bims-meproc 2025-12-28 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–12–28
27 papers selected by
Grigor Varuzhanyan, UCLA

Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression.
Qiling decoction enhances the anti-tumor activity of abiraterone acetate by up-regulating miR-143 expression in abiraterone acetate-resistant prostate cancer cells.
Network Pharmacology and Experimental Validation Reveal Aidi Injection Suppresses Prostate Cancer via EGFR Inhibition and STAT3-Mediated Apoptosis.
Kaempferol suppresses prostate cancer metastasis and tumor angiogenesis via disrupting the LIMK1/Cofilin pathway.
Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.
LC-MS/MS and high-spatial single-cell MSI reveal selective downregulation of PC(16:0_16:0) and PC(18:0_18:1) due to mPGES-1 knockdown in hormone-resistant prostate cancer cell line.
Network and Gene Set Enrichment Analysis of Adipokine Drivers of Prostate Cancer; Unravelling the Mechanistic Link Between Excess Adiposity and Prostate Cancer Risk.
Evaluating Differential Metabolic Profiles by Prostate Cancer Risk Among Prostate Cancer Patients.
Association between ESRα and ESRβ polymorphisms and prostate cancer risk: meta-analysis.
Unraveling diethyl phthalate-induced prostate carcinogenesis: core targets revealed by integrated network toxicology, machine learning, and structural validation.
Discovery of Essential Genes as Possible Targets for Prostate Cancer Drug Development.
Obesogenic Dysregulation of Human Periprostatic Adipose Tissue Promotes the Viability of Prostate Cells and Reduces Their Sensitivity to Docetaxel and Cabazitaxel.
Real-world efficacy of switching androgen receptor signaling inhibitor therapy following apalutamide discontinuation because of adverse events in advanced prostate cancer: a multicenter study.
Aberrantly glycosylated PSMA in urine as a potential marker for prostate cancer.
FAM111B promotes prostate cancer progression by inhibiting apoptosis via ATF3 suppression and MAPK pathway activation: a novel biomarker and therapeutic target.
Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.
Clinical value and molecular role of PRDXs family in prostate cancer.
Targeting secreted PLA2 interactions with EGFR and vimentin to arrest prostate tumour growth.
The Achilles heel of precision AKT-targeted therapies in advanced prostate cancer: therapeutic promise constrained by the test.
Nuclear Myosin VI cooperates with actin to promote transcriptional cluster formation at androgen receptors.
Multiple sessions magnetic fluid hyperthermia: a requisite for apoptosis in prostate cancer cells LNCaP.
Prostate cancer risk and antioxidant biomarkers: the age-dependent reversal of bilirubin's role.
Design and synthesis of Tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives as antiproliferative agents for prostate Cancer cells.
Spatial immune profiling of bone-metastatic castration-resistant prostate cancer reveals radium-223 immunomodulates the bone-tumor microenvironment.
Integration of Darolutamide in the Treatment Landscape for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis of Efficacy and Safety.
Prostate cancer diagnosis using sensitive and sophisticated machine learning classifiers based on non-invasive urinary RNA biomarkers (PCASSO).
Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination.

Int J Biol Macromol. 2025 Dec 19. pii: S0141-8130(25)10367-X. [Epub ahead of print]338(Pt 2): 149810

Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression.

Yifan Liu, Duocheng Qian, Yifan Ding, Denglong Wu, Chenye Tang, Chengdang Xu, Xi Chen.

  With increasing life expectancy, prostate cancer (PCa) has exhibited rising incidence and mortality rates. Although therapies such as androgen deprivation therapy (ADT) effectively extend patient survival, the development of drug resistance remains a major obstacle. Previous studies identified a key enzyme in the androgen metabolic pathway as essential to PCa progression, regulated by the epigenetic reader BRD4. Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion. Mechanistic investigations demonstrated that SRD5A1 promotes androgen receptor (AR) activity by elevating intracellular dihydrotestosterone (DHT) levels, thereby enhancing AR expression and facilitating tumorigenesis. Notably, both BRD4 and SRD5A1 were shown to modulate AR expression in PCa cells. Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development.

Keywords:  Androgen receptor; BRD4; Prostate cancer; SRD5A1

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149810
Front Med (Lausanne). 2025 ;12 1643506

Qiling decoction enhances the anti-tumor activity of abiraterone acetate by up-regulating miR-143 expression in abiraterone acetate-resistant prostate cancer cells.

Lizhi Chen, Hongwen Cao, Peng Sun, Yigeng Feng, Lei Chen, Renjie Gao.

   Introduction: Abiraterone acetate is a key therapeutic agent for castration-resistant prostate cancer (CRPC), but the cancer resistance limits its long-term efficacy. While several mechanisms of abiraterone acetate resistance have been proposed, the role of microRNAs (miRNAs) in this process remains incompletely understood. Here the aim of the study was to investigate miR-143 as a potential tumor suppressor in prostate cancer, and elucidate its involvement in abiraterone acetate resistance. Additionally, Qiling decoction (QLD), a traditional Chinese medicine formulation, was tested for its ability to restore miR-143 expression and enhance abiraterone efficacy.
Methods: Abiraterone acetate-resistant prostate cancer (PC) cell lines, PC3-AbiR and DU145-AbiR, were established through long-term abiraterone exposure. The expression of miR-143 was analyzed using qRT-PCR, and its effects on the JNK/p-Bcl2-Beclin1 signaling axis were examined via Western blot and co-immunoprecipitation assays. Functional experiments, including CCK-8 assays, were carried out to evaluate how miR-143 modulation affects abiraterone acetate sensitivity.
Results: miR-143 expression was significantly downregulated in abiraterone acetate-resistant PC cells. Downregulation of miR-143 was shown to be linked with increased phosphorylation of JNK and p-Bcl2, along with elevated expression of Beclin1, indicating activation of the JNK/p-Bcl2-Beclin1 signaling axis. Functional studies revealed that miR-143 inhibition promoted cell survival and autophagy, while its overexpression restored abiraterone acetate sensitivity. Treatment with QLD upregulated miR-143 expression, suppressed JNK/p-Bcl2-Beclin1 signaling, and enhanced abiraterone acetate-induced cytotoxicity. Inhibition of miR-143 abolished the effects of QLD, confirming its central role in mediating abiraterone acetate resistance. These findings demonstrate that miR-143 downregulation contributes to abiraterone acetate resistance in prostate cancer by activating the JNK/p-Bcl2-Beclin1 signaling axis and promoting autophagy.
Conclusion: Restoration of miR-143 expression through QLD treatment enhances abiraterone acetate sensitivity, suggesting a potential therapeutic strategy for overcoming drug resistance in CRPC.

Keywords:  CRPC; QLD; abiraterone acetate; autophagy; drug resistance

DOI:  https://doi.org/10.3389/fmed.2025.1643506
Biol Proced Online. 2025 Dec 22. 27(1): 48

Network Pharmacology and Experimental Validation Reveal Aidi Injection Suppresses Prostate Cancer via EGFR Inhibition and STAT3-Mediated Apoptosis.

Ganhua You, Chen Qian, Xiaoyue Chen, Qunying An, Jukun Song, Yuehai Xiao.

   BACKGROUND: Prostate cancer (PCa) is the most common male reproductive malignancy, with traditional Chinese medicine (TCM) offering potential complementary treatments. Aidi injection, used for liver, lung, and colorectal cancers, shows promise for PCa, but its mechanisms are unclear. This study aims to uncover the molecular pathways through which Aidi injection affects PCa using network pharmacology and experiments.
METHODS: The study used network pharmacology to identify active components of Aidi injection and their targets from various databases. These targets were cross-referenced with PCa-related targets to uncover therapeutic possibilities. Protein-protein interaction (PPI) and KEGG pathway analyses highlighted key molecular pathways affected by Aidi injection. Molecular docking examined ingredient-target binding. In vitro tests evaluated effects on PCa cell proliferation, apoptosis, and IL-6/STAT3 signaling, while in vivo studies assessed tumor growth and immune response in mice.
RESULTS: The study identified 58 active components and 804 PCa-related target genes, with 49 overlapping therapeutic targets. Key compounds such as quercetin, kaempferol, isorhamnetin, and cantharidin were highlighted. Core targets included ESR1, IL-6, STAT3, HSP90AA1, EGFR, and VEGFA. KEGG analysis revealed the IL-6/STAT3 and EGFR pathways as significant in PCa treatment. In vitro, Aidi injection inhibited PCa cell proliferation, induced apoptosis, and suppressed IL-6/STAT3 activation. In vivo, Aidi injection reduced tumor growth and enhanced immune response in mice.
CONCLUSIONS: Aidi injection influences the IL-6/STAT3 and EGFR pathways, suppressing PCa cell growth, inducing apoptosis, and reducing migration and invasion. These findings offer valuable insights into the therapeutic potential of Aidi injection for prostate cancer.

Keywords:  Aidi injection; Complementary medicine; IL-6/STAT3; Network pharmacology; Prostate cancer

DOI:  https://doi.org/10.1186/s12575-025-00299-w
Biochem Biophys Res Commun. 2025 Dec 17. pii: S0006-291X(25)01861-3. [Epub ahead of print]797 153145

Kaempferol suppresses prostate cancer metastasis and tumor angiogenesis via disrupting the LIMK1/Cofilin pathway.

Peng Li, Linqing Lu, Yixiang Sun.

  Tumor neovascularization promotes prostate cancer (PCa) progression, positioning anti-angiogenic therapy as a promising therapeutic strategy. Secondary metabolites from edible plants, particularly kaempferol, have demonstrated efficacy in suppressing PCa metastasis, yet its underlying mechanisms remain elusive. CCK-8 and colony formation assays were implemented to assess the cytotoxicity of kaempferol. Flow cytometry was executed to detect cell apoptosis and cell cycle arrest. The expression of molecules related to angiogenesis and cell cycle regulation was detected by immunofluorescence and Western blotting. A nude mouse prostate cancer xenograft model was established, with in vivo validation via H&E staining, ELISA, immunohistochemistry, and Western blotting assay. Kaempferol exerted pleiotropic anti-tumor effects on prostate cancer cells, including inhibiting the proliferation, inducing apoptosis and causing cell cycle arrest. Additionally, kaempferol decreased the expression of VEGFA, CDK4, and CDK6. Mechanistically, kaempferol disrupted the LIMK1/Cofilin signaling pathway, thereby inhibiting the angiogenic ability of tumor cells and suppressing the tumorigenic ability. In vivo xenograft experiments further confirmed kaempferol's efficacy in suppressing tumor growth. These findings support potential of kaempferol as a therapeutic agent for metastatic PCa. The identified LIMK1/Cofilin-dependent mechanism underscores the anti-metastasis effect of kaempferol and highlights LIMK1 as a therapeutic target, providing a rationale for further investigating kaempferol in prostate cancer progression.

Keywords:  Angiogenesis; Cell cycle; Kaempferol; LIMK1/Cofilin; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbrc.2025.153145
Cancer Biol Ther. 2026 Dec 31. 27(1): 2604936

Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.

Jing-Ze Yu, Xiao-Pan Zou, Xiao-Bei Wu, Yang-Yang Cui, Tan Wei, Jun Di, Xue-Chao Feng, Xiao-Meng Li.

   BACKGROUND: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms.
MATERIALS AND METHODS: We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects.
RESULTS: ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the N-terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation.
CONCLUSION: ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.

Keywords:  Prostate cancer; ZMIZ2; acetyltransferase; androgen receptor (AR); cell cycle

DOI:  https://doi.org/10.1080/15384047.2025.2604936
Anal Bioanal Chem. 2025 Dec 23.

LC-MS/MS and high-spatial single-cell MSI reveal selective downregulation of PC(16:0_16:0) and PC(18:0_18:1) due to mPGES-1 knockdown in hormone-resistant prostate cancer cell line.

Mst Sayela Afroz, Shuhei Aramaki, Md Muedur Rahman, Maxime Dubail, Zhang Chi, Kyoka Fujii, Mariko Kurosawa, Keita Tamura, Tomoaki Kahyo, Katsumasa Nakamura, Teruo Inamoto, Olof Rådmark, Mitsutoshi Setou, Hiromi Hanaka.

  Prostate cancer is one of the most common cancers in men, and 10-20% of cases progress to a hormone-resistant form, posing a major therapeutic challenge. The microsomal prostaglandin E2 synthase-1 (mPGES-1), a key enzyme in prostaglandin E2 biosynthesis from arachidonic acid, has been predicted as a therapeutic target in suppressing prostate cancer. However, the impact of mPGES-1 on the cellular lipidome has not been systematically investigated. Here, this study applied LC-MS/MS analysis and high-spatial single-cell mass spectrometry imaging (MSI) analysis using atmospheric pressure matrix-assisted laser desorption/ionization-MSI (AP-MALDI-MSI) to investigate the role of the mPGES-1 gene in altering the lipidome of hormone-resistant DU145 prostate cancer cells. LC-MS/MS results revealed significant downregulation of phosphatidylcholine (PC) and triglyceride (TG) species, and upregulation of ceramide species in KD (stable knockdown of the mPGES-1 gene) compared to controls. Upregulation of PCs is the signature of the tumor microenvironment of prostate cancer cells, and the upregulated ceramides are associated with programmed cell death. Consistent findings were observed in high-spatial single-cell MSI analysis for PC(16:0_16:0) and PC(18:0_18:1), which were significantly (p < 0.001) downregulated in KD compared to controls, and also revealed a striking loss of metabolic heterogeneity of these PC molecules. The loss of metabolic heterogeneity due to mPGES-1 knockdown may reduce cancer cells' adaptive capacity, suggesting mPGES-1 inhibition as a strategy to overcome metabolic plasticity in hormone-resistant prostate cancer. Thus, this study highlights that suppressing mPGES-1 can be a future therapeutic target in preventing the progression of hormone-resistant prostate cancer development.

Keywords:  AP-MALDI-MSI; Lipidomics; Phosphatidylcholine; Prostate cancer; Single-cell MSI; mPGES-1

DOI:  https://doi.org/10.1007/s00216-025-06296-y
Cancer Med. 2026 Jan;15(1): e71468

Network and Gene Set Enrichment Analysis of Adipokine Drivers of Prostate Cancer; Unravelling the Mechanistic Link Between Excess Adiposity and Prostate Cancer Risk.

Zachary Dovey, Elena Tomas Bort, Jeffrey I Mechanick.

   BACKGROUND: Adiposity-Based Chronic Disease (ABCD), a novel model housing obesity, insulin resistance, and adipokine-related inflammation, increases the risk of aggressive prostate cancer (PCa), posttreatment PCa recurrence, and PCa mortality. This paper provides a new network analysis of relevant metabolic drivers to provide insight into the ABCD-PCa relationship.
METHODS: A literature search was performed using the terms "prostate cancer" AND "obesity" AND "inflammation", with 629 references found, from which 17 reviews were chosen. Biomarkers identified from these reviews were characterized by cellular origin, signaling pathway, and oncogenic effect. The Webgestalt gene analysis toolkit was then used to generate modular-based network analyses and gene ontology (GO) categories of these biomarkers for interpretation.
RESULTS: 14 prominent biomarkers were identified influencing PCa risk through cellular proliferation, resisting cell death, metabolic reprogramming, tumor-promoting inflammation, avoiding immune destruction, angiogenesis, and activating invasion. Network analyses of biomarker interactions highlighted prominent roles of monocyte chemoattractant protein-1, interleukin-1β, and C-X-C motif chemokine ligand 1. Top GO categories for the wider ABCD-PCa network found key roles of ABCD-gut microbiome dysbiosis and exposure of periprostatic white adipose tissue to the prostate microbiome (involving bacterial and lipopolysaccharide-induced inflammation).
CONCLUSION: Top hypotheses to guide molecular targeted therapies and lifestyle biomarker panels for PCa in ABCD relate to MCP-1, IL-1β, and CXCL1 signaling, as well as gut microbiome dysbiosis and the exposure of the periprostatic adipose tissue to the prostate microbiome. Further research and possible clinical trials allowing histological examination of pre- and post-lifestyle intervention PCa tissue may provide further insights.

Keywords:  adipose based chronic disease; inflammation; lifestyle; network analysis; obesity; oncogenesis; prostate cancer

DOI:  https://doi.org/10.1002/cam4.71468
Metabolites. 2025 Nov 21. pii: 757. [Epub ahead of print]15(12):

Evaluating Differential Metabolic Profiles by Prostate Cancer Risk Among Prostate Cancer Patients.

Tuo Liu, Jahnvi Roorkeewal, Melissa A Furlong, Shawn C Beitel, Jefferey L Burgess, Benjamin R Lee, Juan Chipollini, Justin M Snider, Ken Batai.

  Background: Currently there are no clinically validated biomarkers recommended for prostate cancer (PCa) risk stratification other than prostate-specific antigen (PSA). Objective: This study aimed to identify urine metabolites that are associated with the presence of high-grade PCa at the time of radical prostatectomy. Methods: Urine samples were collected from patients who underwent radical prostatectomy. High-resolution metabolomics were implemented using liquid chromatography mass spectrometry (LC-MS). To enhance metabolic feature identification, sample extracts were analyzed in two modes, C18 chromatography [reverse-phase (RP)] and hydrophilic interaction chromatography (HILIC). Results: This analysis included a total of 22 patients with PCa (10 high-grade and 12 low-grade) and identified 52 differential metabolites, 40 in RP and 12 in HILIC, at the p-value 0.05 level. Among these, methyl alpha-aspartyl phenylalaninate was most significantly differentiated, while 3-methylbutanoicacid had the largest difference (slope -3.488). In the pathway analysis, the histidine metabolism pathway was significantly enriched (p < 0.05) with an enrichment factor of 3.5. Although not statistically significant, alterations were also observed in the vitamin B12, B7 (biotin), B6, and B3 (niacin) pathways. Conclusions: These findings suggest that urinary metabolites may have the potential to differentiate high-grade from low-grade PCa. Our study also highlights the metabolic reprogramming that occurs as PCa becomes more aggressive and potential differences in dietary patterns.

Keywords:  PCa risk; prostate cancer (PCa); urine metabolomics

DOI:  https://doi.org/10.3390/metabo15120757
Front Oncol. 2025 ;15 1630363

Association between ESRα and ESRβ polymorphisms and prostate cancer risk: meta-analysis.

Xiaohui Bai, Li Gao, Jiawei Zhao, Wentao Liao, Yujing Chen, Xiaotong Guo, Jiamin Jin, Bo Ge.

   Background: Gene polymorphisms of ESRα Pvull(rs2234693), Xbal(rs9340799), and ESRβ Alul(rs4986938) and RsaI (rs1256049), have been investigated for their associations with prostate cancer risk. However, the nature of these relationships remains ambiguous. Therefore, the present study aimed to further clarify the association between ESR gene polymorphisms and prostate cancer.
Objective: To investigate the association between ESRα Pvull(rs2234693), Xbal(rs9340799), and ESRβ Alul(rs4986938), Rsal(rs1256049) polymorphisms and prostate cancer risk.
Materials and methods: PubMed, Medline, and CNKI were searched. Associations were assessed using odds ratios (ORs) with 95% confidence intervals (CIs). The false-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and Venetian criteria were used to evaluate the credibility of statistically significant findings.
Results: We found for the first time that, overall, the ESRα PvuII polymorphism was significantly associated with a reduced risk of prostate cancer (pp vs. Pp + PP: OR = 0.83, 95% CI = 0.71-0.97; pp vs. PP: OR = 0.75, 95% CI = 0.57-0.99; p vs. P: OR = 0.88, 95% CI = 0.78-0.99). A similarly reduced risk was observed in Caucasians (pp + Pp vs. PP: OR = 0.01, 95% CI = 0.01-0.04). By contrast, the ESRα PvuII polymorphism increased prostate cancer risk among Africans (pp + Pp vs. PP: OR = 2.38, 95% CI = 1.61-3.51). For ESRβ RsaI, we observed a reduced risk of prostate cancer in Asians (r vs. R: OR = 0.87, 95% CI = 0.77-0.98). However, no significant associations were identified for ESRα XbaI or ESRβ AluI. When evaluating credibility using the FPRP, BFDP, and Venetian criteria, no statistically robust associations were confirmed.
Conclusions: Overall, the results suggest a potential association between the ESRα PvuII and ESRβ RsaI polymorphisms and prostate cancer risk, although the credibility assessments did not support statistically robust relationships.

Keywords:  BFDP; ESR; FPRP; meta-analysis; polymorphism; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2025.1630363
Hum Genomics. 2025 Dec 24. 19(1): 149

Unraveling diethyl phthalate-induced prostate carcinogenesis: core targets revealed by integrated network toxicology, machine learning, and structural validation.

Hao Liu, Junyi Jiang, Ying Tan, Mengying Yang, Hongmei Yang, Canyong Li.

   PURPOSE: Diethyl phthalate (DEP), a widely distributed environmental contaminant, is epidemiologically linked to prostate cancer (PCa). However, its molecular mechanisms beyond endocrine disruption remain poorly defined. We aimed to investigate the core mechanisms potentially underlying DEP-associated prostate carcinogenesis within a genome-exposome interaction framework.
METHODS: We employed an integrated, multi-level framework combining: (1) Integrated chemical structure-based target prediction; (2) Cross-dataset meta-analysis of PCa transcriptomics (7 GEO datasets) for Differentially Expressed Gene (DEG) identification and Weighted Gene Co-expression Network Analysis (WGCNA); (3) Ensemble machine learning (113 models incorporating RF, XGBoost) for core target screening, augmented by SHAP interpretable to predict potential DEP targets.e AI; and (4) Molecular docking validation (AutoDock Vina, binding free energy assessment).
RESULTS: Integration pinpointed 9 key DEP-PCa targets. Functional enrichment implicated calcium signaling dysregulation, neuroendocrine pathway disruption, and smooth muscle dysfunction as central mechanisms. Machine learning distilled five core regulators: TRPM8, CTSB, CA14, GSTM2, and MYLK. SHAP analysis quantified TRPM8 and CA14 as dominant predictors and revealed critical non-linear interactions: synergistic TRPM8-MYLK co-expression and a CTSB expression threshold effect. Computational validation predicted high-affinity binding of DEP to all five core targets, suggesting potential direct interactions.
CONCLUSION: Our integrated analysis suggests that DEP may promote prostate carcinogenesis via a multidimensional network centered on calcium signaling perturbation, neuroendocrine dysregulation, and tumor microenvironment acidification, potentially illustrating a genome-exposome interaction mechanism beyond endocrine disruption. We propose that our analytical framework could serve as a reproducible approach for translational exposomics.

Keywords:  Diethyl phthalate; Machine learning algorithm; Molecular docking; Network toxicology; Prostate cancer

DOI:  https://doi.org/10.1186/s40246-025-00863-1
Int J Genomics. 2025 ;2025 9236117

Discovery of Essential Genes as Possible Targets for Prostate Cancer Drug Development.

Md Amanat Ullah Arman, Md Selim Reza, Muhammad Habibulla Alamin, Tasnia Akter Maya, Md Tofazzal Hossain.

  Prostate cancer (PCa) is a major malignancy affecting men and is a significant contributor to global male mortality. Over the past decade, several new treatments for advanced PCa have been approved; however, opportunities remain for the development of novel therapeutic strategies. Therefore, in this study, we developed an integrated bioinformatics pipeline to identify potential therapeutic targets and repurposed drugs using RNA-seq datasets, aiming to advance treatment options for PCa. Using the LIMMA approach, 458 common differentially expressed genes (cDEGs) were analyzed from three publicly available microarray datasets, leading to the identification of 15 hub genes (HubGs) through a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed their critical roles in PCa, and lower expressions of five HubGs (BIRC5, CDCA5, CENPF, NUSAP1, and TK1) correlated with better survival. All of these genes could potentially serve as biomarkers for the detection and therapy of PCa. Following that, we considered these possible genes as targets for drugs, performed docking analysis with 255 meta-drug agents, and identified the top 10 candidate drugs (adapalene, ergotamine, imatinib, dutasteride, vistusertib, risperidone, zafirlukast, irinotecan hydrochloride, drospirenone, and telmisartan). Finally, we evaluated the binding stability of the top-ranked three complexes-BIRC5-adapalene, BIRC5-imatinib, and TK1-ergotamine-through a 100 nanoseconds (ns) molecular dynamics (MD) simulation conducted using NAMD. The analysis revealed consistent stability across all complexes. This study uniquely combines multidataset transcriptomic integration, HubG prioritization, and MD validation to propose novel biomarker-drug pairings for PCa. The findings offer promising leads for future experimental and clinical validation.

Keywords:  drug screening; potential biomarkers; prostate cancer; protein–protein interaction; survival study

DOI:  https://doi.org/10.1155/ijog/9236117
Med Sci (Basel). 2025 Dec 16. pii: 322. [Epub ahead of print]13(4):

Obesogenic Dysregulation of Human Periprostatic Adipose Tissue Promotes the Viability of Prostate Cells and Reduces Their Sensitivity to Docetaxel and Cabazitaxel.

Mariana Feijó, Lara R S Fonseca, Gonçalo Catarro, Cátia V Vaz, Carlos Rabaça, Bruno J Pereira, Eugenia Gallardo, Endre Kiss-Toth, Sara Correia, Sílvia Socorro.

   BACKGROUND: Periprostatic adipose tissue (PPAT) has been shown to play a significant role in prostate cancer (PCa) development and progression. This relationship is further exacerbated by obesity, as PPAT-secreted factors increase PCa aggressiveness and have also been implicated in chemotherapy resistance. Therefore, identifying the molecular mediators of PPAT-prostate interorgan communication and the factors that disrupt this crosstalk is pivotal for better disease management. Obesogens, i.e., endocrine-disrupting chemicals that dysregulate adipose tissue towards an "obese" phenotype, have recently been implicated in disrupting this crosstalk, with an impact on prostate cell fate.
OBJECTIVES: This study aimed to investigate whether obesogenic dysregulation of human PPAT secretory activity affects PCa cell viability and their response to docetaxel and cabazitaxel.
METHODS/RESULTS: Through ex vivo culture of human PPAT and conditioned medium assays, we demonstrated that exposure to the model obesogen tributyltin (TBT) induced an "obese" phenotype in human PPAT, characterised by adipocyte enlargement and increased secretion of leptin and C-C motif chemokine ligand 7. The TBT-treated PPAT secretome enhanced cell viability and decreased the sensitivity of PCa cells to taxanes.
CONCLUSIONS: This study provides preliminary evidence that lays the groundwork for future investigations, dissecting the molecular pathways underpinning prostate carcinogenesis and resistance to chemotherapy induced by obesogen-dysregulated PPAT.

Keywords:  cabazitaxel; docetaxel; endocrine-disrupting chemicals; obesogens; periprostatic adipose tissue; prostate cancer

DOI:  https://doi.org/10.3390/medsci13040322
Jpn J Clin Oncol. 2025 Dec 26. pii: hyaf205. [Epub ahead of print]

Real-world efficacy of switching androgen receptor signaling inhibitor therapy following apalutamide discontinuation because of adverse events in advanced prostate cancer: a multicenter study.

Yoichiro Tohi, Takuma Kato, Kengo Fujiwara, Yushi Hayashida, Yuki Matsuoka, Hiromi Hirama, Toshifumi Yano, Hiroyuki Tsunemori, Hironobu Arai, Isaku Nomura, Nobuyoshi Yamaoka, Tomohiro Mashima, Kana Kohashiguchi, Yohei Abe, Hirohito Naito, Homare Okazoe, Rikiya Taoka, Nobufumi Ueda, Mikio Sugimoto.

   BACKGROUND: Apalutamide treatment for prostate cancer may require discontinuation because of adverse events, particularly rashes. We evaluated the real-world outcomes of switching to other androgen receptor signaling inhibitors (ARSI) following such discontinuations.
METHODS: This multicenter retrospective cohort study included men with metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) who received apalutamide between July 2019 and August 2025. Those who discontinued apalutamide comprised the switch group. We noted the reasons for discontinuation and compared progression-free survival (PFS) or metastasis-free survival (MFS) and overall survival (OS) between the switch and no-switch groups by disease category. Rash recurrence after switching was also assessed.
RESULTS: Of 117 total patients, 17 (14.5%) comprised the switch group. Rashes accounted for all of the discontinuations, with 40% being grades ≥3. PFS and OS did not differ significantly between the switch and non-switch patients with mCSPC (log-rank P = .225 and P = .785, respectively), and similar MFS and OS results were observed in those with nmCRPC (P = .674 and P = .861, respectively). The rashes recurred after switching to alternative therapies in 5.8% (n = 1) of the patients.
CONCLUSIONS: This real-world multicenter analysis demonstrated that approximately one in seven patients with prostate cancer discontinued apalutamide treatment because they developed rashes. However, switching to other ARSIs preserved oncological outcomes, with no significant differences in PFS, MFS, or OS observed, regardless of prostate cancer subtype. Therefore, this type of switching does not appear to compromise subsequent treatment efficacy if it is done while the disease remains sensitive to ARSIs.

Keywords:  adverse event; apalutamide; metastatic castration-sensitive prostate cancer; non-metastatic castration-resistant prostate cancer; rash

DOI:  https://doi.org/10.1093/jjco/hyaf205
Clin Chim Acta. 2025 Dec 20. pii: S0009-8981(25)00669-2. [Epub ahead of print] 120790

Aberrantly glycosylated PSMA in urine as a potential marker for prostate cancer.

Misba Khan, Md Khirul Islam, Pekka Taimen, Peter J Boström, Urpo Lamminmäki, Janne Leivo.

  Early detection of prostate cancer (PCa) requires the development of reliable non-invasive biomarkers. In this study, we describe a simple, non-invasive assay to detect a prostate-specific membrane antigen (PSMA) glycoisoform directly from unprocessed urine. PSMA was analyzed in urine samples from PCa patients (n = 40) and benign controls (n = 37) using lectin MGL-coated europium-doped nanoparticles. MGL showed enhanced binding to PCa-derived PSMA, indicating aberrant glycosylation. Evaluation of individual samples demonstrated that the PSMA-MGL glycovariant assay significantly discriminated PCa from benign conditions (p = 0.01 pilot, p = 0.02 validation). Moreover, this assay exhibited a three-fold improvement in sensitivity over conventional antibody-based PSMA detection. ROC analysis showed an AUC of 0.648 for PSMA-MGL, which increased to 0.734 when combined with free-PSA and urinary creatinine, highlighting the enhanced diagnostic potential of this multimarker, non-invasive approach.

Keywords:  Lectin; MGL; Nanoparticle; PSMA; Prostate cancer

DOI:  https://doi.org/10.1016/j.cca.2025.120790
Cancer Cell Int. 2025 Dec 26.

FAM111B promotes prostate cancer progression by inhibiting apoptosis via ATF3 suppression and MAPK pathway activation: a novel biomarker and therapeutic target.

Yanan Wang, Zefeng Wang, Zhen Yin, Tianbao Song, Yipeng He, Ming Li, Zitao Wang, Zhongze Li, Peihan Wang, Zhiquan Hu, Zhihua Wang, Weimin Yu, Fan Cheng.



Keywords:  ATF3; Apoptosis; Biomarker; FAM111B; Prostate cancer

DOI:  https://doi.org/10.1186/s12935-025-04111-3
iScience. 2025 Dec 19. 28(12): 113985

Developing therapeutic strategies to target MCL1 and BCLXL in lethal prostate cancer.

Daniel Westaby, Juan M Jiménez-Vacas, Ines Figueiredo, Jonathan Welti, Bora Gurel, Denisa Bogdan, Lorenzo Buroni, Antje J Neeb, Jan Rekowski, Ana Padilha, Souvik Das, Joe Taylor, Wanting Zeng, Nick Waldron, Thomas Goldsmith, Emily Hobern, Florian Gabel, Nicole Pandell, Susana Miranda, Maryou B Lambros, Suzanne Carreira, Amanda Swain, Wei Yuan, Steven P Balk, Marco Bezzi, Johann S de Bono, Adam Sharp.

  Targeting anti-apoptotic BCL2 family proteins is an attractive therapeutic strategy to drive prostate cancer (PCa) cell death. Here, we show that MCL1 is highly expressed in castration-resistant PCa, associating with worse clinical outcome. We demonstrate that targeting MCL1 with BH3 mimetics triggers apoptotic cell death in a subset of PCa cell line models. Furthermore, siRNA targeting of UCHL3, a deubiquitinating enzyme, downregulates MCL1 expression to synergize with BCLXL blockade; however, its impact on MCL1 is driven through an off-target effect, raising an important methodological consideration when studying MCL1 biology. Finally, we demonstrate that co-targeting MCL1 and BCLXL in patient-derived and mouse PCa models drives apoptotic PCa cell death. Taken together, targeting the intrinsic apoptosis pathway remains an attractive therapeutic strategy for lethal PCa. Future studies should focus on identifying strategies and technologies that can deliver cancer specific kill, to improve the outcome for men with this lethal disease.

Keywords:  Pharmacology; cancer; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.113985
Front Oncol. 2025 ;15 1713670

Clinical value and molecular role of PRDXs family in prostate cancer.

Yong Yao, Quan Zheng, Chen Qian, Peng Gu, Minhao Zhang, Zhou Zhang.

   Objectives: The purpose of this study is to explore the clinical value and molecular role of the peroxiredoxins (PRDXs) family in prostate cancer (PCa).
Methods: We first analyzed the differentially expressed genes (DEGs) in Prostatic Adenocarcinoma (PRAD) using the Cancer Genome Atlas (TCGA) database, and then demonstrated the expression of six members of the PRDXs family in PRAD. Subsequently, we evaluated the expression of the PRDXs family using PCa cells and tissues. we also analyzed the diagnosis and overall survival (OS) of the PRDXs family in PCa. We used online tools to analyze the expression of PRDX4 in pan-cancer, the proteins interacting with it, as well as the amino acid regions and sites to pathogenicity. We used CCK8 and transwell assay to detect the proliferation and invasion of PCa cells after silencing PRDX4. Finally, we predicted traditional Chinese medicine drugs targeting PCa with PRDX4.
Results: We found that PRDX2 and PRDX4 were highly expressed in PRAD through the TCGA database. Compared with prostate epithelial cells, PRDX2, PRDX3, PRDX4, and PRDX6 were expressed higher in PCa cells. In PCa tissues, the PRDXs family is widely expressed positively (P<0.05). The PRDXs family has relatively low diagnostic value in PCa, except for PRDX4. Based on the above results, we selected PRDX4 for molecular role detection. We found that the expression of PRDX4 in PCa was higher than that in more than half of the cancer types in pan-cancer. We found that there are eight proteins interacting with PRDX4. The pathogenic amino acid regions and sites of PRDX4 protein mutation that are prone to disease were mainly concentrated in the area after the 50th amino acid. We found that silencing PRDX4 slowed down the proliferation and invasion of PCa cells. Finally, we found that there are 14 traditional Chinese medicines targeting PCa with PRDX4, among which 5 have statistical differences, and Shi Liu Zi may be the best targeted traditional Chinese medicine drug.
Conclusion: This study found that PRDX4 is highly expressed in PCa, which may promote the phenotypic progression of PCa cells and has high clinical value.

Keywords:  PRDXs; clinical value; expression; molecular role; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2025.1713670
Cell Death Dis. 2025 Dec 20.

Targeting secreted PLA2 interactions with EGFR and vimentin to arrest prostate tumour growth.

Timothy J Mann, Ryung Rae Kim, Mila Sajinovic, Shadma Fatima, Vinod Kumar, Abdel Qader Al Bawab, Hiba Bahidh, Edwin Huang, Anya Salih, Enrico Gratton, Nathan Main, Maria George Elias, Isabelle Meyer-Carrive, Peter Galettis, Russell Pickford, David G Harman, Jun Zeng, Winston Liauw, Albert S Mellick, Gregory James Cooney, Qihan Dong, Garry G Graham, W Bret Church, Pamela J Russell, Paul de Souza, Kieran F Scott.

The secreted phospholipase A2 human group IIA (hGIIA) is overexpressed in prostate cancer (PCa), where its expression is closely aligned with malignancy. While its enzymatic activity is important in mediating innate immunity, here we highlight that hGIIA contributes to PCa pathology primarily through specific protein-protein interactions. We have developed cyclic peptides cF and c2, derived from the structure of hGIIA, that selectively inhibit these interactions and inhibit PCa growth. hGIIA interacts directly with epidermal growth factor receptor (EGFR), resulting in increased cytosolic PLA2-α activation and prostaglandin E2 production, which is suppressed by c2. Further, vimentin was identified to bind hGIIA in PCa cells, modulating hGIIA intracellular trafficking. c2 binds vimentin, blocking this interaction and initiating vimentin-mediated aggresome formation and apoptosis even in the absence of hGIIA. cF and c2 suppress androgen-sensitive, castrate-resistant and androgen-independent models of tumour growth in vivo at doses as low as 0.1 mg/kg, are non-toxic, orally bioavailable and cell-permeable. Critically, as with hGIIA, EGFR and vimentin are also increasingly expressed as PCa develops, cF and c2 may represent a novel therapeutic option for incurable metastatic castrate resistant PCa. Our findings identify hGIIA as an innate immune effector that regulates both inflammation and PCa progression and describe a novel class of hGIIA protein-protein interaction inhibitor with therapeutic potential in PCa.

DOI: https://doi.org/10.1038/s41419-025-08280-x
Ann Oncol. 2025 Dec 18. pii: S0923-7534(25)06331-8. [Epub ahead of print]

The Achilles heel of precision AKT-targeted therapies in advanced prostate cancer: therapeutic promise constrained by the test.

Emily Grist, Christopher J Sweeney, Gerhardt Attard.

  The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway is frequently activated in many cancers, including prostate cancer where this is often following loss of phosphatase and tensin homolog (PTEN). The CAPItello-281 trial is the first phase III trial to evaluate AKT inhibition added at start of androgen deprivation therapy for metastatic prostate cancer, specifically in combination with abiraterone acetate and prednisone for patients with loss of PTEN in ≥90% of tumor cells on immunohistochemistry staining. Adverse events were common, including hyperglycaemia, diarrhoea and grade 3 rash. Whilst the efficacy in the full trial cohort was modest, post hoc analyses identified significant efficacy in tumors with complete PTEN loss (∼5% of all tumors). Given an increasing number of treatment options for metastatic hormone sensitive prostate cancer, future work could evaluate capivasertib for tumors with greatest sensitivity and in combination with docetaxel, radioligand therapeutics and radiotherapy.

Keywords:  AKT inhibition; abiraterone acetate; immunohistochemistry; metastatic hormone sensitive prostate cancer; phosphatase and tensin homolog (PTEN)

DOI:  https://doi.org/10.1016/j.annonc.2025.12.010
J Biol Chem. 2025 Dec 22. pii: S0021-9258(25)02940-0. [Epub ahead of print] 111088

Nuclear Myosin VI cooperates with actin to promote transcriptional cluster formation at androgen receptors.

Irma M Jayawardana, Justus M Fleisch, Julian Knerr, Hong Wang, Manuel Holst, Stefan Tholen, Oliver Schilling, Robert Grosse.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds testosterone mediating gene expression for sexual, somatic, and behavioral functions, and is involved in various conditions, including androgen-insensitivity-syndrome (AIS) and prostate cancer. Our previous work revealed the actin-dependent formation of transcriptional hubs consisting of the AR, the mammalian formin Disheveled-Associated Activator of Morphogenesis 2 (DAAM2) and active RNA Polymerase II (RNA Pol-II). Of note, highly dynamic nuclear F-actin polymerization by DAAM2, directly at the AR is essential for androgen signaling. To better understand actin-driven AR transcriptional activity we turned our interest to the unconventional Myosin VI, which was previously proposed to be involved in RNA Pol-II transcription. Indeed, dihydrotestosterone (DHT)-dependent mass spectrometry of immunoprecipitated eGFP-Myosin VI identified the AR as a prominent associator. Consistent with this, structured illumination microscopy (SIM) in prostate cancer cells revealed signal-dependent nuclear enrichment of Myosin VI, which localized in close proximity to AR- as well as RNA Pol-II clusters and the actin nucleator DAAM2. Using live-cell SIM imaging, we directly visualized a ligand-dependent dynamic association between AR, Myosin VI, and nuclear actin, revealing their spatially coordinated reorganization at AR clusters. Pharmacological inhibition of actin polymerization or inhibition of the Myosin VI motor domain disrupted the formation of AR-related transcriptional clusters. Furthermore, reporter gene analysis and proliferation assays supported a critical role for Myosin VI in AR signaling. Our findings thus uncover Myosin VI as an essential regulator for the spatial organization of androgen-dependent transcription.

DOI: https://doi.org/10.1016/j.jbc.2025.111088
Biomed Mater. 2025 Dec 23.

Multiple sessions magnetic fluid hyperthermia: a requisite for apoptosis in prostate cancer cells LNCaP.

Uma Iyer Nilkanth Iyer, Hima Patel, Kinnari Parekh, Neeraj Devendra Jain.

  Magnetic fluid hyperthermia (MFH) is emerging as a promising cancer therapeutic modality due to its minimal side effects and targeted approach. This study presents the synthesis and characterization of temperature-sensitive biocompatible magnetic fluid (MF) containing citric acid-coated Mn0.9Zn0.1Fe2O4 nanoparticles, along with in vitro investigations on the prostate cancer cells LNCaP, to demonstrate the potential of these nanoparticles as a hyperthermic agent for MFH. The biocompatibility of MF was assessed using the MTT assay, which demonstrated no cytotoxic effects at concentrations up to 3 mg/mL. Furthermore, rapid internalization of nanoparticles into LNCaP prostate cancer cells was observed within 10 minutes, as determined by a Prussian blue assay and quantified by Inductively Coupled Plasma Mass Spectrometry. Upon exposure to an alternating magnetic field of 10 kA/m and 332 kHz frequency, the nanoparticles achieved the therapeutic temperature of 42 °C within 27 minutes, while sustaining a hyperthermic range of 42 to 45 °C for one hour. Notably, three MFH treatment sessions were identified as requisite for the elimination of LNCaP cells. Apoptosis was identified using Hoechst-Propidium iodide (PI) staining and further quantified by Annexin-V/PI flow cytometry. These findings underscore the potential of CA-coated Mn-Zn ferrite nanoparticles as effective biocompatible agents for MFH-based cancer therapy, warranting further detailed investigations to elucidate their therapeutic efficacy.

Keywords:  Apoptosis; Citric acid; Magnetic fluid; Magnetic fluid hyperthermia; MnZnFe 2 O 4 Magnetic Nanoparticles; Prostate cancer; Prostate cancer MnZnFe 2 O 4 Magnetic Nanoparticles Citric acid Magnetic fluid Magnetic fluid hyperthermia Apoptosis

DOI:  https://doi.org/10.1088/1748-605X/ae30be
BMC Urol. 2025 Dec 24.

Prostate cancer risk and antioxidant biomarkers: the age-dependent reversal of bilirubin's role.

Jong Won Shin, Jae Woong Sull, Nguyen Thien Minh, Sun Ha Jee.

   BACKGROUND: Prostate cancer incidence increases markedly after midlife, coinciding with age-related hormonal decline and alterations in antioxidant defense mechanisms. This study investigated age-specific associations between endogenous antioxidant markers (total bilirubin, albumin, and uric acid) and prostate cancer risk.
METHODS: Data were derived from the Korean Cancer Prevention Study-II (KCPS-II), and a total of 83,371 men were included after excluding individuals with a history of cancer or missing key variables at baseline. Participants were categorized into four age groups: < 45, 45-55, > 55, and > 65 years. During a mean follow-up of 13.5 years, 705 incident cases of prostate cancer (ICD-10: C61) were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer per 1-standard deviation (SD) increase in each antioxidant marker were estimated using Cox proportional hazards models. Quartile and trend analyses were also performed.
RESULTS: Total bilirubin showed a statistically significant negative association with prostate cancer risk in men aged 45-55 years (HR: 0.86, 95% CI: 0.75-0.98, p = 0.0208), while a significant positive association was observed in men over 65 years (HR: 1.21, 95% CI: 1.02-1.43, p = 0.0285). Albumin was not significantly associated with prostate cancer risk in most age groups, but a significant positive association was found in men under 45 years (HR: 1.41, 95% CI: 1.07-1.86, p = 0.0152). Uric acid showed a consistent positive association with prostate cancer risk in the overall population (HR: 1.13, 95% CI: 1.06-1.21, p = 0.0003), and in men aged < 45 years (HR: 1.15, 95% CI: 1.02-1.30, p = 0.0241), > 55 years (HR: 1.20, 95% CI: 1.08-1.32, p = 0.0005), and > 65 years (HR: 1.20, 95% CI: 1.04-1.38, p = 0.0121).
CONCLUSIONS: Total bilirubin was negatively associated with prostate cancer risk during the andropause period (ages 45-55), but this association reversed with increasing age. Uric acid consistently showed a positive association with prostate cancer risk across all age groups.

Keywords:  Albumin; Bilirubin; Oxidative Stress; Prostatic Neoplasms; Uric acid

DOI:  https://doi.org/10.1186/s12894-025-02029-6
Bioorg Med Chem Lett. 2025 Dec 24. pii: S0960-894X(25)00424-X. [Epub ahead of print] 130515

Design and synthesis of Tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives as antiproliferative agents for prostate Cancer cells.

Hui-Yu Chan, Pin-Shuo Huang, Pei-Fang Chiu, Tzung-Sheng Lin, Li-Jou Huang, Pi-Hui Liang, Jih-Hwa Guh, Mei-Hsiang Lin.

  Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives with pyridine congeners at C-1 position. Notably, 13c and 14c exhibited the GI50 of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that 14c shares a similar binding mode with abiraterone at the CYP17A1 active site.

Keywords:  Abiraterone; Antiproliferation; Castration-resistance prostate cancer

DOI:  https://doi.org/10.1016/j.bmcl.2025.130515
Prostate Cancer Prostatic Dis. 2025 Dec 26.

Spatial immune profiling of bone-metastatic castration-resistant prostate cancer reveals radium-223 immunomodulates the bone-tumor microenvironment.

Paul G Corn, Guoyu Yu, Yibo Fan, Miao Zhang, Patricia Troncoso, Devaki Shilpa Surasi, Suyu Liu, Jaffer A Ajani, Christopher J Logothetis, Guocan Wang, Theocharis Panaretakis, Sue-Hwa Lin.

BACKGROUND: Prostate cancer (PCa) bone lesions are bone-forming, which contribute to an immunosuppressive bone-tumor microenvironment (bone-TME). Targeting PCa-induced bone with the radiopharmaceutical Radium-223 (Ra223) is approved for men with bone-metastatic castration-resistant PCa (bmCRPC). We studied the effect of Ra223 on spatial localization of tumor and immune cells in bmCRPC tumor biopsies to gain insights into therapeutic immunomodulation of the bone-TME.
METHODS: Transiliac bone marrow biopsies were performed at baseline and end of treatment (EOT) in 24 patients with bmCRPC treated with Ra223. In three patients with paired specimens containing tumor, multiplex immunofluorescence was performed with antibodies for a tumor cell marker (CK), T-cell markers (CD3, CD4, CD8, FOXP3, and granzyme B), macrophage markers (CD68 [total macrophages] and CD206 [M2-like macrophages]).
RESULTS: In all three patients, we observed enrichment of CD68+ macrophages, around tumor-induced bone at baseline. CD3 staining revealed T cell depletion where tumor cells formed large sheets but not where tumor cells were scattered. The effects of Ra223 on tumor cells and T cell subsets were heterogeneous. In one patient, tumor cells were reduced, and CD3+/CD8+ T cells were increased. In a second patient who evidenced osteolytic progression, tumor cells were increased while CD3+/CD8+ T cells were decreased. In a third patient, there was high number of tumor cells at baseline that modestly decreased and the number of CD3+/CD8+ T cells modestly increased after Ra223 treatment.
CONCLUSIONS: The changes in tumor cell numbers after Ra223 treatment seemed to be inversely correlated with changes in CD3+/CD8+ and CD4+/FoxP3+ cells, but not with other immune cells, in these 3 patients. Further characterization of immune cells in the bone-TME will be required before developing strategies to enhance immunotherapy efficacy in bmCRPC.
CLINICAL TRIAL REGISTRATION: This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT02135484).

DOI: https://doi.org/10.1038/s41391-025-01069-1
Eur Urol Open Sci. 2026 Jan;83 72-82

Integration of Darolutamide in the Treatment Landscape for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis of Efficacy and Safety.

Felix Melchior, Magdalena Koett, Felix Keller, Nastasiia Artamonova, Giulia Giannini, Mona Kafka, Michael Ladurner, Hannes Neuwirt, Jasmin Bektic, Wolfgang Horninger, Isabel Heidegger.

   Background and objective: Recent advances have led to the introduction of multiple combination treatments for metastatic hormone-sensitive prostate cancer (mHSPC), but their comparative efficacy and toxicity remain uncertain owing to the absence of head-to-head comparisons. We evaluated the efficacy and safety profile of darolutamide plus androgen deprivation therapy (ADT) in comparison to other treatments.
Methods: A systematic search was conducted in the Cochrane Library up to September 30, 2024 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Hazard ratios (HRs) and confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) were extracted. Odds ratios (ORs) for treatment-emergent adverse events (TEAEs) were calculated from the events reported.
Key findings and limitations: Eleven trials involving 11 389 patients were included. Darolutamide triplet therapy was associated with the highest overall PFS (HR 0.24, 95% CI 0.20-0.29) and OS (HR 0.54, 95% CI 0.44-0.66). The highest PFS in low-volume disease was observed with enzalutamide (HR 0.29, 95% CI 0.21-0.38) and darolutamide (HR 0.30, 95% CI 0.15-0.60). All androgen receptor pathway inhibitors (ARPIs) had higher toxicity than ADT, except for darolutamide (OR 0.99, 95% CI 0.71-1.39). In comparison to darolutamide, enzalutamide (OR 2.03, 95% CI 1.08-3.80) and abiraterone (OR 3.18, 95% CI 1.74-5.80) were associated with higher risk of hypertension. Enzalutamide was associated with a higher risk of fatigue (OR 3.22, 95% CI 1.28-8.07). Limited direct comparisons between treatments may affect our conclusions regarding relative efficacy.
Conclusions and clinical implications: Our findings support the role of darolutamide as an effective and well-tolerated ARPI for mHSPC, particularly in low-volume metachronous disease and comorbidity-limited cases. These results may assist clinicians in planning personalized treatment strategies that balance efficacy and safety.
Patient summary: We compared different medical treatment options for metastatic hormone-sensitive prostate cancer, with a special focus on a drug called darolutamide. Darolutamide is well tolerated and is effective, particularly in patients with a low volume of metastasis and patients with other health conditions that may limit their treatment options.

Keywords:  Androgen receptor pathway inhibitors; Darolutamide; Doublet therapy; Metastatic hormone-sensitive prostate cancer; Network meta-analysis; Systematic review; Treatment-emergent adverse events; Triplet therapy

DOI:  https://doi.org/10.1016/j.euros.2025.11.011
Sci Rep. 2025 Dec 25.

Prostate cancer diagnosis using sensitive and sophisticated machine learning classifiers based on non-invasive urinary RNA biomarkers (PCASSO).

Hyunseop Goh, Taeyang Heo, Jeongwon Kim, Yunlim Kim, Bumjin Lim, Myung Kyun Woo, Kwan Yong Choi, Choung-Soo Kim, Jongmin Kim.

  Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. However, current screening tools such as serum prostate-specific antigen (PSA) tests and digital rectal examination (DRE) are limited by low specificity and high false-positive rates, often leading to unnecessary biopsies and overtreatment. To address this clinical challenge, we developed a novel diagnostic framework termed PCASSO (Prostate CAncer diagnosis using Sensitive and Sophisticated ML classifiers based on nOn-invasive urinary RNA biomarkers), which integrates machine learning (ML) algorithms with non-invasive urinary RNA biomarker profiles obtained from DRE-free whole urine. A total of 163 urine samples (112 PCa, 51 benign prostatic hyperplasia [BPH]) were analyzed using quantitative PCR for 20 RNA biomarkers, including 2 long noncoding RNAs, 1 fusion gene, and 17 miRNAs. Among six ML classifiers evaluated, a Gradient Boosting model using an optimized 9-biomarker panel achieved the highest diagnostic performance (AUC: 0.99), with robust cross-validation results (Stratified-K-Fold: 0.912; LOOCV: 0.890). Notably, this classifier retained high accuracy in patients within the PSA gray zone (3-10 ng/mL), where clinical decision-making is often ambiguous. Our results demonstrate that ML-based classifiers using DRE-free urinary RNA biomarkers showed improved performance through robust internal validation, providing a basis for future validation studies.

Keywords:  Artificial intelligence; Digital rectal exam free urine analysis; Machine learning; Prostate cancer diagnosis; Urinary RNA biomarker

DOI:  https://doi.org/10.1038/s41598-025-32334-x
Nat Commun. 2025 Dec 23. 16(1): 11339

Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination.

Tina Keshavarzian, Kira Furlano, Giacomo Grillo, Lisanne Mout, Christopher Arlidge, Faizan Hasan, Ankita Nand, Migle Mikutenaite, Evdoxia Karadoulama, Ashish Goyal, Elisabeth L Pezzuto, Jessica Heilmann, Jakub Sykora, Sarah Minner, Thorsten Schlomm, Guido Sauter, Ronald Simon, Housheng Hansen He, Joachim Weischenfeldt, Christoph Plass, Clarissa Gerhäuser, Mathieu Lupien.

Identifying drivers of cancer progression to guide treatment selection is hindered by our limited understanding of tumor heterogeneity and its impact on tumor evolution. Here, we delineate the phenotypic variability across ~300,000 cells collected from multiple tumor loci in primary prostate and matched locoregional metastases using single-cell chromatin accessibility and gene expression sequencing. We find inter-patient heterogeneity to be confined to malignant populations. Within individual tumor loci, we see phenotypic heterogeneity among malignant cell populations despite a shared clonal genotypic architecture. We also observe that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity across primary tumor loci, while shifting from canonical prostate-cancer states to non-canonical inflammatory-like states. Our findings suggest a bottleneck imposed during the dissemination process, funneling prostate cancer cells toward an inflammatory-like cell state. These insights into the interplay between phenotypic identity and clonal architecture refine our understanding of prostate cancer progression and suggest that convergence of cancer cells towards an inflammatory-like state underlies dissemination to lymph nodes, offering a critical framework for future studies into prostate cancer metastatic potential.

DOI: https://doi.org/10.1038/s41467-025-67856-5