like (CHD1L) has been implicated as an oncogenic driver in multiple cancer types, yet its role in prostate cancer pathogenesis is not fully defined. The purpose of this study is to investigate the biological significance of CHD1L in prostate cancer and to evaluate the therapeutic potential of its selective inhibitor OTI-611.
    METHODS: Bioinformatics analyses were conducted to assess the expression, prognostic significance of CHD1L in PCa patients. In vitro, cell viability, cycle progression, apoptosis, and migration/invasion were evaluated using CCK-8, colony formation, flow cytometry, transwell assays. In vivo treatment potential of OTI-611 was assessed through a nude mouse xenograft model. Protein and mRNA levels were determined by western blot and qPCR, respectively. Synergism of OTI-611 and docetaxel was determined using SynergyFinder 3.0.
    RESULTS: We demonstrated that CHD1L was significantly upregulated in PCa patients and correlates with poor prognosis. Genetic knockdown of CHD1L substantially inhibits PCa cell proliferation and induces apoptosis. Moreover, inhibition of CHD1L by the small molecule OTI-611 significantly suppresses PCa cell proliferation, migration, and invasion, and induces apoptosis both in vitro and in vivo. Mechanistically, inhibition of CHD1L induces the expression of FOXO3 (a classic transcription factor) and its downstream target PUMA (a key apoptosis inducer). Restricting the expression of FOXO3 significantly reverses the anti-tumor effects induced by OTI-611. Furthermore, OTI-611 synergizes with docetaxel to enhance apoptotic cell death, providing a promising strategy to overcome docetaxel resistance.
    CONCLUSIONS: Our study demonstrates that CHD1L is markedly upregulated in prostate cancer and contributes to tumor progression. Pharmacological inhibition of CHD1L with the selective inhibitor OTI-611 significantly suppresses proliferation, migration, and invasion, while inducing apoptosis in vitro and in vivo. Mechanistically, these effects are mediated through activation of the FOXO3-PUMA axis, as FOXO3 suppression abrogates OTI-611-induced apoptosis. Moreover, OTI-611 exhibits strong synergy with docetaxel, enhancing apoptotic cell death and providing a potential strategy to improve therapeutic efficacy in prostate cancer.
    Keywords:  CHD1L; Docetaxel; FOXO3; PUMA; Prostate cancer
    DOI:  https://doi.org/10.1186/s12967-025-07529-5
  9. J Exp Clin Cancer Res. 2025 Dec 02.
    STARD4 suppresses tumorigenesis and attenuates enzalutamide resistance via lipid metabolic reprogramming and AR stabilization in prostate cancer.
    Yi Zhang, Xi Wang, Jiuyi Wang, Ke Ma, Lei Jia, Bo Liu, Xianglin Yuan, Qiang Li, Qinzhang Wang, Qinyu Li, Kai Zeng.
       BACKGROUND: Prostate cancer (PCa) is a globally prevalent malignancy in males and is imposing an increasing epidemiological burden. The androgen receptor (AR) signalling axis is fundamentally implicated in PCa tumorigenesis and disease progression. Although androgen deprivation therapy (ADT) elicits transient therapeutic responses in the majority of cases, progression to castration-resistant prostate cancer (CRPC) remains an almost universal clinical trajectory. Dysregulated lipid homeostasis, manifesting as intracellular lipid deposition, has been mechanistically linked to CRPC pathogenesis and therapeutic failure under enzalutamide regimens. However, effective strategies to mitigate lipid accumulation in PCa remain elusive.
    METHODS: STARD4, a key gene involved in lipid metabolism, was identified as functionally significant in PCa through integrated bioinformatics analysis of public databases. RT‒qPCR, western blot analysis, and IHC staining were performed to evaluate STARD4 expression, while Kaplan-Meier survival analysis, Gleason score, and tumor stage were performed to assess its clinical significance in PCa. The biological functions of STARD4 and its contribution to enzalutamide resistance were elucidated through in vitro and in vivo experiments. The effect of STARD4 on abnormal lipid accumulation in PCa cells was evaluated by Oil Red O (ORO) staining, while its impact on endoplasmic reticulum (ER) stress was assessed through ER-tracking imaging and transmission electron microscopy (TEM). Mechanistic exploration involves a combination of techniques, including RNA-seq analysis, Gene ontology analysis, coimmunoprecipitation (Co-IP), and GST pull-down assay, to analyse the interactions and potential mechanisms involving STARD4, AR, and E3 ubiquitin ligase UBE4B.
    RESULTS: In this study, we observed that STARD4 expression was markedly reduced in PCa tissues and was correlated with an adverse prognosis. STARD4 overexpression inhibited PCa cell proliferation, migration, and lipid accumulation while promoting apoptosis through ER stress. Mechanistically, STARD4 enhanced the interaction between UBE4B and AR, facilitating AR ubiquitination and degradation and thus suppressing AR signalling. Additionally, the upregulation of STARD4 expression enhanced sensitivity to enzalutamide in resistant cells by diminishing lipid accumulation and inhibiting the AR signalling pathway. In summary, STARD4 functions as a tumour suppressor in PCa by regulating cholesterol metabolism and modulating AR signalling.
    CONCLUSIONS: Our findings identify STARD4 as a promising therapeutic target for reversing enzalutamide resistance in PCa while also providing novel insights for future research on lipid metabolism within the tumour microenvironment.
    Keywords:  Androgen receptor; Enzalutamide resistance; Lipid metabolism; Prostate cancer; STARD4
    DOI:  https://doi.org/10.1186/s13046-025-03600-7
  10. J Clin Invest. 2025 Dec 04. pii: e196495. [Epub ahead of print]
    Non-canonical functions of UGT2B17 promote castrate-resistant prostate cancer progression.
    Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A Lack, Jianfei Qi, Bo Han, Xuesen Dong.
      Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP-glucuronosyltransferase 2B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduces tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.
    Keywords:  Cell stress; Clinical Research; Oncology; Prostate cancer; Protein misfolding
    DOI:  https://doi.org/10.1172/JCI196495
  11. J Cell Mol Med. 2025 Dec;29(23): e70972
    Anticancer Activity of Annonacin and Its Synergistic Enhancement of Docetaxel Efficacy in Prostate Cancer.
    Yunbei Xiao, Qinquan Wang, Chen Sun, Haoran Zou, Xiaozhi Cheng, Ruijie Yao, Huiliang Zhou.
      Prostate cancer (PCa) is the second most prevalent malignancy in men, and therapeutic options become severely limited once androgen deprivation therapy (ADT) fails. This study evaluated the antitumor activity of Annonacin, a natural acetogenin, alone or in combination with docetaxel (DTX) in PCa. The antitumor effects and underlying mechanisms of Annonacin and/or DTX were investigated in DU145 cells and a xenograft mouse model by assessing proliferation, migration, apoptosis, colony formation, DNA damage and FAK expression and distribution. Through an integrated strategy combining network pharmacology and a series of in vitro assays, the findings demonstrated that Annonacin exerts significant antitumor activity by inducing DNA damage and downregulating FAK expression and localisation. Co-treatment with DTX further enhanced these effects, with combination index (CI) values < 1, indicating strong synergism. In vivo, the combination therapy achieved more than 74% tumour growth inhibition (p < 0.0001), accompanied by increased tumour cell death, reduced Ki-67 expression and elevated γ-H2AX levels. Collectively, these findings demonstrate that Annonacin exerts potent antitumor activity and synergistically enhances DTX efficacy by promoting DNA damage and suppressing FAK signalling, supporting its potential as a promising adjuvant candidate for PCa treatment.
    Keywords:  Annonacin; DNA; anticancer activity; combination treatment; docetaxel; prostate cancer
    DOI:  https://doi.org/10.1111/jcmm.70972
  12. Front Immunol. 2025 ;16 1708437
    Development of a prognostic model based on immunogenic cell death/ferroptosis-related genes and the study of TREX1 effects on prostate cancer cells.
    Yaoan Wen, Shuyuan Zhan, Jianhui Chen, Jiangbin Yang, Dandong Chen, Song Zheng, Shaoxing Zhu.
       Background: Understanding the interplay between immunogenic cell death (ICD), ferroptosis, and prostate cancer (PCa) is critical for elucidating the underlying mechanisms of PCa pathogenesis. This study aimed to establish a prognostic model for PCa based on ICD- and ferroptosis-related genes (IFRGs) and to evaluate its potential clinical applicability.
    Methods: RNA sequencing data and clinical information of PCa patients were obtained from The Cancer Genome Atlas (TCGA-PRAD) database. Candidate IFRGs were identified through Pearson correlation and differential expression analyses. A prognostic model was constructed using univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and Kaplan-Meier survival analyses, and subsequently validated in an external cohort (GSE70769). In addition, siRNA-mediated knockdown of the key gene TREX1 was performed in PC-3 cells, and EdU and Transwell assays were conducted to assess its effects on tumor cell proliferation, migration, and invasion.
    Results: A three-gene IFRG-based prognostic model was developed, which effectively stratified PCa patients into high- and low-risk groups with significantly different survival outcomes. Multivariate Cox regression analysis confirmed the model as an independent prognostic factor. Functional experiments further demonstrated that TREX1 serves as a critical risk gene, and its knockdown markedly suppressed the proliferative, migratory, and invasive capacities of PCa cells.
    Conclusion: The three-gene IFRG-based prognostic model may serve as a promising prognostic biomarker for PCa, providing predictive value and novel insights into the complex interactions between IFRGs and PCa progression. Moreover, TREX1 was identified as a potential therapeutic target, offering new perspectives for prognostic assessment and the development of immunotherapy strategies in PCa.
    Keywords:  TREX1; ferroptosis; immunogenic cell death; prognostic model; prostate cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1708437
  13. Exp Cell Res. 2025 Nov 29. pii: S0014-4827(25)00447-1. [Epub ahead of print]454(2): 114847
    Ferroptosis modulates invasion and migration in prostate cancer PC-3M subclones.
    Yuliang Rao, Siyu Liu, Aicui Ma, Li Xu, Jun Guo, Zuyue Sun.
      Prostate cancer (PCa) metastasis remains a formidable clinical challenge, underscoring the urgent need to uncover its underlying molecular mechanisms. Leveraging the PC-3M cell line and its sublines with divergent metastatic potentials (PC-3M-1E8, highly metastatic; PC-3M-2B4, low-metastatic), this study investigated the role of ferroptosis, a form of iron-dependent regulated cell death, in PCa metastasis. Functional assays demonstrated that PC-3M-1E8 cells exhibited significantly enhanced proliferation, migration, invasion, and clonogenic capacity compared to PC-3M-2B4 cells. Proteomic analysis identified 5502 differentially expressed proteins, with GSEA pinpointing ferroptosis as the most significantly enriched pathway (NES = 2.8, FDR < 0.001) in PC-3M-1E8 cells. Key ferroptosis regulators, including GPX4 (1.4-fold), GCLM (1.6-fold), GCLC (1.5-fold), and TFRC (1.8-fold), were upregulated in PC-3M-1E8, while ACSL4 (0.7-fold) and VDAC3 (0.6-fold) were downregulated, constructing a ferroptosis-resistant network. Functional validation revealed that PC-3M-1E8 cells were more resistant to ferroptosis induction, evidenced by 3.68-fold higher GPX4 expression, 1.37-fold elevated GSH/GSSG ratios, and blunted iron responses. These findings establish an inverse correlation between ferroptosis sensitivity and PCa metastatic potential, providing a novel perspective on PCa metastasis by linking iron metabolism reprogramming to metastatic competence. Clinically, the identified ferroptosis-related signatures offer potential as predictive biomarkers for metastatic risk, and ferroptosis induction emerges as a promising therapeutic strategy for metastatic PCa. Future research should focus on exploring the crosstalk between ferroptosis and other cancer-related pathways to develop more effective targeted therapies.
    Keywords:  Ferroptosis; Invasion; Metastasis; Migration; Prostate cancer; Proteomic
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114847
  14. Prostate. 2025 Dec 03.
    Megalin (LRP2) Expression Patterns in Prostate Cancer Stem Cells and Metastatic Subtypes: Implications for Tumor Progression and Metabolism.
    Gunel Mukhtarova, Aysegul Murat, Cigir Biray Avci, Eda Acikgoz, Huseyin Aktug, Gulperi Oktem.
       BACKGROUND: Megalin (LRP2) is a multifunctional endocytic receptor whose role in prostate cancer (PCa), particularly in cancer stem cells (CSCs) and metastatic progression, remains largely unexplored.
    METHODS: We analyzed LRP2 mRNA and protein expression in DU-145, PC-3, and RWPE1 cells and their CD133high/CD44high CSCs via qRT-PCR and immunofluorescence, in both 2D and 3D cultures. Public RNA-seq data (TCGA, WCDT-MCRPC) were used to assess LRP2, CD133, and CD44 across normal, primary, and metastatic tumors. Gene Set Enrichment Analysis (GSEA) and correlation with AR, VDR, and stemness genes were performed.
    RESULT: LRP2 was significantly upregulated in DU-145 cells and CSCs in the 3D culture system. In contrast, PC-3 CSCs showed reduced LRP2 expression. In clinical datasets, LRP2 was highest in metastatic tumors (log2FC = 3.58), with bone (M1B) and other parts of the body (M1C) subtypes exhibiting elevated levels compared to primary tumors. CD133 was consistently downregulated in metastases. GSEA highlighted LRP2 involvement in lipid, retinoid, and steroid metabolism. LRP2 correlated positively with VDR and negatively with AR in M1C tumors.
    CONCLUSION: LRP2 shows subtype-specific expression patterns in PCa, with elevated levels in DU-145 CSCs and metastatic tumors. Its link to metabolic pathways and inverse relationship with AR suggest a potential role in therapy resistance and metastasis.
    Keywords:  LRP2/megalin; metastasis; prostate cancer stem cell; three‐dimensional (3D) culture; tumor heterogeneity
    DOI:  https://doi.org/10.1002/pros.70105
  15. Discov Nano. 2025 Dec 02. 20(1): 221
    Monoamine neurotransmitter functionalized poly(amidoamine) dendrimers for targeting of cabazitaxel to human prostate cancer cells.
    Sonali Priyadarshini Choudhury, Mahima Jadav, Bhavana Jodha, Sunita Patel, Hitesh Kulhari, Deep Pooja.
      Prostate cancer ranks as the second most prevalent solid malignancy in men. Androgen deprivation therapy is a common approach of treating metastatic prostate cancer. However, development of castrate resistance in patients over the course of treatment, non-specific drug distribution and low solubility of drugs are major challenges in the treatment of prostate cancer treatment. In this study, serotonin (ST), a monoamine neurotransmitter, was explored for the site-specific delivery of cabazitaxel (CBZ) to 5HT (5-hydroxytryptamine) receptors overexpressing prostate cancer cells. ST was conjugated to G4 PAMAM dendrimers (DEND) which have well defined, highly branched, nanoscale, multifunctional architecture to carry and enhance the solubility of hydrophobic drugs. This study demonstrates the successful synthesis, characterisation, and CBZ delivery using serotonin-polyethylene glycol-dendrimer complex (ST-PEG-DEND) to DU154 human prostate cancer cells. According to the findings, CBZ@PEG-DEND showed significantly higher time- and dose-dependent cytotoxicities and growth-inhibitory effects to DU145 cells in comparison to pure CBZ. Further, the cellular uptake studies revealed high cellular uptake of targeted and fluorescent conjugate (Rho@ST-PEG-DEND) in comparison to non-targeted fluorescent conjugate (Rho@PEG-DEND), highlighting the role of ST in improved delivery of CBZ to 5HT receptor overexpressed cancer cells.
    Keywords:  5HT receptors; Dendrimers; Polyethylene glycol; Prostate cancer; Serotonin; Targeted delivery
    DOI:  https://doi.org/10.1186/s11671-025-04368-7
  16. J Clin Invest. 2025 Dec 01. pii: e192368. [Epub ahead of print]135(23):
    Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion.
    Fen Ma, Sen Chen, Luigi Cecchi, Betul Ersoy-Fazlioglu, Joshua W Russo, Seiji Arai, Seifeldin Awad, Carla Calagua, Fang Xie, Larysa Poluben, Olga Voznesensky, Anson T Ku, Fatima Karzai, Changmeng Cai, David J Einstein, Huihui Ye, Xin Yuan, Alex Toker, Mary-Ellen Taplin, Adam G Sowalsky, Steven P Balk.
      TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor-regulated (AR-regulated) TMPRSS2 expression. T:E fusion is associated with PTEN loss and is highly associated with decreased INPP4B expression, which together may compensate for ERG-mediated suppression of AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses IRS2 and AKT activation. In contrast, ERG downregulation did not increase INPP4B, suggesting its decrease is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression was decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a nonredundant function. As ERG in T:E fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in T:E fusion tumors. A T:E fusion-positive PDX had increased AKT activity in vivo and response to AKT inhibition in vitro after androgen deprivation. Moreover, two clinical trials of neoadjuvant AR inhibition prior to radical prostatectomy showed greater increases in AKT activation in the T:E fusion-positive versus -negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR-targeted therapy in T:E fusion PCa and that these patients may most benefit from combination therapy targeting AR and AKT.
    Keywords:  Cell biology; Inositol phosphates; Oncogenes; Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI192368
  17. J Vis Exp. 2025 Nov 14.
    Establishment and Maintenance of Patient-derived Prostate Cancer Organoids: A Detailed Experimental Protocol.
    Danyan Lin, Mingyi Shui, Tingyu Zhou, Peng Jiang, Xiaoting Wang, Ninghan Feng.
      Prostate cancer (PCa) is a highly heterogeneous malignancy and a leading cause of cancer-related mortality in men, with significant clinical challenges in addressing treatment resistance and disease progression. Existing preclinical models, such as two-dimensional (2D) cell lines and patient-derived xenografts (PDXs), have limitations in faithfully recapitulating the complexity of PCa, including tumor heterogeneity, androgen receptor (AR)-dependent signaling, and microenvironmental interactions. To address this gap, this study presents a robust and reproducible protocol for establishing Patient-derived organoids (PDOs) that preserve the genetic, phenotypic, and histological features of the parental tumors. This method enables the culture of organoids from both localized and advanced PCa, providing a biologically relevant model for studying disease mechanisms, drug response, and biomarker discovery. The results demonstrate the protocol's ability to generate organoids from a variety of clinical specimens, with applications in high-throughput drug screening and precision medicine. By offering a standardized workflow that addresses key technical challenges, this study highlights the importance of PDOs as versatile tools for advancing prostate cancer research and developing more effective therapeutic strategies.
    DOI:  https://doi.org/10.3791/68912
  18. J Nanobiotechnology. 2025 Nov 30.
    Active-targeting biomimetic nanosystem for prostate cancer enhances radiotherapy efficacy by inducing ferroptosis.
    Zhihao Hu, Hongji Li, Kai Gan, Yu Li, Yao Jiang, Keying Zhang, Zhengxuan Li, Yike Zhou, Tong Lu, Chao Xu, Shaojie Liu, Limin He, Fa Yang, Jun Jiang, Hongtao Song, Ying Wang, Li Guo, Changhong Shi, Weihong Wen, Donghui Han, Weijun Qin.
      Radioresistance and off-target toxicity remain major challenges in prostate cancer (PCa) radiotherapy. Here, we report a biomimetic nanoplatform (Au/MOF-FIN@M-gy1) that synergistically enhances radiation deposition and ferroptosis for precision radiosensitization. By engineering macrophage membranes with prostate-specific membrane antigen (PSMA)-targeting nanobodies (gy1), we achieve tumor-selective delivery of Au/MOF nanoparticles preloaded with ferroptosis inducers (FINs). Upon lysosomal release, FINs disrupt redox homeostasis via GPX4 suppression, while Au/MOF amplifies radiation-induced reactive oxygen species (ROS), collectively triggering lethal lipid peroxidation cascades. This dual mechanism is further demonstrated to elicit radiosensitizing effects in both bone-metastatic and radio-refractory PCa models without requiring radiation dose escalation, thereby improving the therapeutic index. Our study demonstrates a nanoparticle-enabled strategy to enhance tumor-specific radiotherapy by dual-targeting metabolic vulnerabilities.
    Keywords:  Ferroptosis; Membrane-coated nanoparticles; Prostate cancer; Prostate-specific membrane antigen; Radiation therapy; Targeted therapy
    DOI:  https://doi.org/10.1186/s12951-025-03879-w
  19. Recent Pat Anticancer Drug Discov. 2025 Nov 26.
    A Metastasis-Competent CAF Subpopulation Defined by MFAP5⁷THY1⁷ Co-expression Drives Prostate Cancer Metastasis via EMT Activation.
    Yongqiang Huang, Yu Wang, Wei Zhang, Wenfeng Wang, Leilei Du, Xingming Zhang, Wenhao Xu, Jianghua Zheng, Guohai Shi, Jianhua Wang.
       BACKGROUND: The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), contributes to prostate cancer (PCa) metastasis, however, the role of CAF heterogeneity remains incompletely characterized. The study aims to identify and functionally characterize a metastasis-competent CAF subpopulation in PCa and evaluate its potential as a biomarker for predicting metastatic progression.
    METHODS: We integrated single-cell RNA sequencing data from 1,214 CAFs across 14 PCa specimens. Metastasis-derived CAFs were functionally validated in vitro. Stromal marker expression was assessed by multiplex immunofluorescence in 78 PCa tissues samples.
    RESULTS: A 20-gene signature stratified CAFs into three subsets, with the MFAP5-expressing subset (CAFa) enriched in metastatic patients. Co-expression of MFAP5 and THY1 specifically identified CAFa with 96.2% specificity. MFAP5 secretion was associated with AKT phosphorylation, Slug upregulation, and epithelial-mesenchymal transition (EMT). Stromal MFAP5⁷THY1⁷ colocalization predicted postoperative metastasis risk independently of Gleason score (multivariate HR = 5.69, p < 0.001).
    DISCUSSION: Our findings establish stromal MFAP5⁷THY1⁷ co-localization as a potential prognostic biomarker that could complement Gleason scoring. Further validation in multi-center cohorts is required to confirm its clinical independence.
    CONCLUSION: We identified a metastasis-competent CAF subpopulation defined by MFAP5⁷THY1⁷ co-expression, where THY1 serves as a spatial anchor for MFAP5 detection and MFAP5 secretion is functionally linked to AKT/EMT pathway activation.
    Keywords:  MFAP5; Prostate cancer; cancer-associated fibroblasts; epithelial-mesenchymal transition; metastasis; prognostic biomarker.
    DOI:  https://doi.org/10.2174/0115748928439833251118072935
  20. Semin Oncol. 2025 Oct 30. pii: S0093-7754(25)00125-3. [Epub ahead of print]53(1): 152433
    Submicron silica particles drives prostate cancer aggressiveness via lipid-metabolic reprogramming.
    Pengpeng Su, Qianfeng Xu, Yan Wang, Wenjie Xie, Jundong Lin, Yangjia Zhuo, Jianheng Ye, Jianming Lu, Zhaodong Han, Fen Zou, Qishan Dai, Weide Zhong.
      Micron-sized (1 µm - 100 µm) and submicron-sized (100 nm-1 µm) silica particles are prevalent in both natural environments and areas influenced by human activities. Their environmental forms, origins, and pathways of human exposure differ markedly from those of nanoscale silica. Empirical studies have demonstrated that silica can induce cellular oxidative stress and mitochondrial dysfunction, as well as inhibit the activity of key enzymes in the tricarboxylic acid (TCA) cycle, such as isocitrate dehydrogenase. This inhibition can promote tumor cell proliferation and invasion. Furthermore, silica may activate the HIF-1α/mTOR signaling axis, leading to the upregulation of glucose transporter GLUT1 and lactate dehydrogenase (LDHA), thereby enhancing glycolytic metabolic flux. Concurrently, it may inhibit fatty acid β-oxidation, resulting in abnormal lipid accumulation and the promotion of pro-inflammatory mediator release. In summary, the accumulation of submicron silica within the bodies of cancer patients has the potential to induce metabolic disorders. Such metabolic reprogramming may influence the progression of prostate cancer (PCa) and adversely impact postoperative quality of life. In this study, we demonstrated that prolonged exposure of the lungs to submicron silica particles can induce alterations in lipid metabolism in PCa and significantly enhance the proliferation and invasive capacity of PCa cells. Consequently, elucidating the mechanisms underlying silica-induced metabolic imbalance holds substantial clinical significance for enhancing the prognosis of patients with tumors related to exposure.
    Keywords:  Lipid metabolism; Prostate cancer; Submicron silica; Tumor prognosis
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152433
  21. Trends Pharmacol Sci. 2025 Dec 03. pii: S0165-6147(25)00257-3. [Epub ahead of print]
    Targeting androgen receptor signaling to enhance cancer immunotherapy.
    David A Bader, Binita Chakraborty, Donald P McDonnell, Matthew D Hirschey.
      Men experience higher cancer incidence and mortality than women, and accumulating evidence implicates androgen receptor (AR) signaling as a key biological driver of these sex-based disparities. AR signaling can suppress adaptive anticancer immunity. Preclinical studies across multiple cancer types show that AR inhibition enhances T cell function and sensitizes tumors to immune checkpoint inhibition. However, recent Phase 3 trials combining AR suppression with immune checkpoint blockade in prostate cancer (PCa) failed to demonstrate clinical benefit. We discuss these developments and summarize recent studies defining the role of AR signaling in anticancer immunity. We propose strategies to translate emerging insights into rational trial designs that optimize the integration of AR suppression with immunotherapy.
    Keywords:  androgen deprivation therapy; androgen receptor; cancer immunotherapy; immune checkpoint blockade; sex-based differences in cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2025.11.003
  22. iScience. 2025 Dec 19. 28(12): 113931
    PROCA11 early activation fuels prostate cancer neuroendocrine traits by regulating cell survival and migration.
    Rocco Cipolla, Marc Gabriel, Ugo Szachnowski, Zhimin Wang, Martina Romani, Giorgia Ianese Regin, Micaela Piemontese, Virginie Firlej, Marina Pinskaya, Antonin Morillon.
      Tumor plasticity drives the emergence of castration-resistant and neuroendocrine prostate cancer following androgen-deprivation therapy (ADT). Non-genetic determinants, including long non-coding (lnc)RNAs, preceding the acquisition of neuroendocrine traits, can disrupt androgen dependence and promote resistance. However, the precise transcriptome dynamics prior to therapy-induced neuroendocrine trans-differentiation remains unknown. Using a prostate cancer model mimicking the onset of castration-resistant and neuroendocrine phenotypes, we uncovered rapid lncRNA changes, with PROCA11 emerging as the most prominent. PROCA11 is highly expressed in advanced adenocarcinoma and neuroendocrine prostate cancer tumors. This predominantly nuclear lncRNA is rapidly activated upon hormone depletion and persists in neuroendocrine-like cells. PROCA11 promotes cell survival, proliferation, and motility by reducing apoptosis and enhancing adhesion, contributing to neuroendocrine traits. PROCA11 binds to the cell-cycle regulator CCAR2/DBC1 and to CTNNA1, controlling cell adhesion and cytoskeleton. We suggest that PROCA11 arises early during tumor plasticity and controls the development of castration-resistant and neuroendocrine phenotypes in prostate cancer.
    Keywords:  Biological sciences; Cancer; Epigenetics; Genomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113931
  23. Sci Rep. 2025 Nov 29.
    Cytotoxicity and cell cycle changes in prostate cancer cells with differing PSMA expression and p53 status after treatment with PSMA-targeting radioligand [212Pb]Pb-AB001.
    Vilde Yuli Stenberg, Rugile Liukaityte, Sandra Kvarsvik Kristiansen, Rina Wangen-Riise, Andrius Kleinauskas, Victoria Dunne, Asta Juzeniene.
      Targeted alpha therapy holds promise for treating advanced prostate cancer, but the interplay between prostate-specific membrane antigen (PSMA) expression, p53 status, and downstream cell fate remains poorly defined. This study evaluates the cytotoxic and cell cycle effects of the alpha-emitting radioligand [212Pb]Pb-AB001 in prostate cancer cell lines with differing PSMA expression and p53 status: C4-2 (PSMA+/TP53-wild-type) and PC-3 PIP (PSMA+++/ TP53-null). [212Pb]Pb-AB001 significantly inhibited proliferation and clonogenic survival in both cell lines in an activity-dependent manner. At 95% clonogenic inhibition, both cell lines exhibited G2-phase arrest, S-phase suppression and reduced mitotic entry on day 1. At higher activities, PC-3 PIP cells showed polyploidy, and features consistent with mitotic catastrophe and senescence. Cytotoxicity was more pronounced in C4-2 3D spheroid models than in 2D monolayers, suggesting contribution of crossfire and bystander effects. Total cell-bound activity, rather than added activity, better predicted radiotoxicity in both TP53-wild-type and TP53-null cell lines, indicating that its therapeutic effect is primarily governed by PSMA-mediated uptake rather than p53 status. These results support the therapeutic potential of [212Pb]Pb-AB001 across cells with varying TP53 status and suggest that combining [212Pb]Pb-AB001 with DNA repair or checkpoint inhibitors may enhance treatment efficacy.
    DOI:  https://doi.org/10.1038/s41598-025-29785-7
  24. Cancer Treat Rev. 2025 Nov 28. pii: S0305-7372(25)00183-5. [Epub ahead of print]142 103061
    Cellular senescence: A novel mechanism of therapeutic resistance in prostate cancer.
    Claire Lin, Matthew J Hadfield, Amol Rathore, Maximilian Pinho-Schwermann, Shengliang Zhang, Shaolei Lu, Petra den Hollander, Sendurai A Mani, Attila A Seyhan, Ariana Santopietro, Anthony Mega, Liang Cheng, Wafik S El-Deiry, Benedito A Carneiro.
      Prostate cancer (PCa) is a leading cause of cancer-related morbidity and mortality. Despite the efficacy of androgen deprivation therapy (ADT), patients with advanced PCa eventually progress to a lethal castration-resistant disease state. Cellular senescence represents a stable growth arrest induced by stress signaling cascades or cancer therapeutics, and escape from a senescent state may be implicated in the development of castration resistance. We discuss the mechanisms promoting cellular senescence in PCa and its contribution to therapeutic resistance to ADT, PARP inhibitors, chemotherapy, and radiation. We also summarize the potential of senolytic and senomorphic therapies in targeting senescent prostate cancer cells in the setting of therapy-induced senescence.
    DOI:  https://doi.org/10.1016/j.ctrv.2025.103061
  25. Metabol Open. 2025 Dec;28 100421
    Novel causal associations between plasma metabolites and prostate cancer risk revealed by mendelian randomization.
    Hanghang Chen, Huiduo Zhao, Bingxin Meng, Qi Liu.
       Background: Prostate cancer (PCa) is a major global health concern for men, yet its underlying metabolic mechanisms are not fully understood. Identifying causal metabolites could reveal novel pathways for risk assessment and prevention.
    Methods: We conducted a comprehensive two-sample Mendelian randomization (TSMR) study following STROBE-MR guidelines. Genetic instruments for plasma metabolites were derived from two independent sources, including the METSIM study, a cohort exclusively comprising Finnish men, and the Canadian Longitudinal Study on Aging (CLSA). Summary-level data for PCa were obtained from the PRACTICAL consortium and FinnGen. Inverse variance weighted (IVW) was the primary analysis method, supplemented by sensitivity analyses and Bayesian colocalization (coloc) to assess shared causal genetic variants, a key methodological strength enhancing causal inference.
    Results: Our analysis identified four plasma metabolites with a significant causal relationship with PCa risk. Ribitol was associated with a reduced risk, while N2,N5-diacetylornithine, N-acetylarginine, and N-acetylcitrulline were associated with an elevated risk. These findings were consistent across datasets and robust in sensitivity analyses. Colocalization analysis provided strong evidence (PP.H4 > 0.8) for a shared causal variant at the rs10201159 locus between N2,N5-diacetylornithine and PCa.
    Conclusion: This study provides robust genetic evidence supporting a causal role of specific plasma metabolites in prostate cancer development. The incorporation of a male-exclusive metabolomic dataset (METSIM) strengthens the validity of our findings for this male-specific cancer. These metabolites represent promising candidates for further mechanistic investigation into prostate cancer etiology and potential translation into clinical biomarkers.
    Keywords:  Male-specific cohort; Mendelian randomization; Plasma metabolites; Prostate cancer
    DOI:  https://doi.org/10.1016/j.metop.2025.100421
  26. PLoS One. 2025 ;20(12): e0338407
    Identification and validation of palmitoylation-related signature genes based on machine learning for prostate cancer.
    Qijun Wo, Jiafeng Shou, Jun Shi, Lei Shi, YunKai Yang, Yifan Wang, Liping Xie.
      Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with challenges in diagnosis and treatment due to tumor heterogeneity. This study identifies palmitoylation-related signature genes as potential diagnostic and therapeutic targets. Integrating GEO datasets, six differentially expressed genes (DEGs) linked to palmitoylation were identified. Machine learning algorithms (LASSO, RF, SVM) selected three core genes: TRPM4, LAMB3, and APOE. A diagnostic model based on these genes achieved an AUC of 0.929, demonstrating robust accuracy in distinguishing PCa from normal tissues. Functional analysis revealed roles in lipid metabolism and immune modulation, with ssGSEA highlighting correlations between key genes and immune cell infiltration. Experimental validation showed that LAMB3 overexpression suppressed PCa cell proliferation, migration, and invasion, while knockdown enhanced these processes. Molecular docking identified diethylstilbestrol as a potential therapeutic agent targeting LAMB3 and APOE. These findings emphasize the clinical relevance of palmitoylation-related genes in PCa diagnosis and therapy, offering novel biomarkers and insights for personalized treatment strategies.
    DOI:  https://doi.org/10.1371/journal.pone.0338407
  27. Cancer Lett. 2025 Nov 29. pii: S0304-3835(25)00755-4. [Epub ahead of print]639 218183
    Overcoming radioresistance in prostate cancer by targeting DNA damage repair.
    Ana Catarina Matos, Maria Lima, Vera Miranda-Gonçalves, Stefano Indraccolo, Carmen Jerónimo, Lucília Saraiva.
      Prostate cancer (PCa) remains one of the most prevalent malignancies among men, with radiotherapy (RT) serving as a cornerstone of treatment. However, radioresistance (RR) remains a major clinical challenge, contributing to treatment failure, disease recurrence, and poor prognosis. A major driver of RR is the enhanced DNA damage repair (DDR) ability of PCa cells, which allows them to evade RT-induced cell death. This review critically examines the molecular basis of RR in PCa, with particular focus on DDR pathways. We address the role of key genetic alterations, including mutations in BRCA2, ATM, and PARP1, on RT response, highlighting their potential as therapeutic targets to overcome RR. We further explore the interplay of DDR inhibition with androgen receptor (AR) signaling and its ability to potentiate antitumor immunity through activation of the cGAS-STING pathway, type I interferon production, and regulation of immune checkpoints. By leveraging insights into DDR mechanisms and therapeutic opportunities, this review provides a comprehensive perspective to enhance RT efficacy and improve clinical outcomes in PCa patients.
    Keywords:  DNA damage repair; Prostate cancer; Radioresistance; Targeted therapy
    DOI:  https://doi.org/10.1016/j.canlet.2025.218183
  28. Front Nutr. 2025 ;12 1630437
    Associations of specific food sources of dietary fat with prostate cancer incidence and mortality: results from a large prospective cohort.
    Yong-Xin Fu, Zi Ye, Ya-Dong Li, Ning Liu, Xue-Song Chen, Xiao-Liang Jiang, Ke Li.
       Background: Although fat intake has been implicated in prostate cancer (PCa) risk, the specific impact of dietary fat from specific food sources on PCa susceptibility in United States populations remains unclear.
    Methods: This prospective cohort included 49,424 men from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox proportional hazards regression was used to evaluate the risk of PCa incidence and mortality. Subgroup and sensitivity analyses were performed to investigate the potential effect modifiers.
    Results: During follow-up, we documented 4,308 incident cases of PCa, of whom 392 died from PCa. Total amount and specific types of fat intakes were not associated with PCa incidence and mortality. When considering available food sources, a greater intake of fat from dairy (HR Q4vs.Q1:1.13; 95% CI: 1.02-1.25; P trend = 0.069) and saturated fatty acids (SFAs) from dairy (HR Q4vs.Q1:1.12; 95% CI: 1.01-1.24; P trend = 0.059) was associated with a higher incidence of PCa in a linear dose-response association (all P non - linearity >0.05). However, a greater intake of plant-based monounsaturated fatty acids (MUFAs; HR Q4vs.Q1: 0.67; 95% CI: 0.48-0.94; P trend = 0.023), plant-based SFAs (HR Q4vs.Q1:0.65; 95% CI: 0.47-0.91; P trend = 0.026) and polyunsaturated fatty acids (PUFAs) from fish (HR Q4vs.Q1: 0.48; 95% CI: 0.48-0.87; P trend = 0.005) was associated with a decreased PCa mortality in a non-linear dose-response relationships (all P non - linearity < 0.05). The reliability of these results was supported by sensitivity and subgroup analyses.
    Conclusion: These findings demonstrate that the specific food sources of fat rather than total amount were significantly associated with PCa incidence and mortality.
    Keywords:  cancer prevention; fat and fatty acids; prospective cohort; prostate cancer (PCa); risk factor
    DOI:  https://doi.org/10.3389/fnut.2025.1630437
  29. NPJ Precis Oncol. 2025 Dec 01.
    Androgen receptor splice variant expression and prostate cancer recurrence after salvage therapy.
    David J Konieczkowski, Keisuke Otani, Zoe Guan, Michael R Drumm, Yukako Otani, Priscilla Oluwakemi Badusi, Ella H Chung, Shulin Wu, Elai Davicioni, Philip J Saylor, Chin-Lee Wu, Jason A Efstathiou, David T Miyamoto.
      Prostate cancer is driven by androgen receptor (AR) signaling, and radiotherapy (RT) with or without androgen deprivation therapy (ADT) offers a second opportunity at cure for men with local or biochemical recurrence after prostatectomy. In the metastatic setting, AR RNA splice variants (ARVs), including ligand-independent AR-V7, modulate ADT response and tumor radiosensitivity. Here, we hypothesized that ARVs in primary prostate cancer may likewise modulate response to subsequent salvage RT+ADT. We performed ultra-deep RNA-seq of the AR transcript pool from prostatectomy specimens from 43 men who later received salvage RT+ADT. Eighty-six percent of patients had detectable ARVs (median 3, range 0-12). Of the thirty-two unique ARVs detected, only AR-V7 (present in 14% of patients) was associated with outcomes after salvage RT+ADT (HR for second biochemical failure, 6.2, 95% CI 2.3-16.5, p=0.0003). These results suggest for the first time that AR-V7 may modulate outcomes for localized in addition to metastatic prostate cancer.
    DOI:  https://doi.org/10.1038/s41698-025-01201-3
  30. Case Rep Oncol. 2025 Jan-Dec;18(1):18(1): 1425-1431
    High-Risk Prostate Cancer in a Patient with Untreated Prolactinoma and Castrate-Level Testosterone Suppression: A Case Report.
    Tara A Seibert, Afreen Shariff, Hannah D McManus.
       Introduction: Prolactinomas can induce castrate-level testosterone suppression by dysregulating the hypothalamic-pituitary-gonadal axis. While hypogonadism typically confers a reduced risk for prostate cancer (PCa), malignancy can still occur and may arise via nonclassical pathways of carcinogenesis. Special consideration must be given when initiating treatment for patients with concurrent prolactinoma and PCa due to the complex hormonal interplay between prolactin and testosterone.
    Case Presentation: A man in his 60s was diagnosed with localized high-risk PCa in the setting of castrate-level testosterone suppression mediated by an untreated prolactinoma. Following consistent treatment with a dopamine receptor agonist, testosterone levels normalized. PCa was managed with external beam radiotherapy and androgen deprivation therapy (ADT), initially with a gonadotropin-releasing hormone (GnRH) antagonist to avoid the flare phenomenon, and now with a GnRH agonist. Trends of prolactin, testosterone, and prostate-specific antigen (PSA) levels throughout his clinical course are illustrated alongside the case presentation.
    Conclusion: Patients with prolactinoma-induced hypogonadism remain at risk for PCa. Dopamine agonists for treatment of prolactinoma may worsen PCa due to testosterone rebound; GnRH agonists for treatment of PCa may precipitate pituitary apoplexy in patients with preexisting pituitary adenoma. GnRH antagonists may be a theoretically safer alternative. Cautious and tailored selection of therapy alongside close clinical monitoring are essential to optimize care of this complex patient population.
    Keywords:  Androgen deprivation therapy; Hypogonadism; Pituitary apoplexy; Prolactinoma; Prostate cancer
    DOI:  https://doi.org/10.1159/000548162
  31. Arch Esp Urol. 2025 Nov;78(9): 1132-1142
    Metabolomics in Prostate Cancer: A Minimally Invasive Method Using Urine after Prostatic Massage to Predict Gleason Grade.
    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: In this study, biomarkers that can predict prostate cancer with a Gleason grade of 8 or higher were explored through nuclear magnetic resonance (NMR).
    METHODS: Patients scheduled for transrectal prostate biopsy were enrolled, and urine samples were collected after prostate massage. Patients with cancer were categorised as having Gleason grades of 6-7 or ≥8. All spectra were acquired using a Bruker Avance III DRX 600 spectrometer. For statistical analysis, univariate and multivariate analyses were conducted using metabolites and clinical variables, and the presence of tumours with Gleason grades of ≥8 was predicted.
    RESULTS: Data were obtained from 107 patients with prostate cancer: 73 (68.2%) with Gleason grades of 6-7 and 34 (31.8%) with Gleason grades of ≥8. A predictive model incorporating the 29 most significant metabolites identified through partial least squares-discriminant analysis was established. Suspicious digital rectal examination (DRE) results were considered. The model predicted a Gleason grade of ≥8, demonstrating an area under the curve of 0.92, sensitivity of 82%, specificity of 92%, positive predictive value of 84% and negative predictive value of 90%. Metabolites associated with amino acid metabolism and glycolysis were prominent in this model.
    CONCLUSIONS: Our study demonstrates that a model combining urinary metabolites with clinical data, specifically DRE findings, can effectively stratify risk in patients with biopsy-confirmed prostate cancer according to Gleason grade. Metabolites linked to glycolysis and amino acid metabolism were particularly relevant. This minimally invasive approach may assist clinical decision-making, although validation in larger multi-centre cohorts is required to confirm its robustness and generalisability.
    Keywords:  Gleason grade; biomarker; metabolomics; prostate cancer
    DOI:  https://doi.org/10.56434/j.arch.esp.urol.20257809.148
  32. Ann Surg Oncol. 2025 Dec 06.
    ASO Author Reflections: Shifting Age Demographics in Prostate Cancer Surgery: Insights from 17 Years of German Data.
    Martin Baunacke, Johannes Huber, Lennard Haak, Christian Thomas, Christer Groeben.
      
    DOI:  https://doi.org/10.1245/s10434-025-18827-z
  33. Chem Biodivers. 2025 Dec 03. e02681
    Real-Time Antiproliferative Activity of Carthamus tinctorius L. (Safflower) Against PC3 and C6 Cell Lines: A Correlative Chemical Profile Assessment.
    Muhammed Altun, Ali Rıza Tüfekçi, Melike Demirdağ Yağci.
      In this study, Carthamus tinctorius was separated into distinct parts (flower [F], stem-leaf [SL], and root [R]) and subjected to two different extraction protocols (water-ethyl acetate [WEA] and methanol-chloroform [MC]). The chemical profiles of the extracts were comprehensively characterized using HPLC-TOF/MS. Analytical results identified p-coumaric acid as the predominant compound in the WEA, whereas syringic acid was found to be the major constituent in the MC extracts. The antiproliferative activities of the extracts were assessed in the xCELLigence real-time cell analysis (RTCA) SP system on human prostate cancer (PC3) and rat glioma (C6) cell lines. RWEA showed the strongest antiproliferative activity against PC3 cells (IC50 = 21.044 µg/mL), whereas SLWEA was most effective on C6 cells (IC50 = 12.759 µg/mL). This study offers novel and significant insights into the bioactive constituents of C. tinctorius by presenting, for the first time in real-time analyses, compelling evidence of its potent antiproliferative activity against PC3 and C6 cell lines.
    Keywords:  Carthamus tinctorius L.; HPLC–TOF/MS; antiproliferative activity; phenolic compounds; real‐time cell analysis
    DOI:  https://doi.org/10.1002/cbdv.202502681
  34. Front Endocrinol (Lausanne). 2025 ;16 1737201
    Editorial: New potential biomarkers and cellular strategies for the study of prostate cancer and testicular cancer cells.
    Sabrina Bossio, Anna Grazia Recchia, Jorge Adrián Ramírez De Arellano Sánchez.
      
    Keywords:  epigenetic regulation; immunotherapeutic approaches; molecular mechanisms; precision medicine; prostate cancer (PCa); testicular germ cell tumors (TGCTs); tumor progression
    DOI:  https://doi.org/10.3389/fendo.2025.1737201
  35. BMC Urol. 2025 Dec 05.
    Preoperative predictors about lymph node metastasis and biochemical recurrence in high-risk prostate cancer patients: a clinic pathological retrospective study.
    Chuanyu Wang, Guipeng Wang, Lihua Xiao, Haotian Du, Youcheng Xu, Shengxian Li, Xuecheng Yang.
      
    Keywords:  Biochemical recurrence; Lymph node metastasis; Prognostic factors; Prostate cancer; Ratio of high grade cores
    DOI:  https://doi.org/10.1186/s12894-025-01999-x
  36. Chem Biodivers. 2025 Dec 05. e01594
    Aminated Quinolinequinones With EDG(s) as a Prostate Cancer Inhibitor: Mechanistic Insights and Pharmacokinetic Limitations.
    Ayse Tarbin Jannuzzi, Ayse Mine Yilmaz, Abanish Biswas, Subodh Mondal, Vinay N Basavanakatti, Hatice Yıldırım, Mahmut Yıldız, Nilüfer Bayrak, Venkatesan Jayaprakash, Amaç Fatih TuYuN.
      In this study, we investigated the effects of aminated quinolinequinones (AQQ6-16) on cancer cell lines previously selected by the National Cancer Institute (NCI). Analysis of the NCI-60 screening data from the Developmental Therapeutics Program (DTP) of the NCI revealed that 11 AQQs exhibited significant growth inhibitory activity across multiple cancer cell lines and were subsequently advanced to the five-dose assay. Most AQQs effectively suppressed the proliferation of all leukemia cell lines in the single-dose and five-dose assays. Encouraged by these findings, we further examined the cytotoxic effects of selected AQQs (AQQ6 and AQQ9) in three human cancer cell lines, including HCT-116 (colon cancer), DU-145 (prostate cancer), and MDA-MB-231 (breast cancer), as well as in a normal cell line (HUVEC). Among the tested compounds, AQQ6 demonstrated the highest potency against DU-145 cells, with an IC50 value of 3.13 ± 0.15 µM. To gain mechanistic insights, the effects of AQQ6 on apoptosis, cell cycle distribution, and oxidative stress were evaluated. AQQ6 inhibited DU-145 cell proliferation by inducing apoptosis/necrosis, accompanied by G0/G1 phase cell cycle arrest. In metabolic stability assays using human liver microsomes, AQQ6 exhibited relatively low intrinsic clearance (Clint) and an improved half-life (T1/2) compared to verapamil. However, pharmacokinetic studies in rats indicated poor oral bioavailability (%F = 4.2), likely due to extensive hepatic metabolism in rat liver microsomes. Molecular dynamics simulations targeting MAPK8, the protein likely involved in AQQ6 activity, were conducted to elucidate molecular-level binding interactions.
    Keywords:  ADME; breast cancer; colon cancer; cytotoxicity; molecular dynamics; prostate cancer
    DOI:  https://doi.org/10.1002/cbdv.202501594
  37. Biomed Pharmacother. 2025 Dec 02. pii: S0753-3322(25)01043-1. [Epub ahead of print]193 118849
    Androgen receptor blockade and its effect on PSMA-localization in prostate cancer: Implications for radioligand therapy.
    Flavien Devaux, Kareem Beltagi, Thomas Frank Ermler, Sven Gerlach, Anna Herrmann, Jennifer Kranz, Radu Alexa, Agnieszka Morgenroth, Andreas Theodor Josef Vogg, Laura Schäfer, Najaf Mammadbayli, Matthias Saar, Marco Hoffmann.
      Prostate-specific membrane antigen (PSMA) is a key target for radioligand therapy (RLT) in prostate cancer (PCa). However, its subcellular localization is critical, as ligand uptake via PSMA mediated endocytosis influences therapeutic efficacy. This study examines the impact of androgen receptor blockade (ARB) on PSMA membrane trafficking and its modulation by endoplasmic reticulum (ER) stress in PCa cell-lines and tissue samples from ARB pretreated patients. LNCaP and VCaP cells were treated with enzalutamide (0.1-10 µM) for 1-7 days. PSMA localization was assessed via optical sectioning, fluorescence profiling, membrane protein isolation, and Western blotting. ER stress markers BiP and PERK were quantified. To evaluate PSMA targeting and therapeutic response, cellular uptake of [¹ ⁷⁷Lu]Lu-PSMA-Imaging and Therapy (I&T) was quantified via gamma counting, while treatment efficacy was assessed through MTS and Live/Dead-staining. ARB significantly increased PSMA membrane localization, with a maximal effect at 1 µM (7 days) or 10 µM (4 days). Optimized conditions led to a fourfold increase in PSMA uptake in LNCaP and a twofold increase in VCaP. However, prolonged or high dose ARB induced ER stress, evidenced by BiP/PERK upregulation, correlating with reduced PSMA trafficking in vitro and in vivo and diminished [177Lu]Lu-PSMA-I&T uptake in vitro. Optimized ARB-RLT combinations significantly enhanced therapeutic efficacy. These findings highlight ARB's potential to enhance RLT-efficiency by optimizing PSMA membrane localization. Crucially, ER stress markers correlated with PSMA trafficking, suggesting serum-based profiling could enable individualized ARB adjustments. Future studies should validate these biomarkers to establish personalized ARB-RLT strategies for improved clinical outcomes.
    Keywords:  Androgen; Membrane; PSMA; Prostate; Radioligand
    DOI:  https://doi.org/10.1016/j.biopha.2025.118849
  38. Food Chem Toxicol. 2025 Nov 27. pii: S0278-6915(25)00638-6. [Epub ahead of print]208 115870
    High-fat diet exacerbates risk of prostate cancer in arecoline-induced prostatic hyperplasia via modulation of periprostatic adipose tissues in rats.
    Kunal Pramanik, Ananya Banerjee, Niloy Chatterjee, Alok Ghosh, Pubali Dhar, Mitali Chatterjee, Sanghamitra Sengupta, Urmi Chatterji.
      Albeit their nutritional and culinary value, the US-FDA has classified several natural foods, like certain fruits, nuts, mushrooms, shellfish, raw meats, as hazardous because of toxic chemicals produced within them. However, the precise mechanisms and extent of their toxicological impacts remain incompletely understood. Unawares, humans regularly consume such substances, leading to debilitating effects on their physiology and health. Likewise, lifestyle habits, like chronic chewing of betel nuts, are established contributors to physiological dysregulation. This study investigates the synergistic effects of arecoline (10 mg/kg) and HFD on metabolic reprogramming and disease trajectories in the prostate gland and surrounding adipose tissues using an animal model. Histopathology delineated deteriorating morphological architecture of interscapular BAT, PPAT, and prostate in arecoline and HFD co-administered animals. Arecoline-induced adipocyte hypertrophy was markedly exacerbated in HFD-fed rats, as evidenced by whitening of BAT, aberrant lipid composition, enhanced fatty acid biosynthesis, and reduced mitochondrial DNA copy numbers in BAT and PPAT. Concurrently, prostate tissues exhibit accumulation of saturated fatty acids, upregulation of key lipogenic and lipolytic enzymes, increased cellular proliferation, activation of AR and TGF-β/SMAD oncogenic signaling pathways, elevated pro-inflammatory cytokines, VEGF and EMT-associated factors. These observations culminate in pronounced epithelial hyperplasia and emergence of early-grade carcinoma in prostate glands. Our findings underscore that perilous synergy between arecoline and HFD drives an immune-metabolic remodelling in the prostate-adipose microenvironment. On a therapeutic standpoint, the study underscores lipid metabolism to be a potential target for prostate health intervention, reinforcing the necessity of lifestyle modifications to counteract diet- and habit-induced metabolic disruptions.
    Keywords:  Arecoline; High-fat diet; Lipid metabolism; Mitochondrial DNA copy number; Periprostatic adipose tissue; Prostate; TGF-β
    DOI:  https://doi.org/10.1016/j.fct.2025.115870
  39. bioRxiv. 2025 Nov 23. pii: 2025.11.21.689851. [Epub ahead of print]
    Systematic characterization of cancer-associated SPOP mutants reveals novel and reprogrammable degradative activities.
    Alana G Caldwell, Harshil Parmar, Xiaokang Jin, Chen Zhou, Xiaoyu Zhang.
      Speckle-type POZ protein (SPOP) functions as the substrate adaptor of the Cullin3-RING ligase (CRL3) complex and is recurrently mutated in multiple cancer types. Among these, F102C and F133L are frequent prostate cancer mutations within the substrate-binding domain, yet their biochemical consequences remain incompletely understood. Using quantitative proteomics, we show that SPOP-F133L, unlike SPOP-F102C, retains degradative activity toward the nuclear basket proteins NUP153 and TPR, indicating substrate-dependent loss-of-function. Moreover, SPOP-F133L induces partial down-regulation of p53 through a CRL-dependent, post-translational mechanism, revealing a potential neo-substrate relationship. Finally, we demonstrate that both SPOP-F102C and SPOP-F133L support targeted protein degradation (TPD) in an engineered cellular system. These findings define the degradative capacities of SPOP mutants and highlight opportunities to repurpose these variants as mutant-selective E3 ligases for therapeutic applications.
    DOI:  https://doi.org/10.1101/2025.11.21.689851
  40. J Exp Clin Cancer Res. 2025 Dec 01.
    Unraveling the YAP1-TGFβ1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts.
    Elena Brunner, Elisabeth Damisch, Melanie Emma Groninger, Francesco Baschieri, François Tyckaert, Lukas Nommensen, Lucy Neumann, Georgios Fotakis, Zlatko Trajanoski, Georg Schäfer, Martin Puhr, Isabel Heidegger, Michael J Ausserlechner, Christian Ploner, Sofia Karkampouna, Francesco Bonollo, Marianna Kruithof-de Julio, Natalie Sampson.
      
    Keywords:  Autophagy; CAF; Patient-derived xenograft; Stroma; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-025-03578-2
  41. Int J Oncol. 2026 Feb;pii: 15. [Epub ahead of print]68(2):
    Emerging biomarkers in prostate cancer diagnosis and treatment: Insights into genetic, RNA and metabolic markers (Review).
    Yuanshe Huang, Jingxin Mao, Xiaobing Li.
      Prostate cancer remains one of the most prevalent malignancies and a major cause of cancer‑related mortality among men worldwide. Despite widespread use of prostate‑specific antigen testing, current diagnostic approaches suffer from low specificity and limited ability to distinguish between indolent and aggressive disease, resulting in overdiagnosis and overtreatment. Advances in molecular biology, genomics and metabolomics have led to the identification of novel biomarkers that have potential for improving the precision of prostate cancer diagnosis, prognosis and therapy. The present review provides a comprehensive overview of emerging prostate cancer biomarkers, including genetic (such as BRCA1/2, HOXB13 and PTEN), RNA‑based (such as PCA3 and miRNAs), metabolic (such as citric acid and polyamines) and methylation markers (such as GSTP1, APC and RASSF1A). These biomarkers not only enhance diagnostic accuracy but also facilitate risk stratification, prediction of therapeutic response and real‑time disease monitoring through liquid biopsy technologies. Moreover, integrating multi‑omics data with artificial intelligence and machine learning may further improve early detection and personalized treatment strategies. Overall, the development and clinical implementation of these biomarkers represent a transformative step toward precision medicine in prostate cancer, enabling earlier diagnosis, optimized therapy selection and improved patient outcomes.
    Keywords:  RNA biomarkers; biomarkers; liquid biopsy; methylation markers; multi‑omics; precision medicine; prostate cancer
    DOI:  https://doi.org/10.3892/ijo.2025.5828
  42. Cancer Genet. 2025 Nov 26. pii: S2210-7762(25)00240-6. [Epub ahead of print]300-301 25-27
    Altered expression of nucleotide excision repair genes ERCC2 and ERCC5 in prostate cancer tissues.
    Adila Abdulla, Vahid Rouhi, Sanaz Habibi, Hikmet Koseoglu, Emre Ari, Mehmet Guven.
      Disruptions in the genome's maintenance capacity pose a problem for every organism, potentially leading to carcinogenesis. Therefore, it is extremely important to determine the relationship between factors affecting genome stability and disease pathogenesis. Nucleotide Excision Repair (NER) is a key mechanism maintaining genomic stability, repairing major DNA lesions caused by environmental factors like UV light, chemical agents, and cigarette smoke. In our study, we investigated the role of two NER-related genes, XPD/ERCC2 and XPG/ERCC5, in the pathogenesis of prostate cancer and their relationship with patients' clinical and pathological findings. Gene expression of ERCC2 and ERCC5 was analyzed using the RT-PCR method on pathologically verified matched tumor and normal biopsy samples collected from 50 prostate cancer patients. ERCC5 expression was significantly upregulated by 5.94-fold in tumor tissues (p = 0.005), whereas ERCC2 exhibited a non-significant 2.25-fold increase (p = 0.12). There was no significant correlation between ERCC2 and ERCC5 expression levels. Furthermore, the expression of both genes remained unaffected by key clinical variables, including smoking, diabetes, hypertension, nodule presence, PSA level, Gleason, and PIRADS scores. The high expression of the ERCC5 gene in prostate cancer suggests that the NER pathway plays a significant role in this disease, and that ERCC5 may be considered a potential biomarker.
    Keywords:  DNA repair; Nucleotide excision repair; Prostate cancer; XPD/ERCC2; XPG/ERCC5
    DOI:  https://doi.org/10.1016/j.cancergen.2025.11.011
  43. Eur Urol Oncol. 2025 Dec 04. pii: S2588-9311(25)00325-6. [Epub ahead of print]
    Germline DNA Repair and Immune-metabolic Alterations Suggest a Potentially Distinct Form of Early-onset Prostate Cancer in Men of African Descent.
    Jean-Samuel Loger, Emeline Colomba, Alexis Vallard, Mylène Annonay, Sarah Malsa, Taina Labeau, Sylviane Ulric-Gervaise, Sabrina Pennont, Ainara Martin-Martinez, Mickaelle Rose, Odile Béra, Sylvie Merle, Celine Minchaca, Johan Rose-Dite-Modestine, Régine Marlin.
       BACKGROUND AND OBJECTIVE: Early-onset prostate cancer (PCa) is more frequent in men of African descent; yet, the biological mechanisms underlying susceptibility remain unclear. While most germline studies have focused on DNA repair genes (DRGs), alternative pathways may also contribute to tumor initiation, which we aim to assess in this study.
    METHODS: We analyzed 71 Afro-Caribbean men diagnosed with early-onset PCa (≤51 yr old for sporadic cases and ≤56 yr old for familial cases). Germline testing combined targeted sequencing of 175 genes-including major DRGs-with whole-exome sequencing in patients without DRG alterations. Variants were filtered for rarity (minor allele frequency <0.01 in African populations) and their clinical classification as pathogenic or likely pathogenic (P/LP; ClinVar and ACMG/AMP guidelines). Genes were grouped by biological function.
    KEY FINDINGS AND LIMITATIONS: Rare P/LP germline variants were identified in 37 patients (52.1%). Among these patients, ten carried a DRG variant (including one also harboring HOXB13 X285K), 26 carried at least one variant in immune-metabolic pathways (one also with HOXB13 X285K), and one carried only HOXB13 X285K. Recurrent truncating variants were found in FLG, PGAM2, and TYRP1. Although no statistically significant association was observed between molecular subgroups and clinical aggressiveness, DRG variants tended to occur in more high-risk tumors, whereas immune-metabolic alterations were more frequent in patients with low- or intermediate-risk disease.
    CONCLUSIONS AND CLINICAL IMPLICATIONS: This study reveals a broader germline landscape in early-onset PCa among men of African descent. Inherited immune-metabolic dysfunction may contribute to tumorigenesis through microenvironmental dysregulation, highlighting novel pathways for investigation in larger and ancestrally diverse cohorts.
    Keywords:  African ancestry; DNA repair genes; Early onset; Germline variants; Innate immunity; Metabolic pathways; Prostate cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.euo.2025.11.015
  44. Eur Urol Focus. 2025 Dec 04. pii: S2405-4569(25)00345-1. [Epub ahead of print]
    Prostate Cancer: Current Status of Novel Molecular Imaging and Future Prospects.
    Donald C Wunsch, Baris Turkbey.
      Molecular imaging has become an essential component of diagnosis, treatment planning, and monitoring in prostate cancer. Prostate-specific membrane antigen-targeted positron emission tomography is now the most widely used molecular imaging approach in prostate cancer. This mini review provides an overview of the status and prospects of novel molecular imaging in prostate cancer management. PATIENT SUMMARY: Recent years have seen improvements in scans for prostate cancer. Our mini review focuses on PSMA PET (prostate-specific membrane antigen positron emission tomography) for diagnosis of prostate cancer, especially metastatic disease, and treatment planning and monitoring. The results show that in the right setting, PSMA PET has benefits in improving outcomes for patients with prostate cancer.
    Keywords:  Biochemical recurrence; Molecular imaging; Prostate cancer; Prostate-specific membrane antigen; Staging
    DOI:  https://doi.org/10.1016/j.euf.2025.11.013
  45. bioRxiv. 2025 Nov 21. pii: 2025.11.20.689623. [Epub ahead of print]
    How small molecules stabilize oligomers of a phase-separating disordered protein.
    Jiaqi Zhu, Thomas R Sisk, Borja Mateos, Stasė Bielskutė-Garcia, Xavier Salvatella, Paul Robustelli.
      Small molecule inhibitors of the intrinsically disordered androgen receptor activation domain have been tested in clinical trials for the treatment of castration-resistant prostate cancer. These compounds have been shown to stabilize oligomeric forms of the androgen receptor activation domain in solution and alter the properties of androgen receptor condensates. The molecular mechanisms by which small molecules modulate these processes have been poorly understood in atomic detail. Here, we use long-timescale all-atom molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy to determine how small molecules stabilize highly dynamic, heterogeneous intermolecular interfaces that mediate oligomerization of the androgen receptor activation domain. The mechanisms determined here explain the relative potencies of androgen receptor activation domain inhibitors and suggest general strategies for designing small molecules that target oligomeric and, potentially, condensed forms of intrinsically disordered proteins.
    DOI:  https://doi.org/10.1101/2025.11.20.689623
  46. BJUI Compass. 2025 Dec;6(12): e70101
    Multivariable model integrating PHI and mpMRI for detecting csPCa in biopsy-naïve men.
    Mario Dominguez Esteban, Ester Fernandez Guzman, Enrique Ramos Barselo, Ernesto Herrero Blanco, Sergio Zubillaga Guerrero, Roberto Ballestero Diego, Alejandro Fernandez Florez, Jose Javier Gomez Roman, Jaime Garcia Herrero, Marina Sanchez Gil, Guillermo Velilla Diez, Felix Campos Juanatey, Maria Teresa Garcia Unzueta, Jose Luis Gutierrez Baños.
       Background: The integration of blood-based biomarkers and multiparametric magnetic resonance imaging (mpMRI) has been proposed to improve prostate cancer (PCa) diagnosis. However, few validated models combine both tools to support risk-adapted clinical decision-making.
    Objective: The study's aim is to evaluate and internally validate a multivariable model integrating clinical, analytical and imaging parameters-including the Prostate Health Index (PHI) and mpMRI-for predicting clinically significant prostate cancer (csPCa) in biopsy-naïve men.
    Design setting and participants: This prospective observational study included 183 biopsy-naïve men aged 50-75 years with PSA levels of 4-10 ng/mL and/or abnormal digital rectal examination. All patients underwent PHI testing, and 47.5% received prebiopsy mpMRI. All underwent systematic biopsy; targeted cognitive fusion biopsy was performed for PIRADS ≥ 3 lesions.
    Outcome measurements and statistical analysis: A multivariable logistic regression model was constructed using PHI, PSA density, PSA free/total ratio, PIRADS score and age. The model was internally validated with bootstrap resampling and converted into a clinical nomogram. Diagnostic accuracy (AUC, sensitivity, specificity, NPV and PPV) was assessed and compared with simplified strategies using PHI or PIRADS alone, as well as a sequential approach (PHI → PIRADS).
    Results and limitations: The model achieved an AUC of 0.841 (95% CI 0.76-0.91), with 100% sensitivity and 66.7% specificity for csPCa in the mpMRI cohort at the optimal 17% risk threshold (65.5 points). It safely avoided 49.4% of biopsies without missing any csPCa cases. Simpler strategies using PHI or PIRADS alone showed lower efficiency, particularly in balancing sensitivity and biopsy reduction. As an additional analysis, the PHI-mpMRI nomogram by Siddiqui et al. (2023) was externally validated in our cohort, confirming robust diagnostic accuracy (AUC 0.89, 95% CI 0.82-0.95). Limitations include the modest size of the mpMRI cohort and the historical nature of recruitment (2014-2018), although PHI and mpMRI remain standard in contemporary practice.
    Conclusions: This model accurately predicts csPCa and outperforms individual tools such as PHI or PIRADS alone. Its application may improve diagnostic efficiency and reduce unnecessary procedures.
    Patient summary: A model combining a blood test (PHI) and MRI can help avoid unnecessary prostate biopsies while reliably detecting aggressive cancers.
    Keywords:  PHI; PIRADS; clinically significant; mpMRI; multivariable model; nomogram; prostate cancer; prostate health index; risk stratification
    DOI:  https://doi.org/10.1002/bco2.70101
  47. Int J Radiat Oncol Biol Phys. 2025 Nov 28. pii: S0360-3016(25)06341-2. [Epub ahead of print]
    Enhanced Antitumor Efficacy of 225Ac-NM600 Compared to 177Lu-NM600 in Murine Prostate Cancer Models.
    Carolina A Ferreira, Hemanth K Potluri, Ahmed A Tantawy, Christopher Massey, Joseph J Grudzinski, Amanda Carston, Nathan Clemons, Malick Bio Idrissou, Anna Thickens, Zachary Rosenkrans, Cynthia Choi, Caroline Kerr, Anatoly Pinchuk, Ohyun Kwon, Justin J Jeffery, Bryan Bednarz, Zachary Morris, Jamey Weichert, Douglas G McNeel, Reinier Hernandez.
       RATIONALE: Several individuals with Prostate Cancer (PCa) develop metastatic castration-resistant prostate cancer (mCRPC) after current treatment, that has a death rate of more than 50%. Although many approaches target mCRPC and show promising results, mCRPC is still incurable. Therefore, we aimed to investigate the efficacy and dosimetry of alpha (225Ac) versus beta (177Lu) radiopharmaceutical therapy (RPT) using NM600 in murine prostate cancer models.
    METHODS: NM600 was radiolabeled with 177Lu and 225Ac for targeted radionuclide therapy, and therapeutic efficacy. 177Lu-NM600 SPECT/CT imaging was conducted on syngeneic Myc-CaP and TRAMP-C1 prostate cancer mouse models, and they were administered 7.4 MBq of 177Lu-NM600 in the tail vein. We calculated the dosimetry of 177Lu-NM600 therapy using the SPECT/CT imaging data and the biodistribution study. The complete blood count (CBC), comprehensive metabolic panel (CMP), and histology analysis were carried out to assess toxicity in Myc-CaP and TRAMP-C1-beering mice (n = 9), that were given 5.55 (low IA) or 18.5 MBq (high IA) of 177Lu-NM600, and 7.4 (low IA) or 18.5 KBq (high IA) of 225Ac-NM600. Finally, the overall survival and tumor growth rate were monitored for all groups.
    RESULTS: Both 225Ac/177Lu-NM600 demonstrated tumor-specific uptake and retention. 225Ac-NM600 exhibited superior antitumor effects and significantly improved overall survival compared to 177Lu-NM600 at similar doses. The enhanced efficacy of 225Ac-NM600 was attributed to its higher relative biological effectiveness. Toxicity studies revealed transient, dose-dependent hematological changes for both agents, with no significant long-term adverse effects.
    CONCLUSION: 225Ac-NM600 demonstrated enhanced antitumor efficacy compared to 177Lu-NM600 in murine prostate cancer models, with a favorable toxicity profile. These outcomes reveal a strong rationale for further developing alpha-emitting RPT agents for prostate cancer treatment.
    Keywords:  (225)Ac-NM600; Prostate Cancer; Radiopharmaceutical Therapy; SPECT/CT; Targeted Alpha Therapy
    DOI:  https://doi.org/10.1016/j.ijrobp.2025.09.072
  48. Front Cell Dev Biol. 2025 ;13 1685857
    Unravelling targeted therapy in prostate cancer: from molecular mechanisms to translational opportunities.
    Litong Wu, Junfeng Qiu, Zhiming Hong, Quan Wang, Qixin Li, Wenbin Zhou.
      Prostate cancer, ranking among the most prevalent malignancies in males worldwide, is undergoing a significant evolution in therapeutic paradigms from conventional approaches to precision medicine, with recent advances in targeted therapies offering novel strategic insights. This review delineates the molecular foundations of prostate carcinogenesis, elucidating pivotal domains including genetic mutations, hormonal regulation, tumor microenvironment dynamics, cell cycle dysregulation, epigenetic modifications, and tumor heterogeneity. Furthermore, we evaluate the clinical translation of targeted strategies such as AR signaling axis inhibition, PI3K/AKT/mTOR pathway modulation, DNA damage repair machinery exploitation, prostate-specific membrane antigen -directed interventions, and combinatorial immunotherapy. Concurrent challenges-AR-driven heterogeneity, adaptive drug resistance mechanisms, spliceosomal vulnerabilities, and scarcity of selective molecular targets-are critically analyzed. Notwithstanding these obstacles, targeted therapies exhibit considerable potential to enhance therapeutic efficacy while mitigating systemic toxicities, paving the way for more personalized and precision-oriented oncologic care. By underscoring the imperative to decode prostate cancer's molecular architecture, this work outlines future research priorities and advances a robust scientific framework for innovation in therapeutic development.
    Keywords:  PROTACs; androgen receptor; molecular mechanisms; prostate cancer; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2025.1685857
  49. Mol Imaging Biol. 2025 Dec 05.
    Staging Prostate Cancer with AI: A Comparative Study of Large Language Models and Expert Interpretation on PSMA PET-CT Reports.
    Rashad Ismayilov, Ayse Aktas, Esra Arzu Gencoglu, Arzu Oguz, Ozden Altundag, Zafer Akcali.
       PURPOSE: Accurate staging of prostate cancer is essential for therapeutic decision-making. While PSMA PET-CT reports offer rich clinical data, their unstructured format hinders large-scale analysis. Recent advances in large language models (LLMs) offer new opportunities to extract structured information from narrative radiology reports. However, their ability to perform multi-step clinical reasoning, particularly for cancer staging, remains underexplored.
    METHODS: In this feasibility study, 80 anonymized, Turkish-language PSMA PET-CT reports were independently interpreted by two LLMs-Gemini 2.5 Pro (Google) and ChatGPT 4o (OpenAI). Using a structured prompt containing an embedded knowledge base (AJCC/CHAARTED criteria) and few-shot examples, both LLMs generated classifications for T, N, M, and overall clinical stage/disease volume. Outputs were benchmarked against expert classifications by a senior nuclear medicine specialist. Performance was evaluated using accuracy, precision, recall, F1-score, and Cohen's kappa.
    RESULTS: For the composite task of classifying clinical stage and disease volume, Gemini 2.5 Pro achieved an accuracy of 93.8% (95% CI: 86.0-97.9) and a Cohen's kappa of 0.910 (95% CI: 0.834-0.986), while ChatGPT 4o achieved 91.3% accuracy (95% CI: 82.8-96.4) with a kappa of 0.874 (95% CI: 0.786-0.962). For T staging, Gemini showed a higher accuracy point estimate (95.0% [95% CI: 87.7-98.6] vs. 91.3% [95% CI: 82.8-96.4]), while both models excelled at the binary N and M classifications, achieving accuracies above 95% and kappa values indicating near-perfect agreement (κ > 0.900).
    CONCLUSIONS: LLMs, when guided by expert-informed prompt engineering, can accurately stage prostate cancer from free-text PSMA PET-CT reports and may serve as a powerful assistive tool for data automation, research acceleration, and quality assurance.
    Keywords:  Artificial intelligence; Cancer staging; Classification; Large language models; Natural language processing; PSMA PET-CT; Prostate cancer
    DOI:  https://doi.org/10.1007/s11307-025-02072-7
  50. NPJ Digit Med. 2025 Dec 03.
    Clinically informed intermediate reasoning enables generalizable prostate cancer prognostication through machine learning in limited settings.
    Jun Akatsuka, Kotaro Tsutsumi, Mami Takadate, Yasushi Numata, Hiromu Morikawa, Atsushi Marugame, Hayato Takeda, Yuki Endo, Yuka Toyama, Takayuki Takahashi, Kaori Ono, Junya Iwazaki, Ryuji Ohashi, Akira Shimizu, Tomoharu Kiyuna, Maki Ogura, Masao Ueki, Takuma Kato, Toshiyuki China, Mikio Sugimoto, Hisamitsu Ide, Naoto Sassa, Naonori Ueda, Shigeo Horie, Toyonori Tsuzuki, Go Kimura, Yukihiro Kondo, Yoichiro Yamamoto.
      Machine learning has shown promise in medical image classification. However, its generalizability remains challenging. Here, we show that data-efficient pre-surgical prognostication of prostate cancer from biopsy specimens is enabled by versatile feature extraction from whole-mount histopathology and a clinically informed intermediate reasoning step. With data from multiple institutions, our pipeline resolved dual-domain shifts across specimen types and institutions and achieved consistent external validation, reinforced by comprehensive analyses of generalizability. This highlights the robustness of our prognostic approach when compared to the Gleason grading system. We establish an equitable, interpretable, and clinically applicable framework, supporting actionable decisions for prognosis and treatment planning, even in limited real-world clinical environments.
    DOI:  https://doi.org/10.1038/s41746-025-02193-x
  51. Discov Oncol. 2025 Dec 03.
    Mendelian randomization analysis integrating GWAS and eQTL data identified potential regulatory genes associated with prostate cancer in neural cells.
    Jiahao Guo, Hao Xie, Quanting Yin, Changming Dong, Yufan Yang, Jiazi Cha, Jinshan Yang, Xinxin Li, Yue Li, Fuyi Xu, Chunhua Lin.
      
    Keywords:  Causal relationship; Mendelian randomization; Neural cell; Prostate cancer; eQTL
    DOI:  https://doi.org/10.1007/s12672-025-03711-9
  52. BMC Cancer. 2025 Dec 04.
    Updated dose-response meta-analysis of sexual activity and prostate cancer risk.
    Abouzar Raeisvandi, Sanaz Omidi, Massoumeh Javaheri, Hanieh Moradi, Jalal Poorolajal.
       BACKGROUND: This systematic review and meta-analysis aimed to update the evidence on how sexual activity factors, including frequency of intercourse, number of female sexual partners, age at first intercourse, and number of ejaculations and masturbations relate to prostate cancer.
    METHODS: We conducted a comprehensive search across PubMed, Web of Science, and Scopus up to October 19, 2025. We also reviewed existing study references for additional relevant research. To assess study consistency, we used I2 statistics. Publication bias was evaluated using Begg and Egger tests. Our analysis reported pooled odds ratios (OR) with 95% confidence intervals using a random-effects model. The research protocol was approved by PROSPERO, ID CRD42024549018.
    RESULTS: From 5,311 identified studies, 29 (315,193 participants) met the inclusion criteria. Positive but non-significant associations were observed between prostate cancer and more frequent sexual intercourse (OR = 1.02; 95% CI: 0.88, 1.18), a higher number of female partners (OR = 1.01; 95% CI: 0.90, 1.12), and masturbation frequency (OR = 1.12; 95% CI: 0.82, 1.54). Older age at first intercourse showed a negative but non-significant association (OR = 0.99; 95% CI: 0.90, 1.08), whereas higher ejaculation frequency demonstrated a significant protective effect (OR = 0.83; 95% CI: 0.77, 0.90).
    CONCLUSION: These findings suggest that most sexual behaviors are not significantly associated with prostate cancer risk. However, higher ejaculation frequency appears to have a protective effect. The results highlight the multifactorial nature of prostate cancer and emphasize the need for further research to clarify the role of sexual activity in disease prevention.
    Keywords:  Intercourse; Meta-analysis; Prostate cancer; Sexual activity; Sexual partners
    DOI:  https://doi.org/10.1186/s12885-025-15410-3
  53. Front Med (Lausanne). 2025 ;12 1713863
    Comparative analysis of ultrasound-guided magnetic resonance imaging-cognitive fusion transrectal versus transperineal prostate biopsy: a 10-year single-center retrospective analysis.
    Jincheng Luo, Jie Sun, Hui Wang, Cheng Yang.
       Objectives: Prostate cancer (PCa) remains a leading malignancy among men worldwide. The diagnostic approach, particularly the biopsy route and integration with imaging, is crucial for accuracy. This study aimed to directly compare the diagnostic efficacy and safety of two ultrasound-guided, MRI-cognitively fused prostate biopsy approaches using a consistent extended 12 + X-core sampling scheme: the transperineal (TPB) versus the transrectal (TRB) route.
    Methods: We conducted a comparative, retrospective analysis of 3,208 patients who underwent prostate biopsy at our institution between January 2015 and January 2024. Patients were categorized into two cohorts: a historical TRB cohort (n = 1,078) from 2015-2018 and a subsequent TPB cohort (n = 2,130) from 2018-2024. Crucially, both cohorts were investigated using an identical 12 + X-core protocol under MRI-cognitive fusion guidance. Pathological outcomes, PCa detection rates, and perioperative complications were systematically compared. Multivariable logistic regression was employed to identify predictors of PCa detection.
    Results: The TPB cohort demonstrated a significantly higher overall PCa detection rate (55.73% [1,187/2,130]) compared to the TRB cohort [50.46% (544/1,078); * p < 0.05]. Furthermore, TPB was associated with a superior safety profile, with minor complications (e.g., hematuria, low-grade fever, transient urinary symptoms) occurring in only 5.82% (124/2,130) of cases. Multivariable analysis confirmed established clinical predictors for PCa. Stratification of the detected cancers revealed that 1,701 patients (63.85%) were diagnosed with high-risk disease (Gleason score ≥8), outlining the distribution within our PCa population.
    Conclusion: In this comparative study, the ultrasound-guided TPB with MRI-cognitive fusion and a 12 + X-core protocol demonstrated superior diagnostic efficacy and a more favorable safety profile compared to the TRB. These findings support the adoption of the TPB approach as a preferred clinical strategy for prostate biopsy.
    Keywords:  complications; magnetic resonance imaging-cognitive fusion; prostate cancer; transperineal prostate biopsy; ultrasound-guided
    DOI:  https://doi.org/10.3389/fmed.2025.1713863
  54. Cent European J Urol. 2025 ;78(3): 255-262
    Prostate cancer diagnostics: the independent and combined roles of SelectMDx and mpMRI.
    Petrino-Cristian Călinoiu, Ovidiu-Cătălin Nechita, Daniel Bădescu, Cristian-Valentin Toma, Ştefan Raşcu, Razvan-Cosmin Petca, Justin Aurelian, Traian Constantin, Viorel Jinga.
       Introduction: Prostate cancer is a major global health concern, affecting one in every eight men over the course of their lives. Early detection and precise risk stratification are essential for distinguishing indolent types from aggressive cancer that necessitates immediate treatment. Prostate-specific antigen (PSA), although its widespread use in prostate cancer screening, lacks specificity, resulting in unnecessary biopsies and overtreatment of clinically insignificant malignancies. The SelectMDx test, a non-invasive molecular diagnostic tool, and multiparametric magnetic resonance imaging (mpMRI) have shown promise in enhancing diagnostic precision. This study compares the independent and combination diagnostic performance of SelectMDx and mpMRI in patients with intermediate PSA levels.
    Material and methods: A retrospective analysis of 126 patients was conducted in an academic hospital in southern Romania from 2022 to 2023. The requirements for inclusion included PSA values ≥3 ng/ml, SelectMDx evaluation, mpMRI, and a prostate biopsy. SelectMDx used mRNA expression levels of ****HOXC6 and DLX1, in addition to clinical data, to create a risk score for clinically significant prostate cancer (PCa) (grade group ≥2). PI-RADS version 2.1 was used to rate mpMRI images. Lesions with a grade of ≥3 were considered suspicious. Logistic regression models were used to determine the predictive power of SelectMDx, PI-RADS, and their combination. The diagnostic performance was assessed using sensitivity, specificity, positive predictive value, and negative predictive value. The medical relevance of reducing unnecessary biopsies has been studied using decision curve analysis.
    Results: SelectMDx showed a sensitivity of 89.2%, a specificity of 61.8%, a PPV of 49.25%, and an negative predictive value (NPV) of 93.22%. Patients with positive SelectMDx results had a 13.35-fold greater risk of clinically severe PCa (p <0.001). Using mpMRI with PI-RADS scoring improved detection of high-grade PCa. A PI-RADS score of ≥4 corresponded to a 7.13-fold higher probability of aggressive cancer (p <0.001). In multivariate analysis, adjusting for SelectMDx and patient age reduced the predictive value of PI-RADS ≥4 (adjusted OR = 1.49; p = 0.555). Standalone SelectMDx outperformed its combination with mpMRI in terms of diagnostic accuracy, as shown by higher AUC values and better DCA results.
    Conclusions: The SelectMDx test is a highly effective and reliable diagnostic tool for predicting clinically severe PCa in individuals with intermediate PSA levels. Its high NPV avoids unnecessary biopsies and their associated morbidity. While integrating SelectMDx with mpMRI provides new diagnostic insights, the molecular test revealed superior accuracy when used alone, confirming its importance in precision medicine.
    Keywords:  PSA; molecular diagnostic tehniques; prostate cancer; risk assessement
    DOI:  https://doi.org/10.5173/ceju.2024.0284
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