bims-meproc 2025-03-16 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–03–16
thirteen papers selected by
Grigor Varuzhanyan, UCLA

Cepharanthine hydrochloride: a novel ferroptosis-inducing agent for prostate cancer treatment.
The bioactivity of atraric acid as an inducer of cellular senescence in prostate cancer cells is retained by lipophilic derivatives.
Polyamine metabolism in prostate cancer.
S-Methyl Methanethiosulfonate, the Main Human Metabolite of S-Methyl-L-Cysteine Sulfoxide, Alters Energy Metabolism in Prostate Cancer Cells.
Depletion of Acetyl-CoA Carboxylase 1 Facilitates Epithelial-Mesenchymal Transition in Prostate Cancer Cells by Activating the MAPK/ERK Pathway.
Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer.
MSI1 Accelerates Prostate Cancer Cell Proliferation, Migration and Glycolysis by Promoting ABHD2 Transcription.
Integrated analysis of single-cell and bulk transcriptomes uncovers clinically relevant molecular subtypes in human prostate cancer.
Toosendanin promotes prostate cancer cell apoptosis, ferroptosis and M1 polarization via USP39-mediated PLK1 deubiquitination.
Fatty acid binding protein 5 inhibitors as novel anticancer agents against metastatic castration-resistant prostate cancer.
Drug-drug interactions in metastatic hormone-sensitive prostate cancer (mHSPC): practical considerations for treating men with androgen receptor pathway inhibitors and common medications in this stage.
Systematic multi-omics investigation of androgen receptor driven gene expression and epigenetics changes in prostate cancer.
Pre-diagnostic circulating metabolomics and prostate cancer risk: A systematic review and meta-analysis.

Front Pharmacol. 2025 ;16 1536375

Cepharanthine hydrochloride: a novel ferroptosis-inducing agent for prostate cancer treatment.

Jing-Song Guan, Jing Jia, Ze-Xiu Huang, Yu-Qing Zhou, Jing-Jie Zheng, Qi-Man Lin, Yi-Fei Wang, Jiang-Lin Fan, Yao Wang.

   Background: Ferroptosis is an intracellular iron-dependent cell death that is distinct from apoptosis, necrosis, and autophagy. Increasing evidence indicated that ferroptosis plays a crucial role in suppressing tumors, thus providing new opportunities for cancer therapy. The drug cepharanthine, commonly used to treat leukopenia, has been discovered to function as an anticancer agent to multiple types of cancer via diverse mechanisms. However, the effect of cepharanthine on prostate cancer remains unclear.
Methods: A semi-synthetic derivative of cepharanthine, cepharanthine hydrochloride (CH), is used in this study due to its better water solubility and bioavailability. The prostate cancer cell lines LNCaP, 22Rv1, PC3 and xenograft mouse models are used for detecting the anti-tumor effect of CH in vitro and in vivo. Types of cell death including ferroptosis are detected by flow cytometry using annexin V and total/lipid reactive oxygen species probes, drug combination of CH with ferroptosis inhibitor/ion chelator, and the appearance of mitochondria under a transmission electron microscopy. The mechanism is investigated by high-throughput transcriptome analysis and transcription factor function analysis of androgen receptor.
Results: CH inhibits cellular functions and trigger ferroptosis in prostate cancer cells. Mechanistic research revealed both common and distinct pharmacological mechanisms of CH-induced ferroptosis in different prostate cancer cells. High-throughput transcriptome analysis revealed that ferroptosis-related genes are significantly regulated in androgen receptor-dependent cells 22Rv1 and LNCaP, and less significantly in androgen receptor-independent cell PC3. Furthermore, CH was found to reduce the gene expressions and protein levels of GPX4 and FSP1 through modulating the activity of the androgen receptor signaling pathway, but not through its transcription factor activity. In addition, CH upregulated ACSL4 and downregulated DHODH, with the combined regulatory outcomes synergistically inducing ferroptosis. An in vivo experiment employing CH and ion chelator-treated nude mice validated the mechanism by which CH induces ferroptosis to combat prostate cancer.
Conclusion: This study has identified CH as a novel ferroptosis-inducing agent for the treatment of prostate cancer. The multiple mechanisms we found provides strong evidence for the eventual clinical application of the drug.

Keywords:  androgen receptor; cepharanthine; combination therapy; ferroptosis; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2025.1536375
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 12.

The bioactivity of atraric acid as an inducer of cellular senescence in prostate cancer cells is retained by lipophilic derivatives.

Adina Asara Baniahmad, Golnaz Atri Roozbahani, Manfred Jung, Aria Baniahmad.

  Esters have been described as bioactive chemical compounds. However, the presence of an ester as a functional group is often associated with hydrolytic liability. Therefore, it is often unclear whether esters serve as pro-drugs and are rather converted into bioactive drugs in cells. The small molecule atraric acid (AA) has an ester group and had been identified as the first natural androgen receptor antagonist that inhibits prostate cancer cell growth and induces cellular senescence in cancer cells. Based on the presence of the ester group, it is unclear whether AA is a prodrug being hydrolyzed to generate the bioactive compound intracellularly. Here, we addressed this issue by synthesizing novel compounds for which the ester group has been replaced by a stable isoster. To replace the methylester group of atraric acid, a ketone with a propanoyl side chain and a N-methoxy-N-methyl-amide derivative were synthesized. Functional assays suggest that both non-ester atraric acid derivatives are bioactive in inducing cellular senescence. Treatment of human prostate cancer cells with these compounds suggest that both inhibit cell growth and induce cellular senescence in a dose-dependent manner. This was observed in two different human prostate cancer cell lines that serve as model systems for androgen-sensitive and castration-resistant prostate cancer, respectively. Computational modeling suggests that these two compounds bind to the androgen receptor ligand binding domain to similar receptor residues as AA. Thus, the data suggest that replacing the ester of AA by a ketone with a propanoyl group or by the N-methoxy-N-methyl-amide group the bioactivity as an androgen receptor antagonist is retained.

Keywords:  Androgen receptor antagonist; Atraric acid; Cellular senescence; Prostate cancer

DOI:  https://doi.org/10.1007/s00210-025-03989-0
Curr Opin Oncol. 2025 Feb 21.

Polyamine metabolism in prostate cancer.

Laura A Sena.

PURPOSE OF REVIEW: Normal and malignant prostate engage in high rates of de novo polyamine synthesis. This review considers how polyamine metabolism regulates prostate cancer initiation and progression.
RECENT FINDINGS: The androgen receptor (AR) establishes a metabolic program to drive robust polyamine synthesis in the normal prostate. Upon malignant transformation, this AR-driven metabolic program persists and is optimized for oncogenesis by the proto-oncogene MYC and/or alterations to PI3K signaling. A deeper understanding of the function of polyamines in prostate cancer may be obtained by considering their function in the normal prostate.
SUMMARY: Recent findings support ongoing research into the role of polyamines in driving prostate cancer initiation and progression and suggest targeting polyamine metabolism remains a promising therapeutic strategy for prevention and treatment of prostate cancer.

DOI: https://doi.org/10.1097/CCO.0000000000001134
Mol Nutr Food Res. 2025 Mar 09. e70008

S-Methyl Methanethiosulfonate, the Main Human Metabolite of S-Methyl-L-Cysteine Sulfoxide, Alters Energy Metabolism in Prostate Cancer Cells.

Gemma Beasy, Federico Bernuzzi, Priscilla Day-Walsh, Perla Tronsco-Rey, Marianne Defernez, Shikha Saha, Richard F Mithen, Maria H Traka, Paul A Kroon.

  Cruciferous and allium vegetables contain the sulfur compound S-methyl-L-cysteine-sulfoxide (SMCSO). Considering SMCSO is found at a higher abundance compared to the glucosinolates, there are limited reports on its effect on health, with the majority of the evidence on the beneficial effects on glucose metabolism in rodent models. In the current study, we investigated the metabolic effects of SMCSO and its metabolite, S-methyl methanethiosulfonate (MMTSO), on prostate cancer metabolism. DU145 prostate cancer cells were cultured in 5.5 mM (basal), 10 mM (intermediate) and 25 mM (high) glucose concentrations in the presence of SMCSO or MMTSO (100 µM). Using Seahorse technology, MMTSO but not SMCSO reduced mitochondrial metabolism, mitochondrial ATP, and the percentage of oxidative phosphorylation and increased the fatty acid dependency of DU145 cells. Transcriptomic and metabolomic analyses observed cellular and energy metabolism pathways and immune response changes. These data show that MMTSO alters several features of energy metabolism in DU145 prostate cancer cells, shifting them towards a non-cancerous phenotype. These data are consistent with the notion that MMTSO may contribute to the beneficial effects of a broccoli-rich diet and metabolic effects of prostate cancer.

Keywords:  DU145 prostate cancer cells; MMTSO; SMCSO; broccoli; energy metabolism

DOI:  https://doi.org/10.1002/mnfr.70008
MedComm (2020). 2025 Mar;6(3): e70126

Depletion of Acetyl-CoA Carboxylase 1 Facilitates Epithelial-Mesenchymal Transition in Prostate Cancer Cells by Activating the MAPK/ERK Pathway.

Jiarun Lai, Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Shengbang Yang, Yongding Wu, Huijing Tan, Junchen Liu, Huichan He, Weide Zhong.

  Hyperactivation of fatty acid biosynthesis holds promise as a targeted therapeutic strategy in prostate cancer (PCa). However, inhibiting these enzymes could potentially promote metastatic progression in various other cancers. Herein, we found that depletion of acetyl-CoA carboxylase 1 (encoded by ACACA), the enzyme responsible for the first and rate-limiting step of de novo fatty acid biosynthesis, facilitated epithelial-mesenchymal transition (EMT) and migration of PCa cells. This finding was validated in vitro through cell migration assays and in vivo using a metastatic model established by tail vein injection of ACACA-depleted cells into BALB/c nude mice. Additionally, depletion of ACACA activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinases (ERK) pathway. Inhibition of the MAPK/ERK signaling pathway reduced EMT and migration in ACACA-depleted cells. Our study is the first to indicate targeting ACACA induces an "unexpected" escape program through activation of the MAPK/ERK signaling pathway in PCa, ultimately leading to EMT and metastasis. Therefore, we strongly recommend that the potential adverse effects of targeting ACACA or its derived therapeutic agents must be given extreme attention, especially in MAPK-related cancers.

Keywords:  ACACA; EMT; MAPK; fatty acid biosynthesis; metastasis; prostate cancer

DOI:  https://doi.org/10.1002/mco2.70126
Signal Transduct Target Ther. 2025 Mar 14. 10(1): 87

Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer.

Sheng Ma, Zixian Wang, Zezhong Xiong, Yue Ge, Meng-Yao Xu, Junbiao Zhang, Yuzheng Peng, Qin Zhang, Jiaxue Sun, Zirui Xi, Hao Peng, Wenjie Xu, Yanan Wang, Le Li, Chunyu Zhang, Zheng Chao, Baojun Wang, Xu Gao, Xu Zhang, Gong-Hong Wei, Zhihua Wang.

Enhancer RNAs (eRNAs), a subclass of non-coding RNAs transcribed from enhancer regions, have emerged as critical regulators of gene expression; however, their functional roles in prostate cancer remain largely unexplored. In this study, we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues. By incorporating chromatin immunoprecipitation sequencing data, we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways. Among these, lactotransferrin-eRNA (LTFe) was markedly downregulated in prostate cancer tissues, with functional analyses revealing its tumor-suppressive role. Mechanistically, LTFe promotes the transcription of its target gene, lactotransferrin (LTF), by interacting with heterogeneous nuclear ribonucleoprotein F (HNRNPF) and facilitating enhancer-promoter chromatin interactions. Furthermore, we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport. Notably, androgen receptor (AR) signaling disrupts LTFe-associated chromatin looping, leading to ferroptosis resistance. Therapeutically, co- administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth, offering a promising strategy for castration-resistant prostate cancer. Collectively, this study provides novel insights into the mechanistic role of eRNAs in prostate cancer, highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.

DOI: https://doi.org/10.1038/s41392-025-02170-6
Biochem Genet. 2025 Mar 11.

MSI1 Accelerates Prostate Cancer Cell Proliferation, Migration and Glycolysis by Promoting ABHD2 Transcription.

Dingping Huang, Qingqi Zheng, Liying Zhou.

  Musashi-1 (MSI1) has been proposed as a potential prognostic biomarker in prostate cancer (PCa), but its role and underlying molecular mechanisms in PCa progression remain unclear. The mRNA and protein levels of MSI1 and α/β-hydrolase domain 2 (ABHD2) in PCa tissues and cells were examined using qRT-PCR and western blot. Cell proliferation, cycle, apoptosis, and migration were detected by EdU assay, flow cytometry and transwell assay. Glucose uptake and lactate production were assessed to measure cell glycolysis. The interaction between SP1 and PLA2G6 was evaluated using dual-luciferase reporter assay and ChIP assay. MSI1 had increased expression in PCa tissues and cells. MSI1 downregulation could repress PCa cell proliferation, cycle, migration, glycolysis, and enhanced apoptosis. ABHD2 was upregulated in PCa tissues and cells, and MSI1 could bind to ABHD2 promoter region to increase its expression. Knockdown of ABHD2 suppressed PCa cell growth, migration and glycolysis, and ABHD2 overexpression also abolished the effect of MSI1 downregulation on PCa cell progression. Furthermore, interference of MSI1 reduced PCa tumor growth by decreasing ABHD2 expression in vivo. MSI1 facilitated PCa cell proliferation, migration and glycolysis via activating ABHD2 transcription, providing a novel target for PCa treatment.

Keywords:  ABHD2; MSI1; Proliferation; Prostate cancer; Transcription

DOI:  https://doi.org/10.1007/s10528-025-11079-2
Chin J Cancer Res. 2025 Jan 30. 37(1): 90-114

Integrated analysis of single-cell and bulk transcriptomes uncovers clinically relevant molecular subtypes in human prostate cancer.

Tao Ding, Lina He, Guowen Lin, Lei Xu, Yanjun Zhu, Xinan Wang, Xuefei Liu, Jianming Guo, Fanghong Lei, Zhixiang Zuo, Jianghua Zheng.

   Objective: Prostate cancer (PCa) is a complex disease characterized by diverse cellular ecosystems within the tumor microenvironment (TME) and high tumor heterogeneity, which challenges clinically stratified management and reinforces the need for novel strategies to fight against castration-resistant PCa (CRPC).
Methods: We performed single-cell RNA sequencing (scRNA-seq) on 10 untreated primary PCa tissues and integrated public scRNA-seq resources from three normal prostate tissues, two untreated primary PCa tissues, and six CRPC tumors to portray a comprehensive cellular and molecular interaction atlas of PCa. We further integrated the single-cell and bulk transcriptomes of PCa to establish a molecular classification system.
Results: scRNA-seq profiles revealed substantial inter- and intra-tumoral heterogeneity across different cell subpopulations in untreated PCa and CRPC tumors. In the malignant epithelial reservoir, cells evolved along decoupled paths in treatment-naive PCa and CRPC tumors, and distinct transcriptional reprogramming processes were activated, highlighting anti-androgen therapy-induced lineage plasticity. Based on the specifically expressed markers of the epithelial subpopulations, we conducted unsupervised clustering analysis in The Cancer Genome Atlas prostate adenocarcinoma (TCGA-PRAD) cohort and identified three molecularly and clinically distinct subtypes. The C1 subtype, characterized by high enrichment of CRPC-enriched epithelial cells, had a high risk of rapid development of anti-androgen resistance and might require active surveillance and additional promising intervention treatments, such as integrin A3 (ITGA3) + integrin B1 (ITGB1) inhibition. The C2 subtype resembled the immune-modulated subtype that was most likely to benefit from anti-LAG3 immunotherapy. The C3 subtype had a favorable prognosis.
Conclusions: Our study provides a comprehensive and high-resolution landscape of the intricate architecture of the PCa TME, and our trichotomic molecular taxonomy could help facilitate precision oncology.

Keywords:  Single-cell RNA sequencing; lineage plasticity; molecular classification; prostate cancer; tumor heterogeneity

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.01.07
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 08.

Toosendanin promotes prostate cancer cell apoptosis, ferroptosis and M1 polarization via USP39-mediated PLK1 deubiquitination.

Siyao Shen, Guifeng Xue, Zhigang Zeng, Liang Peng, Weidong Nie, Xiaochun Zeng.

  Toosendanin (TSN) can inhibit the malignant process of many cancers, and has the potential to be developed as an anti-tumor drug. However, the role and mechanism of TSN in prostate cancer (PCa) progression remain unclear. PCa cells (DU145 and LNCaP) were treated with TSN. Cell viability was detected by cell counting kit 8 assay. Cell proliferation, apoptosis and metastasis were assessed by colony formation assay, flow cytometry and transwell assay. Cell ferroptosis was evaluated by examining Fe2+, MDA and lipid-ROS levels. M1 polarization markers were analyzed by flow cytometry. Immunohistochemical staining, quantitative real-time PCR and western blot were used to detect ubiquitin-specific protease 39 (USP39) and polo-like kinase 1 (PLK1) expression. Cycloheximide treatment, Co-IP assay and ubiquitination assay were performed to confirm the regulation of USP39 on PLK1. In vivo experiments were employed to determine the effect of TSN and USP39 on PCa tumor growth. TSN treatment suppressed PCa cell proliferation, cell cycle, migration, and invasion, while enhanced apoptosis, ferroptosis, and M1 polarization. USP39 was upregulated in PCa tissues and cells, and its protein expression was reduced by TSN. USP39 overexpression reversed the regulation of TSN on PCa cell functions. PLK1 had elevated expression in PCa, and USP39 stabilized its protein expression by deubiquitination. USP39 knockdown inhibited PCa cell behaviors, and its regulation was abolished by PLK1 overexpression. Meanwhile, TSN reduced PCa tumor growth by regulating USP39/PLK1. TSN played anti-tumor role in PCa, which promoted PCa cell apoptosis, ferroptosis, and M1 polarization by inhibiting USP39/PLK1 axis.

Keywords:  PLK1; Prostate cancer; Toosendanin; USP39

DOI:  https://doi.org/10.1007/s00210-025-03916-3
Bioorg Med Chem. 2025 Feb 27. pii: S0968-0896(25)00077-X. [Epub ahead of print]122 118136

Fatty acid binding protein 5 inhibitors as novel anticancer agents against metastatic castration-resistant prostate cancer.

Hehe Wang, Chuanzhou Zhu, Manojit M Swamynathan, Shubhra Rajput, Kalani Jayanetti, Dominick Rendina, Kathryn Takemura, Diane Bogdan, Liqun Wang, Robert C Rizzo, Martin Kaczocha, Lloyd C Trotman, Agnieszka B Bialkowska, Iwao Ojima.

  Prostate cancer (PCa) is one of the most common malignancies diagnosed among men and is the second leading cause of cancer-related death. Despite recent advancements in early diagnosis of PCa, androgen deprivation therapy (ADT) remains the most common treatment of PCa. Docetaxel (DTX) and Cabazitaxel (CTX) are two of the most extensively used drugs for metastatic castration-resistant prostate cancer (mCRPC). However, there is a clear medical need for newer and more efficacious therapies for CRPC. FABP5 is overexpressed in prostate cancer cells and chaperones fatty acids to PPARs, which leads to the upregulation of proangiogenic factors, resulting in cell survival and metastasis. The critical role and upregulation of FABP5 in PCa make FABP5 an excellent druggable target for CRPC. We reported a promising anti-PCa activity of truxillic acid monoester (TAME)-based FABP5 inhibitors (SB-FIs) and their synergy with DTX and CTX in vitro and in vivo against PC-3 cells and PC-3 tumor xenografts. In the present work, we performed an extensive SAR study on the potencies of 2nd- and 3rd-generation SB-FIs against PC-3 and RCaP cell lines. RCaP is a mouse PCa cell line, resistant to anti-androgen and first-line taxane chemotherapies, and shows a high level of the Fabp5-gene. This SAR study led to the identification of a number of 3rd-generation SB-FIs with strong cytotoxicity against these two PCa cell lines. Cell cycle analysis of selected SB-FIs revealed a clear evolution of apoptotic potency in the 1st-, 2nd- and 3rd-generation SB-FIs. Since taxanes, DTX and CTX, are ineffective against RCaP cell line, we selected a topoisomerase I inhibitor, topotecan (TPT) as a replacement for taxanes. We screened the library of SB-FIs for synergy with TPT and identified 3 SB-FIs (L3, α-11 and α-4), exhibiting strong synergy, which could remarkably expand the therapeutic window of TPT.

Keywords:  Computer-aided drug design; Fatty acid binding protein; Metastatic castration-resistant prostate cancer; Truxillic acid monoester

DOI:  https://doi.org/10.1016/j.bmc.2025.118136
Expert Opin Drug Metab Toxicol. 2025 Mar 14.

Drug-drug interactions in metastatic hormone-sensitive prostate cancer (mHSPC): practical considerations for treating men with androgen receptor pathway inhibitors and common medications in this stage.

Cristina Ibáñez, Manuel Touris-Lores, Álvaro Montesa, Fernando López-Campos, Emilio Ríos, Paola Usán, Cristina Moretones, David Conde-Estévez.

   INTRODUCTION: New androgen receptor pathway inhibitors (ARPIs) are an essential part of the treatment strategy for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Despite the good tolerability of ARPIs, after treatment is started, drug-drug interactions (DDIs) between these and other medications frequently taken by these patients may appear. DDIs may reduce the therapeutic effect of both and lead to increased adverse events. DDIs should be carefully assessed before an ARPI is started.
AREAS COVERED: We first review the current therapeutic landscape for mHSPC, common age-related comorbidities and other comorbidities or adverse events arising from previous or current treatments for prostate cancer, and patients' symptomatology. We then analyze the potential toxicities arising from medications for these conditions and those of mHSPC: ARPIs (abiraterone acetate plus prednisone/prednisolone, enzalutamide, apalutamide, and darolutamide) and docetaxel.
EXPERT OPINION: Before mHSPC patients are treated with an ARPI, careful assessment of patient eligibility for each treatment alternative and potential DDIs between these and treatments for current comorbidities is a fundamental component in clinical decision-making. ARPIs with low potential DDIs allow keeping current concomitant medications without significant relevant dose adjustments and help reduce the risk of toxicities and comorbidity-related decompensation.

Keywords:  Abiraterone; Apalutamide; Comorbidities; Darolutamide; Drug–drug interactions; Enzalutamide; Safety; androgen receptor pathway inhibitor; prostate cancer

DOI:  https://doi.org/10.1080/17425255.2025.2478167
Comput Biol Med. 2025 Mar 07. pii: S0010-4825(25)00351-8. [Epub ahead of print]189 110000

Systematic multi-omics investigation of androgen receptor driven gene expression and epigenetics changes in prostate cancer.

Lin Li, Kyung Hyun Cho, Xiuping Yu, Siyuan Cheng.

BACKGROUND: Prostate cancer, a common malignancy, is driven by androgen receptor (AR) signaling. Understanding the function of AR signaling is critical for prostate cancer research.
METHODS: We performed multi-omics data analysis for the AR+, androgen-sensitive LNCaP cell line, focusing on gene expression (RNAseq), chromatin accessibility (ATACseq), and transcription factor binding (ChIPseq). High-quality datasets were curated from public repositories and processed using state-of-the-art bioinformatics tools.
RESULTS: Our analysis identified 1004 up-regulated and 707 down-regulated genes in response to androgen deprivation therapy (ADT) which diminished AR signaling activity. Gene-set enrichment analysis revealed that AR signaling influences pathways related to neuron differentiation, cell adhesion, P53 signaling, and inflammation. ATACseq and ChIPseq data demonstrated that as a transcription factor, AR primarily binds to distal enhancers, influencing chromatin modifications without affecting proximal promoter regions. In addition, the AR-induced genes maintained higher active chromatin states than AR-inhibited genes, even under ADT conditions. Furthermore, ADT did not directly induce neuroendocrine differentiation in LNCaP cells, suggesting a complex mechanism behind neuroendocrine prostate cancer development. In addition, a publicly available online application LNCaP-ADT (https://pcatools.shinyapps.io/shinyADT/) was launched for users to visualize and browse data generated by this study.
CONCLUSION: This study provides a comprehensive multi-omics dataset, elucidating the role of AR signaling in prostate cancer at the transcriptomic and epigenomic levels. The reprocessed data is publicly available, offering a valuable resource for future prostate cancer research.

DOI: https://doi.org/10.1016/j.compbiomed.2025.110000
medRxiv. 2025 Feb 28. pii: 2025.02.27.25321444. [Epub ahead of print]

Pre-diagnostic circulating metabolomics and prostate cancer risk: A systematic review and meta-analysis.

Harriett Fuller, Orietta P Agasaro, Burcu F Darst.

Background: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong clinical potential to act as biomarkers. However, evidence of circulating metabolite associations has not been quantitively aggregated.
Methods: Systematic searches were performed in PubMed and Embase (October 17 th , 2024) to identify pre-diagnostic untargeted serum metabolomic studies of PCa risk. After harmonizing metabolite names across studies, restricted maximum likelihood was used to conduct meta-analyses to quantify associations between metabolites and risk of overall PCa, low- to intermediate-risk PCa, high- to very high-risk PCa and lethal PCa, as defined by the NCCN. Statistical significance was defined as FDR-adjusted P<0.05. Enrichment analyses were conducted on significant metabolites to identify biologically relevant pathways. Correlation of effect estimates between PCa outcomes was assessed via Pearson correlation.
Results: We identified 12 untargeted pre-diagnostic circulating metabolomic studies in a systematic review and meta-analyzed associations between up to 408 metabolites with four PCa outcomes. Three, eleven and nineteen metabolites were significantly associated with risk of overall, high/very high-risk and lethal PCa, respectively. Metabolites associated with high/very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. Follow-up analyses found that 13 of the significant metabolites were drug and/or dietary modifiable.
Conclusions: These findings suggest the strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.

DOI: https://doi.org/10.1101/2025.02.27.25321444