bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2026–02–08
forty-five papers selected by
Grigor Varuzhanyan, UCLA
  1. Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.
  2. CEP55 Promotes Prostate Cancer Progression via TPX2-Dependent Activation of AURKA/PI3K/AKT Signaling and Inhibition of Ferroptosis.
  3. Loss of IL1RA promotes prostate cancer growth and metastasis by activating Akt signaling pathway.
  4. The proteostasis paradox: from systemic collapse in aging to pathway-specific addiction in prostate cancer.
  5. COL8A1 promotes prostate cancer progression via modulating tumor immune infiltration and activating the FAK/PI3K/AKT pathway through ADAMTS2 regulation.
  6. The role of sleep deprivation in prostate cancer and a preliminary exploration of its mechanisms.
  7. A trifluoromethyl quinoline derivative targets SGK1 and modulates the PI3K/AKT pathway to inhibit prostate cancer progression.
  8. Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer.
  9. TGF-β1/TRAF-6 and IL-6/STAT-3 pathways in PSA-PSMA phenotypes of hormone-sensitive and hormone-refractory prostate Cancer.
  10. Enhancing docetaxel efficacy in prostate cancer: the synergistic role of thymus vulgaris extract in inducing apoptosis and autophagy.
  11. A comprehensive analysis reveals the molecular mechanisms linking preservatives to prostate cancer risk.
  12. Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.
  13. Prognostic Significance of PPFIA2 in Localized Prostate Cancer: Integrative Analysis and Functional Validation.
  14. Implemented one-pot two step fully automated synthesis of [18F]FPIA for metabolic imaging applications.
  15. Integrated regulation of ferroptosis in prostate cancer covering mechanisms, resistance, and translational opportunities.
  16. Happening in the Prostate Tumor Microenvironment: Ion Channels and Extrachromosomal DNA Driving Phenotypic Plasticity.
  17. Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy.
  18. A nanosystem targeting genomic instability and mitochondrial damage to stimulate STING pathway for synergistic immunotherapy for advanced prostate cancer.
  19. Intercellular Horizontal Transfer of TXNDC5 mRNA via Extracellular Vesicles Contributes to Tumor-Associated Macrophage-Mediated Prostate Cancer Metastasis.
  20. Targeting PKMYT1 enhances antitumor immune responses to PD-L1 blockade in castration-resistant prostate cancer.
  21. Exosomal miR-93-5p Modulates Macrophage Polarization to Enhance Prostate Cancer Progression.
  22. Expression of Antioxidant Defense Genes Determines Synergistic Ferroptosis Induction by the Combination of Erastin and Omega-3 Docosahexaenoic Acid in Prostate Cancer Cells.
  23. GRIN3A defines an immunosuppressive niche in advanced prostate cancer.
  24. Radio-pathomic maps of histo-morphometric features trained with whole mount prostate histology distinguish prostate cancer on MP-MRI.
  25. Overexpression of the ERG oncogene in prostate cancer identifies candidates for PARP inhibitor-based radiosensitization.
  26. RETRACTED: Lee et al. Machine-Learning-Based Survival Prediction in Castration-Resistant Prostate Cancer: A Multi-Model Analysis Using a Comprehensive Clinical Dataset. J. Pers. Med. 2025, 15, 432.
  27. Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer.
  28. Identification and diagnostic evaluation of an aptamer targeting prostate-cancer-derived small extracellular vesicles.
  29. Metabolic crosstalk in the metastatic prostate cancer-bone microenvironment: mechanism, detection and therapeutic strategies.
  30. Single-cell sequencing-guided design of synergistic chemo-immunotherapy nanodrugs for cGAS-STING activation in prostate cancer therapy.
  31. Risk factors of negative prostate biopsies: A CHAID decision tree analysis.
  32. Analysis of the transcriptomic and metabolomic landscape of prostate cancer with different anatomical origins using snFLARE-seq and mxFRIZNGRND.
  33. Oligometastatic prostate cancer: time to integrate metastasis-directed therapy.
  34. Rhabdoid tumors as a novel target for PSMA-directed CAR T cell therapy.
  35. Prostate Cancer Screening: Evidence, Endpoints, and Expert Opinion.
  36. Exploring the biology of metastatic hormone-sensitive prostate cancer: on the road to precision medicine.
  37. The temporal dynamics of the immune response to neoadjuvant androgen deprivation therapy suggests a window-of-opportunity for checkpoint inhibitor therapy in prostate cancer.
  38. Six IL-8 gene polymorphisms and the entire cancer susceptibility according to a comprehensive analysis especially in prostate cancer.
  39. Prostate Cancer Characterization Based on Rapid SHG Imaging of Collagen Fiber Combined With Denoising Algorithm.
  40. Oncolytic virus OH2 induces PD-L1 upregulation via NF-κB signaling and synergizes with anti-PD-L1 therapy in prostate cancer through a targeted extracellular vesicle delivery system.
  41. FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity.
  42. Time to castrate the cost? the rising expense of chemical castration for the management of prostate cancer.
  43. Diagnostic Value of Transabdominal Ultrasound-based Versus Magnetic Resonance Imaging-based Prostate-specific Antigen Density for Clinically Significant Prostate Cancer.
  44. Prolonged Castration Prior to Docetaxel Reduces Febrile Neutropenia in Patients With Metastatic Hormone-sensitive Prostate Cancer Receiving Triple Therapy.
  45. Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years.
  1. Cell Death Discov. 2026 Feb 04.
    Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.
    Xianchao Sun, Ying Zhang, Wei Zhang, Liang Jin, Shiyong Xin.
      While androgen receptor (AR) pathway inhibitors such as enzalutamide have demonstrated significant therapeutic efficacy in prostate cancer (PCa) treatment, the inevitable development of acquired resistance continues to pose a major clinical challenge in managing advanced PCa. We characterized Neurexophilin 4 (NXPH4) as a contributor to enzalutamide resistance (EnzR). Gain- and loss-of-function studies were conducted in PCa cell lines and mouse subcutaneous xenograft models to elucidate the role of NXPH4 in castration-resistant prostate cancer (CRPC). Additionally, the regulatory mechanisms of gene expression were assessed using a series of molecular and biochemical experiments. Our study demonstrates that AR as a transcriptional activator of NXPH4. Elevated NXPH4 expression facilitated PCa proliferation under enzalutamide treatment through mitochondrial metabolic reprogramming. We identified that NXPH4 partially localizes to mitochondria and physically interacts with aldehyde dehydrogenase 1 family member L2 (ALDH1L2), a critical enzyme in one-carbon metabolism. Androgen deprivation stimulated NXPH4 mitochondrial translocation and enhanced its binding to ALDH1L2. NXPH4-mediated metabolic reprogramming promotes PCa progression. Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.
    DOI:  https://doi.org/10.1038/s41420-026-02944-z
  2. J Biol Chem. 2026 Jan 28. pii: S0021-9258(26)00088-8. [Epub ahead of print] 111218
    CEP55 Promotes Prostate Cancer Progression via TPX2-Dependent Activation of AURKA/PI3K/AKT Signaling and Inhibition of Ferroptosis.
    Lizhe Xu, Jinzhuo Ning, Jinrun Wang, Pengcheng Jiang, Xu Zhang, Fan Cheng.
      Prostate cancer (PCa) is a highly heterogeneous malignancy with variable clinical outcomes. Centrosomal protein 55 (CEP55) has been involved in the progression of multiple cancers, but its function in PCa is still largely uncharacterized. CEP55 expression was evaluated in clinical samples and cell lines via bioinformatics analysis, qRT-PCR, and Western blot (WB). Functional assessments, such as wound healing, Cell Counting Kit-8 (CCK-8), and Transwell invasion, were carried out to evaluate the impact of CEP55 upregulation or knockdown on PCa cell growth and metastasis. Co-Immunoprecipitation (Co-IP) was utilized to observe the interaction between CEP55 and TPX2 microtubule nucleation factor (TPX2). The role of CEP55 in ferroptosis regulation was assessed by measuring IC50 values of ferroptosis inducers, lipid reactive oxygen species (ROS) levels, and the expression of ferroptosis-correlated proteins Solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Xenograft tumor models were created to evaluate the in vivo effects of CEP55 suppression. CEP55 showed a significant upregulation in PCa tissues and cell lines. CEP55 overexpression was linked to advanced clinicopathological features and poor prognosis. Mechanistically, CEP55 interacted with TPX2 to activate the Aurora Kinase A (AURKA)-PI3K/AKT signaling cascade. This activation led to increased expression of SLC7A11 and GPX4, reduced lipid ROS accumulation, and conferred resistance to ferroptosis. Pharmacological inhibition of the TPX2/AURKA interaction with CAM2602 reversed these effects. In vivo trials illustrated that CEP55 knockdown inhibited tumor growth and downregulated key proteins in the TPX2/AURKA/PI3K/AKT and ferroptosis resistance pathway. Our findings demonstrate that CEP55 enhances PCa progression by stimulating the TPX2/AURKA/PI3K/AKT signaling pathway and inhibiting ferroptosis. Targeting this axis may represent a potential therapeutic approach for PCa.
    Keywords:  AURKA; CEP55; PI3K/AKT pathway; TPX2; ferroptosis; prostate cancer
    DOI:  https://doi.org/10.1016/j.jbc.2026.111218
  3. PLoS One. 2026 ;21(2): e0339611
    Loss of IL1RA promotes prostate cancer growth and metastasis by activating Akt signaling pathway.
    Cheng Zhang, Junjie Yu, Taoze Ji, Kai Zhao, Mingquan Chen.
       BACKGROUND: Interleukin-1 receptor antagonist (IL1RA) blocks the interaction between IL-1 and its receptors. It modulates inflammatory responses, cell proliferation, and the invasion of cancer cells. In this study, we examined the biological functions of IL1RA and the mechanisms that influence its effects on prostate cancer (PCa).
    MATERIALS AND METHODS: We performed RT-qPCR and Western blot analyses to evaluate IL1RA expression levels in various cell lines. For functional studies, we employed MTT, colony formation, soft agar, wound healing, and transwell migration and invasion assays. Then, we analyzed Western blots to elucidate the underlying mechanisms involved. Xenograft mouse models were ultimately established after the overexpression of IL1RA.
    RESULTS: IL1RA was expressed at higher levels in prostate epithelial cells compared with the PCa cell lines. BPH cells with lower IL1RA expression exhibited an increased cell proliferation. The PCa cell lines C4-2B and LNCap, which overexpressed IL1RA, demonstrated suppressed tumorigenic properties in vitro. The in vivo experiment demonstrated an inhibitory effect on tumor growth in xenograft mice. Furthermore, Western blot results indicated elevated phosphorylated AKT levels in BPH cells with IL1RA knockdown, and phosphorylated AKT and GSK-3[Formula: see text] levels were reduced in C4-2B and LNCap cells that overexpressed IL1RA.
    CONCLUSION: This study revealed that IL1RA low expression is associated with PCa progression. Our finding has great clinical and translational significance. The potential clinical application of IL1RA as a therapeutic target for PCa requires further investigation.
    DOI:  https://doi.org/10.1371/journal.pone.0339611
  4. Front Cell Dev Biol. 2026 ;14 1755668
    The proteostasis paradox: from systemic collapse in aging to pathway-specific addiction in prostate cancer.
    Danhong Guo, Yaoyao Peng, Yanlan Yu.
      Aging is the primary risk factor for prostate cancer (PCa), characterized biologically by a systemic collapse of proteostasis networks. Paradoxically, rather than succumbing to this decline, PCa cells exploit it, developing a "proteostasis addiction" to cope with persistent intrinsic stress. This review elucidates this paradox through three conceptual frameworks: the dynamic transition from age-related functional decay to tumorigenic hijacking; the specificity of oncogenic protein regulation; and the functional dichotomy (or "double-edged sword") of proteostatic components in tumor suppression versus promotion. We examine how declining molecular chaperone networks are co-opted to selectively stabilize the androgen receptor (AR) and its variants. Furthermore, we explore how the ubiquitin-proteasome system (UPS) is re-engineered via E3 ligases and deubiquitinases (DUBs) to orchestrate the precise turnover of tumor suppressors and oncoproteins. Special attention is given to chaperone-mediated autophagy (CMA), which undergoes a reversal from age-associated suppression to hyperactivation in advanced PCa, thereby fueling metabolic adaptation and therapy resistance. Beyond the intracellular context, we discuss how proteostatic imbalances drive the senescence-associated secretory phenotype (SASP) to remodel the tumor microenvironment. Finally, we assess emerging therapeutic strategies, arguing that precision modulation of specific proteostasis nodes-such as distinct E3/DUBs or CMA pathways-represents a promising frontier to overcome castration-resistant prostate cancer (CRPC).
    Keywords:  androgen receptor signaling; cellular senescence; prostate cancer progression; proteostasis dysregulation; therapeutic targeting
    DOI:  https://doi.org/10.3389/fcell.2026.1755668
  5. Sci Rep. 2026 Jan 30.
    COL8A1 promotes prostate cancer progression via modulating tumor immune infiltration and activating the FAK/PI3K/AKT pathway through ADAMTS2 regulation.
    Jinrun Wang, Jinzhuo Ning, Lizhe Xu, Fan Cheng.
      Collagen type VIII alpha 1 chain (COL8A1) is a part of the collagen family and has been involved in tumor progression in numerous cancers. Nevertheless, its expression pattern, functional role, and underlying mechanisms in prostate cancer (PCa) remain largely unexplored. COL8A1 expression was analyzed using public datasets and clinical samples. Functional roles of COL8A1 in PCa cells were assessed via CCK-8, Transwell, wound healing, and flow cytometry assays. Protein interactions were assessed by co-immunoprecipitation and pull-down assays. The underlying mechanism was explored using Western blot (WB), bioinformatics analysis, and in vivo xenograft models. COL8A1 was significantly increased in PCa tissues and cell lines, and its expression related to advanced clinicopathological features and poor progression-free survival. Functional studies showed that COL8A1 promotes cell proliferation, invasion, and migration while inhibiting apoptosis. Mechanistically, COL8A1 interacts with ADAMTS2, and its modulation affects ADAMTS2 protein expression. This interaction results in stimulation of the FAK/PI3K/AKT pathway. ADAMTS2 suppression partially reversed the oncogenic effects of COL8A1 overexpression. Moreover, COL8A1 expression was positively linked to immune cell infiltration in the tumor microenvironment. In vivo experiments confirmed that COL8A1 knockdown suppresses tumor growth. Our findings identify COL8A1 as an innovative oncogenic driver in PCa that promotes tumor progression via modulation of the ADAMTS2-FAK/PI3K/AKT axis and immune infiltration. COL8A1 may be a potential prognostic biomarker and therapeutic target for PCa.
    Keywords:  ADAMTS2; COL8A1; FAK/PI3K/AKT signaling pathway; Immune infiltration; PCa
    DOI:  https://doi.org/10.1038/s41598-026-37799-y
  6. Pathol Res Pract. 2026 Jan 27. pii: S0344-0338(26)00030-0. [Epub ahead of print]280 156379
    The role of sleep deprivation in prostate cancer and a preliminary exploration of its mechanisms.
    Jialong Zhang, Lexing Yang, Jun He, Weiyi Li, Hongzhi Wang, Chaozhao Liang.
      Previous studies suggested the link between sleep deprivation and prostate cancer, but its impact on disease progression is unclear. Moreover, clarifying this relationship could offer insights into prostate cancer mechanisms and potential treatments. In the present study, questionnaire and sleep monitoring of prostate cancer patients indicate that worse sleep quality correlates with higher Gleason scores. Subsequently, to study the effects of sleep deprivation in vivo, a sleep deprivation mouse model was established. Our findings show that sleep deprivation could accelerate tumor growth. Then, we performed transcriptome sequencing to infer the underlying mechanism. RNA sequencing found inflammation related pathways were activated in the sleep deprivation model. Moreover, we identified CXCL13 as a key mediator of sleep deprivation induced prostate progression. And inhibition of CXCR5, the receptor of CXCL13, reduced its tumor promoting effects. Molecular mechanism studies showed that CXCL13 enhanced cancer cell proliferation via activating JNK signaling pathway. In summary, our findings suggest that sleep deprivation may accelerate prostate cancer progression by activating the CXCL13/CXCR5/JNK signaling axis. These results provide preliminary insights into a potential therapeutic direction.
    Keywords:  CXCL13; CXCR5; JNK signaling，inflammatory response; Prostate cancer; Sleep deprivation
    DOI:  https://doi.org/10.1016/j.prp.2026.156379
  7. Med Oncol. 2026 Feb 07. 43(3): 146
    A trifluoromethyl quinoline derivative targets SGK1 and modulates the PI3K/AKT pathway to inhibit prostate cancer progression.
    Xianhui Yang, Rui Wang, Guangcan Xu, Ziqi Yang, Xingsheng Yao, Guangyang Liu, Jia Yu, Bixue Xu, Heng Luo, Ying Cao.
      Prostate cancer (PCa) is one of the most prevalent malignant tumors among men globally, with limited treatment options, especially in cases that progress to castration-resistant prostate cancer (CRPC). Identifying novel molecular targets and effective therapeutic strategies is crucial for improving patient outcomes. In this study, we identified serum and glucocorticoid-regulated kinase 1 (SGK1) as a potential target of the trifluoromethylquinoline derivative TKL007. A series of in vitro assays, including CCK-8, colony formation, Transwell migration and invasion assays, and flow cytometry, were performed to systematically evaluate the anti-tumor effects of TKL007 on the PC3 and LNCaP prostate cancer cell lines. Western blot analysis revealed that TKL007 significantly inhibited the activation of the PI3K/AKT signaling pathway. Further transfection experiments confirmed that SGK1 expression levels regulate the activity of the PI3K/AKT pathway, suggesting that SGK1 may modulate this signaling axis. In vivo xenograft experiments in nude mice demonstrated that TKL007 effectively inhibited tumor growth without causing significant toxicity. Taken together, these results suggest that TKL007 exerts anti-prostate cancer effects by downregulating SGK1 protein levels and inhibiting the PI3K/AKT pathway, providing a new candidate molecule and theoretical foundation for targeted therapy.
    Keywords:  PI3K/AKT pathway; Prostate cancer; SGK1; Trifluoromethyl quinoline derivative
    DOI:  https://doi.org/10.1007/s12032-026-03256-z
  8. Nat Prod Bioprospect. 2026 Feb 05. 16(1): 34
    Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer.
    Qiuyu Liu, Mengjing Cong, Chenghai Gao, Yonghong Liu, Junfeng Wang, Xueni Wang.
      Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀ = 10.30 μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but it directly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.
    Keywords:  Androgen receptor; Ferroptosis; Heat shock protein 70; Marine natural product; Membrane-associated O-acyltransferase domain protein 2; Prostate cancer
    DOI:  https://doi.org/10.1007/s13659-025-00586-9
  9. Clin Immunol. 2026 Feb 04. pii: S1521-6616(26)00017-3. [Epub ahead of print] 110679
    TGF-β1/TRAF-6 and IL-6/STAT-3 pathways in PSA-PSMA phenotypes of hormone-sensitive and hormone-refractory prostate Cancer.
    Awatef Ben Jemaa, Mouna Ben Azaiez, Sataa Sallami, Yassine Nouira, Ezzeddine Ghazouani, Ridha Oueslati.
      This study explored the relationship between systemic cytokines and PSA-PSMA phenotypes in benign prostatic hyperplasia (BPH) and prostate cancer (PCa), including hormonal therapy response. Serum cytokines (IL-6, TNF-α, IL-10, IL-17 A, TGF-β1) and PSA were quantified, while tissue PSA, PSMA, CD34, TRAF-6, and phosphorylated STAT3 (Ser727, Tyr705) were evaluated immunohistochemically. AR and AR-V7 mRNA expression were assessed by RT-PCR. PCa patients exhibited elevated IL-6 and TGF-β1, higher PSMA and CD34, and reduced tissue PSA compared to BPH. pSTAT3 (Tyr705) increased, whereas pSTAT3 (Ser727) decreased in PCa. In hormone-refractory PCa, TGF-β1 and PSMA were elevated, while PSA declined. AR-V7 was largely absent, and TRAF-6 showed no hormonal difference. These findings suggest IL-6/STAT3 and TGF-β1/TRAF-6 pathways modulate PSA-PSMA dynamics, with TGF-β1/TRAF-6 particularly linked to hormone-refractory progression. Cytokine-mediated signaling may inform PCa diagnosis, prognosis, and therapeutic targeting.
    Keywords:  Circulating cytokines profiles; Hormone therapy; Inflammation; PSA; PSMA; Prostate Cancer
    DOI:  https://doi.org/10.1016/j.clim.2026.110679
  10. Toxicol Res (Camb). 2026 Feb;15(1): tfag004
    Enhancing docetaxel efficacy in prostate cancer: the synergistic role of thymus vulgaris extract in inducing apoptosis and autophagy.
    Nazmiye Bitgen, Gozde Ozge Onder, Munevver Baran, Fatma Esen Karakus, Sedat Carkit, Arzu Hanım Yay.
      Prostate cancer (PC) is a common malignancy in men, and resistance to treatment in advanced stages remains a significant clinical problem. Docetaxel (DTX) is widely used in advanced PC therapy; however, its efficacy can be limited by toxicity and acquired resistance. Therefore, plant-derived compounds are being explored as supportive therapeutic agents. This study investigated the cytotoxic and antiproliferative effects of Thymus vulgaris (T. vulgaris) extract on PC-3 prostate cancer cells, both alone and in combination with DTX. PC-3 cells were treated with varying concentrations of T. vulgaris and DTX individually and in combination. Cell viability was measured using the MTT assay, and proliferative activity was assessed by AgNOR staining. Cell cycle distribution was analyzed using a Muse cell analyzer, apoptosis was detected via the TUNEL assay, and autophagy-associated protein expression (LC3 and p62) was examined immunohistochemically. T. vulgaris extract exhibited dose-dependent cytotoxicity with an IC50 of 8 μg/mL. The combined treatment with T. vulgaris and DTX resulted in greater inhibition of cell viability, significant G0/G1 cell cycle arrest, increased apoptosis, and enhanced autophagy. Additionally, AgNOR analysis indicated reduced proliferative capacity. These findings suggest that T. vulgaris may enhance DTX efficacy and serve as a promising natural adjuvant in PC therapy.
    Keywords:  Thymus vulgaris; apoptosis; autophagy; cell cycle arrest; phytochemicals; prostate cancer
    DOI:  https://doi.org/10.1093/toxres/tfag004
  11. Discov Oncol. 2026 Feb 01.
    A comprehensive analysis reveals the molecular mechanisms linking preservatives to prostate cancer risk.
    Xinyao Zhu, Yuqi Li, Zhiyu Liu, Qilong Wu, Qingfu Deng.
       BACKGROUND: Preservatives, widely used in food and skincare products, may influence prostate cancer (PCa) development. This study explores the effects of common preservatives, especially parabens, on PCa and their potential molecular associations via computational and database-based analyses.
    METHODS: This study identified potential preservative targets linked to prostate cancer through database screening (Swiss Target Prediction, STITCH, GeneCards) and extracted overlapping genes for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A core gene network was constructed via the STRING database and Cytoscape software, and the top 20 genes by interaction strength were further analyzed using 10 machine learning algorithms to develop an optimal prognostic model. Multivariate Cox regression identified key genes as independent prognostic factors, which were preliminarily evaluated via molecular docking for preservative binding affinity. Tissue expression differences of these genes were also confirmed using the Human Protein Atlas (HPA).
    RESULTS: This study identified 135 preservative-PCa-related genes; GO enrichment analysis showed these genes were mainly involved in apoptosis regulation, oxidative stress, signal transduction, and biosynthesis processes, while KEGG enrichment analysis linked them to endocrine resistance, chemical carcinogenesis, and lipid metabolism. The results of the machine learning prediction model showed that the Ridge model achieved the best prediction performance among the combinations of 101 prediction models with a C-index score of 0.709 and was validated across four external datasets (Cambridge, Taylor, CancerMap, GEO46602). Multivariate Cox regression identified 8 key genes (AR, BCL2L1, CASP3, CDK1, HDAC6, MMP2, PIK3CA, XIAP) as independent PCa prognostic factors-with AR, CASP3, CDK1, HDAC6, MMP2 as risk factors and BCL2L1, PIK3CA, XIAP as protective factors. Molecular docking showed all 8 genes could bind spontaneously to four parabens (methylparaben, ethylparaben, propylparaben, butylparaben), and HPA data confirmed significant expression differences of these genes between normal prostate and PCa tissues.
    CONCLUSION: This study uses computational and database-based approaches to systematically explore potential associations between parabens and PCa, identifying 8 key genes that may mediate this association and providing a theoretical foundation for formulating safer preservative usage guidelines and exploring PCa prognostic markers. Importantly, the current findings are derived from in silico prediction and public database analysis, not from experimental verification involving paraben exposure controls. The study identifies potential correlations rather than verifying direct molecular mechanisms of parabens in PCa; thus, it generates valuable scientific hypotheses that require further validation via in vitro cell experiments, animal models, and human exposure cohort studies to confirm the actual molecular mechanisms linking parabens to PCa.
    Keywords:  Machine learning; Molecular docking; Network toxicology; Preservative; Prostate cancer
    DOI:  https://doi.org/10.1007/s12672-026-04531-1
  12. Oncogene. 2026 Feb 06.
    Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer.
    G N Brooke, D A Leach, R L Culley, A Azadova, L Latonen, E Rees, M A Alkheilewi, A C Pine, F M Fioretti, C S Reader, S M Powell, V Reebye, J Waxman, T Visakorpi, C L Bevan.
      Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.
    DOI:  https://doi.org/10.1038/s41388-026-03682-3
  13. Anticancer Res. 2026 Feb;46(2): 757-770
    Prognostic Significance of PPFIA2 in Localized Prostate Cancer: Integrative Analysis and Functional Validation.
    Jipu Liu, Cheng Ya Hsu, Jianming Lu, L E Zhang, Yuwei Zhong, Weide Zhong.
       BACKGROUND/AIM: Prostate cancer (PCa) is a leading malignancy in men, with biochemical recurrence (BCR) indicating potential disease progression in up to 50% of patient's post-curative therapy. The liprin-α family gene PPFIA2 has emerged as a potential biomarker in PCa, yet its prognostic role in localized disease remains underexplored.
    MATERIALS AND METHODS: PPFIA2 expression was analyzed using high throughput data from TCGA-PRAD, CPC, Stockholm, and GSE54460 cohorts, with validation in an in-house cohort via immunohistochemistry (IHC). Kaplan-Meier and Cox regression analyses assessed its prognostic value for BCR and overall survival. In vitro, PPFIA2 knockdown effects were evaluated in LNCaP and C4-2 cell lines using CCK-8 and Transwell assays. Gene Set Enrichment Analysis (GSEA) explored biological pathways, and mutation profiles were analyzed using maftools.
    RESULTS: High PPFIA2 expression was associated with earlier BCR across multiple cohorts. IHC confirmed elevated PPFIA2 protein levels in PCa tissues, correlating with poorer prognosis. PPFIA2 knockdown reduced proliferation and migration in PCa cell lines. GSEA revealed PPFIA2's activation of proliferation-related pathways and suppression of protein synthesis. High PPFIA2 expression was linked to a lower SPOP mutation frequency.
    CONCLUSION: PPFIA2 is an unfavorable prognostic biomarker for localized PCa. Its oncogene effect highlights its potential for risk stratification and targeted therapy.
    Keywords:  Localized prostate cancer; PPFIA2; biochemical recurrence; multi-omics analysis; prognosis
    DOI:  https://doi.org/10.21873/anticanres.17985
  14. Nucl Med Biol. 2026 Jan 23. pii: S0969-8051(26)00004-1. [Epub ahead of print]154-155 109605
    Implemented one-pot two step fully automated synthesis of [18F]FPIA for metabolic imaging applications.
    José S Enriquez, Vincenzo Paolillo, Ryan Armijo, Aldo Morales, Peter D A Shepherd, Muxin Wang, Pratip K Bhattacharya, Federica Pisaneschi.
       BACKGROUND: [18F]Fluoropivalate ([18F]FPIA), also known as 18F-pivalate or 18F-RAD101, is the fluorinated analogue of pivalic acid and has shown promise in ongoing clinical trials for the detection of brain metastases. The original synthesis of [18F]FPIA involved a two-step procedure that was not fully automated, limiting its suitability for large-scale or GMP production. A subsequent report described an improved two-step, one-pot synthesis on a cassette-based module, although with certain limitations. Here, we present an optimized two-step, one-pot synthesis of [18F]FPIA using a vial-based automated synthesizer and demonstrate its successful implementation under GMP conditions. We also report [18F]FPIA-PET imaging in prostate cancer patient-derived xenograft (PDX) models.
    RESULTS: [18F]FPIA was successfully produced with the optimized synthetic strategy with a total synthesis time of 75 min and a 25.4 ± 3.8% (n = 9) activity yield at end of synthesis (EOS), with >99% radiochemical purity. In a GMP setting, the scale-up synthesis was successful with a 37 ± 9% (n = 37) activity yield at EOS and a > 99% radiochemical purity. In the proof-of-concept PET imaging study of [18F]FPIA in androgen receptor (AR)-negative and -positive prostate cancer PDX animal models, uptake was observed in both groups when the tumor reached a size of 50-300 mm3. The AR-negative group showed significantly higher [18F]FPIA uptake compared to the AR-positive group, with average tumor-to-muscle ratios of 1.6 and 1.2, respectively.
    CONCLUSIONS: In summary, an optimized one-pot, two-step synthesis of [18F]FPIA on a vial-based automated synthesizer was successful and a seamless transition into a GMP facility is reported, enabling a streamlined transition to clinical production. Furthermore, we have demonstrated the use of [18F]FPIA for noninvasive metabolic imaging in prostate cancer and its potential to distinguish between different prostate cancer subtypes.
    Keywords:  (18)F-RAD101; (18)F-pivalate; Lipid metabolism; Metabolic imaging; PET; Positron emission tomography; Prostate cancer imaging; [(18)F]FPIA; [(18)F]Fluoropivalate
    DOI:  https://doi.org/10.1016/j.nucmedbio.2026.109605
  15. J Mol Med (Berl). 2026 Feb 04. 104(1): 40
    Integrated regulation of ferroptosis in prostate cancer covering mechanisms, resistance, and translational opportunities.
    Zhihong Wang, Guo Chen, Zhihong Liu.
      Ferroptosis, an iron dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal process in prostate cancer biology and therapy. This review summarizes the multifaceted regulation of ferroptosis in prostate cancer from molecular, metabolic, and microenvironmental perspectives. Core regulators such as GPX4, SLC7A11, and ACSL4 coordinate redox balance, glutathione metabolism, and lipid peroxidation, together determining ferroptotic sensitivity. Transcriptional, epigenetic, and post translational mechanisms including STAT3, the JMJD6 ATF4 axis, and TRIM family proteins further refine ferroptosis regulation. Metabolic reprogramming involving APOC1, SLC25A10, and BCAT2, as well as mitochondrial dynamics governed by VSTM2L and RPS6KC1, establishes metabolic dependencies that influence resistance or susceptibility to ferroptosis. Within the tumor microenvironment, cancer-associated fibroblasts and extracellular matrix components modulate ferroptosis through lactate signaling, exosomal microRNAs, and detachment resistance. Clinically, ferroptosis-related gene signatures provide valuable prognostic tools and predict responses to radiotherapy, antiandrogen therapy, and immunotherapy, linking ferroptotic dysregulation with immune suppression and treatment resistance. Emerging therapeutic strategies that inhibit GPX4 or system Xc-, modulate iron metabolism, and employ PSMA-targeted nanoplatforms have shown potent antitumor efficacy, especially in castration resistant disease. Repurposed drugs such as flubendazole and the ezetimibe derivative L14-8, along with natural compounds including evodiamine and luteolin, demonstrate translational potential for ferroptosis induction. Collectively, ferroptosis represents a promising therapeutic vulnerability for precision treatment of advanced prostate cancer.
    Keywords:  Disease progression; Ferroptosis; Prostate cancer
    DOI:  https://doi.org/10.1007/s00109-026-02641-5
  16. Prostate. 2026 Feb 03.
    Happening in the Prostate Tumor Microenvironment: Ion Channels and Extrachromosomal DNA Driving Phenotypic Plasticity.
    Sara Darbandi, Alfonso Urbanucci, Sini Hakkola, Juanita Gujral, Mahsa Darbandi, Ahmed Eraky, Sujit Nair, Goutam Chakraborty, Ashutosh Tewari, Natasha Kyprianou.
       BACKGROUND: Plasticity of cancer, including epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) self-renewal, and microenvironmental adaptation, drives metastasis, therapy resistance, and poor outcomes in prostate cancer (PCa). Ion channels and extrachromosomal DNA (ecDNA) have emerged as key drivers of such adaptive processes by influencing signaling, metabolism, and immune interactions.
    METHODS: We evaluated available evidence on ion channel biology, ecDNA dynamics, and their roles in tumor plasticity and drug resistance in PCa. Further, we analyzed two publicly accessible single-cell RNA-sequencing (scRNA-seq) datasets (primary PCa and castration-resistant PCa) to determine ion channel and transporter expression profiles in tumor and stromal cell populations.
    RESULTS: Our analysis showed cell type-specific expression of many ion channels, including KCNJ10, CACNA1H, and CLIC1, and identification of six transporters (SLC25A1, SLC25A10, SLC25A33, SLC25A42, SLC29A2, SLC7A11) strongly enriched in luminal tumor cells. The discovered genes regulate mitochondrial metabolism, redox homeostasis, nucleotide biosynthesis, immune modulation, and resistance to ferroptosis, all contributing to tumor growth. ecDNA facilitates oncogene amplification (e.g., MYC, EGFR), induction of EMT, and immune evasion, driving intratumoral heterogeneity and therapy-resistant clones.
    CONCLUSIONS: Ion channels and ecDNA are central to the disease progression and treatment resistance of PCa through regulation of EMT, CSC phenotype, and tumor microenvironment (TME) interactions. Targeting the drivers-through ion channel modulators, ferroptosis induction, and ecDNA-targeting interventions (BET/HDAC inhibitors, CRISPR-based methods) offers a promising way to overcome resistance. Integration of multi-omics, and combination treatments will be key to construct precision medicine strategies and improve clinical outcomes in advanced PCa.
    Keywords:  Epithelial‐Mesenchymal Transition (EMT); Ion Channels; Mesenchymal‐Epithelial Transition (MET); Metastasis; Microenvironment; Phenotypic Landscape; Prostate Cancer; Therapeutic Targeting; Tumor Recurrence
    DOI:  https://doi.org/10.1002/pros.70139
  17. EMBO Mol Med. 2026 Feb 02.
    Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy.
    Manon Baurès, Anne-Sophie Vieira Aleixo, Emeline Pacreau, Aysis Koshy, Vanessa Friedrich, Marc Diedisheim, Martin Raigel, Yichao Hua, Charles Dariane, Florence Boutillon, Lukas Kenner, Jean-Christophe Marine, Gilles Laverny, Daniel Metzger, Florian Rambow, Jacques-Emmanuel Guidotti, Vincent Goffin.
      A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.
    Keywords:  Castration-Resistance; Club Cells; DNPC; FOSL1; LSCmed Cells
    DOI:  https://doi.org/10.1038/s44321-026-00375-y
  18. Biomaterials. 2026 Jan 27. pii: S0142-9612(26)00042-6. [Epub ahead of print]330 124018
    A nanosystem targeting genomic instability and mitochondrial damage to stimulate STING pathway for synergistic immunotherapy for advanced prostate cancer.
    Dongming Xiao, Jinhan Zou, Yajian Li, Hanchen Zhang, Meifang Shen, Haiyang Wang, Yingjie Yu, Haihua Xiao, Li Gao.
      Taxane-based chemotherapy and immunotherapy are standard treatments for advanced prostate cancer, yet their efficacy is often limited by drug resistance and an immunosuppressive, "cold" tumor microenvironment (TME). To address these challenges, we develop a reactive oxygen species (ROS)-responsive nanoparticle, PTX-Zn NP, for the co-delivery of paclitaxel (PTX) and zinc ions (Zn2+). Within tumor cells, elevated ROS triggers the release of PTX, promoting micronuclei formation and cytosolic double-stranded DNA exposure. Concurrently, Zn2+ amplifies cGAS-STING signaling by enhancing cGAS-DNA binding and inducing mitochondrial damage. In vitro, PTX-Zn NP suppressed tumor cell proliferation, generated ROS and micronuclei, and activated the STING pathway to promote dendritic cell maturation. In vivo, PTX-Zn NP preferentially accumulated in prostate tumors, inhibited tumor growth, and reprogrammed the "cold" TME toward a "hot" phenotype. When combined with anti-PD-L1 therapy, PTX-Zn NP significantly improved antitumor efficacy and promoted long-term immune memory. Overall, this dual-action approach provides a promising strategy to overcome both chemoresistance and immune evasion in advanced prostate cancer.
    Keywords:  Micronucleus; Mitochondrial damage; Nanosystem; Prostate cancer; cGAS-STING pathway
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124018
  19. Adv Sci (Weinh). 2026 Feb 03. e11052
    Intercellular Horizontal Transfer of TXNDC5 mRNA via Extracellular Vesicles Contributes to Tumor-Associated Macrophage-Mediated Prostate Cancer Metastasis.
    Cong Hu, Tianyang Wu, Jiayi Wang, Xinxing Du, Xinrui Wu, Yanhao Dong, Zehong Peng, Penghui Liao, Zirui Guo, Zheyu Liu, Kenneth J Pienta, Yinjie Zhu, Jiahua Pan, Liang Dong, Wei Xue.
      As one of the predominant male malignancies globally, prostate cancer (PCa) transitions to a treatment-refractory phase upon metastasis, for which no curative modalities currently exist. Tumor-associated macrophages (TAMs), a crucial component of the tumor microenvironment (TME), primarily adopt a metastasis-promoting M2 phenotype. However, the mechanisms underlying the TAM-cancer cell crosstalk and resultant PCa metastasis remain elusive. In this study, primary lesions of metastatic PCa (mPCa) exhibit both greater infiltration of M2 macrophages and a higher proportion of M2 macrophage-derived extracellular vesicles (M2 EVs) compared to those of non-metastatic PCa (nmPCa). Furthermore, M2 EVs can be internalized by PCa cells, promoting a mesenchymal-like state (MLS) in PCa and affecting tumor metastasis. Mechanistically, thioredoxin domain-containing 5 (TXNDC5) mRNA encapsulated in M2 EVs contributes to MLS of DU145 and PC3 cells, enhancing migration and invasion. Single-vesicle particle analysis confirms that TXNDC5 mRNA encapsulated within M2 EVs can be horizontally transferred to target cells, where it is translated to produce functional proteins. In conclusion, our study demonstrates that M2 macrophages can promote MLS and metastasis of PCa through EV-mediated horizontal mRNA transfer. A novel role of EVs in the communication between the TME and tumor cells is discovered, offering new insights into tumor metastasis.
    Keywords:  extracellular vesicles; mesenchymal‐like state; metastasis; prostate cancer; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/advs.202511052
  20. J Immunother Cancer. 2026 Jan 30. pii: e013247. [Epub ahead of print]14(1):
    Targeting PKMYT1 enhances antitumor immune responses to PD-L1 blockade in castration-resistant prostate cancer.
    Lin Gao, Baozhen Wang, Hui Liu, Ping Liu, Long Liu, Jingying Han, Xin Wang, Baokai Dou, Feifei Sun, Wenyao Liu, Xinpei Wang, Tingting Feng, Ru Zhao, Xiaorong Yang, Weiwen Chen, Jing Hu, Bo Han.
       BACKGROUND: Although immunotherapy has revolutionized cancer treatment, its efficacy in castration-resistant prostate cancer (CRPC) remains limited, largely due to an immunologically "cold" tumor microenvironment with scarce T-cell infiltration. Unraveling the molecular mechanisms underlying immune evasion and developing novel strategies to activate innate antitumor immunity are therefore critical to overcoming immunotherapy resistance in CRPC.
    METHODS: Using bioinformatic approaches, we analyzed the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) expression and its correlation with immune cell infiltration and response to immune checkpoint blockade (ICB) in public databases. PKMYT1 protein expression was further evaluated via immunohistochemistry in a clinical cohort of prostate cancer (PCa) specimens. Mechanistic investigations were conducted in PCa cell lines and mouse models. The immunological impact of PKMYT1 inhibition was delineated using single-cell RNA sequencing, and the therapeutic efficacy of RP-6306, either as monotherapy or in combination with programmed death-ligand 1 (PD-L1) blockade, was evaluated in syngeneic mouse models.
    RESULTS: PKMYT1 expression was significantly overexpressed in CRPC compared with primary PCa. High PKMYT1 expression correlated with a suppressed antitumor immunity and poor clinical response to ICB. Mechanistically, PKMYT1 inhibition activated the cyclic guanosine monophosphate-adenosine monophosphate adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway, potentiated both type I and II interferon signaling, and upregulated chemokines, including CCL5 and CXCL10. The selective PKMYT1 inhibitor, RP-6306, enhanced the efficacy of ICB in the presence of CD8+ T cells. Treatment with a PKMYT1 inhibitor alone or in combination with PD-L1 blockade significantly increased the infiltration of activated CD8+ T cells and induced significant tumor suppression in vivo.
    CONCLUSION: PKMYT1 is a pivotal dual regulator of tumor progression and immune evasion in CRPC. Our findings provide a compelling preclinical rationale for targeting PKMYT1 as a novel strategy to reprogram the tumor immune microenvironment and overcome resistance to immunotherapy.
    Keywords:  Combination therapy; Genitourinary Cancer; Immune Checkpoint Inhibitor; Immunotherapy; Prostate Cancer
    DOI:  https://doi.org/10.1136/jitc-2025-013247
  21. Arch Biochem Biophys. 2026 Jan 28. pii: S0003-9861(26)00024-X. [Epub ahead of print] 110753
    Exosomal miR-93-5p Modulates Macrophage Polarization to Enhance Prostate Cancer Progression.
    Yarong Wang, Wenjun Chen, Bei Yu, Liang Wang, Wei Tang.
       BACKGROUND: Prostate cancer (PC) remains a major public health challenge, with emerging evidence suggesting that microRNA-93-5p (miR-93-5p) plays a critical role in cancer progression.
    AIM: This study investigated how exosomal miR-93-5p derived from PC cells modulates tumor-associated macrophage (TAM) polarization and influences PC progression, while elucidating the underlying molecular mechanisms.
    METHODS: We analyzed miR-93-5p expression levels in PC tissues and serum samples, followed by detailed characterization of PC cell-derived exosomes. Subsequently, we evaluated the capacity of these exosomes to induce macrophage polarization, examined the regulatory relationship between miR-93-5p and suppressor of cytokine signaling 6 (SOCS6), and assessed the activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.
    RESULTS: Elevated miR-93-5p levels in PC tissues and serum were significantly associated with metastatic features. We demonstrated that PC cell-derived exosomes enriched with miR-93-5p effectively reprogram macrophages toward an immunosuppressive M2 phenotype. Mechanistically, this polarization was mediated through miR-93-5p-induced downregulation of SOCS6, a negative regulator of cytokine signaling, leading to subsequent activation of the JAK2/STAT3 pathway, which enhances PC cell motility and invasiveness. Importantly, xenograft experiments confirmed that miR-93-5p-enriched macrophages substantially accelerated tumor growth in vivo.
    CONCLUSION: Our findings reveal that exosomal miR-93-5p from PC cells drives M2 macrophage polarization and disease progression through SOCS6 suppression and JAK2/STAT3 pathway activation. These results identify exosomal miR-93-5p as a promising therapeutic target and provide new avenues for developing innovative treatment strategies against PC.
    Keywords:  Exosomal miR-93-5p; JAK2/STAT3 Signaling; Macrophage Polarization; Prostate Cancer; Tumor-Associated Macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.abb.2026.110753
  22. Dokl Biochem Biophys. 2026 Feb 04.
    Expression of Antioxidant Defense Genes Determines Synergistic Ferroptosis Induction by the Combination of Erastin and Omega-3 Docosahexaenoic Acid in Prostate Cancer Cells.
    M O Silkina, T A Kulagin, K V Klycheva, A D Shatsillo, M D Mastykina, A V Razumovskaya, K M Nyushko, S V Nikulin.
      Ferroptosis is considered a promising strategy for inducing the death of tumor cells. However, the effectiveness of known ferroptosis inducers, such as erastin, is in some cases limited, which stimulates the search for new combined application strategies. In this study, the combined effect of erastin and docosahexaenoic acid (DHA) on prostate cancer cells was examined over time. It was shown that the combination of these agents is more toxic compared to their separate use for all tumor cells considered. At the same time, known ferroptosis inhibitors, ferrostatin-1 and deferoxamine, effectively prevented cell death, indicating the specificity of the mechanism of action. Transcriptomic analysis of cell lines differing in sensitivity to the combination revealed activation of antioxidant systems in more resistant cells (in particular, pronounced expression of the NQO1 and GCLM genes responsible for the reduction of quinones to hydroquinones and the synthesis of glutathione, respectively). The obtained results indicate the high synergistic potential of the erastin-DHA combination for ferroptosis induction and open new possibilities for the development of combined approaches to the therapy of resistant tumors.
    Keywords:  docosahexaenoic acid; erastin; ferroptosis; polyunsaturated fatty acids; prostate cancer
    DOI:  https://doi.org/10.1134/S1607672925601660
  23. Med Oncol. 2026 Feb 05. 43(3): 128
    GRIN3A defines an immunosuppressive niche in advanced prostate cancer.
    Xinglin He, Yaohua Hu, Zhite Zhao, Tong Lu, Qinlong Li, Kankan He, Jianhui Bai, Liting Fang, Wei Peng, Xiaoyong Gong, Lijun Yang, Changhong Shi.
      Early-stage prostate cancer is typically manageable with standard therapies, yet the eventual development of castration-resistant prostate cancer (CRPC) remains a significant barrier to effective clinical management. Specifically, the response to immunotherapy in CRPC remains limited, primarily due to a lack of predictive biomarkers and specific therapeutic targets. This study systematically integrates single-cell transcriptomic data across various disease stages, coupled with multi-dimensional validation, to reveal that glutamate ionotropic receptor NMDA type 3A (GRIN3A) expression is persistently elevated throughout tumor evolution and correlates significantly with advanced pathological stages and poor prognosis. Notably, during the transition to CRPC, tumor subpopulations with high GRIN3A expression exhibit pronounced immunoregulatory properties. Experimental validation demonstrated that GRIN3A levels inversely correlate with T-cell infiltration and promote an immunosuppressive microenvironment, partially mediated by TGF-β signaling activation. Furthermore, GRIN3A expression predicts the efficacy of immune checkpoint blockade (ICB) therapy and sensitivity to multiple chemotherapeutic agents. Collectively, these results suggest that GRIN3A has the potential to serve as a biomarker for tumor heterogeneity and immunotherapy resistance, providing a rationale for further exploration of strategies to overcome immune evasion in advanced PCa.
    Keywords:  GRIN3A; Immune checkpoint blockade; Prostate cancer; TGF-β signaling; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12032-026-03244-3
  24. medRxiv. 2026 Jan 13. pii: 2026.01.09.26343808. [Epub ahead of print]
    Radio-pathomic maps of histo-morphometric features trained with whole mount prostate histology distinguish prostate cancer on MP-MRI.
    Savannah R Duenweg, Samuel A Bobholz, Allison K Lowman, Aleksandra Winiarz, Biprojit Nath, Michael J Barrett, Fitzgerald Kyereme, Stephanie Vincent-Sheldon, Kathleen Bhatt, Katherine Troy, Michael Kim, Eric Fair, Kenneth A Iczkowski, Kenneth M Jacobsohn, Anjishnu Banerjee, William A Hall, Andrew S Nencka, Peter S LaViolette.
       Background: Prostate cancer (PCa) is the most prevalent male cancer in the U.S., accounting for 29% of new cancer diagnoses. Multiparametric MRI (MP-MRI), including T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) maps, is an effective tool for detecting PCa; however, accuracy varies, and false-positives may lead to unnecessary biopsies or overtreatment. Radio-pathomic maps (RPMs), derived from MP-MRI and machine learning, have been advantageous in differentiating clinically significant PCa. This study tested whether RPMs of tissue density and histo-morphometric features could better predict cancer presence than conventional MR imaging.
    Materials and Methods: MP-MRI from 236 patients prospectively recruited between 2014 and 2023 with confirmed PCa were analyzed. Whole-mount prostate sections sliced to match the MRI were processed, digitized, and Gleason-pattern annotated by a GU pathologist. Automated algorithms identified glands and calculated quantitative histo-morphometric features, which were mapped across whole slide images. Slides were nonlinearly aligned to each patient's T2WI using in-house software, enabling direct comparison of slides, features, and annotations in MR-space. A multi-step prediction model was trained using a 2/3 - 1/3 train/test split to predict histo-morphometric features using 5×5 voxel tiles from T2WI and ADC. These feature maps were then used generate tumor probability maps.
    Results: Histological feature models produced RMSE values approximately within one standard deviation of the ground truth's variability, indicating acceptable performance. The best RPM, using histological density features, achieved an accuracy of ∼80%. Visual inspection of RPMs showed good concordance to high-grade cancer annotations.
    Conclusion: This study demonstrates that the use of MRI intensities can predict complex histo-morphometric features and delineate regions of PCa non-invasively. Future research is warranted to determine the clinical benefit of using RPMs in treatment guidance.
    DOI:  https://doi.org/10.64898/2026.01.09.26343808
  25. J Clin Invest. 2026 Feb 03. pii: e194949. [Epub ahead of print]
    Overexpression of the ERG oncogene in prostate cancer identifies candidates for PARP inhibitor-based radiosensitization.
    Sabrina Köcher, Mohamed E Elsesy, Ayham Moustafa, Wahid Mohammadi, Adriana Perugachi Heinsohn, Yamini Nagaraj, Su Jung Oh-Hohenhorst, Jan Hahn, Bente Siebels, Thomas Mair, Susanne Burdak-Rothkamm, Pierre Tennstedt, Ronald Simon, Tobias Lange, Derya Tilki, Thorsten Frenzel, Tobias Maurer, Cordula Petersen, Hartmut Schlüter, Carsten Bokemeyer, Gunhild von Amsberg, Kai Rothkamm, Wael Y Mansour.
      Radiotherapy (RT) is a central treatment for prostate cancer (PCa), acting by inducing DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. Therefore, tumor-specific radiosensitization strategies are critically needed for PCa. Approximately 50% of PCa cases harbor the TMPRSS2-ERG gene fusion, leading to overexpression of the ERG transcription factor (ERG+). We demonstrate that ERG+ tumors shift DSB repair toward the PARP1-dependent end-joining (PARP1-EJ) pathway. Proteomic and western blot analyses revealed elevated PARP1, XRCC1, and LIG3 in ERG+ cells. PARP inhibition with olaparib increased residual γH2AX/53BP1 foci post-irradiation in ERG+ cells, indicating enhanced radiosensitization. In tissue-slice-cultures (TSCs) from 53 tumors of 40 high-risk PCa patients, olaparib selectively increased H2AX/53BP1 foci selectively in ERG+ samples. ERG+ patient-derived organoids also showed significantly delayed growth and survival when treated with olaparib plus RT compared to either treatment alone. Interestingly, ERG-negative cells within ERG+ TSCs were similarly radiosensitized by olaparib, likely through bystander effect, with residual 53BP1 foci levels comparable to ERG+ cells, confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on PARP1-EJ, rendering ERG+ PCa more susceptible to PARP inhibition. Combining PARP inhibitors with RT may offer a tumor-selective radiosensitization for ERG+ PCa patients.
    Keywords:  Clinical Research; DNA repair; Oncology; Prostate cancer; Radiation therapy
    DOI:  https://doi.org/10.1172/JCI194949
  26. J Pers Med. 2026 Feb 02. pii: 83. [Epub ahead of print]16(2):
    RETRACTED: Lee et al. Machine-Learning-Based Survival Prediction in Castration-Resistant Prostate Cancer: A Multi-Model Analysis Using a Comprehensive Clinical Dataset. J. Pers. Med. 2025, 15, 432.
    Jeong Hyun Lee, Jaeyun Jeong, Young Jin Ahn, Kwang Suk Lee, Jong Soo Lee, Seung Hwan Lee, Won Sik Ham, Byung Ha Chung, Kyo Chul Koo.
      The journal retracts the article "Machine-Learning-Based Survival Prediction in Castration-Resistant Prostate Cancer: A Multi-Model Analysis Using a Comprehensive Clinical Dataset" [...].
    DOI:  https://doi.org/10.3390/jpm16020083
  27. J Med Chem. 2026 Feb 06.
    Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer.
    Yi-Zhe Zhang, Hui-Juan Zhu, Xiao-Xiao Zhou, Shi-Jie Li, Di Han, Feng-Xiang Liu, Hui-Min Zhou, Xin-Yu Jiang, Yuan-Yuan Guan, Hui-Ru Ren, Ying Wang, Wen-Jing Dai, Yi-Bo Ban, Nan Su, Yong-Cheng Ma, Yong-Tao Xu, Sai-Qi Wang, Ying-Chao Duan.
      CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03168
  28. Mol Ther Nucleic Acids. 2026 Mar 12. 37(1): 102836
    Identification and diagnostic evaluation of an aptamer targeting prostate-cancer-derived small extracellular vesicles.
    Ting Ding, Yue Li, Li Xue, Chaoliang Xiong, Lijuan Yu, Qian He, Jiayun Liu, Xiaoke Hao, Dan Zhao.
      Prostate cancer (PCa) lacks convenient, non-invasive, and highly specific diagnostic markers. Aptamers have emerged as preferred probes for biosensors that target extracellular vesicles (EVs). This study aimed to explore the diagnostic value of PCa-specific EVs aptamer probes. We used EV-SELEX to identify aptamers that selectively target PCa small EVs (sEVs). Surface plasmon resonance (SPR) and nanoflow cytometry were used to verify aptamer affinity. The diagnostic value of PCa was evaluated using clinical samples from patients. We screened and validated an aptamer, seq25, which exhibited high specificity for PCa-derived sEVs. The SPR assay revealed a strong binding affinity, with a KD of 24.02 nM and a dose-dependent binding response. Nanoflow cytometry demonstrated that seq25 could distinguish sEVs from PCa and normal prostate cell lines. In clinical specimens, the proportion of seq25-positive sEVs isolated from urine samples was significantly higher in patients with PCa than in those with benign prostatic hyperplasia. Our study integrated the diagnostic advantages of EVs with the technical benefits of aptamers to develop a PCa-specific sEVs aptamer probe that offers a promising non-invasive approach for PCa diagnosis.
    Keywords:  MT: Special Issue: Innovations in Aptamer Technology; aptamer; extracellular vesicle; liquid biopsy; prostate cancer; urine biomarker
    DOI:  https://doi.org/10.1016/j.omtn.2026.102836
  29. Eur J Pharmacol. 2026 Jan 30. pii: S0014-2999(26)00093-2. [Epub ahead of print]1016 178611
    Metabolic crosstalk in the metastatic prostate cancer-bone microenvironment: mechanism, detection and therapeutic strategies.
    Ruoxuan Zheng, Yingchao Zhao, Luyao Gong, Yuanyuan Wang, Ke Xu, Yuan Gao.
      Androgen deprivation therapy is the main treatment for prostate cancer (PCa). However, the majority of cases will advance to castration-resistant prostate cancer (CRPC) and then to metastatic CRPC (mCRPC), with bone metastasis accounting for over 90% of mCRPC cases. PCa bone metastasis appears predominantly osteosclerotic, and the processes of bone formation and bone resorption are dysregulated in the presence of PCa. It has been highlighted that cancer cells can adjust their metabolism selectively and dynamically at each stage of the metastatic cascade. More evidence has shown that metabolic reprogramming in the tumor-bone microenvironment plays a key role in promoting disease progression. Therefore, understanding the complex process between bone metastasis and metabolism in PCa could uncover novel targets to tackle these difficult questions in cancer. This review aims to present the latest discovery in the metabolic shifts (including glucose, lipid, and amino acid metabolism) in the bone microenvironment and the crosstalk between PCa cells and the bone local resident cells (such as adipocytes, osteoblasts, osteoclasts, and immune cells). The metabolism-associated and bone-targeted therapeutic strategies and biomarkers are also explored.
    Keywords:  Bone metastasis; Bone microenvironment; Metabolism; Prostate cancer; Therapy
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178611
  30. J Nanobiotechnology. 2026 Feb 01.
    Single-cell sequencing-guided design of synergistic chemo-immunotherapy nanodrugs for cGAS-STING activation in prostate cancer therapy.
    Yu Jiang, Yaowu Zhang, Jingqi Hou, Heng Liu, Xianyu Dai, Yuchuan Hou.
      Characterizing the tumor immune microenvironment (TIME) to explore potential therapeutic targets is fundamental to advancing precision tumor immunotherapy. However, the immunosuppressive nature of "cold" tumors, notably prostate cancer, poses a significant barrier to immunotherapy, demanding new approaches to simultaneously reinvigorate anti-tumor immunity and modulate the molecular drivers of immune evasion. Here, we identified VSIG4 as a key regulator of prostate tumor-resident macrophage fate through single-cell sequencing analysis. Meanwhile, a shikonin (Shik)-mediated downregulation of VSIG4 in macrophages is verified, potentially attenuating its immunosuppressive effects. Building on these findings, cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-modified manganese (Mn)-Shik metal-polyphenol network nanodrugs (Mn/Shik@CpG NDs) are designed to reverse the "cold" immune environment of prostate tumor. In this scenario, Mn/Shik@CpG NDs release monomeric components under the stimulation of acidic and glutathione-rich tumor microenvironment (TME), thus exerting their immunomodulatory effects synergistically. Since the released Shik can induce DNA damage by necroptosis promoting reactive oxygen species production, cGAS-STING signaling pathway is initiated, which further activates interferon production in the TME. In addition, the necroptosis of Shik initiates immunogenic cell death, further activating innate immunity and promoting adaptive immune responses. Mn2+ is a cGAS-STING sensitizer, which amplifies the intratumoral interferon response. As an immune adjuvant, CpG ODN effectively promotes the maturation of dendritic cells, as well as the helper T cell differentiation and pro-inflammatory cytokine secretion, thus activating both innate and adaptive immunity. In vivo studies suggest that Shik-mediated VSIG4 downregulation, combined with innate and adaptive immune activation, remodels the TIME to evoke a significant anti-tumor response. Furthermore, transcriptomic analysis of rechallenged tumors indicated this durable protection was driven by a genuine immune memory response, revealing a gene signature of T cell activation and immune reprogramming. Collectively, beyond presenting a novel therapeutic candidate for converting immunologically "cold" tumors into "hot" ones, our work validates a data-guided design pipeline, offering a conceptual blueprint to inform the precise engineering of future nanodrugs.
    DOI:  https://doi.org/10.1186/s12951-026-04062-5
  31. BJUI Compass. 2026 Feb;7(2): e70162
    Risk factors of negative prostate biopsies: A CHAID decision tree analysis.
    Pierre Allainguillaume, Coralie Uthe-Spencker, Laura Larnaudie, Mathilde Sibony, Anthony Kanbar, Albert Semaan, Nicolas Barry Delongchamps, Michael Peyromaure, Julien Anract.
       Objectives: This study aimed to perform a risk analysis of any prostate cancer (Pca) and of clinically significant prostate cancer (csPCa) in a contemporary cohort of prostatic biopsies.
    Materials and Methods: We conducted a retrospective analysis of patients who underwent prostate biopsies in our centre between December 2020 and December 2022. We calculated Pca and csPCa rate (ISUP grade ≥2). Univariate and multivariate regression models were constructed to assess independent predictive factors for Pca and csPCa. We used χ 2 automatic interaction detection (CHAID) for decision tree analysis.
    Results: We included 255 patients in the analysis, of whom 69.8% had positive biopsies for Pca and 36.9% for csPCa. Multivariate analysis found PSA density (PSAd) (OR = 1.001) (1.000; 1.001), PIRADS score (OR = 1.393) (1.234; 1.571) as independent predictive factors of csPCa. For the detection of any PCa, CHAID analysis revealed that patients with PIRADS score ≤4 doubled the risk of negative biopsies (from 22.6% to 54.3%) when the prostate volume was >46 mL.
    Conclusion: For patients with a PIRADS ≤4, a large prostate volume (>46 mL) was a predictor of negative biopsies, independently of PSAd. MRI interpretation and targeting in these patients should therefore be performed with particular caution.
    Keywords:  prostate biopsies; prostate cancer; risk factors
    DOI:  https://doi.org/10.1002/bco2.70162
  32. Nat Commun. 2026 Feb 07.
    Analysis of the transcriptomic and metabolomic landscape of prostate cancer with different anatomical origins using snFLARE-seq and mxFRIZNGRND.
    Dongyin He, Haoran Hu, Kai Xiao, Yuhang Zhang, Yongbing Cheng, Shaozhuo Jiao, Yimei Hao, Yuanyuan Cai, Ziqun Liu, Xinran Yan, Qinsheng Chen, Xiyan Mu, Qi Wang, Shan Peng, Guoqin Sang, Xiaoling Zhi, Yanxia Chang, Qing Ye, Yuyao Yang, Meixia Che, Shengsong Huang, Hongqian Guo, Luonan Chen, Huiru Tang, Xuefeng Qiu, Zhenfei Li.
      Prostate cancer cells of different anatomical locations display remarkable heterogeneity. This poses a challenge to the clinical relevance of pre-clinical models and the efficacy of contemporary therapeutic approaches. Here we develop the snFLARE-seq and mxFRIZNGRND methodologies to directly investigate the transcriptomic and metabolomic landscape of prostate cancer patients utilizing formalin-fixed paraffin-embedded (FFPE) specimens. A retrospective analysis reveals the clinical disparities of prostate cancer from peripheral zone (PZ), transition zone (TZ), and across PZ and TZ. The snFLARE-seq, refined for enhanced single-nucleus sequencing, unveils distinct cell type distributions and signaling pathways between PZ and TZ samples. Hormone therapy substantially affects cancer cells and microenvironment, leading to a polarized feature of epithelial cells and a subverted immune microenvironment. With improvements in metabolite extraction, mxFRIZNGRND reveals unique metabolic features of prostate cancer from different origins. The metabolomic results indicate that PZ cancer cells are in a metabolic-dormant status, which are probably awaken by hormone therapy. Integrative analysis of results from snFLARE-seq, mxFRIZNGRND, and TCGA database uncovers four metabolic pathways and related genes associated with disease aggressiveness. Our work could accelerate investigations on disease heterogeneity and evolution in real-world clinical settings, stimulating patient-specific precision healthcare solutions.
    DOI:  https://doi.org/10.1038/s41467-026-69347-7
  33. Lancet Oncol. 2026 Feb;pii: S1470-2045(25)00760-0. [Epub ahead of print]27(2): 139-141
    Oligometastatic prostate cancer: time to integrate metastasis-directed therapy.
    Simon K B Spohn, Anca-Ligia Grosu.
      
    DOI:  https://doi.org/10.1016/S1470-2045(25)00760-0
  34. Mol Ther Oncol. 2026 Mar 19. 34(1): 201125
    Rhabdoid tumors as a novel target for PSMA-directed CAR T cell therapy.
    Aroshi Mitra, Tianyi Zhou, Jacky Wu, Tran Nguyen, Chengtai Yu, Amrita Barua, Luping Huang, Xiaoting Jiang, Rajkumar Venkatramani, Moonsoo M Jin, Bin He, Qin Feng.
      Rhabdoid tumor is an ultra-rare and highly aggressive pediatric malignancy with a poor prognosis and limited therapeutic options. To identify novel immunotherapeutic targets, transcriptomic data from the Cancer Cell Line Encyclopedia were analyzed, and we found that two rhabdoid tumor cell lines exhibit high expression of prostate-specific membrane antigen (PSMA), with levels comparable to well-established PSMA-positive prostate cancer cell lines. PSMA expression in rhabdoid tumors was subsequently validated in cell lines and in a subset of primary clinical rhabdoid tumor specimens. While PSMA-directed therapies have primarily been explored in prostate cancer, we evaluated their potential in rhabdoid tumors by employing PSMA-directed chimeric antigen receptor (CAR) T cells. These CAR T cells demonstrated potent and antigen-specific cytotoxicity against PSMA-positive rhabdoid tumor cells in vitro. In addition, the in vivo efficacy was also assessed in xenograft mouse models of non-CNS tumors, where PSMA CAR T cell treatment resulted in significant tumor regression and robust accumulation of CAR T cells within the tumor microenvironment. Together, these findings establish PSMA as a promising surface antigen beyond prostate cancer and provide preclinical evidence supporting the development of PSMA-directed therapies for this highly lethal pediatric cancer.
    Keywords:  CAR T cell therapy; MT: Special Issue - Advancements in pediatric cancer therapy; PSMA; pediatric cancer; rhabdoid tumor; targeted immunotherapy
    DOI:  https://doi.org/10.1016/j.omton.2026.201125
  35. J Prim Care Community Health. 2026 Jan-Dec;17:17 21501319261420570
    Prostate Cancer Screening: Evidence, Endpoints, and Expert Opinion.
    Takeshi Takahashi.
      
    DOI:  https://doi.org/10.1177/21501319261420570
  36. J Clin Invest. 2026 Feb 02. pii: e200920. [Epub ahead of print]136(3):
    Exploring the biology of metastatic hormone-sensitive prostate cancer: on the road to precision medicine.
    Alice Bernard-Tessier, Himisha Beltran.
      Metastatic hormone-sensitive prostate cancer (mHSPC) is a clinically and molecularly heterogeneous disease. Recent insights into the biology underlying disease presentation, volume of disease, and response to therapies are starting to point toward biomarkers to improve selection for intensified and deintensified treatment strategies. In addition, the therapeutic landscape is rapidly changing, with new biomarker-driven studies targeting genotype (e.g., BRCA or PTEN mutant) and phenotype (e.g., prostate-specific membrane antigen status) in development for mHSPC. A better understanding of tumor heterogeneity, clonal evolution, and metastatic homing in prostate cancer will hopefully inform future strategies for local and systemic disease control, personalized monitoring strategies, and improved patient outcomes.
    DOI:  https://doi.org/10.1172/JCI200920
  37. medRxiv. 2026 Jan 13. pii: 2026.01.10.26343859. [Epub ahead of print]
    The temporal dynamics of the immune response to neoadjuvant androgen deprivation therapy suggests a window-of-opportunity for checkpoint inhibitor therapy in prostate cancer.
    Anmbreen Jamroze, Renyuan Zhang, Kriti Ahuja, Lei Deng, Karan Jatwani, Uyen Nguyen, Bailey Farmer, Gaybrielle James, Michalis Mastri, Kevin H Eng, Bo Xu, Yvonne M Saenger, Yuanquan Yang, John J Krolewski, Dean G Tang, Gurkamal Chatta, Kent L Nastiuk.
       Purpose: Novel therapies to prevent lethal castration resistant prostate cancer in response to standard-of-care androgen deprivation therapy (ADT) are required. Unfortunately, most prostate cancers are "immune cold" and fail to respond to checkpoint inhibitors (CPIs). To assess whether ADT induces changes that enable more effective CPI therapy, we examined the tumor immune micro-environment (TiME) following neoadjuvant ADT (nADT).
    Design: Radical prostatectomy specimens from 43 nADT-treated patients were stratified into three duration groups and compared to each other and matched controls. RNA sequencing and quantitative multispectral immunofluorescence (qmIF) staining were performed to analyze transcriptomic and TiME abundance and cellular spatial relationship differences after nADT.
    Results: Immune and inflammatory pathways, particularly of antigen presentation and adaptive immune response, were increased, most notably in tumors receiving 3-5 months nADT. qmIF revealed a complex temporal response in the TiME, with a dramatic influx of CTLs and T-helper cells after 3-5 months of nADT. However, after 6 months nADT, M2-like tumor associated macrophages (TAMs) and Tregs were strikingly increased while CTLs decreased. Spatially, CTLs and T-helper cells, clustered near tumor cells at 3-5 months nADT, were replaced by M2-TAMs in tumors receiving ≥ 6 months of nADT.
    Conclusion: These data reveal the induction of a bi-phasic response in the TiME: robust CTL activation 3-5 months after nADT is initiated, followed by myeloid immunosuppression in tumors receiving prolonged nADT. This ADT-induced reprogramming of the TiME suggests a critical window of opportunity where short-duration ADT might augment CPI efficacy, converting cold into immunologically responsive tumors.
    Translational Relevance: Immune Checkpoint inhibitors (CPIs) have not been effective in treating most human prostate cancers. This study describes the temporal dynamics of the immune response of primary prostate cancers to neoadjuvant androgen deprivation therapy (nADT), and suggests a strategic approach to improve the efficacy of CPIs in prostate cancer. After several months of nADT, inflammation and immune-related pathways were activated, accompanied by a robust infiltration of both CD8 + and CD4 + T cell into prostate tumors, indicating effector T cell education and activation. In contrast, six or more months nADT leads to an immunosuppressive shift, evidenced by increased M2-like tumor associated macrophages and regulatory T cells. Thus, our findings suggest a critical window of opportunity following nADT for initiating CPIs. This provides a rationale for the precise sequencing of nADT and CPI regimens to maximize therapeutic benefit.
    DOI:  https://doi.org/10.64898/2026.01.10.26343859
  38. Clinics (Sao Paulo). 2026 Feb 02. pii: S1807-5932(26)00003-7. [Epub ahead of print]81 100862
    Six IL-8 gene polymorphisms and the entire cancer susceptibility according to a comprehensive analysis especially in prostate cancer.
    Xiao Zhang, Jian Sun, Xiqi Ding.
       OBJECTIVES: Interleukin-8 (IL-8) is a key cytokine regulating immunity and inflammation, and its genetic polymorphisms have been increasingly linked to cancer susceptibility. However, findings on the role of specific IL-8 polymorphisms across different cancers remain inconsistent, necessitating a comprehensive meta-analysis.
    METHODS: The authors systematically searched Embase, PubMed, Chinese databases, Google Scholar, and Web of Science up to June 25, 2023. A total of 104 case-control studies (26,029 cases and 31,577 controls) were included in a high-powered meta-analysis. Summary Odds Ratios (ORs) with 95% Confidence Intervals (95% CIs) were calculated using Stata. Additionally, the authors performed an ELISA-based validation study to measure serum IL-8 levels in Prostate Cancer (PCa) patients grouped by genotype.
    RESULTS: The +2767 polymorphism was associated with a significant reduction in overall cancer risk. The +781 polymorphism increased cancer risk specifically in Caucasian populations. In contrast, the -251 polymorphism demonstrated a strong pan-cancer risk association, particularly in Mixed/Asian ethnicities, gastric cancer, lung cancer, and hospital-based studies. Mechanistically, patients with the -251 AA/AC genotypes had elevated serum IL-8 levels, which were linked to more aggressive PCa pathogenesis.
    CONCLUSION: This pioneering meta-analysis identifies the IL-8 -251 polymorphism as a high-risk biomarker and +2767 as a protective variant. By functionally validating that the -251 risk allele promotes PCa progression via IL-8 overexpression, the present study establishes IL-8 genotyping as a potential tool for ethnic-specific risk stratification and prognostic prediction, with broad implications for precision oncology.
    Keywords:  Interleukin-8; Meta-analysis; Polymorphism; Prostate cancer; Risk
    DOI:  https://doi.org/10.1016/j.clinsp.2026.100862
  39. J Biophotonics. 2026 Feb;19(2): e70233
    Prostate Cancer Characterization Based on Rapid SHG Imaging of Collagen Fiber Combined With Denoising Algorithm.
    Jia He, Xinpeng Huang, Yating Fang, Hong Chen, Chaoran Ban, Hua Zheng, Yuanying Zhang, Xiaoqin Zhu.
      Second harmonic generation (SHG) imaging technique can specifically image components such as collagen fibers, which provides diagnostic information for prostate cancer (PCa). Gleason grading serves as the primary criterion for assessing PCa. However, obtaining high signal-to-noise ratio (SNR) SHG images requires prolonged acquisition, limiting clinical feasibility. In this study, rapid SHG imaging was combined with a deep-learning-based denoising network, Selective Residual M-Net (SRMNet), to reconstruct high-fidelity images from low-SNR inputs. The denoising procedure markedly enhanced image quality while preserving collagen alignment features essential for quantitative assessment. The enhanced image fidelity enabled more robust extraction of collagen orientation metrics under low-SNR conditions, facilitating accurate assessment of stromal organization with reduced acquisition time. These results highlight that deep-learning-assisted SHG imaging provides an effective strategy for reliable collagen orientation analysis in PCa, supporting the development of rapid and objective optical histopathology.
    Keywords:  Gleason pattern; collagen; deep learning denoising; fast imaging; prostate cancer; second harmonic generation (SHG)
    DOI:  https://doi.org/10.1002/jbio.70233
  40. J Immunother Cancer. 2026 Feb 02. pii: e013818. [Epub ahead of print]14(2):
    Oncolytic virus OH2 induces PD-L1 upregulation via NF-κB signaling and synergizes with anti-PD-L1 therapy in prostate cancer through a targeted extracellular vesicle delivery system.
    Jin-Zhou Xu, Ye An, Jian-Xuan Sun, Yi-Fan Xiong, Chen-Qian Liu, Si-Han Zhang, Zhi-Yu Xia, Jia Hu, Zi-Yi Zhang, Ci-Xiang Guo, Bin-Lei Liu, Wei Guan, Shao-Gang Wang, Qi-Dong Xia.
       BACKGROUND: Prostate cancer (PCa) is a prevalent malignancy with limited treatment options for advanced stages. Oncolytic virotherapy represents a promising immunotherapeutic approach, but its efficacy and underlying mechanisms in PCa, particularly concerning immune checkpoint regulation, remain unclear.
    METHODS: The antitumor effects of the oncolytic virus oncolytic herpes simplex virus type 2 (OH2) were evaluated in PCa cell lines and mouse models. Transcriptome sequencing, western blot, chromatin immunoprecipitation-sequencing-quantitative PCR, and flow cytometry were employed to investigate the mechanism of programmed death 1 ligand 1 (PD-L1) regulation. A targeted delivery system, reactive oxygen species (ROS)-responsive aptamer-conjugated anti-prostate-specific membrane antigen (PSMA) extracellular vesicles (RRA-AP-EVs), was engineered from anti-PSMA single chain variable fragment (scFv)-modified extracellular vesicles and an ROS-responsive PD-L1 blocking aptamer. OH2 was loaded via membrane extrusion, and the resulting OH2@RRA-AP-EVs were tested for targeting and therapeutic efficacy following intravenous administration.
    RESULTS: OH2 effectively killed PCa cells but simultaneously activated the IKK/I-κBα/p65 pathway, leading to PD-L1 upregulation and adaptive immune resistance. While combining OH2 with anti-PD-L1 improved outcomes, clinical translation was hindered by delivery challenges. The novel OH2@RRA-AP-EVs system demonstrated precise tumor targeting and ROS-triggered local PD-L1 blockade. Intravenous injection of OH2@RRA-AP-EVs showed superior tumor control (inhibiting tumor growth by 70% vs free OH2) and enhanced CD8+T cell infiltration and function compared with free OH2 (greater than twofold increase in intratumoral CD8+T cell infiltration along with over twofold upregulation of key effector molecules).
    CONCLUSION: This study identifies a mechanism of OH2-induced PD-L1 expression in PCa and provides a versatile, targeted delivery platform that enables effective intravenous viro-immunotherapy, overcoming key translational barriers.
    Keywords:  Immunosuppression; Oncolytic virus; Prostate Cancer; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-013818
  41. Cell Rep. 2026 Jan 31. pii: S2211-1247(26)00028-8. [Epub ahead of print]45(2): 116950
    FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity.
    Erik M Ladewig, Abbas Nazir, Tyler Park, Vinson B Fan, Zhendong Cao, Jacob Hawk, Lauren Kelly, Robert Tjian, Christina S Leslie, Charles L Sawyers.
      Mutations in the pioneer transcription factor FOXA1 occur in 10%-40% of prostate cancers and broadly alter chromatin accessibility. In a cohort of 874 primary and metastatic tumors, we confirm frequent Wing2 missense mutations and indels, as well as C-terminal truncating frameshifts. To define their functional impact, we performed single-nucleus multiome profiling in mouse prostate organoids expressing representative alleles, including overexpressed wild-type FOXA1. Each subgroup produces distinct chromatin and transcriptional changes, but all perturb epithelial lineage specification. Indel mutants promote basal-like states, whereas C-terminal truncations, Wing2 missense mutations, and elevated wild-type FOXA1 drive secretory L1-like luminal fates. Integrated RNA-seq, ATAC-seq, and ChIP-seq reveal that L1-like specification involves a hybrid androgen receptor/FOXA1 motif and cooperation with POU2F1. In vivo, these same alleles, combined with Trp53/Pten loss, shift tumor histology from basal-like to secretory luminal phenotypes.
    Keywords:  CP: cancer; CP: molecular biology; FOXA1; POU2F1; basal; luminal; prostate
    DOI:  https://doi.org/10.1016/j.celrep.2026.116950
  42. Prostate Int. 2025 Sep;13(3): 142-147
    Time to castrate the cost? the rising expense of chemical castration for the management of prostate cancer.
    Alice Thomson, Haidar Al Saffar, Jake Tempo, Nathan Lawrentschuk, Declan G Murphy, Marlon Perera.
       Background: Androgen deprivation therapy (ADT) remains the backbone of treatment of advanced prostate cancer. Conventionally, this is achieved by means of Gonadotropin Releasing Hormone (GnRH) analogs, though in recent years, four novel androgen receptor pathway inhibitors (nARPIs) have been approved for the treatment of advanced prostate cancer. We aim to analyze the increase in cost of chemical castration in advanced prostate cancer associated with the introduction of these medications.
    Methods and methods: The publicly available Pharmaceutical Benefits Scheme database was accessed for conventional ADT and nARPI prescription data between January 2010 and January 2024. The number of prescriptions and cost of prescriptions were categorized by month and state. A descriptive analysis was performed outlining the therapy-prescribing patterns and discordances at a national and state-/territory-based level.
    Results: From January 2010 to January 2024, over 1.7 million scripts were dispensed for conventional ADT compared to 412,925 for nAPRI therapy. The average cost for ADT rose from $9.9 million to 10.9 million. The average cost for nARPI therapy rose from $5.2 million to $17.3 million. There was significant difference between state-prescribing practices despite population-adjusted analysis.
    Conclusions: While intensified treatment has proven to improve prostate cancer survival, this had led to an exponential increase in the cost of treatment. Clinicians must exercise caution when prescribing these medications to ensure patients will appropriately benefit from their advantage to cancer-specific survival in the context of their overall health to ensure appropriate distribution of resources.
    Keywords:  Advanced prostate cancer; Androgen deprivation therapy; Chemical castration; Novel androgen receptor inhibitors
    DOI:  https://doi.org/10.1016/j.prnil.2025.01.003
  43. Eur Urol Open Sci. 2026 Feb;84 70-76
    Diagnostic Value of Transabdominal Ultrasound-based Versus Magnetic Resonance Imaging-based Prostate-specific Antigen Density for Clinically Significant Prostate Cancer.
    Zheng Xu, Haifeng Song, Haiwen Huang, Meng Fu, Yuzhe Tang, Peizhi Zhang, Gang Zhang, Jianxing Li.
       Background and objective: Prostate-specific antigen (PSA) density (PSAD) improves risk stratification for clinically significant prostate cancer (csPCa) but depends on prostate volume estimation. Transrectal ultrasound is used widely, whereas transabdominal ultrasound (TAUS) is underexplored due to accuracy concerns. We compared PSAD derived from manual magnetic resonance imaging (MRI) segmentation, MRI ellipsoid, and TAUS ellipsoid.
    Methods: In a single-centre retrospective cohort, men who underwent biopsy or prostatectomy with histopathological confirmation were included. (1) Manual MRI segmentation versus (2) ellipsoid formulae derived from MRI and TAUS diameters were compared. We evaluated discrimination (area under the curve [AUC]), decision curve net benefit, method agreement, and clinical utility defined by biopsy burden across illustrative PSAD thresholds.
    Key findings and limitations: Of 486 men, 299 had complete MRI and TAUS data (mean age 71.5 [standard deviation 8.3] yr; median PSA 10.3 ng/ml); 98 (32.8%) had csPCa. Both ellipsoid formula underestimated volume, with TAUS marginally closer to the reference. However, at the illustrative threshold of PSAD = 0.15 ng/ml/cc, the estimated biopsy burden was comparable: 53.5 (manual), 57.2 (MRI), and 56.5 (TAUS) biopsies per 100 men, with identical sensitivity (0.837). Discrimination was similar, with AUCs of 0.83 (manual), 0.82 (MRI), and 0.81 (TAUS), and a decision curve analysis demonstrated overlapping net benefits. The main limitations are the retrospective single-centre design and the lack of external validation.
    Conclusions and clinical implications: Despite volume differences, PSAD derived from TAUS and MRI ellipsoid formulae demonstrated discrimination and net benefit comparable with those of manual segmentation. TAUS-based PSAD represents a pragmatic alternative for risk stratification, particularly in resource-limited settings where MRI segmentation is infeasible.
    Patient summary: We compared three ways to measure prostate volume to calculate prostate-specific antigen (PSA) density. All three ways showed similar accuracy for finding important prostate cancers, suggesting that ultrasound-based PSA density can be used when detailed magnetic resonance imaging measurements are not practical.
    Keywords:  Clinically significant prostate cancer; Magnetic resonance imaging; Prostate volume estimation; Prostate-specific antigen density; Transabdominal ultrasound
    DOI:  https://doi.org/10.1016/j.euros.2026.01.003
  44. Anticancer Res. 2026 Feb;46(2): 1107-1116
    Prolonged Castration Prior to Docetaxel Reduces Febrile Neutropenia in Patients With Metastatic Hormone-sensitive Prostate Cancer Receiving Triple Therapy.
    Yasutaka Yamada, Tomoki Shirafuji, Kodai Sato, Takuya Tsujino, Satoshi Yamamoto, Takayuki Arai, Hiroaki Sato, Kosuke Higuchi, Manato Kanesaka, Nobushige Takeshita, Takaaki Tamura, Tomokazu Sazuka, Yusuke Imamura, Kazuo Mikami, Kazuyoshi Nakamura, Satoshi Fukasawa, Akira Kurozumi, Noriyuki Suzuki, Haruhito Azuma, Shinichi Sakamoto.
       BACKGROUND/AIM: Triplet therapy, combining androgen deprivation therapy (ADT), darolutamide, and docetaxel has recently emerged as the standard first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC). Febrile neutropenia (FN) is a major clinical issue not only as a serious infection but also as a cause for early cessation or dose reduction of chemotherapy. However, little is known regarding the predictive factors for the development of FN in patients with mHSPC receiving triplet therapy.
    PATIENTS AND METHODS: This study enrolled 60 patients diagnosed with mHSPC across multiple institutions from 2023 to 2025. We examined clinical characteristics, treatment schedules, adverse events, and oncological outcomes. We focused particularly on the development of FN and used logistic regression analysis to investigate the predictive factors.
    RESULTS: The median age was 72 years old, and 43 patients (73.3%) had high-volume disease at diagnosis. Nine patients (15%) developed FN. Multivariate logistic regression analysis identified older age [≥75, p=0.0161; hazard ratio (HR)=7.49], high-volume disease (p=0.0335), and shorter interval from ADT to docetaxel (<40 days) (p=0.0389; HR=7.86) as independent predictive factors of the development of FN. Notably, prolonged castration period prior to docetaxel (≥40 days) significantly reduced the risk of FN from 23.5% to 3.8% (p=0.0001). Patients who developed FN tended to have shorter castration-resistant prostate cancer progression-free survival (CRPC-PFS) compared to those who did not (p=0.0812; HR=3.2).
    CONCLUSION: Older age and high-volume disease were independent risk factors for FN in patients with mHSPC receiving triplet therapy. A longer interval from ADT initiation to docetaxel (≥40 days) was associated with a significantly lower risk of FN, suggesting that extending the pre-docetaxel castration period is a practical, adjustable scheduling strategy to improve treatment safety. These findings may support treatment selection and proactive prevention of FN.
    Keywords:  Prostate cancer; docetaxel; febrile neutropenia; metastatic hormone-sensitive prostate cancer; triplet therapy
    DOI:  https://doi.org/10.21873/anticanres.18013
  45. JAMA Netw Open. 2026 Feb 02. 9(2): e2556732
    Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years.
    Maximilian Lindholz, Robin Bülow, Ivo G Schoots, Marc Kölln, Saskia Nolte, Georg L Baumgärtner, Jean-Francois Chenot, Carsten O Schmidt, Martin Burchardt, Matthias Nauck, Henry Völzke, Mark O Wielpütz, Tobias Penzkofer, Norbert Hosten, Charlie A Hamm.
       Importance: Prostate cancer incidence is projected to double by 2040, yet optimal risk stratification approaches for screening remain unclear despite recent international endorsements of organized programs that call for risk-adapted algorithms using readily available biomarkers.
    Objective: To identify biomarkers for risk-adapted prostate cancer screening in men without prostate cancer.
    Design, Setting, and Participants: This cohort study used data from the Study of Health in Pomerania (SHIP), a prospective population-based research initiative in Germany that randomly invited participants aged 20 to 79 years who underwent comprehensive examinations with structured 20-year follow-up. Data were collected from October 17, 1997, through September 14, 2021, with final analysis completed November 16, 2025.
    Exposures: Baseline clinical and liquid biomarkers, including body mass index, waist-to-hip ratio, and glycated hemoglobin, together with prostate cancer-specific biomarkers of serum prostate-specific antigen (PSA) and magnetic resonance imaging-derived prostate volume and PSA density.
    Main Outcomes and Measures: The primary outcome was long-term prostate cancer incidence. Cumulative incidence functions for prostate cancer and death were treated as competing risks. Cause-specific Cox models were used to estimate risk and assess the association between baseline biomarkers and long-term incidence.
    Results: Among 2651 men included in the study (median [IQR] age, 54.0 [48.0-62.0] years), 1482 (55.9%) had low baseline PSA levels (<1.00 ng/mL), with a cumulative prostate cancer incidence of 0.1% (95% CI, 0.0%-0.4%), 0.6% (95% CI, 0.3%-1.2%), and 3.3% (95% CI, 2.1%-4.8%) at 5, 10, and 20 years, respectively. In 958 men (36.1%) with intermediate PSA levels (1.00-3.00 ng/mL), prostate cancer incidence was 1.4% (95% CI, 0.7%-2.3%), 5.0% (95% CI, 3.6%-6.6%), and 11.8% (95% CI, 9.2%-14.8%) at 5, 10, and 20 years, respectively. In 211 men (8.0%) with high PSA levels (>3.00 ng/mL), prostate cancer incidence was 14.5% (95% CI, 10.1%-19.7%), 28.3% (95% CI, 22.2%-34.8%), and 34.8% (95% CI, 27.5%-42.2%) at 5, 10, and 20 years, respectively. Cumulative prostate cancer incidence differed significantly among the PSA groups (P < .001). In univariable and multivariable Cox regression, age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.07), PSA (HR, 1.06; 95% CI, 1.04-1.07), and PSA density (HR, 1.41; 95% CI, 1.30-1.52) remained consistently associated with prostate cancer risk, whereas other variables showed either no association or inconsistent results across models.
    Conclusions and Relevance: This cohort study found that a low baseline PSA level was associated with low long-term prostate cancer risk among men aged 45 to 70 years, supporting risk-adapted screening with extended intervals for men with low PSA levels.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.56732
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