bims-meproc 2025-12-21 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–12–21
thirty-two papers selected by
Grigor Varuzhanyan, UCLA

CDC7 is a targetable regulator of advanced prostate cancer.
Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation.
Neuroendocrine prostate cancer (NEPC)-associated CEP55 promotes cisplatin resistance in prostate cancer by regulating CDK1 phosphorylation.
Graded Notch Signaling Functions as a Rheostat of Lineage Plasticity and Therapy Resistance in Prostate Cancer.
CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.
Serotonin modulates lineage plasticity in neuroendocrine prostate cancer via epigenetic reprogramming.
CDK12-Mediated Phosphorylation of FOXA1 Promotes Prostate Cancer Progression via the MDM2-p53 Axis.
Comprehensive bioinformatics and in vitro studies reveal the carcinogenic role and molecular basis of endocrine disruptors in prostate cancer.
Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer.
Senescence-related gene signature predicts prostate cancer progression and identifies PCNA as a therapeutic target via multi-omics machine learning integration.
[Effect of dephosphorylation of tumor metastasis suppressor gene LASS2 on vacuolar ATPase activity and invasiveness of prostate cancer].
Navigating the winding road toward precision prostate cancer care.
Roles of KHDRBS2 and KHDRBS3 in prostate cancer progression and AR-V7 regulation.
Comparison of prostate cancer cell line growth in fetal bovine serum and animal free supplements.
Identification and validation of critical mitochondrial hub genes for prostate cancer.
Characteristics of the immune microenvironment, metabolic microenvironment, and gut microbiota in prostate cancer.
Metabolic medications modify prostate cancer progression through exosome reprogramming.
Unravelling TPX2-centered co-expression networks as key drivers of aggressive prostate cancer.
Menin-driven mTOR signaling sustains taxane resistance in CRPC and reveals a targetable vulnerability for combination therapy.
A comparative analysis of CXCR4 gene expression from published datasets and cell surface protein levels in breast and prostate cancer models.
E2F1-mediated PKMYT1 upregulation promotes prostate cancer progression by inhibiting the PPAR signaling pathway.
Epigenetic approaches to prostate cancer: Present landscape and future prospects.
Stromal-derived high-molecular-weight hyaluronan mediates radioresistance in the prostate cancer microenvironment.
SLC45A2 drives prostate cancer progression through tumor promotion and immune suppression.
Hedyotis diffusae herba -Scutellaria Barbata herba drug pair suppresses prostate cancer by inducing apoptosis.
Machine learning-DeepSurv prediction model integrating mpMRI radiomics and genomic biomarkers for BCR-free survival and tumor response in prostate radiotherapy.
Types of biomimetic materials and their emerging clinical applications in the field for prostate cancer.
Analysis of MRPL23 protein expression and its role in prostate cancer pathogenesis.
Causal role of 46 pathogen-derived antibodies in prostate disease insights from two-sample and Bayesian-weighted Mendelian randomization.
Unveiling the therapeutic mechanism of Epimedium Herba on prostate cancer through network pharmacology and experimental validation.
Diagnostic Value of Rapid On-Site Evaluation Combined With Prostate Biopsy in Prostate Cancer.
Docetaxel induced activation of GSDME pathway and pyroptosis enhance immune lethality in prostate cancer cells.

Sci Rep. 2025 Dec 18.

CDC7 is a targetable regulator of advanced prostate cancer.

Alifiani B Hartono, HyeonJi Hwang, Sidharth Paparaju, Shiqin Liu, James D Brooks, Eva Corey, Tanya Stoyanova.

Prostate cancer is estimated to contribute to over 35,000 deaths of men residing in the United States, with the majority fatality due to metastatic disease. CDC7 is a kinase that regulates DNA replication and is found elevated during neuroendocrine transdifferentiation in lung and prostate cancer. In this study, we demonstrate that CDC7 is highly expressed in treatment-resistant prostate cancer, with even higher levels observed in treatment-resistant prostate cancer with neuroendocrine phenotype (NEPC). We further identify CDC7 as a critical regulator of prostate tumorigenesis. Downregulation of CDC7 significantly reduces prostate cancer cells growth and invasion in vitro and silencing CDC7 suppresses prostate tumor growth in vivo. Furthermore, we demonstrate that the inhibition of CDC7 using TAK-931, a selective CDC7 inhibitor, significantly reduces the proliferation, migration, and invasion of aggressive prostate cancer cells. TAK-931 treated prostate cancer cells exhibit an abnormal cell cycle profile, suggesting that CDC7 inhibition induces replication stress and promotes apoptosis. Collectively, our findings demonstrate that CDC7 is a regulator of tumor progression in prostate cancer and represents new therapeutic target in advanced prostate cancer.

DOI: https://doi.org/10.1038/s41598-025-29574-2
bioRxiv. 2025 Nov 29. pii: 2025.11.25.690552. [Epub ahead of print]

Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation.

N Patterson, A Badoi, G P Vadla, M Hasani, J Moyer, C De la Nuez Ramirez, Y C Chabu.

Aberrant activation of the androgen receptor (AR) pathway drives prostate cancer (PCa). Androgen deprivation therapy (ADT) and next-generation AR blockade (e.g., enzalutamide) are initially effective, but virtually all patients develop castration-resistant prostate cancer (CRPC), which frequently transitions to treatment-emergent neuroendocrine PCa (tNEPC) following AR suppression. The molecular logic that links AR blockade to lineage plasticity remains incompletely understood. Here, we identify PSMA2 (Proteasome Subunit Alpha 2) as a treatment-induced effector that mechanistically connects AR blockade to tNEPC evolution. Enzalutamide induces PSMA2 expression in AR-expressing PCa cells. Enforced PSMA2 expression accelerates HSP90 turnover, hypersensitizes AR to residual post-castration androgen, drives AR nuclear activity under androgen-poor conditions, and confers enzalutamide resistance. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes CRPC to androgen, and re-sensitizes resistant cells to enzalutamide-induced cell death. Importantly, PSMA2 also promotes lineage plasticity: treatment-induced PSMA2 enhances transcriptional and phenotypic conversion toward tNEPC. Thus, we uncover a single stress-induced node (PSMA2) that both maintains AR-dependent survival under ADT and fuels the neuroendocrine transition. PSMA2 marks an AR-hypersensitized transitional state and is itself a therapeutically actionable driver of tNEPC evolution, revealing an opportunity for rational interception of the lethal ADT-CRPC-tNEPC trajectory.

DOI: https://doi.org/10.1101/2025.11.25.690552
Cancer Pathog Ther. 2026 Jan;4(1): 51-63

Neuroendocrine prostate cancer (NEPC)-associated CEP55 promotes cisplatin resistance in prostate cancer by regulating CDK1 phosphorylation.

Zhuocheng Lai, Chenxi Hu, Jirong Jie, Yongyuan Xiao, Yuanchao Zhu, Xueni Guo, Yintong Liu, Yiwei Wang, Shiyu Pang, Xiangbo Zeng, Wanlong Tan, Qiong Wang.

  Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of castration-resistant prostate cancer (CRPC) that is typically resistant to nearly all current therapies. In this study, single-cell RNA sequencing (scRNA-seq) and dataset analyses identified Centrosomal Protein 55 (CEP55) as a critical factor in the transformation from hormone-sensitive prostate cancer (HSPC) to CRPC and, ultimately to, NEPC. Subsequent bioinformatics analyses and validation with clinical samples demonstrated that CEP55 is significantly upregulated in NEPC tissues compared to HSPC and CRPC. Furthermore, while CEP55 show no significant association with the immune microenvironment or cancer-associated fibroblasts (CAFs), our findings indicate that it directly mediates the plasticity of prostate cancer cells, thereby driving NEPC progression. Specifically, in vivo and in vitro experiments confirmed that CEP55 enhances cell proliferation, migration, invasion and the expression of NEPC biomarkers in prostate cancer. Importantly, although cisplatin is the primary treatment for NEPC clinically, CEP55 has been shown to regulate cisplatin resistance through the phosphorylation of CDK1 at the tyrosine 15 (Tyr15) site. In summary, our study identifies a key gene that influences the neuroendocrine differentiation process in prostate cancer, suggesting its potential as an important therapeutic target.

Keywords:  CEP55; Castration-resistant prostate cancer; Cisplatin resistance; Neuroendocrine prostate cancer; Prostate cancer

DOI:  https://doi.org/10.1016/j.cpt.2025.06.008
bioRxiv. 2025 Nov 26. pii: 2025.11.23.690056. [Epub ahead of print]

Graded Notch Signaling Functions as a Rheostat of Lineage Plasticity and Therapy Resistance in Prostate Cancer.

Yuyin Jiang, Siyuan Cheng, Catherine Yijia Zhang, Xiao Jin, Longjun Li, Melanie Fraidenburg, Choushi Wang, Isaac Yi Kim, Ping Mu.

Resistance to androgen receptor (AR)-targeted therapies such as enzalutamide in castration-resistant prostate cancer (CRPC) often arises through lineage plasticity, yet the molecular mechanisms that define this process remain incompletely understood. While previous studies reported that Notch1 and Notch2 exert distinct and sometimes opposing effects in prostate cancer differentiation, the integrated role of Notch pathway activity has not been systematically explored. Here, we identify Notch signaling as a graded Rheostat that governs prostate cancer cell fate transitions. Integrative transcriptomic and functional analyses revealed that intermediate Notch activity maintains a stem-like progenitor state, whereas reduced or elevated signaling drives divergent differentiation trajectories toward luminal or neuroendocrine lineages, respectively. During CRPC progression and enzalutamide resistance, Notch signaling becomes dynamically rewired, peaking in progenitor-like populations that sustain plasticity and survival. Both CRISPR-mediated knockout and pharmacologic inhibition of Notch signaling depleted these progenitor cells and restored enzalutamide sensitivity. These findings demonstrate that the level, rather than the binary presence, of Notch signaling dictates lineage directionality and therapeutic response in CRPC, establishing it as a tunable and actionable driver of resistance.

DOI: https://doi.org/10.1101/2025.11.23.690056
Cell Death Dis. 2025 Dec 19.

CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.

Feifei Sun, Ying Qu, Shuyu Mei, Lin Zhang, Xianhao Shao, Xinpei Wang, Shijia Liu, Meng Wang, Wenyao Liu, Muyi Yang, Jing Hu, Benkang Shi, Lin Gao, Bo Han.

Although androgen receptor (AR)-targeted therapies, such as enzalutamide, initially improve outcomes of prostate cancer (PCa) patients, resistance inevitably develops, partly driven by prostate cancer stem-like cells (PCSCs). However, the molecular mechanisms linking the maintenance of PCSCs to enzalutamide resistance (ENZR) remain incompletely elucidated. Here, we implicate Ca²⁺/calmodulin-dependent protein kinase 1D (CAMK1D) in PCSC-mediated ENZR. CAMK1D was consistently upregulated in PCa with ENZR and contributed to ENZR by enhancing mitophagy in PCa cells both in vitro and in vivo. Mechanistically, CAMK1D promotes the expansion of PCSCs by enhancing mitophagy through activation of the AMP-activated protein kinase (AMPK)/PINK1 signaling pathway, thereby facilitating cellular adaptation. We revealed that CAMK1D interacts with and phosphorylates AMPK at Thr172, which in turn activates PINK1 to modulate mitophagy, ultimately supporting the expansion of PCSCs under enzalutamide treatment. In a mouse orthotopic PCa model, targeting the CAMK1D/AMPK pathway with the siCAM/HLNP nanoformulation suppresses tumor growth by depleting the PCSCs population, achieving a synergistic effect with enzalutamide therapy. Our findings identify CAMK1D as a key regulator of ENZR that maintains stemness by orchestrating mitophagy, thereby establishing mitophagy as an important nexus between CAMK1D-mediated ENZR and AMPK-driven PCSC enrichment. Therapeutically, we developed a CAMK1D-targeted approach that potently reverses ENZR and improves treatment responses.

DOI: https://doi.org/10.1038/s41419-025-08342-0
Cancer Discov. 2025 Dec 19.

Serotonin modulates lineage plasticity in neuroendocrine prostate cancer via epigenetic reprogramming.

Yiyi Ji, Cheng-Wei Ju, Lei Chen, Kai Shen, Ruopeng Su, Ang Li, Xinyu Liu, Bo Liu, Xinran Zhang, Ruitu Lyu, Peng Xia, Han Li, Yiqian Pan, Yunzheng Liu, Man Hin Tse, Yizheng Xue, Hongyang Qian, Na Jing, Helen He Zhu, Liangliang Wang, Li-Sheng Zhang, Shu-Heng Jiang, Weiwei Zhang, Liang Dong, Zejun Yan, Jiahua Pan, Yinjie Zhu, Jiangbo Wei, Qi Wang, Wei Xue.

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0974
Research (Wash D C). 2025 ;8 0990

CDK12-Mediated Phosphorylation of FOXA1 Promotes Prostate Cancer Progression via the MDM2-p53 Axis.

Binyuan Yan, Mengjun Huang, Jinxiang Wang, Hanqi Lei, Tongyu Tong, Bin Xu, Fei Cao, Qiliang Teng, Jinsheng Huang, Yupeng Guan, Wenjun Mao, Haojie Huang, Jun Pang.

Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12-FOXA1-MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12-FOXA1-MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.

DOI: https://doi.org/10.34133/research.0990
Front Cell Dev Biol. 2025 ;13 1712195

Comprehensive bioinformatics and in vitro studies reveal the carcinogenic role and molecular basis of endocrine disruptors in prostate cancer.

Feng Yu, Bangwei Che, Wei Li.

   Background: In recent years, growing attention has been paid to the carcinogenicity of endocrine disruptors (EDs). However, their relationship with prostate cancer (PCa) remains unclear. This study investigates the association between EDs and PCa to identify key genes that may bridge this relationship.
Methods: The ADME properties and carcinogenicity of the selected endocrine-disrupting chemicals EDs were predicted using the ADMETlab 3.0 and ProTox 3.0 platforms, respectively. Potential target genes related to EDs and PCa were obtained by integrating multiple public databases. A protein-protein interaction (PPI) network of the overlapping genes was constructed and visualized, followed by GO and KEGG enrichment analyses to explore their potential biological mechanisms. From 101 machine learning algorithm combinations, the most relevant key genes for PCa progression were screened. Molecular docking analysis was used to evaluate the binding properties between ED compounds and key targets. Pan-cancer analysis was employed to examine the general role of key genes across multiple cancer types. The Comparative Toxicogenomics Database (CTD) was used to identify natural active products potentially targeting the core genes. Finally, in vitro cell experiments were conducted to validate the effects of EDs on PCa cells and the intervention effects of related natural products.
Results: Initially, predictions from the ADMETlab 3.0 and ProTox 3.0 platforms indicated significant in vivo accumulation, endocrine-disrupting effects, and carcinogenicity for the 12 common EDs. Subsequently, the integration of multiple databases identified 233 overlapping targets associated with PCa. GO and KEGG enrichment analyses revealed that these targets are primarily involved in regulating cell proliferation, inflammatory responses, and cancer cell metabolism. Among the evaluated machine learning algorithms, the CoxBoost + SuperPC hybrid model demonstrated superior predictive performance and robustness. Subsequent analysis pinpointed three key regulatory genes: CD38, MMP11, and PLK1. Molecular docking simulations confirmed potential interactions between EDs compounds and the core target, PLK1. Furthermore, five natural active products were identified as potential agents to mitigate the adverse effects induced by EDs exposure. Finally, in vitro cell experiments demonstrated that Benzo[a]pyrene promotes PLK1 expression and PCa progression, whereas Cryptotanshinone effectively counteracts these effects.
Conclusion: This multidisciplinary study unveils PLK1 as a pivotal molecular target through which EDs drive PCa progression. Furthermore, we identify five natural compounds, notably Cryptotanshinone, that counteract the carcinogenic effects of EDs by targeting PLK1. These findings provide crucial molecular insights into ED-induced carcinogenesis and reveal promising targets for the prevention and intervention of PCa.

Keywords:  PLK1; endocrine disruptors; natural active products; network toxicology; prostate cancer

DOI:  https://doi.org/10.3389/fcell.2025.1712195
bioRxiv. 2025 Dec 09. pii: 2025.12.05.691672. [Epub ahead of print]

Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer.

Alana Battad, Francisco Nunez, Mya S Walker, Sydney Hodge, Kelani Sun, Elise Desjarlais, Edwin Dj Lopez Gonzalez, Seigmund W T Lai, Leanne Woods-Burnham, Stanley Hooker, Rayyan Aburajab, Qianhua Feng, Min Talley, Sharon Baumel-Alterzon, David W Craig, Rick A Kittles, Yun Rose Li, John Termini, Sarah C Shuck.

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men, with African American/Black (AA/B) men experiencing higher incidence and mortality than European American (EA) men. Obesity, which disproportionately affects AA/B men, is linked to increased PCa mortality, potentially through metabolic dysregulation. We hypothesize that methylglyoxal (MG), a reactive byproduct of glucose, lipid, and protein metabolism that is elevated in obesity, contributes to PCa progression. MG forms covalent adducts on DNA, RNA, and protein. We found that MG-adducts are elevated in AA/B men with PCa compared to EA men with PCa, as well as men without PCa. AA/B men with PCa had a higher frequency of SNP rs1049346 in glyoxalase 1 (GLO1), the primary MG detoxification enzyme. PCa cell lines from EA (C4-2) and AA/B (MDA-PCa-2b) men showed differential rs1049346 status, with C4-2 cells heterozygous and MDA-PCa-2b cells homozygous for the variant. This was associated with altered GLO1 expression and activity, with MDA-PCa-2b cells exhibiting reduced GLO1 function and increased MG-adducts compared to C4-2 cells. MG altered DNA repair and RNA processing pathways and induced distinct metabolic shifts in MDA-PCa-2b compared to C4-2 cells, including increased glycolysis and reduced oxidative phosphorylation. Transcriptomic analysis revealed unique MG-induced stress responses including a tenfold higher induction of TXNIP in MDA-PCa-2b vs. C4-2 cells, a gene inversely linked to GLO1 expression and activity. These findings suggest that MG stress may contribute to PCa progression in AA/B men through metabolic reprogramming and impaired detoxification, offering insight into potential precision medicine applications.
Statement of Significance: Patients with obesity and diabetes have an elevated risk of cancer mortality. Defining how metabolic alterations contribute to this link is critical to understanding disease progression and identifying strategies to improve outcomes.

DOI: https://doi.org/10.64898/2025.12.05.691672
Br J Cancer. 2025 Dec 18.

Senescence-related gene signature predicts prostate cancer progression and identifies PCNA as a therapeutic target via multi-omics machine learning integration.

Renxuan Lin, Hiocheng Un, Youmei Kang, Jiahao Lei, Lingwu Chen, Ren Liu, Zongren Wang.

BACKGROUND: Senescence plays a critical role in prostate cancer, influencing disease onset and progression. However, the alterations of senescence-associated genes during prostate cancer progression and their potential value in predicting disease advancement remain to be further elucidated.
METHODS: 117 machine learning methods were applied to construct the senescence-related gene signature (SRGS). Temporal trajectory analysis based on bulk and single-cell transcriptomic datasets was performed to link SRGS with prostate cancer progression. Functional validations of PCNA were conducted both in vitro and in vivo to support our analytical findings.
RESULTS: Using 117 machine learning methods, we developed the SRGS, which demonstrated robust predictive capability across multiple cohorts, including our own cohort of 90 patients. The SRGS also showed strong potential in predicting overall survival in patients treated with second-generation AR inhibitors. Temporal trajectory analysis of bulk RNA-seq and single-cell data revealed the biological significance of SRGS and identified Proliferating Cell Nuclear Antigen (PCNA) as a potential driver of PCa progression. Pharmacological inhibition of PCNA with AOH1996 significantly suppressed tumor growth and enhanced the efficacy of androgen deprivation therapy.
CONCLUSION: We developed the SRGS that effectively predicts prostate cancer prognosis and progression. Moreover, our findings highlight PCNA as a promising therapeutic target in PCa. Integrated analysis of multi-cohort transcriptomic data developed an SRGS enabling accurate prognostication and identification of high-risk patients. Results highlight SRGS's clinical utility and nominate PCNA as a promising therapeutic target in high-risk and castration-resistant prostate cancer (CRPC).

DOI: https://doi.org/10.1038/s41416-025-03309-6
Beijing Da Xue Xue Bao Yi Xue Ban. 2025 Dec 18. 57(6): 1113-1123

[Effect of dephosphorylation of tumor metastasis suppressor gene LASS2 on vacuolar ATPase activity and invasiveness of prostate cancer].

Yanhua Liu, Min Lu, Xuyang Zhao, Kuan'gen Zhang, Rui Wu, Fang Mei, Zhihao Dai, Jiangfeng You, Fei Pei.

OBJECTIVE: To explore the effects and the molecular mechanisms of homo sapiens longevity assurance homolog 2 of yeast LAG1(LASS2) dephosphorylation on the biological functions of prostate cancer cells.
METHODS: Firstly, we examined the expression profiles of LASS2 by immunohistochemical staining using microarray sections from 90 human patients with prostate cancer; then FLAG-tagged LASS2 plasmid was transferred into HEK 293T cells and phosphorylation sites was detected by mass spectrometry. Furthermore, we constructed five phosphorylation-deficient mutants of LASS2 and stably transfected the variants to human prostate cancer cell line PC-3M-1E8 cell with high metastatic potential. The cell biology functions of LASS2 and its five mutants were studied using growth curve, MTT assay, plate colony formation assay, wound migration assay, matrigel invasion study and flow cytometry; and the effect of LASS2 and its phosphorylation-deficient mutants on the physical interaction between LASS2 and ATP6V0C (C subunit of V0 domain of the vacuolar ATPase), ATP6V0C expression, vacuolar ATPase (V-ATPase) activity, extracellular hydrogen ion concentration and secretion of active matrix metalloproteinase 2(MMP-2) was detected. Finally, we examined the effect of protein phosphatase inhibitor calyculin A on growth, migration and invasion of aggressive prostate cancer cells.
RESULTS: LASS2 levels decreased with increasing Gleason scores of prostate cancer tissues by immunohistochemical staining; moreover, proteome analysis by mass spectrometry had identified that three residues in the C-terminal region of LASS2(Ser-341, Ser-348, and Ser-349) were phosphorylated. Dephosphorylation of LASS2 at serine residue 348 significantly enhanced growth, migration (from 49.11%±5.62% to 74.28%±8.77%, P < 0.001) and invasion (from 129.67±13.65 to 206.67±13.50, P < 0.001) of prostate cancer cells, decreased S phase arrest (from 44.17% to 37.90%, P < 0.05) and inhibited cell apoptosis (from 48.540%±0.269% to 29.700%±0.778%, P < 0.05) in vivo through increasing V-ATPase activity, extracellular hydrogen ion concentration and secretion of active MMP-2. Calyculin A significantly reduced growth and invasion of metastatic human prostate cancer cells.
CONCLUSION: Phosphorylation of LASS2 is essential for regulation of V-ATPase activity, and serine residue 348 of LASS2 is illustrated to be a key phosphorylation site. Phosphorylated LASS2 inhibits prostate cancer cell invasion via negative regulation of V-ATPase activity and protein phosphatase inhibitors are potential therapeutic strategy in aggressive prostate cancer.

Keywords: Gene expression regulation, neoplastic; LASS2 gene; Neoplasm invasiveness; Prostatic neoplasms; Vacuolar proton-translocating ATPases
Gene. 2025 Dec 17. pii: S0378-1119(25)00756-5. [Epub ahead of print] 149966

Navigating the winding road toward precision prostate cancer care.

Syed Rahman, Adith S Arun, Isaac Yi Kim, William K Oh, Joseph W Kim, William J Kim.

  Prostate cancer (PCa) remains the second leading cause of cancer-related mortality among U.S. men, driven in large part by metastatic castration-resistant prostate cancer (mCRPC) despite initial responses to androgen-receptor (AR)-targeted therapies. Over the last two decades, treatment options for mCRPC have significantly expanded to include novel therapeutic modalities that integrate biomarker-guided patient selection. These biomarker-driven therapies have ushered us into the era of "precision oncology" in prostate cancer care, and we highlight key developments. In light of these promising early results, we also review key opportunities and challenges ahead. Additionally, we share a conceptual roadmap to leverage multi-omics molecular data in the era of artificial intelligence/machine learning (AI/ML) to accelerate progress in prostate cancer precision medicine. Specifically, we discuss how these tools may help better facilitate the development of near-patient preclinical models for prostate cancer towards capturing key aspects of prostate cancer tumor biology, and a potential path toward accelerating translation of laboratory discoveries into clinical practice for mCPRC patients.

Keywords:  Androgen receptor pathway inhibitors (ARPI); Androgen-receptor (AR); Machine-learning; Metastatic castration resistance prostate cancer (mCRPC); Multi-omics; Patient-derived organoids (PDOs); Patient-derived xenog; Precision oncology; Prostate cancer (PCa)

DOI:  https://doi.org/10.1016/j.gene.2025.149966
Discov Oncol. 2025 Dec 19.

Roles of KHDRBS2 and KHDRBS3 in prostate cancer progression and AR-V7 regulation.

XuDong Yang, Xia Liu, Ran Xiao, YiLin Cao.

   OBJECTIVE: To investigate the biological functions of KHDRBS2 and KHDRBS3 in prostate cancer (PCa) progression and their potential roles in regulating androgen receptor splice variant 7 (AR-V7) expression, a key factor in castration-resistant prostate cancer (CRPC).
METHODS: We performed a comprehensive analysis of publicly available datasets to examine the expression patterns of KHDRBS family members in PCa, including CRPC and neuroendocrine subtypes. In vitro experiments were conducted using AR-positive 22RV1 and AR-negative PC3 cell lines to assess the expression and regulatory interactions of KHDRBS2 and KHDRBS3. Functional assays evaluated their effects on cell proliferation and tumor growth in vivo. Additionally, KHDRBS2 protein levels were manipulated in 22RV1 cells to assess their impact on AR-V7 and full-length AR expression.
RESULTS: Our dataset analysis revealed distinct expression patterns of KHDRBS2 and KHDRBS3, with higher alteration frequencies in CRPC and neuroendocrine PCa. In vitro, KHDRBS2 and KHDRBS3 exhibited mutually exclusive expression, with KHDRBS2 predominantly found in AR-positive 22RV1 cells and KHDRBS3 in AR-negative PC3 cells. Reciprocal regulation between the two proteins was observed in both cell lines. Functional studies showed that both KHDRBS2 and KHDRBS3 promoted cell proliferation and tumor growth. Notably, silencing KHDRBS2 in 22RV1 cells led to a selective reduction in AR-V7 expression, without affecting full-length AR levels.
CONCLUSIONS: These findings uncover novel roles for KHDRBS2 and KHDRBS3 in PCa progression, with KHDRBS2 identified as a potential key regulator of AR-V7 expression. Our results provide new insights into AR splice variant regulation and highlight potential therapeutic targets for PCa treatment.

Keywords:  AR-V7; Alternative splicing; Androgen receptor (AR); Castration-resistant prostate cancer; KHDRBS family; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-04294-1
Mol Biol Rep. 2025 Dec 18. 53(1): 209

Comparison of prostate cancer cell line growth in fetal bovine serum and animal free supplements.

Emma Itting, Anette Gjörloff Wingren, Helena Tassidis.

  Fetal bovine serum (FBS) is widely used as a growth supplement in cell culture due to its richness in embryonic growth-promoting factors, but presents ethical concerns, batch-to-batch variability, high cost, and biosafety issues. Alternative supplements are needed to support consistent and reliable cell growth in vitro. Human platelet lysate (hPL) and chemically defined supplements offer potential substitutes, but they require evaluation across different cell types. This study aimed to evaluate the effectiveness of two commercial serum supplements, PLTGold (an hPL product) and FastGro (a chemically defined supplement), as alternatives to FBS for supporting the growth and proliferation of the prostate cancer cell lines PC-3 and LNCaP. These cell lines were cultured in media supplemented with different concentrations of FBS, PLTGold, or FastGro. Cell viability was assessed using the MTT assay after 3, 4, and 7 days. Cell cycle distribution was analyzed using propidium iodide staining and flow cytometry after 3 days of culture. Finally, BrdU incorporation assays were conducted to evaluate cell proliferation. Interestingly, PLTGold demonstrated cell viability comparable to or even greater than FBS in PC-3 cells and maintained LNCaP viability, whereas FastGro reduced the viability in both cell lines. FastGro-induced cell cycle arrest was observed in PC-3 cells, indicating a more pronounced inhibitory effect. PLTGold is a promising alternative to FBS, particularly for PC-3 cells, whereas FastGro requires optimization. These results suggest that serum supplements can be used as substitutes for FBS, but further optimization and validation are required.

Keywords:  Cell cycle; FBS; FastGro; LNCaP; PC-3; PLTGold; Proliferation; Prostate cancer; Viability

DOI:  https://doi.org/10.1007/s11033-025-11362-w
Oncol Lett. 2026 Feb;31(2): 66

Identification and validation of critical mitochondrial hub genes for prostate cancer.

Sha Liu, Liang Huang, Li Lin, Hong Shan, Yueming Wan.

  Prostate cancer (PCa) is one of the most common malignant tumors in men. In recent years, mitochondrial dysfunction has been found to be closely related to cancer progression. However, the role of mitochondria-related genes in PCa remains unclear. The aim of the present study was to discover novel biomarkers based on differentially expressed mitochondrial-related genes (DeMRGs) to aid in PCa diagnosis. In the present study, gene expression data from the Gene Expression Omnibus and The Cancer Genome Atlas databases were combined with a mitochondrial-related gene list provided by the MitoCarta database to identify DeMRGs. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis were then used to investigate the functions and related pathways of these DeMRGs. Subsequently, Cytoscape software and the STRING website were used to explore the transcription factors and microRNAs related to the DeMRGs. The degree of infiltration of immune cells in the immune landscape of patients with PCa and the controls was assessed using CIBERSORT. Finally, the correlation between characteristic DeMRGs and immune cell infiltration and mitochondrial respiration was analyzed. The results indicated that 6 characteristic genes, including acetyl-CoA carboxylase β (ACACB), pyruvate dehydrogenase kinase 4 (PDK4), glycine amidinotransferase (GATM), methylcrotonyl-CoA carboxylase subunit 2, mitochondrial ribosomal protein L12 (MRPL12) and fatty acid synthase, were identified from the 60 DeMRGs. The results showed a close association between the characteristic DeMRGs and immune infiltrating cells. In addition, it was found that MRPL12, PDK4, ACACB and GATM were correlated with mitochondrial respiration. These 4 genes were selected as hub genes as they are closely related to gluconeogenesis, the tricarboxylic acid cycle, lipid metabolism, amino acid metabolism and other mitochondrial metabolic pathways in PCa. In conclusion, 4 novel mitochondrial-related gene signatures that influence mitochondrial metabolism within the immune microenvironment were identified in PCa.

Keywords:  mitochondria metabolism; mitochondrial related genes; mitochondrial respiration; prostate cancer

DOI:  https://doi.org/10.3892/ol.2025.15419
Int J Surg. 2025 Dec 19.

Characteristics of the immune microenvironment, metabolic microenvironment, and gut microbiota in prostate cancer.

Fangmei Xie, Birong Zhou, Yinghui Hao, Shengjun Pan, Zeping Han, Xiaoyu Song, Wenfeng Luo, Ying Zhao, Jian Shen, Xin Ruo, Jinghui Fan, Jinhua He.

  The tumor microenvironment (TME) is a complex ecosystem comprising tumor cells and their surrounding components, such as stromal cells, extracellular matrix, blood vessels, and signaling molecules. It functions as the "soil" that sustains tumor survival and progression, critically influencing tumor growth, invasion, metastasis, and drug resistance. As a key component of the TME, the tumor immune microenvironment (TIME) refers specifically to the interactive network between tumor cells and the immune system. This interplay dictates whether tumors are recognized and eliminated by immune surveillance or succeed in evading immune detection.The gastrointestinal microecology (GM) system encompasses the gut microbiota and their respective habitats. Gut microbiota influence tumor progression through immune regulation, metabolic modulation, and genotoxic effects, thereby shaping therapeutic responses. Meanwhile, tumor cells employ diverse metabolic pathways to meet heightened bioenergetic and biosynthetic demands and to mitigate oxidative stress-processes essential for their proliferation and survival. These metabolic adaptations significantly shape TME characteristics, including nutrient availability, hypoxia, and the induction of immunosuppression.This review summarizes the roles of the immune microenvironment, metabolic microenvironment, and gut microbiota in the initiation, progression, and treatment of prostate cancer (PCa). It further illustrates how these three components interact to collectively regulate PCa development and therapeutic outcomes. By integrating recent advances in these areas, we aim to provide new insights into the molecular mechanisms of PCa pathogenesis and to inform comprehensive clinical strategies.

Keywords:  gut microbiota; prostate cancer; tumor immune microenvironment; tumor metabolic microenvironmen

DOI:  https://doi.org/10.1097/JS9.0000000000004449
bioRxiv. 2025 Dec 10. pii: 2025.12.07.692844. [Epub ahead of print]

Metabolic medications modify prostate cancer progression through exosome reprogramming.

Michael Seen, Pablo Llevenes, Heejoo Kang, Yuhan Qiu, Christina Ennis, Andrew Chen, Sara Alexanian, Devin Steenkamp, Stefano Monti, Gerald V Denis.

Among prostate cancer patients, co-morbid Type 2 Diabetes (T2D) is associated with faster progression to biochemical recurrence and increased risk of mortality. Previous work from our lab provides evidence that exosomes purified from media of insulin resistant adipocytes or T2D patient plasma likely drives these outcomes by delivering miRNAs that exacerbate tumor aggressiveness in several breast and prostate cancer models. Here, we build on our previous findings to investigate whether treatment with metabolic medications attenuates the tumor promoting effects of exosomes. We found that human DU145 cells, a model for prostate cancer, treated with plasma exosomes from T2D patients, shows patterns in global gene transcription that resolve by patient treatment with metformin. To test the effects of metformin experimentally, we used a murine model of insulin resistance (IR). Treating DU145 cells with miRNAs purified from the plasma exosomes of IR mice, we found that cells transfected with miRNAs from the metformin-treated IR group displayed significantly less migration than cells transfected with miRNAs from the unmedicated IR group. We suggest that metformin may partially reverse effects of T2D to exacerbate tumor aggressiveness by modifying the miRNA payload of plasma exosomes.

DOI: https://doi.org/10.64898/2025.12.07.692844
Sci Rep. 2025 Dec 16. 15(1): 43908

Unravelling TPX2-centered co-expression networks as key drivers of aggressive prostate cancer.

Raheleh Sheibani-Tezerji, Carlos Uziel Perez Malla, Gabriel Wasinger, Katarina Misura, Astrid Haase, Anna Malzer, Jessica Kalla, Loan Tran, Gerda Egger.

  Prostate cancer (PCa) progression is driven by complex molecular reprogramming, yet distinguishing indolent from aggressive disease remains a challenge. We performed an integrative transcriptomic analysis of 1232 PCa samples spanning normal prostate and all major disease stages including primary localized tumors, metastatic hormone-sensitive PCa (mHSPC), and metastatic castration-resistant PCa (mCRPC). By integrating unsupervised consensus clustering (ATC:hclust), weighted gene co-expression network analysis (WGCNA), and explainable machine learning (ML), we identified key transcriptional programs and biomarkers associated with cancer initiation and disease progression. Our analysis revealed persistent dysregulation of mitotic control, DNA damage repair, transcriptional regulation, and cytoskeletal remodeling, underscoring their functional relevance for PCa progression. We uncovered TPX2 as a central hub gene, consistently upregulated across all disease stages and co-expressed with 21 commonly upregulated genes. ML-based gene ranking and interaction analysis identified connections among the commonly upregulated genes, highlighting CENPA-MYBL2 for primary localized PCa, EXO1-NEIL3 for mHSPC and CENPA-RRM2 for mCRPC. Stage-specific analysis further identified key drivers of distinct disease transitions including EZH2 and PLK1 as major regulators of androgen dependence in mHSPC, and TERT as a hallmark of mCRPC, highlighting its role in telomere maintenance and tumor progression. This study demonstrates that unsupervised clustering combined with WGCNA and ML enables the discovery of clinically relevant molecular signatures in PCa. Our findings establish TPX2-centered networks together with biological pathways implicated in mitotic regulation and DNA damage repair as key drivers of tumor evolution, providing a biologically informed source for biomarker development, drug testing and mechanistic studies.

Keywords:  Biomarker; Machine learning; Prostate cancer; RNA-Seq; SHAP; Unsupervised consensus clustering; WGCNA

DOI:  https://doi.org/10.1038/s41598-025-27704-4
Cell Commun Signal. 2025 Dec 18.

Menin-driven mTOR signaling sustains taxane resistance in CRPC and reveals a targetable vulnerability for combination therapy.

Ipek Bulut, Buse Cevatemre, Neslihan Yuksel-Catal, Hamzah Syed, Tamer Onder, Ceyda Acilan.

Prostate cancer (PC) progression is predominantly driven by androgen signaling, making androgen deprivation therapy (ADT) the standard treatment. However, the transition to castration-resistant prostate cancer (CRPC) significantly reduces ADT efficacy. While taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz) are widely employed, therapeutic resistance remains a major clinical obstacle. To address this, we established docetaxel-resistant CRPC models and performed an epigenetic drug screen, identifying MLL-Menin and MLL-WDR5 inhibitors as potent agents capable of restoring taxane sensitivity through G2/M arrest and apoptosis induction. Functional depletion of Menin (MEN1) revealed its critical role in sustaining chemoresistance, selectively impairing proliferation in resistant cells, and preventing resistance emergence in parental lines.Integrative transcriptomic (RNA-seq) and epigenomic (CUT&RUN-seq) analyses suggested that Menin may play a regulatory role in mTOR signaling and E2F target pathways. Menin binding to the promoters of mTOR and Cyclin D1 was confirmed, and rescue experiments further validated its regulatory role. Analysis of TCGA datasets demonstrated co-expression of MEN1 and mTOR in advanced metastatic PC, supporting clinical relevance. Moreover, combination treatment with the mTOR inhibitor Torin-1 and docetaxel synergistically enhanced therapeutic response in Menin-depleted resistant cells. MEN1 knockdown also abrogated tumor growth in vivo.These findings identify Menin as one of the key mediator of taxane resistance in CRPC through the regulation of mTOR. Targeting Menin, alone or in combination with mTOR inhibition, represents a promising strategy to overcome resistance and improve therapeutic outcomes in taxane-refractory PC.

DOI: https://doi.org/10.1186/s12964-025-02594-1
Biochem Biophys Res Commun. 2025 Dec 13. pii: S0006-291X(25)01826-1. [Epub ahead of print]795 153110

A comparative analysis of CXCR4 gene expression from published datasets and cell surface protein levels in breast and prostate cancer models.

Veli Kaan Aydın, Yasemin Adalı, Aylin Köseler.

The CXCL12/CXCR4 signaling axis is a critical mediator of cancer metastasis, particularly in the homing of breast and prostate cancer cells to the bone. Consequently, characterizing the CXCR4 status of preclinical cancer models is essential for designing meaningful experiments. However, prior reports show conflicting CXCR4 status in these models, with reported positivity rates varying from <5 % to >90 % across studies, highlighting the urgent need for systematic comparison. This study provides a systematic comparison of CXCR4 expression patterns by analyzing gene expression data from breast cancer cell lines (MDA-MB-231, MDA-MB-468) and prostate cancer cells (PC3) across multiple published datasets using batch effect correction. Additionally, flow cytometry experiments were conducted to directly quantify CXCR4 surface protein levels in these same cell lines, integrating transcriptomic analyses with proteomic evidence. The comparative analysis revealed a marked divergence between transcript abundance and surface protein expression. The highly metastatic MDA-MB-231 cells exhibited the highest levels of CXCR4 mRNA, which correlated with a strong enrichment of metastasis-related signaling pathways. Conversely, MDA-MB-468 and PC3 cells displayed relatively lower CXCR4 transcript levels but contained a significantly higher proportion of CXCR4-positive cells at the protein level. These findings indicate that high transcriptional activity does not necessarily translate to high surface protein availability, likely due to active post-translational regulation, such as rapid receptor internalization. Overall, these results emphasize the importance of validating both gene and protein expression in specific cell line models prior to conducting CXCR4-focused mechanistic or therapeutic studies. Such validation is crucial, as expression patterns may vary considerably between laboratories due to differences in passage number, culture conditions, and genetic drift.

DOI: https://doi.org/10.1016/j.bbrc.2025.153110
Sci Rep. 2025 Dec 13.

E2F1-mediated PKMYT1 upregulation promotes prostate cancer progression by inhibiting the PPAR signaling pathway.

Zengshun Kou, Yu Wang, Jiaxi Zhu, Shuaizhi Zhu, Zi'ang Si, Hai Zhu.



Keywords:  E2F1; PKMYT1; PPAR signaling pathway; Prostate cancer; Tumor treatment

DOI:  https://doi.org/10.1038/s41598-025-32218-0
Crit Rev Oncol Hematol. 2025 Dec 14. pii: S1040-8428(25)00471-8. [Epub ahead of print]218 105083

Epigenetic approaches to prostate cancer: Present landscape and future prospects.

Konstantinos Mesiakaris, Efthalia Kontogianni, Souzana Logotheti, Vasiliki Tzelepi.

  Genetic profiles alone do not fully describe the development and evolution of prostate cancer (PCa), whereas epigenetic alterations are emerging as promising therapeutic targets. This review explores FDA-approved and experimental epigenetic strategies, including DNA methyltransferase inhibitors (DNMTis), histone deacetylase inhibitors (HDACis), histone methyltransferase inhibitors, bromodomain and extra-terminal domain inhibitors (BETi), non-coding RNA therapies, antisense oligonucleotides, and future prospects such as chromatin remodeling, DNA hydroxymethylation, and RNA methylation. Although DNMTis and HDACis have historically dominated clinical trials, mainly in hematologic cancers, the 2020 approval of an epigenetic therapy for a solid tumor marked an important breakthrough. Despite this, epigenetic drugs remain underexplored in PCa: among 2254 clinical studies of such agents, only 58 (2.57 %) included PCa patients. This disparity highlights an urgent need for novel therapeutic approaches beyond chemotherapy and androgen deprivation. By assessing current progress and outlining opportunities in drug repositioning and novel targets, this review underscores epigenetics as a critical frontier for advancing PCa treatment.

Keywords:  BET inhibitors; DNA methyltransferase inhibitors (DNMTis); Epigenetic therapy; Epigenetics; Histone deacetylase inhibitors (HDACis); Histone demethylases; Histone methyltransferase inhibitors; Prostate cancer

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105083
Int J Radiat Biol. 2025 Dec 15. 1-7

Stromal-derived high-molecular-weight hyaluronan mediates radioresistance in the prostate cancer microenvironment.

Ryo Saga, Kenta Iwamori, Yoichiro Hosokawa.

   PURPOSE: Radiotherapy (RT) is a key treatment for localized prostate cancer (PCa); however, resistance and recurrence remain major challenges. Hyaluronan (HA), a key component of the extracellular matrix, has been implicated in cancer progression and therapeutic resistance. However, its role in the modulation of radiosensitivity, particularly in the tumor microenvironment, remains unclear. In this study, we aimed to investigate the role of HA in the radiosensitivity of PCa cells.
MATERIALS AND METHODS: 22Rv1 PCa epithelial cells and WPMY-1 myofibroblast cells were cultured to mimic tumor-stroma interactions. The effect on radiosensitivity was evaluated using colony formation assays. HA levels and molecular weight from cell culture supernatants were analyzed using enzyme-linked immunosorbent assays and agarose gel electrophoresis. Hyaluronidase expression was assessed using quantitative RT-PCR.
RESULTS: WPMY-1 cells exposed to supernatants had significantly higher HA secretion than 22Rv1 cells. WPMY-1-derived HA enhanced the radioresistance of 22Rv1 cells, which was reversed by hyaluronidase. HA induced by 22Rv1-derived factors appears to be necessary for colony formation. The induced HA showed a shift toward a higher molecular weight owing to the downregulation of the degrading enzymes Hyal1 and PH20. The molecular weight of HA played a key role in modulating these effects.
CONCLUSION: Our findings suggest that stromal cells may contribute to the radioresistant tumor microenvironment in PCa partly through alterations in high-molecular-weight HA. While targeting HA metabolism holds potential to improve the efficacy of RT by disrupting this protective niche, further studies are needed to clarify the underlying mechanisms and validate these effects in vivo.

Keywords:  Radioresistance; hyaluronan; hyaluronan molecular weight

DOI:  https://doi.org/10.1080/09553002.2025.2599221
Sci Rep. 2025 Dec 15.

SLC45A2 drives prostate cancer progression through tumor promotion and immune suppression.

Run Tang, Cheng Wang, Yingxiang Zhu, Kai Liu, Zeming Wu.



Keywords:  Immune evasion; Prognostic biomarker; Prostate adenocarcinoma; SLC45A2; Tumor metabolism

DOI:  https://doi.org/10.1038/s41598-025-32340-z
Sci Rep. 2025 Dec 17.

Hedyotis diffusae herba -Scutellaria Barbata herba drug pair suppresses prostate cancer by inducing apoptosis.

Junfeng Qiu, Litong Wu, Zhiming Hong, Yahong Shi, Yi Wei, Quan Wang, Zilong Chen, Weitian Chen, Qing Zhang, Xujun J You, Wenbin B Zhou, Wenban Zhou.

  Prostate cancer (PCa), a globally prevalent male malignancy, necessitates breakthroughs in treating its hormone-refractory stage. The Traditional Chinese Medicine drug pair Hedyotis Diffusae Herba - Scutellaria Barbatae Herba (HDH-SBH) shows significant antitumor value, but its multi-component synergistic mechanisms remain unclear. This study elucidated HDH-SBH's molecular mechanisms in suppressing PCa via apoptosis pathways. Network pharmacology predicted active components (quercetin, ursolic acid, apigenin) and core targets (AKT1, BCL2, NFKB) enriched in apoptosis (P < 0.05). Molecular docking revealed strong binding (e.g., ursolic acid-AKT1: -7.76 kcal/mol), confirmed by stable 100 ns molecular dynamics simulations (RMSD < 5.0 Å). In vitro, HDH-SBH significantly inhibited PC-3 cell proliferation (48 h IC50 = 1.094 mg/mL), reduced migration (36 h rate decreased by 64.2%), and induced apoptosis (rate 13.57% vs. control 4.79%). It downregulated BCL2 and p-65 protein expression (P < 0.05) while suppressing AKT1 phosphorylation. Thus, HDH-SBH targets the AKT1/BCL2/NFKB axis to regulate apoptosis and suppress PCa progression, providing a theoretical and experimental foundation for modernizing TCM in antitumor research.

Keywords:  Apoptosis; Hedyotis diffusae herba; Network pharmacology; PC-3; Prostate cancer; Scuttellaria barbatae herba

DOI:  https://doi.org/10.1038/s41598-025-32757-6
J Radiat Res. 2025 Dec 18. pii: rraf079. [Epub ahead of print]

Machine learning-DeepSurv prediction model integrating mpMRI radiomics and genomic biomarkers for BCR-free survival and tumor response in prostate radiotherapy.

Hossein Taheri, Mohammadbagher Tavakoli, Maryam Farghadani, Sheyda Lafzlenjani, Hamed Taheri.

  The purpose of this study was to design a radiogenomics machine learning-DeepSurv model for biochemical recurrence-free (BCR-free) survival and treatment response (TR) prediction for radiotherapy (RT) of prostate cancer (PCa). In this study, radiomic features were extracted from pre and post treatment multiparametric MRI (mpMRI), including T2-weighted (T2W), diffusion-weighted MR imaging (DWI) and apparent diffusion coefficient (ADC). Also, genomic biomarkers such as Ki-67 (a cell proliferation marker reflecting tumor growth activity and also prognostic information in cancer progression), PTEN (tumor suppressor gene regulating cell growth and survival, have a prominent role for TR and cancer progression) and Decipher (a genomic signature predicting cancer recurrence risk and TR based on gene expression patterns) were collected. Radiomics feature selection and dimensionality reduction methods were employed, followed by training machine learning (ML) models. Moreover, time to event data and survival models including Random Survival Forest (RSF) and DeepSurv neural networks were used. For model performance, the concordance index (C-index) and integrated Brier score (IBS), and for improving interpretability, the SHapley Additive exPlanations (SHAP) were applied. Radiomic feature of MRI including Kurtosis demonstrated a near-perfect positive correlation with Ki-67 expression (r = 0.64), however skewness showed a strong negative correlation with PTEN status (r = -0.88). Entropy and kurtosis of MRI were also highly correlated with the Decipher genomic risk score (r = 0.90 and r = -0.96, respectively). The integrated ML-DeepSurve model performance overall F1-score was 0.93 for TR. The model also offered robust stratification for patients based on BCR-free survival probability. Our findings underscore the potential of radiogenomic signatures as non-invasive biomarkers to personalized PCa RT decisions and provide a novel clinically explainable predictive model based on radiomic and molecular biomarkers for BCR-free survival and TR of mentioned cancer.

Keywords:  BCR-free survival; Ki-67; PTEN; decipher; machine learning (ML); prostate cancer (PCa); radiogenomics; radiotherapy (RT); treatment response (TR)

DOI:  https://doi.org/10.1093/jrr/rraf079
Int J Biol Macromol. 2025 Dec 16. pii: S0141-8130(25)10253-5. [Epub ahead of print] 149696

Types of biomimetic materials and their emerging clinical applications in the field for prostate cancer.

Chen Guo, Jiandong Gui, Anjie Chen, Sixin Li, Chenwei Gu, Yujie Deng, Leisheng Wang, Rong Wang, Jiang Ni, Jian Wang, Jun Wang, Dongjie Yang, Yan Qin, Lijie Zhu, Sheng Wu, Yuanyuan Mi.

  Among the myriad of challenges confronting modern medicine, few rival the complexity and persistence of cancer. This disease has long stood as a formidable obstacle to therapeutic innovation. Recently, the emergence of biomimetic materials has heralded a transformative shift in oncology, offering novel strategies for precise drug delivery and integration with advanced technologies such as 3D-printing. In this paper, we begin by categorizing biomimetic materials according to their origins and structural classifications, and subsequently detail their applications in the context of prostate cancer (PCa) treatment. Finally, we provide a comprehensive analysis of the benefits and limitations of these biopolymers, discuss the key barriers hindering their broader application, and propose future research directions to guide progress in this promising domain (Fig. 1).

Keywords:  Biomimetic materials; Drug delivery; Liposomes; Polysaccharides; Prostate cancer; Proteins

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149696
Carcinogenesis. 2025 Nov 21. pii: bgaf078. [Epub ahead of print]46(4):

Analysis of MRPL23 protein expression and its role in prostate cancer pathogenesis.

Edyta Podemska, Damian Łukasik, Jędrzej Borowczak, Dariusz Grzanka, Justyna Durślewicz.

  Prostate cancer (PCa) is the fourth most commonly diagnosed malignancy worldwide and remains a major clinical challenge due to its heterogeneous course and lack of reliable prognostic biomarkers. Mitochondrial ribosomal protein L23 (MRPL23) has recently emerged as a potential contributor to cancer progression, but its role in prostate cancer remains poorly understood. Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 67 PCa patients who underwent radical prostatectomy were analyzed. MRPL23 expression was assessed by immunohistochemistry using a semi-quantitative immunoreactive scale (IRS). Clinicopathological data were collected for correlation analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards models. MRPL23 expression differed significantly across all tissue types, with higher levels in prostate cancer tissues compared with normal epithelium, and the highest expression observed in lymph node metastases (P < .001). High MRPL23 expression was associated with shorter overall survival (P = .003) and remained an independent prognostic factor in the multivariate analysis (HR 3.99, 95% CI 1.63-9.77, P = .002). Complementary TCGA analysis confirmed elevated MRPL23 mRNA levels in prostate adenocarcinomas compared with normal tissues (P = .01) and demonstrated that high expression predicted shorter disease-free survival (10-year DFS: 75.98% versus 92.92%, log-rank P = .01). MRPL23 is a potential prognostic biomarker in prostate cancer, linked to aggressive tumor behavior and poor outcomes. Its expression in metastatic tissue suggests a role in disease progression, while TCGA data confirm its prognostic value for recurrence risk. MRPL23 may also serve as a therapeutic target in advanced PCa.

Keywords:  MRPL23; immunohistochemistry; patient survival; prognostic biomarker; prostate cancer

DOI:  https://doi.org/10.1093/carcin/bgaf078
Comput Biol Chem. 2025 Dec 16. pii: S1476-9271(25)00519-5. [Epub ahead of print]121 108855

Causal role of 46 pathogen-derived antibodies in prostate disease insights from two-sample and Bayesian-weighted Mendelian randomization.

Bin Wan, Xinxi Deng, Zhoulin Wu, Wensheng Zhang, Xungang Li, Tao Tao.

   BACKGROUND: Prostate diseases, including prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa), are common in men and involve complex pathogenesis. Increasing evidence suggests that pathogen infections may influence prostate disease development through immune activation and chronic inflammation. However, causal relationships remain unclear.
METHODS: We conducted two-sample Mendelian randomization (MR) and Bayesian weighted MR (BWMR) analyses to investigate the causal association between pathogen-specific antibody levels and prostate disease risk. Genetic data for pathogen antibodies were obtained from the UK Biobank, and GWAS summary statistics for prostatitis, BPH, and PCa were sourced from large public databases. Multiple sensitivity analyses were performed to validate the robustness of the findings.
RESULTS: Positive levels of herpes simplex virus-2 (HSV-2) mgG-1, Epstein-Barr virus (EBV) EBNA-1, and human herpesvirus-6 (HHV-6) IE1B antibodies were associated with an increased risk of prostatitis, whereas EBV ZEBRA and HHV-7 U14 antibodies were protective. For PCa, HHV-6 E1A antibodies were risk factors, while HHV-7 IgG and Helicobacter pylori VacA antibodies exhibited protective effects. In BPH, EBV VCA p18, HSV-2 IgG, and Helicobacter pylori IgG antibodies increased risk, whereas Helicobacter pylori peroxidase, OMP, and EBV ZEBRA antibodies showed protective associations. No evidence of reverse causality was found.
CONCLUSION: This study provides genetic evidence supporting a potential causal role of specific pathogen infections in the development of prostate diseases. Targeted prevention of certain infections may contribute to reducing prostate disease risk. Future studies are warranted to validate these findings across diverse populations and to elucidate the underlying biological mechanisms.

Keywords:  Causal inference; Mendelian Randomization; Pathogen antibody; Prostate diseases

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108855
Chin J Nat Med. 2025 Dec 18. pii: S1875-5364(25)00036-6. [Epub ahead of print]23(12): 100016

Unveiling the therapeutic mechanism of Epimedium Herba on prostate cancer through network pharmacology and experimental validation.

Zhiliang Xiao, Sicong Jiang, Shengqiang Fu, Xiaohai Zhang, Xueliang Qi, Changhao Li.

  Epimedium Herba (EH) demonstrates significant therapeutic potential against prostate cancer (PC), though its mechanisms of action remain incompletely understood. This study investigates the pharmacological mechanisms of EH in treating PC through network pharmacology analysis and experimental validation. Active components and potential targets of EH were identified using network pharmacology from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The STRING database facilitated the construction of a protein-protein interaction (PPI) network for shared targets and the identification of core anti-PC targets. Messenger ribonucleic acid (mRNA) and protein expression of core target genes in normal prostate and PC tissues, along with their correlation to overall PC survival, were analyzed using The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the potential targets. Molecular docking of quercetin with key targets (TP53, TNF, heat shock protein 90 alpha family class A member 1 (HSP90AA1), AKT1, CASP3, and ESR1) was conducted, with results visualized using PyMOL. In vitro experiments validated the network pharmacology predictions. Twenty-three active ingredients of EH were identified, and the intersection of potential targets with PC targets yielded 183 potential targets. PPI network analysis revealed six key genes: targets (TP53), TNF, HSP90AA1, AKT1, CASP3, and ESR1. GO enrichment analysis identified 2369 biological processes (BP), 77 cellular components (CC), and 215 molecular functions (MF). KEGG pathway enrichment analysis demonstrated that EH's anti-cancer effects were mediated through interleukin-17 (IL-17), TNF, phosphatidylinositol 3-kinase (PI3K)-AKT, apoptosis, p53, HIF-1, mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and EGFR tyrosine kinase inhibitor resistance pathways. Core target validation confirmed consistency with the study's findings. Molecular docking indicated stable binding between the six core targets and quercetin. In vitro experiments confirmed quercetin's inhibition of proliferation and induction of apoptosis in ACT-1 cells. This investigation identifies potential therapeutic targets for PC through network pharmacology and experimental validation.

Keywords:  Epimedium Herba; Experimental validation; Molecular docking; Network pharmacology; Prostate cancer

DOI:  https://doi.org/10.1016/j.cjnm.2025.100016
Prostate. 2025 Dec 19.

Diagnostic Value of Rapid On-Site Evaluation Combined With Prostate Biopsy in Prostate Cancer.

Hong Ma, Anzi Cao, Huiming Hou, Pengjie Wu, Ben Wan, Ming Liu.

   OBJECTIVE: To investigate the application value of Rapid On-Site Evaluation (ROSE) in prostate biopsy.
METHODS: All consecutive subjects who attended our clinic to underwent magnetic resonance imaging (MRI)-ultrasound fusion biopsy due to highly suspicious findings on MRI for prostate cancer (PCa) and met the inclusion criteria were enrolled into our prospective study between October 2020 and January 2025. ROSE was performed concurrently in the same operating room with MRI-ultrasound fusion biopsy. For each lesion with Prostate Imaging-Reporting and Data System (PI-RADS) 4-5, one to two additional needle passes were taken for ROSE, in addition to the standard biopsy. The results of ROSE during the biopsy were recorded. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were assessed using paraffin-embedded histopathology of the biopsy specimens as the gold standard.
RESULTS: A total of 313 lesions with PI-RADS 4-5 from 147 patients were ultimately included in this study. All biopsies were performed smoothly, with no severe complications occurring postoperatively. 192 lesions were pathologically diagnosed with PCa, yielding a positive detection rate of 61.3% (192/313). With paraffin-embedded histopathology of the biopsy specimens serving as the gold standard, the sensitivity of ROSE for detecting PCa was 71.9% (138/192), specificity was 100% (121/121), accuracy was 82.7% (259/313), positive predictive value was 100% (138/138), and negative predictive value was 69.1% (121/175).
CONCLUSIONS: The application of ROSE technology in the diagnosis during prostate biopsy is accurate and reliable, with specificity and positive predictive value both reaching 100%.

Keywords:  Prostate cancer; prostate biopsy; rapid on‐site evaluation

DOI:  https://doi.org/10.1002/pros.70113
J Exp Clin Cancer Res. 2025 Dec 18.

Docetaxel induced activation of GSDME pathway and pyroptosis enhance immune lethality in prostate cancer cells.

Ruoyang Liu, Long Zhang, Guoqing Xie, Xiang Li, Yu Liu, Ningyang Li, Aravind Raveendran, Yuankang Feng, Fubo Lu, Xiyue Deng, Junyi Li, Jinjian Yang, Zhenlin Huang, Zhankui Jia.



Keywords:  Combination therapy; GSDME; Immunity; Prostate cancer; Pyroptosis; SKP2

DOI:  https://doi.org/10.1186/s13046-025-03614-1