bims-meproc 2025-10-26 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–10–26
33 papers selected by
Grigor Varuzhanyan, UCLA

Preclinical Activity of the DLL3-Targeted T-cell Engager MK-6070 in Neuroendocrine Prostate Cancer.
Neuroscience in prostate cancer.
The intersection of race and adiposity in prostate cancer: a narrative review.
Aggressive prostate cancer is associated with pericyte dysfunction.
A microRNA CRISPR screen reveals microRNA-483-3p as an apoptotic regulator in prostate cancer cells.
ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.
Comprehensive pan-cancer evaluation of NUP85 prognosis, immune infiltration response, and validation in prostate cancer.
RAD51-AS1 inhibits the migration and invasion of prostate cancer cells by up-regulating RARA to activate ZYX transcription.
PFKFB3 as a multifaceted driver and therapeutic target in castration-resistant prostate cancer.
USP21/YBX1/HIF1-α promotes the progression of prostate cancer.
PACT is requisite for prostate cancer cell proliferation.
Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance.
NN-PCP: Screening phenotype-related core pathways to construct a prostate cancer metastasis prediction model based on multiple types of mutation data.
Zingerone Induces Apoptosis and Ferroptosis in Prostate Cancer DU145 Cells.
Spatial and maturity heterogeneity of tertiary lymphoid structures shapes immune microenvironment and progression in prostate cancer.
RETRACTION: Dieckol Prevents Prostate Cancer Cell Proliferation by Transcriptionally Attenuating JAK/STAT3 Signaling Pathway.
Curcumin in prostate cancer: a systematic review of molecular mechanisms and nanoformulated therapeutic strategies.
Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study.
Strategic Nanosuspension of Darolutamide for Enhanced Dissolution, Bioavailability, and Potentiated Prostate Cancer Treatment: Insights from Multiscale Computational Modeling.
Revisiting the impact of cathepsin Z in prostate cancer: concerns and insights.
ROS-mediated antiproliferative effects of dihydrotestosterone-derived ferrocene-steroid conjugates toward human cancer cell lines of variable androgen dependence.
FBXL22, a circadian-regulated immune biomarker with pan-cancer prognostic value and therapeutic potential in prostate cancer.
[Design, Synthesis, and Efficacy Evaluation of a Novel BRD4/HDAC Dual-Target Small-Molecule Inhibitor in Prostate Cancer].
Investigation of the association of tRNA-derived fragments (tRF-17-79MP9PP and tRF-18-79MP9P04) with prostate cancer.
Construction and validation of a novel diagnostic model with palmitoylation-related genes for prostate cancer.
Histopathology-based Artificial Intelligence Algorithms for the Prediction of Prostate Cancer Metastasis After Radical Prostatectomy.
Identification of Novel Molecular Subtypes of Prostate Cancer Based on Genes Related to Metabolic Reprogramming to Assess Prognosis and Immune Landscape.
Transcriptomic predictors of prostate cancer recurrence following focal cryotherapy: a pooled analysis of phase II trial and prospective cohort data.
Diving into High Concentration of EGCG: Assessing its Effects on miR-34 and miR-93, PSA, and AR Expression in Prostate Cancer LNCaP Cell Line.
Association between periodontal disease and prostate disease: a mini review.
The combination of prostate health index and multiparametric magnetic resonance imaging in prostate cancer diagnosis: efficacy analysis in different PSA ranges and its clinical decision-guiding value.
The impact of second-generation androgen receptor pathway inhibitors on skeletal muscle morphology and strategies to mitigate their effects in prostate cancer patients.
Utility of the PROSTest, a Novel Blood-Based Molecular Assay, Versus PSA for Prostate Cancer Stratification and Detection of Disease.

Mol Cancer Ther. 2025 Oct 24. OF1-OF9

Preclinical Activity of the DLL3-Targeted T-cell Engager MK-6070 in Neuroendocrine Prostate Cancer.

Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran.

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell-surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell-activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase I/II trial of MK-6070 is currently underway, which includes an NEPC cohort (NCT04471727). In this study, we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and antitumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T-cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates antitumor activity in mixed tumors, affecting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate the promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0453
Prostate Cancer Prostatic Dis. 2025 Oct 18.

Neuroscience in prostate cancer.

Ziteng Liu, Qiang Peng, Yuliang Wang, Peter Ka-Fung Chiu, Jeremy Yuen-Chun Teoh, Rongjiang Wang, Xiaodong Liu, Dinglan Wu, Chi-Fai Ng.

BACKGROUND: Emerging evidence in cancer neuroscience indicates that the nervous system interacts directly or indirectly with cancer cells, promoting tumor progression. The prostate gland contains an extensive neural network essential for regulating key physiological functions of prostate cells, and the significant neural distribution observed in prostate cancer highlights its critical role in driving cancer pathogenesis. Unfortunately, Comprehensive reviews systematically summarizing progress in cancer neuroscience for prostate cancer are currently lacking.
METHOD: We synthesize existing research on interactions between the nervous system and prostate cancer cells, explore the neural distribution within the prostate, and evaluate the impact of neural innervation on prostate cancer development and progression. Additionally, we also assess the potential neural regulation mechanisms in neuroendocrine prostate cancer (NEPC).
RESULT: We found that neural interactions significantly influence prostate cancer development. Neural circuitry within the tumor microenvironment drives progression and contributes to the aggressiveness of lethal subtypes like NEPC. Targeting neuromodulation emerges as a promising therapeutic approach, potentially allowing the repurposing of established medications for treating advanced tumors.
CONCLUSION: Neuromodulation offers a promising therapeutic option for advanced prostate cancer, particularly NEPC, which faces limited treatment options. However, further research is necessary to fully understand the neural regulatory mechanisms involved in prostate cancer development and to identify new therapeutic targets and strategies for advanced stages.

DOI: https://doi.org/10.1038/s41391-025-01042-y
Eur J Cancer Prev. 2025 Oct 20.

The intersection of race and adiposity in prostate cancer: a narrative review.

Matthew Smith, Tarek Lawen, Rebekka S Garcia, Jeissen Pyo, Andrew Hahn, Daniel Frigo, Hilary Ma, Peng Wei, Margaux Robert, Lisly Chery, Brian F Chapin, Carrie R Daniel, Curtis Pettaway, Justin R Gregg.

  Prostate cancer (PCa) is among the most common malignancies worldwide, with Black men experiencing significantly higher incidence, earlier onset, and more aggressive disease. These disparities reflect a complex interplay of factors. Adiposity, particularly visceral and periprostatic adipose tissue (PPAT), has emerged as a potential contributor to PCa progression, though its role in modifying racial disparities remains unclear. We conducted a narrative review to evaluate the relationship between obesity, visceral adiposity, PPAT, and PCa risk and aggressiveness, with attention to racial differences. A directed acyclic graph was developed to illustrate hypothesized pathways. Strong evidence supports associations between obesity, visceral fat, and aggressive PCa. Black men tend to have lower visceral and PPAT volumes than White men. However, these depots may exert greater biological effects in Black men, possibly due to differences in inflammatory signaling or fat composition. PPAT and waist-hip ratio may amplify aggressive PCa features in Black men while downplaying them in non-Black men. Adiposity may serve as a biomarker and modifier of racial disparities in PCa. An improved study design is needed to clarify mechanisms and inform targeted interventions. Understanding these interactions is essential to reducing PCa disparities in high-risk populations.

Keywords:  adiposity; prostatic neoplasms; race

DOI:  https://doi.org/10.1097/CEJ.0000000000000992
Mol Oncol. 2025 Oct 21.

Aggressive prostate cancer is associated with pericyte dysfunction.

Anabel Martinez-Romero, Ane Martinez-Larrinaga, Joaquim Grego-Bessa, Saioa Garcia-Longarte, Hielke van Splunder, Ianire Astobiza, Amaia Ercilla, Laura Bozal-Basterra, Isabel Mendizabal, Pilar Villacampa, Arkaitz Carracedo, Mariona Graupera.

  Pericytes are intrinsic components of vessels that regulate vascular stability and permeability. Aberrant vascularization is a hallmark of cancer, although the contribution of pericytes to this process is poorly understood. Here, we undertook a combined computational and experimental approach to identify the molecular reprogramming of prostate pericytes during cancer pathogenesis and progression. Analysis of human prostate cancer and murine models showed that prostate tumors exhibit a disequilibrium between endothelial and pericyte content with prognostic potential. Deeper molecular analysis revealed that there is no overt loss of pericytes in prostate tumors but rather a dysfunction that is concomitant with altered expression of a subset of cellular markers. We translate this finding into a simplified signature that discriminates pericyte abundance versus function. Leveraging single-cell RNA sequencing data, we find that TGF-β governs the molecular changes that underlie pericyte dysfunction in tumors. This mechanism is associated with reduced expression of contractility markers, enlargement of the vascular lumen, and increased permeability in prostate cancer. This study revisits the paradigm of the reduced number of pericytes in favor of their dysfunction in tumors and the importance of paracrine signaling in this process.

Keywords:  TGFβ signaling; pericytes; prostate cancer; vessels

DOI:  https://doi.org/10.1002/1878-0261.70135
Cell Death Dis. 2025 Oct 24. 16(1): 752

A microRNA CRISPR screen reveals microRNA-483-3p as an apoptotic regulator in prostate cancer cells.

Jonathan Tak-Sum Chow, Ayeisha Desjardins, Daniel K C Lee, Iulia A Grigore, Linda Lee, Norman J Fu, Stephanie Chau, Byeong Yeop Lee, Martino Marco Gabra, Leonardo Salmena.

The development of traditional protein-targeted cancer therapies is a slow and arduous process, often taking years or even decades. In contrast, RNA-based therapies targeting crucial microRNA (miRNA) offer a faster alternative due to the sequence-specific nature of miRNA inhibitor binding. This, combined with the capacity of individual miRNA to influence multiple cellular pathways, makes these small RNA attractive targets for cancer therapy. While miRNA are known to be dysregulated in prostate cancer (PCa), identifying their individual contributions to disease progression and the identification of therapeutically actionable miRNA targets in PCa has been challenging due to limited profiling and lack of screening tools. To address this need, we developed miRKOv2, a miRNA-only CRISPR knockout library enabling systematic, genome-wide loss-of-function screens to identify miRNA essential for PCa cell survival. Our screens uncovered 70 potential essential miRNA candidates, with miR-483 demonstrating the most significant impact on PCa cell viability. Functional characterization revealed that miR-483 disruption potentiated apoptosis in PCa cell lines. Mechanistically, we uncovered a novel regulatory axis wherein miR-483-3p directly modulates a BCLAF1/PUMA/BAK1 apoptotic signaling network, highlighting its critical role in maintaining PCa cell survival. Our findings provide novel insights into the complex regulatory role of miRNA in PCa progression and offer a potential therapeutic strategy for targeting miRNA-mediated pathways in metastatic disease.

DOI: https://doi.org/10.1038/s41419-025-08098-7
Adv Sci (Weinh). 2025 Oct 23. e14077

ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.

Shuai Shao, Wei Li, Yulong Hong, Ruijiang Zeng, Liang Zhu, Lu Yi, Yuan Li, Yinhuai Wang, Haojie Huang, Xuewen Jiang, Xin Jin.

  Ferroptosis represents a promising vulnerability to overcome therapeutic resistance in castration-resistant prostate cancer (CRPC). While S-palmitoylation of lipid peroxide-scavenging proteins such as GPX4 and SLC7A11 has been shown to suppress ferroptosis, whether palmitoylation modulates the lipid peroxidation generation remains unclear. Here, we identified the palmitoyltransferase ZDHHC2 as a critical driver of enzalutamide resistance through destabilizing ACSL4. ZDHHC2 is transcriptionally upregulated by a FOXA1/CXXC5/TET2 complex and promotes S-palmitoylation of the deubiquitinase USP19, which impairs its interaction with ACSL4. This disrupts USP19-mediated ACSL4 stabilization, promoting its ubiquitin-proteasome degradation and consequently suppressing lipid peroxidation and ferroptosis. We developed a small-molecule ZDHHC2 inhibitor, TTZ1, which restores ACSL4 protein, reactivates ferroptosis, and reverses enzalutamide resistance in CRPC cell lines and patient-derived xenograft models. This study uncovers a previously unrecognized mechanism by which palmitoylation regulates ferroptosis through modulating ACSL4 stability, and highlights the ZDHHC2-USP19-ACSL4 axis as a druggable target for overcoming resistance in advanced prostate cancer.

Keywords:  ACSL4; CRPC; ZDHHC2; ferroptosis; lipid peroxide production

DOI:  https://doi.org/10.1002/advs.202514077
Discov Oncol. 2025 Oct 22. 16(1): 1953

Comprehensive pan-cancer evaluation of NUP85 prognosis, immune infiltration response, and validation in prostate cancer.

Zhijun Chen, Han Guan, Long Chen, Xinwei Yuan, Wenyan Sun, Ming Chen.

   BACKGROUND: Although NUP85 is a member of the nuclear pore complex (NPC) and is associated with chromosome variation and tumor regulation, its specific role in cancer development remains unclear and requires further research.
METHODS: This study analyzes the mRNA and protein levels of NUP85 in normal and tumor tissues using the TCGA, GTEx, and HPA databases. We investigated the relationship between NUP85 and survival rates, as well as clinical features, in various tumors by analyzing the TCGA database. The expression pattern of NUP85 in cancer cells is analyzed using single-cell sequencing data from the TISCH database. Two types of prostate cancer cell lines are utilized to investigate the impact of NUP85 on cell proliferation, migration, invasion, and apoptosis, as well as its regulatory mechanism. These analyses aim to uncover the role of NUP85 in cancer, particularly in prostate cancer.
RESULTS: NUP85 is observed to exhibit elevated expression levels across multiple malignancies, with its heightened expression showing consistent associations with poorer clinical prognoses. Bioinformatic analyses further reveal that NUP85 expression patterns demonstrate significant correlations with the activity of cancer-related pathways and immunological interactions involving macrophages and T cell populations. Notably, experimental studies using prostate cancer models have documented reduced cellular proliferation following NUP85 knockout, suggesting a potential functional connection warranting further mechanistic investigation.
CONCLUSIONS: The results indicate that elevated NUP85 expression shows strong correlations with cancer initiation and progression. These findings support its potential utility as a candidate biomarker for disease monitoring across various malignancies, though mechanistic validation remains necessary to establish clinical applicability.

Keywords:   NUP85 ; Immune tumor microenvironment; Pan cancer analysis; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03735-1
Discov Oncol. 2025 Oct 24. 16(1): 1964

RAD51-AS1 inhibits the migration and invasion of prostate cancer cells by up-regulating RARA to activate ZYX transcription.

Zhijun Chen, Xinwei Wang, Likai Mao, Han Guan, Ming Chen.

   BACKGROUND: Prostate cancer (PCa) is one of the most prevailing cancers threatening men health around the world. Mounting studies have revealed that dysregulated long non-coding RNAs (lncRNAs) might contribute to cancer development. RAD51-AS1 has been reported as an tumor-suppressor in different diseases, but not in PCa. Therefore, we aimed to explore the role of RAD51-AS1 and the underlying regulatory mechanism in PCa.
METHODS: RT-qPCR was conducted for the measurement of RNA levels. Bioinformatics analysis was performed for screening out possible research targets. Mechanism assays were implemented for detecting relations among different factors, while functional assays were employed to determine the function of genes in PCa cells.
RESULT: RAD51-AS1 expression was found to be low in PCa cells, which resulted in exacerbated PCa cell migration and invasion. RAD51-AS1 recruited HNRNPC in PCa cell nucleus to bind with pre-RARA, thus positively modulating RARA expression. RARA activated ZYX transcription to enhance ZYX expression in PCa cells. Rescue assay substantiated RAD51-AS1 inhibited PCa cell migration and invasion through modulating ZYX expression.
CONCLUSION: The anti-oncogenic role of RAD51-AS1 was realized through HNRNPC/RARA/ZYX axis, which might offer a novel insight for understanding PCa.

Keywords:  HNRNPC; Prostate cancer; RAD51-AS1; RARA; ZYX

DOI:  https://doi.org/10.1007/s12672-025-03567-z
Cell Death Dis. 2025 Oct 24. 16(1): 760

PFKFB3 as a multifaceted driver and therapeutic target in castration-resistant prostate cancer.

Lin Chen, Yu-Xin Xu, Ying-Ying Ren, Zhi-Da Wang, Xue-Man Dong, Yi-Min Chen, Pu Wu, Tong Wu, Fei Xiang, Tian Xie, Qi Zhang, Jian-Liang Zhou.

Castration-resistant prostate cancer (CRPC) is the advanced stage of prostate cancer (PCa) progression, characterized by limited therapeutic options and significant challenges from drug resistance development. We show that PFKFB3, an essential regulator of glycolytic metabolism, is significantly upregulated in PCa tissues and CRPC cell lines, where it plays a pivotal role in driving CRPC progression. Knockdown of PFKFB3 or inhibition by a small molecule inhibitor significantly inhibits the growth and invasion of CRPC cells, whereas overexpression promotes malignant behaviors. Mechanistically, PFKFB3 modulates the PI3K/Akt-Wnt/β-catenin pathway, resulting in enhanced tumor cell proliferation. Additionally, combining a PFKFB3 inhibitor with docetaxel produces synergistic anti-CRPC effects and reduces toxicity. Therefore, PFKFB3-mediated metabolic reprogramming underlies CRPC progression, highlighting its potential as a therapeutic target and emphasizing the need for further exploration in the development of safe and effective PFKFB3 inhibitors for precise targeted therapy in CRPC.

DOI: https://doi.org/10.1038/s41419-025-08089-8
J Transl Med. 2025 Oct 23. 23(1): 1164

USP21/YBX1/HIF1-α promotes the progression of prostate cancer.

Zhuoran Gu, Libin Zou, Cheng Jiang, Feng Qi, Dan Huang, Ji Liu, Yadong Guo, Shiyu Mao, Junfeng Zhang, Yue Zhang, Donghui Shi, Jiang Geng, Yifan Chen, Wentao Zhang, Xudong Yao.

   BACKGROUND: Prostate cancer (PCa) is one of the prevalent cancers in men. Although deubiquitinating enzymes are implicated in tumorigenesis and progression, the specific role of ubiquitin specific peptidase 21 (USP21) in PCa remains unclear. This study provides the first comprehensive analysis of USP21 as a key oncogene driving PCa progression.
METHODS: Prognosis-related deubiquitinating enzymes in PCa were initially identified through PCa cohorts from TCGA and GEO databases, followed by experimental validation. USP21 expression in PCa tissues and cell lines using tissue microarray immunohistochemistry, western blotting, and RT-qPCR. The biological functions of USP21 were evaluated through patient-derived organoids, in vitro and in vivo experiments. USP21 substrate proteins were identified by co-immunoprecipitation (Co-IP) coupled with mass spectrometry, revealing Y-box binding protein 1 (YBX1) as the primary target. YBX1 transcriptional activity was quantified using dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP). The effect of USP21 inhibition was evaluated using the USP21-targeted inhibitor Bay-805 in PCa cells.
RESULTS: USP21 is upregulated in PCa and correlates with poor prognosis. Functional assays demonstrated that USP21 knockdown significantly inhibited PCa cells proliferation, migration, and invasion. RNA-sequencing further revealed that USP21 modulates the HIF1 signaling pathway. Mechanistically, USP21 deubiquitinates and stabilizes YBX1, which in turn enhances HIF1A (encoding HIF1-α) transcription. Notably, pharmacological inhibition of USP21 with Bay-805 suppressed PCa progression, highlighting its therapeutic potential.
CONCLUSIONS: USP21 promotes PCa malignancy by interacting with YBX1 to upregulate HIF1-α expression. These findings suggest Bay-805 as a promising therapeutic candidate for PCa.

Keywords:  HIF1-α; Prostate cancer; USP21; YBX1

DOI:  https://doi.org/10.1186/s12967-025-07199-3
Sci Rep. 2025 Oct 21. 15(1): 36610

PACT is requisite for prostate cancer cell proliferation.

Dianne J Beveridge, Andrew J Woo, Kirsty L Richardson, Rikki A M Brown, Lisa M Stuart, Manjot Singh, Andrew D Redfern, Peter J Leedman.

  PACT (encoded by the PRKRA gene) is a double-stranded RNA binding protein with defined antiviral defense and cytoplasmic RNA-induced silencing actions in mammals. We previously described a further role for PACT as a modulator of nuclear receptor (NR)-regulated gene expression. Here, we investigated the role of PACT in prostate cancer (PCa) using a loss-of-function approach. Depletion of PACT in multiple PCa cell lines resulted in a reduction in cell proliferation, but viability was maintained. RNA-sequencing analysis of LNCaP PCa cells ± PACT revealed a depletion of biological processes involved in cell cycle, mitochondrial function, and NR-response pathways in the PACT knockout (KO) cells. In the PACT KO cells, downregulated genes included the androgen-regulated KLK3 (prostate specific antigen, PSA), together with H2AFJ, PSMD5, AQP3, TMEM45B, and SLC22A3, and siRNA-mediated knockdown of these genes reduced cell growth and proliferation in LNCaP cells. Further, reducing PACT or PSA induced cell cycle arrest at G0/G1. Additionally, the hormone-mediated upregulation and AR antagonist-driven downregulation of PSA gene expression were respectively attenuated and enhanced in PACT KO cells. Taken together, these data support a pro-proliferative role for PACT in PCa, and siRNA therapeutic targeting of PACT, or downregulated genes with PACT KO, could represent a new therapeutic approach.

Keywords:  Cell-cycle; PACT; PSA; Proliferation; Prostate cancer

DOI:  https://doi.org/10.1038/s41598-025-20494-9
Matrix Biol. 2025 Oct 17. pii: S0945-053X(25)00104-0. [Epub ahead of print]

Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance.

Asher R Utz, Linlin Ma, Dalton Hilovsky, Brenna M Zimmer, Emily Allego, Jade Fluharty, Pooja Narasimhan, Jeffrey R Enders, George Grady, Monica Milici, Pengda Liu, Xiaojing Liu, Joseph J Barycki, Melanie A Simpson.

  UDP-glucose 6-dehydrogenase (UGDH) is an essential enzyme that catalyzes the oxidation of UDP-glucose to UDP-glucuronate. UGDH is elevated in multiple cancers, including prostate cancer, and is functionally implicated in castration resistant recurrence. UGDH is composed of three dimeric units that associate stably as a hexamer in cellular conditions. The dynamic reorganization of noncovalent interactions at the dimer contact interfaces is essential for UGDH activity. In this study, we examined the functional relevance of a putative AGC kinase motif located at the dimer-dimer interface. We demonstrated that UGDH is phosphorylated in LNCaP cells, specifically at serine 316, by RSK2, p70S6K, and SGK1. To determine the functional implications of UGDH S316 phosphorylation, we generated and characterized phosphomimetic (S316D) and phosphodeficient (S316A) point mutations. Intrinsic properties of the purified recombinant proteins were only modestly affected by the substitutions. The stable overexpression of UGDH S316D in LNCaP cells significantly increased the rate of N- and O-glycan synthesis, as well as the production of hyaluronan and sulfated glycosaminoglycans, while reducing DHT glucuronidation, resulting in significant increases in growth of tumor spheroids, cell proliferation and motility, and resistance to enzalutamide. In contrast, UGDH S316A expression reduced the production of glycans and glycosaminoglycans, restored DHT glucuronidation, and impaired growth and motility. Overall, our results support UGDH phosphorylation as a point of control for intracellular and cell surface glycan production, thereby regulating cell proliferation, anchorage dependence, motility, and tumor cell therapeutic resistance.

Keywords:  N-linked glycosylation; O-linked glycosylation; cell growth; cell motility; dehydrogenase; glycosaminoglycan; hyaluronan; phosphorylation; prostate cancer

DOI:  https://doi.org/10.1016/j.matbio.2025.10.004
Comput Methods Programs Biomed. 2025 Oct 10. pii: S0169-2607(25)00534-6. [Epub ahead of print]273 109118

NN-PCP: Screening phenotype-related core pathways to construct a prostate cancer metastasis prediction model based on multiple types of mutation data.

Li Zhou, Jie Li.

   BACKGROUND AND OBJECTIVE: Prostate cancer causes >400,000 deaths annually worldwide, being the fifth leading cause of cancer-related death in men. However, accurate prediction of prostate cancer metastasis based on mutations remains a challenge.
METHODS: We proposed a novel neural network constructed with phenotype-related core pathways, called NN-PCP, to accurately predict prostate cancer metastasis. NN-PCP comprises three main modules: IORA-driven modules, IGSEA-driven modules, and a hierarchy with two differential layers. IORA-driven modules are constructed using highly variable genes and core pathways that are gained with an improved over-representation analysis. They are applied to extract pathway features from each type of mutation data. IGSEA-driven modules are constructed using the phenotype-related core pathways that are obtained with an improved gene set enrichment analysis. They are used to transform pathway features from each type of mutation data into differential features. Finally, the hierarchy with two differential layers is employed to mimic the synergy effect of differential features from different types of mutation data to gain deeply differential features.
RESULTS: NN-PCP outperformed four state-of-the-art methods, with improvements of 5.7 %, 7.8 %, 1.2 %, 0.058, 0.031, and 0.047 in accuracy, precision, recall, F1-score, AUC, and AUPR, respectively. Furthermore, NN-PCP identified some important genes and pathways in prostate cancer metastatic prediction, such as PIK3R1, PIK3CA, and the PI3K-AKT signaling pathway.
CONCLUSIONS: The proposed method outperforms other pathway-based deep learning methods, which can be used as an auxiliary tool for doctors to improve the accuracy of disease diagnosis.

Keywords:  Biological pathways; Metastasis; Mutations; Neural network

DOI:  https://doi.org/10.1016/j.cmpb.2025.109118
Curr Top Med Chem. 2025 Oct 16.

Zingerone Induces Apoptosis and Ferroptosis in Prostate Cancer DU145 Cells.

Nawaf Alshammari, Meenakshi Verma, Motrih Al-Mutiry, Sorabh Lakhanpal, Suhas Ballal, Anurag Kumar Singh, Renu Arya, Mohd Saeed, Pratibha Pandey, Fahad Khan.

   INTRODUCTION: Prostate cancer is among the most prominent malignant tumors in the male population, characterized by growing morbidity, a high fatality rate, and currently limited therapeutic options, necessitating the urgent development of novel clinical medications. The objective of the current study was to examine the therapeutic potential of zingerone in prostate cancer cells.
METHODS: In this study, we investigated the underlying mechanism by which zingerone exerts its anticancer effects in prostate cancer cells. We conducted various in vitro and in silico experiments to determine the therapeutic efficacy and mechanism of action of zingerone.
RESULTS: Cytotoxicity analysis of zingerone revealed its substantial cytotoxic impact and ability to elevate lactose dehydrogenase levels in DU145 cells. Using the MTT assay, we determined that a concentration of 24.84 μM zingerone in DU145 cells grown for 24 h resulted in an IC50 value. Zingerone effectively induced apoptosis by increasing the levels of cytochrome c and caspase in DU145 cells. Regarding the identification of signs of ferroptosis, evidence has been shown for the presence of heightened mitochondrial ROS, disrupted mitochondrial membrane potential, increased levels of glutathione (GSH) and malondialdehyde (MDA), and reduced expression of SCL7A11 and GPX4.
DISCUSSION: Importantly, our study confirms that zingerone triggered both apoptosis and ferroptosis in DU145 cells by downregulating SLC7A11 and GPX4 expression.
CONCLUSION: This study provides evidence that makes zingerone a potent therapeutic agent for prostate cancer.

Keywords:  Zingerone; apoptosis; ferroptosis; natural compound.; prostate cancer

DOI:  https://doi.org/10.2174/0115680266411570250929101928
J Natl Cancer Cent. 2025 Oct;5(5): 501-514

Spatial and maturity heterogeneity of tertiary lymphoid structures shapes immune microenvironment and progression in prostate cancer.

Zhongyuan Wang, Qintao Ge, Ren Mo, Jiahe Lu, Xi Tian, Aihetaimujiang Anwaier, Shiqi Ye, Siqi Zhou, Weihang Guo, Chuanhai Cai, Jianfeng Yang, Hailiang Zhang, Xiaojian Qin, Dingwei Ye, Wenhao Xu.

   Background: Tertiary lymphoid structure (TLS), ectopic lymphoid aggregates formed in response to chronic inflammation, have emerged as potential prognostic biomarkers and mediators of anti-tumor immunity in various cancers. However, the heterogeneity of TLS spatial distribution, maturity, and their prognostic and immunological significance in prostate cancer (PCa) remain poorly characterized.
Methods: We utilized immunohistochemistry, multispectral fluorescence immunohistochemistry (mIHC) and spatial multi-omics analyses to evaluate the heterogeneity of TLS and its relationship with immune components in the tumor microenvironment (TME). Prognostic implications were assessed in 701 PCa patients from the TCGA and Fudan University Shanghai Cancer Center cohorts. The association between TLS heterogeneity and immunoreactivity was assessed through the quantification of immune cell infiltration. CellTreck and robust cell type decomposition deconvolution algorithms were used to decipher the colocalization features of each cell, cell-cell communication and ligand-receptor features within TLS regions.
Results: In PCa, TLSs were detected in approximately 20 % of patients across both cohorts, with intratumoral TLS (intra-TLS) being twice as prevalent as peritumoral TLS (peri‑TLS). Patients harboring intra-TLS exhibited significantly longer disease-free and progression-free survival. Compared to peri‑TLS, intra-TLS were more mature, characterized by increased T-effector cell infiltration, activation of interferon pathways, and the presence of follicular dendritic cell centers and B cell aggregates. Notably, compared with immature TLS, mature TLS were markedly associated with reduced PD-L1 expression, lower regulatory T cells (Tregs) infiltration, and increased high endothelial venules (HEVs) density, indicative of an immunologically active microenvironment. Spatial multi-omics analysis revealed that mature TLS exhibited enriched immune cell diversity and HEVs density, suggesting enhanced anti-tumor immunity. Furthermore, cell-cell communication analysis identified significant interactions between CCL5+ dendritic cells and ACKR1+ activated B cells within mature TLS, reflecting the enhanced capacity of mature TLS to orchestrate robust antigen presentation and B-cell-driven immune responses.
Conclusions: In conclusion, this study highlights the prognostic and immunological implications of TLS heterogeneity in PCa, demonstrating that the spatial distribution and maturity of TLSs are closely linked to TME activation and improved clinical outcomes. These findings provide novel insights into the immune landscape of PCa and establish a foundation for immune-based precision stratification and therapeutic development.

Keywords:  High endothelial venules; Prostate cancer; Spatial multi-omics; Tertiary lymphoid structures; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jncc.2025.06.003
Environ Toxicol. 2025 Oct 24.

RETRACTION: Dieckol Prevents Prostate Cancer Cell Proliferation by Transcriptionally Attenuating JAK/STAT3 Signaling Pathway.

RETRACTION: V. Karuppaiya, A. Annamalai, S. Krishnamurthy, and K. Soundarapandian, "Dieckol Prevents Prostate Cancer Cell Proliferation by Transcriptionally Attenuating JAK/STAT3 Signaling Pathway," Environmental Toxicology 39, no. 3 (2024): 1187-1196, https://doi.org/10.1002/tox.24006. The above article, published online on 27 October 2023 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, April Rodd; and Wiley Periodicals LLC. Following an investigation by the publisher, the parties have concluded that this article was accepted solely on the basis of a compromised peer review process. Therefore, the article must be retracted. Author V. Karuppaiya agrees with the retraction. Authors A. Annamalai and K. Soundarapandian did not respond to communications from the Publisher regarding the retraction. Author S. Krishnamurthy could not be reached for comment regarding the retraction.

DOI: https://doi.org/10.1002/tox.24585
BMC Cancer. 2025 Oct 18. 25(1): 1609

Curcumin in prostate cancer: a systematic review of molecular mechanisms and nanoformulated therapeutic strategies.

Mojtaba Esmaeli, Maryam Dehghanpour Dehabadi.

   BACKGROUND: Prostate cancer (PCa) is one of the most prevalent malignancies in men, often progressing to castration-resistant forms and resisting conventional therapies. Curcumin, a polyphenol from Curcuma longa, has emerged as a potent anti-cancer agent by modulating several molecular pathways.
OBJECTIVE: This systematic review seeks to synthesize current preclinical evidence on the molecular mechanisms underlying curcumin's effects in PCa and to evaluate nanoformulation strategies developed to enhance its pharmacokinetics and therapeutic efficacy.
METHODS: A comprehensive search of five major databases up to March 1, 2025 identified 22 eligible studies on curcumin and PCa. Data on molecular pathways, therapeutic outcomes, and delivery systems were extracted and assessed using ToxRTool and SYRCLE guidelines.
RESULTS: Curcumin modulated key pathways including PI3K/Akt/mTOR (8 studies), NF-κB (7), AR signaling (6), and apoptosis-related regulators (13). Therapeutic outcomes included apoptosis, necroptosis, cell cycle arrest, and suppression of migration and angiogenesis. Nanoformulations (e.g., Theracurmin®, PLGA-curcumin) demonstrated improved bioavailability and tumor-targeted delivery. Synergistic combinations with docetaxel, quercetin, or phototherapy enhanced its anti-cancer effects.
CONCLUSION: Curcumin exerts multi-targeted anticancer effects in PCa models, but clinical translation is hindered by poor bioavailability. Advanced nanoformulations and rational combination therapies offer promising strategies to overcome these limitations. Clinical trials evaluating optimized curcumin delivery systems in well-defined PCa populations are strongly recommended.

Keywords:  Apoptosis; Curcumin; Drug Delivery; Molecular Pathways; Nanoparticles; PI3K/Akt/mTOR; Prostate Cancer

DOI:  https://doi.org/10.1186/s12885-025-15152-2
Ann Oncol. 2025 Oct 19. pii: S0923-7534(25)04936-1. [Epub ahead of print]

Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study.

CAPItello-281 Study Group

   BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC), PTEN deficiency results in PI3K/AKT pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes.
PATIENTS AND METHODS: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1:1) plus abiraterone, prednisone/prednisolone and androgen deprivation therapy (ADT). Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post-hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed.
RESULTS: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n=507, median 33.2 months) versus placebo plus abiraterone (n=505, 25.7 months; Hazard Ratio [HR] 0.81, 95% CI 0.66-0.98, P=0.034). Post-hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed the capivasertib plus abiraterone arm performed consistently across cutoffs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P=0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%) and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively.
CONCLUSIONS: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone.

Keywords:  CAPItello-281; Capivasertib; PTEN; abiraterone; mHSPC; prostate

DOI:  https://doi.org/10.1016/j.annonc.2025.10.004
ACS Appl Bio Mater. 2025 Oct 21.

Strategic Nanosuspension of Darolutamide for Enhanced Dissolution, Bioavailability, and Potentiated Prostate Cancer Treatment: Insights from Multiscale Computational Modeling.

Ekta Pardhi, Rahul Khemchandani, Avinash Pawar, Akash Kharwar, Gananadhamu Samanthula, Manoj Dandekar, Neelesh Kumar Mehra.

  Darolutamide (DA), a nonsteroidal antiandrogen, demonstrates significant potential as a targeted therapeutic agent for prostate cancer; however, its clinical application is limited due to its poor aqueous solubility and low oral bioavailability. To overcome these limitations, we developed a nanosuspension-based formulation (DA-NS) with a mean particle size (PS) of 143.36 ± 5.24 nm, which, upon lyophilization, yielded nanocrystals (DA-NC) with a mean PS of 156.26 ± 7.58 nm, aimed at enhancing the solubility and dissolution rate. Molecular dynamics simulations provided mechanistic insights into the stabilization and formation of DA-NS at the atomic level. In vitro studies demonstrated superior antitumor activity of DA-NC in PC3 prostate cancer cells, characterized by enhanced cellular internalization, nuclear condensation, and apoptotic morphology under fluorescence microscopy. Mechanistic investigations further validated its pro-apoptotic action via elevated reactive oxygen species generation and induction of DNA damage. Western blot analysis confirmed the molecular signature of apoptosis, showing downregulation of antiapoptotic Bcl-2 and upregulation of caspase-3. Pharmacokinetic evaluation revealed a 5.81-fold increase in Cmax and a 3.33-fold enhancement in AUC0-48 over pure DA, confirming a significant improvement in oral bioavailability (p < 0.0001). Importantly, DA-NC exhibited a favorable safety profile, underscoring its potential as a biocompatible and efficacious oral therapeutic strategy for advanced prostate cancer.

Keywords:  darolutamide; nanosuspension; prostate cancer; simulation; soluplus

DOI:  https://doi.org/10.1021/acsabm.5c01473
J Transl Med. 2025 Oct 21. 23(1): 1147

Revisiting the impact of cathepsin Z in prostate cancer: concerns and insights.

Zhiguo Zhu, Huisheng Qin, Zesong Jiang, Zhonghai Li.

DOI: https://doi.org/10.1186/s12967-025-07126-6
Eur J Med Chem. 2025 Oct 17. pii: S0223-5234(25)01041-4. [Epub ahead of print]302(Pt 1): 118276

ROS-mediated antiproliferative effects of dihydrotestosterone-derived ferrocene-steroid conjugates toward human cancer cell lines of variable androgen dependence.

Vidak Raičević, Sandra Aranđelović, Nevenka Gligorijević, Biljana Dojčinović, Marko Rodić, André Stephan Ćulum, Niko Radulović.

  Ferrocene appendages often endow organic scaffolds with reactive-oxygen-species (ROS)-mediated cytotoxicity, yet ferrocene-androgen conjugates remain somewhat poorly explored, especially those linked at the steroid A-ring, known to modulate androgen receptor (AR) binding. Three C-2-substituted ferrocene-steroid conjugates derived from dihydrotestosterone (DHT) - the most potent human androgen - were synthesized; the structure of 1 was confirmed by single-crystal X-ray crystallography. Antiproliferative activity was quantified in AR-positive (LNCaP, OVCAR-3) and AR-negative (PC-3) cancer cells and in non-malignant MRC-5 fibroblasts. The balance of androgenicity and inherent cytotoxicity brought about by the presence of ferrocene proved adequate, as all conjugates acted in an antiproliferative manner toward the two hormone-responsive cancerous cell lines. Conjugate 2 (2α-ferrocenylmethyl-DHT) was the most potent analogue, inhibiting OVCAR-3 growth with an IC50 = 2.8 μM and a selectivity index of 3.0 relative to cisplatin. In OVCAR-3 cells, 2 triggered S-phase arrest, a 21-fold rise in intracellular iron, and ROS-dependent loss of viability; co-treatment with N-acetyl-l-cysteine, but not the caspase inhibitor Ac-DEVD-CHO, rescued cells. In multicellular tumor spheroids, 2 disrupted spheroid integrity (IC50 = 14 μM). These findings indicate the potential of A-ring substituted androgen-ferrocene conjugates as antiproliferative agents for hormone-dependent cancers, with 2 emerging as a promising candidate that surpasses cisplatin in potency and appears to act through a distinct mechanism.

Keywords:  Androgens; Antiproliferative activity; Dihydrotestosterone; Ferrocene; Ferrocene–steroid conjugates; Ovarian cancer; Prostate cancer

DOI:  https://doi.org/10.1016/j.ejmech.2025.118276
Oncol Lett. 2025 Dec;30(6): 570

FBXL22, a circadian-regulated immune biomarker with pan-cancer prognostic value and therapeutic potential in prostate cancer.

Jin Liu, Maoyuan Feng, Jian Zhou, Shijie Yang, Yue Shi, Wenping Li.

  F-box and leucine-rich repeat protein 22 (FBXL22) has been implicated in breast and prostate cancer types; however, comprehensive pan-cancer analyses and detailed investigations of its role in cancer development are still needed. To address this, the present study used The Cancer Genome Atlas, Genotype-Tissue Expression, University of ALabama at Birmingham CANcer data analysis Portal, Kaplan-Meier-Plotter and cBioPortal databases to analyze the correlation between FBXL22 expression and prognosis, gene mutations, DNA methylation, immune cell infiltration and immune-related gene regulation in several types of cancer. The findings of the present study demonstrated that FBXL22 was predominantly downregulated in several cancer types and may serve as a prognostic and diagnostic marker in certain cancer types, particularly prostate cancer. Strong correlations between FBXL22 expression and immune checkpoint genes were observed, which suggests a role in the tumor immune microenvironment. Additionally, FBXL22 expression was associated with infiltration of cancer-associated fibroblasts and endothelial cells, which may affect immunotherapy outcomes. Mechanistically, FBXL22 was involved in circadian rhythm regulation, ubiquitin-mediated proteolysis, focal adhesion signaling and cGMP-protein kinase G signaling. In prostate cancer, FBXL22 upregulation suppressed cell viability, invasion and metastasis, while promoting apoptosis, potentially through modulation of the polo-like kinase 1 pathway. To the best of our knowledge, the present study provides the first comprehensive pan-cancer analysis of FBXL22, which highlights its potential as an immune biomarker and therapeutic target for multiple cancer types with implications for precision medicine.

Keywords:  F-box and leucine-rich repeat protein 22; biomarkers; pan-cancer; prostate cancer; tumor immune microenvironment

DOI:  https://doi.org/10.3892/ol.2025.15316
Sichuan Da Xue Xue Bao Yi Xue Ban. 2025 Jul 20. 56(4): 1137-1144

[Design, Synthesis, and Efficacy Evaluation of a Novel BRD4/HDAC Dual-Target Small-Molecule Inhibitor in Prostate Cancer].

Shuyang Feng, Yanxiang Shao, Kan Wu, Weixiao Yang, Xiang Li.

   Objective: To design a novel bromodomain-containing protein 4 (BRD4) and histone deacetylase (HDAC) dual-target inhibitor (11b), and to elucidate its therapeutic efficacy and mechanisms in suppressing prostate cancer through epigenetic regulation.
Methods: BRD4 and HDAC expression levels were assessed via immunohistochemistry (IHC) using prostate cancer tissue microarrays. The inhibitory activity of 11b was screened across three prostate cancer cell lines, with the half-maximal inhibitory concentration (IC50) determined by CCK-8 assay. Western blot was employed to analyze changes in the expression of target proteins, including BRD4, c-Myc proto-oncogene protein (c-Myc), and Ac-H3K27, with parallel comparisons to single-target agents, including suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, and JQ-1, a BRD4 inhibitor. Cell invasion and proliferation were evaluated using Transwell and colony formation assays, and the autophagy mechanism was validated using 3-methyladenine (3-MA), an autophagy inhibitor. A PC-3 xenograft model was established in nude mice. Then, 11b (7.5 mg/kg or 15 mg/kg), normal saline, SAHA, and JQ-1 were administered via intraperitoneal injection, and their tumor growth inhibition effects were observed. The percentage of target protein-positive cells and the expression levels of target genes were quantified via IHC and RT-PCR, respectively.
Results: BRD4 and HDAC expression levels were both higher in tumor tissues than those in normal tissues (P < 0.01). 11b exhibited the strongest inhibitory activity against PC-3 cells (IC50 = 8.28 μmol/L), outperforming SAHA (22.61 μmol/L) and JQ-1 (22.09 μmol/L). Treatment with 11b reduced BRD4 and c-Myc expression by (41.58 ± 3.28)% and (63.21 ± 6.91)%, respectively (P < 0.01), and increased the Ac-H3K27 level to 6.52-fold that of the negative control (NC) group (P < 0.01), demonstrating greater modulation than either SAHA or JQ-1 did. The in vitro experiment showed that 8 μmol/L 11b treatment reduced PC-3 colony formation and migration by 97.5% and 96.3%, respectively (P < 0.001), and co-treatment with 3-MA reversed its cytotoxic effects. The in vivo experiment showed that 11b at both 7.5 mg/kg and 15 mg/kg significantly reduced tumor volume and weight compared with the control, SAHA, and JQ-1 groups (all P < 0.01), with the proportion of percentage of target protein-positive cells and the expression of target genes showing trends consistent with in vitro findings.
Conclusion: The dual-target inhibitor 11b exerts potent antitumor effects in prostate cancer by synergistically modulating the BRD4/HDAC pathways. 11b demonstrates therapeutic efficacy superior to that of the single-target agents SAHA and JQ-1 in suppressing prostate cancer progression, highlighting its potential for clinical translation.

Keywords:  Dual-target inhibitor; Epigenetic repression; Epigenomics; Prostate cancer

DOI:  https://doi.org/10.12182/20250760204
Mol Biol Rep. 2025 Oct 23. 53(1): 6

Investigation of the association of tRNA-derived fragments (tRF-17-79MP9PP and tRF-18-79MP9P04) with prostate cancer.

Sercan Ergun, Kadir Önem, Deniz Bayçelebi, Ümmet Abur, Özlem Terzi, Senanur Olfaz Aslan, Neslihan Taşkurt Hekim, Sezgin Güneş, Dilbeste Demir Yeşilyurt, Yeda Keleş.

   INTRODUCTION: This study investigates the association between the levels of two tRNA-derived fragments, tRF-17-79MP9PP and tRF-18-79MP9P04, and the pathophysiology of prostate cancer (PCa).
MATERIALS AND METHODS: Forty patients were included: 8 with benign prostatic hyperplasia (BPH) and 32 with different PCa grades. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissues, and the levels of tRF-17-79MP9PP and tRF-18-79MP9P04 were analyzed.
RESULTS: The abundance of tRF-17-79MP9PP increased progressively with cancer grade (p < 0.001), with the highest levels observed in advanced PCa. Interestingly, BPH also showed higher tRF-17-79MP9PP level than low- and mild-grade PCa. Level of tRF-18-79MP9P04 was comparable between BPH and low-grade PCa, but significantly higher in mild, high, and advanced grades (p < 0.001). Furthermore, PSA levels were significantly correlated with both tRF-17-79MP9PP and tRF-18-79MP9P04 in PCa patients (p < 0.001), but not in the BPH group.
DISCUSSION: Both tRF-17-79MP9PP and tRF-18-79MP9P04 appear to play important roles in prostate cancer, demonstrating potential oncogenic behavior in advanced stages, which contrasts with previous studies reporting tumor-suppressive effects.
CONCLUSION: These findings indicate that elevated levels of these tRNA-derived fragments may serve as potential biomarkers for distinguishing between different grades of PCa.

Keywords:  Expression analysis; Prostate cancer; TRNA-derived fragments

DOI:  https://doi.org/10.1007/s11033-025-11176-w
Cytotechnology. 2025 Dec;77(6): 186

Construction and validation of a novel diagnostic model with palmitoylation-related genes for prostate cancer.

Ling Fu, Jing Huang, Yi Sun, YueFeng Jia.

  Prostate cancer (PC) continues to represent a significant contributor to male cancer mortality worldwide, necessitating the discovery of innovative diagnostic indicators and molecular targets. Our investigation utilized computational biology approaches combining multi-omics analysis with machine intelligence to elucidate the role of palmitoylation-related genes (PRGs) in PC pathogenesis and prognosis. By harmonizing transcriptomic datasets from TCGA and GEO repositories, we identified dysregulated PRGs and stratified PC into two molecularly distinct subtypes via unsupervised clustering. These subtypes exhibited divergent clinical outcomes, immune microenvironment heterogeneity (e.g., Dendritic cells, CD8+ T cells, and Macrophages infiltration), and distinct drug sensitivity profiles. Single-cell RNA sequencing further localized key PRGs-ZDHHC2, ZDHHC5, ZDHHC15, ZDHHC9, and LYPLA1-within tumor cell populations, linking their expression to immune evasion and metabolic reprogramming. A robust diagnostic model, integrating 101 machine learning algorithms, demonstrated high predictive accuracy for survival and immunotherapy response. Functional validation in DU145 cells confirmed that modulating these PRGs significantly suppressed proliferation and colony formation, highlighting their pathobiological relevance. Collectively, this multidimensional analysis delineates a comprehensive framework for understanding palmitoylation-driven oncogenesis and establishes a precision medicine toolkit for risk stratification and treatment optimization in PC.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00842-3.

Keywords:  Bioinformatics; Diagnostic; Palmitoylation; Prostate cancer

DOI:  https://doi.org/10.1007/s10616-025-00842-3
Eur Urol. 2025 Oct 23. pii: S0302-2838(25)00495-6. [Epub ahead of print]

Histopathology-based Artificial Intelligence Algorithms for the Prediction of Prostate Cancer Metastasis After Radical Prostatectomy.

Eumee Cha, Zhike Lin, Jiayun Lu, Lia DePaula Oliveira, Eric Erak, Adrianna A Mendes, Oluwademilade Dairo, Onur Ertunc, Ibrahim Kulac, Javier A Baena-Del Valle, Tracy Jones, Jessica L Hicks, Stephanie Glavaris, Gunes Guner, Igor Damasceno Vidal, Bruce J Trock, Nilanjan Chattopadhyay, Uttara Joshi, Chaith Kondragunta, Saikiran Bonthu, Misop Han, Lorelei A Mucci, Corinne Joshu, Angelo M De Marzo, Konrad H Stopsack, Nitin Singhal, Tamara L Lotan.

   BACKGROUND AND OBJECTIVE: Multimodal artificial intelligence (AI) algorithms have been validated to predict prostate cancer (PCa) metastasis using combined histopathology and clinical-pathologic parameters in clinical trial cohorts. Here, we used purely histopathology-based AI algorithms to predict the probability of lethal PCa in surgically treated population- or hospital-based cohorts, comparing with genomic classifiers and standard clinical risk tools.
METHODS: This study included representative whole slide images (WSIs) of radical prostatectomy (RP) and needle biopsy samples, or tissue microarrays (TMAs) constructed from RP specimens across five surgically treated PCa cohorts. A concatenated feature-based classification system using histopathologic data from each image generated an AI risk score for metastasis.
KEY FINDINGS AND LIMITATIONS: In Cox models for time to metastasis, an AI risk score from prostatectomy WSIs showed similar performance (C-index: 0.81-0.85) to the Decipher or Prolaris genomic classifiers (C-index: 0.72-0.80) in testing cohorts. A modified TMA AI score analyzing ∼1 mm2 of prostatectomy tumor tissue from a nationwide study of 1351 patients had a C-index of 0.71 (95% confidence interval [CI]: 0.67-0.75). In a needle biopsy cohort followed for metastasis after prostatectomy, the TMA AI score had a C-index of 0.74 (95% CI: 0.70-0.79), and models combined with the Cancer of the Prostate Risk Assessment (CAPRA) score showed improved performance (C-index: 0.83 [95% CI: 0.82-0.87]) compared with CAPRA alone (C-index: 0.79 [95% CI: 0.73-0.84]). Limitations include relatively older cohorts, with many biopsies performed before the adoption of modern magnetic resonance imaging-guided techniques.
CONCLUSIONS AND CLINICAL IMPLICATIONS: This study is among the first to show that histopathology-based AI algorithms applied to small samples of tumor tissue can predict the risk of lethal PCa. These algorithms perform comparably to commonly used genomic classifiers, and their predictive performance is enhanced when combined with clinicopathologic variables.

Keywords:  Artificial intelligence; Biopsy; Deep learning; Genomic classifier; Histopathology; Lethal; Metastasis; Prostate cancer; Prostatectomy; Tissue microarray

DOI:  https://doi.org/10.1016/j.eururo.2025.08.018
Crit Rev Eukaryot Gene Expr. 2025 ;35(7): 11-25

Identification of Novel Molecular Subtypes of Prostate Cancer Based on Genes Related to Metabolic Reprogramming to Assess Prognosis and Immune Landscape.

Wentao Fan, Desheng Zhu, Jiawen Zheng, Min Xu.

Prostate cancer (PRAD) progression varies significantly among patients, with metabolic reprogramming linked to oncogenesis and immune response. However, the prognostic and immune-related roles of metabolic reprogramming-related genes (MRGs) in PRAD remain unclear. PRAD transcriptomic, mutation, and clinical data from TCGA were analyzed. WGCNA identified PRAD-associated gene modules. NMF clustering stratified patients into two molecular subgroups. Prognostic MRGs were screened via univariate Cox and LASSO regression. A gene-based prognostic model was established and validated using ROC, PCA, and Kaplan-Meier analyses. A clinical-variable nomogram predicted survival, with external validation via GEO data set GSE70770. Immune traits of subtypes/risk groups were assessed via ESTIMATE, CIBERSORT, and ssGSEA. Drug sensitivity and gene expression (qRT-PCR) were evaluated. Two metabolic subtypes with distinct survival and immune patterns were identified. A four-gene signature (AKR1C2, PITPNM3, PLA2G5, UCK2) formed a prognostic model. Risk stratification revealed groups with divergent survival rates. High-risk patients exhibited poorer outcomes, reduced immune infiltration, and altered drug sensitivity. The MRG prognostic model stratifies PRAD patients by survival and immune landscape, aiding precision immunotherapy and drug discovery.

DOI: https://doi.org/10.1615/CritRevEukaryotGeneExpr.2025060696
J Natl Cancer Cent. 2025 Oct;5(5): 515-523

Transcriptomic predictors of prostate cancer recurrence following focal cryotherapy: a pooled analysis of phase II trial and prospective cohort data.

Kae Jack Tay, Boon Hao Hong, Enya Hui Wen Ong, Kah Min Tan, Gianella Cabuhat Pacho, Samantha Jingxuan Wong, Yu Guang Tan, Yan Mee Law, Nye Thane Ngo, Puay Hoon Tan, John S P Yuen, Henry S S Ho, Kenneth Chen, Jiping Peng, Clare Wei Tian Foo, Xin Xiu Sam, Jeffrey K L Tuan, Ravindran Kanesvaran, Rajan T Gupta, Steven Rozen, Thomas J Polascik, Yang Liu, James Proudfoot, Elai Davicioni, Li Yan Khor, Melvin Lee Kiang Chua.

   Objective: Focal therapy (FT) is a potential treatment option for limited-volume clinically-significant prostate cancer (csPCa). However, despite rigorous selection, approximately 20% of patients experience early failure. We investigated the association of transcriptomic profiles and csPCa recurrence post-FT.
Methods: 52 men from a phase II trial (NCT04138914) and a prospective observational cohort underwent focal cryotherapy for csPCa. Patients underwent multiparametric magnetic resonance imaging, and targeted and systematic-saturation biopsy before- and 1-year post-FT. Recurrence was defined as grade-group (GG) ≥2 cancer in the 1-year post-FT biopsy. Pre-treatment lesions were profiled using the Decipher genomic classifier (GC). GC scores, luminal-basal status, tumor microenvironment and cancer hallmark pathways were correlated with csPCa recurrence.
Results: Median PSA was 7.0 ng/dl; 37/52 (71.1%) men had GG2, 12/52 (23.1%) GG3, and 3/52 (5.8%) GG4 cancer. Recurrence was observed in 9/52 (17.3%) men. Median GC score was higher in patients with recurrence (0.60 vs 0.38, P = 0.014) and remained significantly associated with recurrence after adjustment for GG (adjusted OR: 1.37 [95% CI: 1.01-1.93], P = 0.04). Luminal-proliferative tumors based on the prostate cancer-specific subtyping classifier (PSC) had more csPCa recurrence compared with luminal-differentiated (LD) and basal subtypes (30.4% vs 0% [LD] vs 15.4% [basal-neuroendocrine] and 14.3% [basal-immune], P = 0.027). Higher expression of DNA repair pathway was also associated with recurrence (OR: 2.12 [95% CI: 1.09-4.57], P = 0.025).
Conclusions: Higher GC score is associated with risk of csPCa recurrence post-FT. Patients with GC low-risk and PSC-LD csPCa may represent the ideal subgroup for FT. Prospective validation in a large cohort is warranted.

Keywords:  Cryotherapy; Decipher genomic classifier; Focal therapy; Prostate cancer

DOI:  https://doi.org/10.1016/j.jncc.2025.04.002
Adv Biomed Res. 2025 ;14 101

Diving into High Concentration of EGCG: Assessing its Effects on miR-34 and miR-93, PSA, and AR Expression in Prostate Cancer LNCaP Cell Line.

Hossein Mokhtari, Ali Ebrahimi, Parisa Bahavar, Mahdi Bagheri, Mohammad Eavazi, Sara Banihashemi, Yalda Malekzadegan, Zeinab Barartabar.

   Background: Increased miR-93 and decreased miR-34a expressions have been shown in prostate cancer (PC). Prostate-specific antigen (PSA) and androgen receptor (AR) exert a significant role in the onset and progression of PC. This research tried to investigate the effect of EGCG on the expression of miR-34 and 93 and the expression of PSA and AR in PC cell lines.
Materials and Methods: The effect of 5, 20, and 40 µg/ml concentrations of EGCG on the expression of miR-34a and miR-93 on the LNCaP cell line was evaluated through RT-PCR. LNCaP cells were treated with a miR-34a mimic and a miR-93 inhibitor combined with 40 µg/ml of epigallocatechin-3-gallate (EGCG) and then assessed gene expressions using real-time analysis. Cell migration was investigated by scratch assay.
Results: At concentrations of 5 and 20 µg/ml EGCG, the miR-34a and miR-93 expression levels exhibited a reduction compared to the control cohort. Conversely, at a concentration of 40 µg/ml EGCG, there was a notable elevation in the expression levels of miR-93 and miR-34a compared to the control group. Furthermore, a combination of high concentration of EGCG with a miR-34a mimic and miR-93 inhibitor led to a significant change in the expression of PSA and AR in contrast to the EGCG group.
Conclusion: Given the potential cytotoxicity of high concentrations of EGCG toward cancer cells and the conceivable impact on nonmalignant cells, it is imperative to approach its consumption with greater care.

Keywords:  Androgen receptor; epigallocatechin gallate; microRNAs; prostate cancer; prostate-specific antigen

DOI:  https://doi.org/10.4103/abr.abr_193_24
Front Cell Infect Microbiol. 2025 ;15 1669490

Association between periodontal disease and prostate disease: a mini review.

Shuxin Li, Hongliang Cao, Yueqiu Zhang, Tong Yang, Mingxuan Li, Chensen Lv, Xin Lian.

  Periodontal disease (PD) is one of the most common chronic diseases in the oral cavity, typically referring to chronic inflammation caused by infection with pathogenic microorganisms in the oral cavity. PD primarily affects the tissues surrounding the teeth, leading to inflammation of the gums and periodontal tissues, destruction of the alveolar bone, and even loosening of the teeth. Numerous studies have shown that PD is not limited to the oral cavity but is also associated with the occurrence of diseases in multiple systems throughout the body. In recent years, increasing attention has been directed toward the interaction between PD and prostate diseases. This article reviews the potential associations between PD and prostate conditions such as chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). It explores the pathological mechanisms underlying this interaction and its clinical implications. Additionally, this article aims to identify potential pathogenic mechanisms and propose possible approaches for preventing and treating prostate diseases through the management of PD.

Keywords:  benign prostatic hyperplasia; inflammatory factors; oral microbiota; periodontal disease; prostate cancer; prostatitis; systemic inflammation

DOI:  https://doi.org/10.3389/fcimb.2025.1669490
World J Urol. 2025 Oct 22. 43(1): 622

The combination of prostate health index and multiparametric magnetic resonance imaging in prostate cancer diagnosis: efficacy analysis in different PSA ranges and its clinical decision-guiding value.

Jin-Feng Pan, Yin-Zhi Chen, Su-Ying Wang, Zhen-Ya Zhao, Da-Wei Ren, Rui Su, Xiao-Long Jia, Jun-Hui Jiang, Qi Ma.

   PURPOSE: This study aims to investigate the diagnostic accuracy of prostate health index (PHI) in combination with multi-parametric magnetic resonance imaging (mpMRI) for the detection of prostate cancer (PCa). Furthermore, the study also seeks to evaluate the diagnostic performance of this combined approach across various PSA levels, with the goal of developing a personalized biopsy protocol.
METHODS: This retrospective study enrolled 120 patients who underwent PSA, PHI, and mpMRI tests prior to prostate biopsy and were divided into the PCa group and the benign prostatic hyperplasia (BPH) group. Patients with ISUP >2 were classified as clinically significant prostate cancer (csPCa). MpMRI images were interpreted according to the Prostate Imaging Reporting and Data System, version 2. Diagnostic accuracy of each indicator was assessed using receiver operating characteristic (ROC) curve analysis. Independent predictors were identified through univariate and multivariate logistic regression analyses. Furthermore, the diagnostic performance of PHI, mpMRI, and their combination was evaluated.
RESULTS: Based on the pathological biopsy results, 48 (40%) were diagnosed with PCa, while 72 (60%) patients had a benign lesion. The area under the curve (AUC) of PHI and PI-RADS score for PCa diagnosis was 0.747 and 0.790, respectively, both significantly higher than that of PSA (0.645) (p < 0.05). When PHI and PI-RADS score were used in combination, the sensitivity and specificity for PCa diagnosis were 81.3% and 68.1%, respectively.. Compared to the use of PSA, PHI or PI-RADS score alone, the specificity is enhanced while maintaining comparable sensitivity, potentially avoiding 50 (69.4%) cases of negative biopsies. Subgroup analysis stratified by PSA level showed that: (1) In the PSA ≤ 10 ng/ml subgroup, the AUC of PHI, PI-RADS score and PSA for PCa diagnosis was 0.698, 0.753 and 0.587 respectively, (p < 0.05). When the PHI and PI-RADS score are used in combination, the diagnostic sensitivity and specificity are 75.0% and 71.2%, respectively, which are superior than those of using either indicator alone; (2) In the PSA>10 ng/ml subgroup, PHI did not provide additional diagnostic benefits when used combined with PI-RADS score, with a diagnostic sensitivity of 65.0% and specificity of 90.0%. Correlation analysis of clinical indicators revealed that PHI was significantly correlated with PI-RADS score, Gleason score, and the number of positive biopsy cores.
CONCLUSIONS: This study demonstrates that PHI outperforms PSA in detecting PCa, with elevated PHI levels correlating with more advanced disease. Furthermore, combining PHI with mpMRI significantly enhances the detection rate of PCa, particularly among patients with low PSA levels.

Keywords:  Diagnosis; Multiparameter magnetic resonance; Prostate biopsy; Prostate cancer; Prostate health index

DOI:  https://doi.org/10.1007/s00345-025-06003-7
Front Rehabil Sci. 2025 ;6 1655422

The impact of second-generation androgen receptor pathway inhibitors on skeletal muscle morphology and strategies to mitigate their effects in prostate cancer patients.

Sarah Edwards, Tea Lulic-Kuryllo, Anupam Batra.

  The standard of care for metastatic castrate sensitive prostate cancer (mCSPC) involves the use of doublet therapies, which prolong survival and delay disease progression. Doublet therapies include the addition of second-generation androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT). ADT monotherapy has been associated with adverse effects on skeletal muscle morphology, muscle strength, and physical function. Our findings suggest that the addition of ARPIs to ADT may further exacerbate these adverse effects. This review provides an overview of the current evidence to initiate exercise during treatment as an intervention to mitigate these adverse effects. Despite growing research in exercise oncology, research on the effects of exercise in men with mCSPC treated with doublet therapy is lacking. Much of the current supporting evidence is based on men with metastatic castrate resistant prostate cancer. Nonetheless, this review examines the available research on the efficacy and benefits of participating in a regimented exercise program in men with metastatic prostate cancer. We highlight the emerging evidence that exercising during treatment has the potential to protect against the adverse effects of doublet therapy. Future research to uncover the effects of different doublet therapies on muscle health in mCSPC is needed. Moreover, an improved understanding of the optimal training dose and timing that would elicit the most optimal benefits on muscle health in men with mCSPC is required.

Keywords:  exercise; metastatic castrate sensitive; metastatic prostate cancer; muscle morphology and function; muscle strength; physical function

DOI:  https://doi.org/10.3389/fresc.2025.1655422
Prostate. 2025 Oct 23.

Utility of the PROSTest, a Novel Blood-Based Molecular Assay, Versus PSA for Prostate Cancer Stratification and Detection of Disease.

Mark Kidd, Grzegorz Rempega, Michal Kepinski, Szymon Slomian, Krystyna Mlynarek, Abdel B Halim.

   BACKGROUND: Prostate cancer (PCa) is the most common solid organ cancer in men and the fifth leading cause of cancer-related deaths globally. PSA helps identify men at risk but has low specificity and has resulted in unnecessary biopsies. The PROSTest, a novel machine learning-based 27-gene mRNA liquid biopsy assay, was developed to detect PCa. We evaluated its utility as a stratification tool in symptomatic men undergoing biopsy or surgery for PSA > 2 ng/mL.
METHODS: Of 123 men assessed, 105 (85%) met eligibility criteria (age > 55 years, PSA > 2 ng/mL, symptomatic) and underwent image-guided biopsy or surgery. Blood samples for PROSTest were collected prebiopsy, and RNA-stabilized samples underwent RNA isolation and cDNA production. PCR results were analyzed using a machine learning algorithm, generating a 0-100 score with a cutoff of 50 for a binary (positive/negative) readout. The performance of PROSTest was against PSA using AUROC and evaluated for Gleason Grade (GG) 1 versus GG2-5 patients.
RESULTS: Median age was 68 years (55-86 years); median PSA was 8.2 ng/mL (IQR: 7.2-92 ng/mL). PCa was diagnosed in 65 men (62%) (27 GG1; 38 GG2-5). PROSTest was positive in 63/65 (97%) of those with PCa and in 2/40 (5%) without PCa. Sensitivity was 97%, specificity 96%. PROSTest outperformed PSA (AUROC: 0.99 vs. 0.61, p < 0.0001). GG2-5 had significantly higher (p < 0.0001) PROSTest scores (92 ± 3).
CONCLUSIONS: PROSTest demonstrated superior sensitivity and specificity compared to PSA for detecting prostate cancer across all Gleason grades. Additionally, it showed potential for distinguishing GG2-5 from GG1 + BPH, which could help guide clinical decision-making and reduce unnecessary biopsies. By leveraging a machine learning-based approach, PROSTest may offer a more accurate and less invasive diagnostic tool for prostate cancer stratification. However, larger prospective studies are needed to validate these findings and further define its clinical utility.

Keywords:  PCR; PROSTest; PSA; prostate cancer; screening

DOI:  https://doi.org/10.1002/pros.70086