bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–10–12
sixteen papers selected by
Grigor Varuzhanyan, UCLA
  1. Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.
  2. Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective.
  3. Proteomic Profiling of Extracellular Vesicles Distinguishes Prostate Cancer Molecular Subtypes.
  4. Androgen receptor pathway signaling inhibitors in development for prostate cancer therapy.
  5. Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation.
  6. Borax Triggers Ferroptosis by Modulating the TfR1/GPX4/ACSL4 Pathway in Prostate Cancer Cells with Differential Androgen Sensitivity.
  7. Androgen receptor-mediated regulation of BRCA1 modulates the antioxidant defense in prostate cancer.
  8. Protein arginine methyltransferase 7 regulates the cell cycle and promotes the progression of prostate cancer.
  9. Androgen receptor inhibitory activity of dihydrocapsaicin: Insights from in vitro, in vivo and in silico studies.
  10. ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA.
  11. PPP1R14B promotes the progression of prostate cancer by regulating the JAK2/STAT3/AR pathway and alters the sensitivity and resistance to enzalutamide.
  12. Disulfidptosis-Associated CCNB2: A Prognostic Biomarker and Immune Microenvironment Modulator in Prostate Cancer.
  13. Oxadiazole derivatives as potent androgen receptor inhibitors: Design, synthesis, and anticancer evaluation.
  14. Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.
  15. A novel Rhein derivative AQ-NC inhibits prostate cancer by suppressing the PI3K/AKT pathway.
  16. Statin and other antilipemic use and prostate cancer : Results from the EPICAP study.
  1. Neoplasia. 2025 Oct 07. pii: S1476-5586(25)00115-0. [Epub ahead of print]70 101235
    Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.
    Fahim Ahmad, Margaret White, Kazutoshi Yamamoto, Daniel R Crooks, Supreet Agarwal, Ye Yang, Brian Capaldo, Sonam Raj, Aian Neil Alilin, Anita Ton, Stephen Adler, Jurgen Seidel, Colleen Olkowski, Murali Krishna Cherukuri, Peter L Choyke, Kathleen Kelly, Jeffrey R Brender.
      Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.
    Keywords:  FDG-PET; Metabolic reprograming; Metabolism; Prostate cancer; RB1; TP53
    DOI:  https://doi.org/10.1016/j.neo.2025.101235
  2. J Cell Commun Signal. 2025 Dec;19(4): e12032
    Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective.
    Dun Xue, Long Tan, Fengshuai Yang, Xiaolan Tian, Qian Zuo, Xinghui Wu.
      Prostate cancer (PCa) is a leading cause of cancer-related death in men, with its progression and treatment response being complex. The study focuses on the role of HIC1 (Hypermethylated in cancer 1) in PCa, revealing its downregulation in PCa tissues compared to normal counterparts. Using transcriptome sequencing and bioinformatics, it was found that HIC1 influences key cellular processes like cell growth, proliferation, invasion, and androgen receptor (AR) signaling in PCa. Specifically, AR was identified as a transcription factor for insulin receptor substrate 2 (IRS2), which activates the PI3K/AKT pathway, enhancing PCa cell proliferation and invasion. However, this effect could be reversed by IRS2 inhibition using NT157. Furthermore, HIC1 overexpression reduced castration resistance in PCa cells, with in vivo studies showing that HIC1 silencing increased PCa xenograft growth and resistance, and elevated Ki-67, Cleaved-caspase-3, EMT markers, and prostate-specific antigen (PSA) levels. Conversely, AR and IRS2 inhibitors like EPI-7170 and NT157 negatively affected PCa progression. These results underscore HIC1's potential as a therapeutic target in PCa, offering new insights into its role in cancer biology and treatment.
    Keywords:  HIC1; IRS2; PI3K/AKT axis; androgen receptor; castration resistance; prostate cancer
    DOI:  https://doi.org/10.1002/ccs3.12032
  3. J Extracell Vesicles. 2025 Oct;14(10): e70176
    Proteomic Profiling of Extracellular Vesicles Distinguishes Prostate Cancer Molecular Subtypes.
    Megan L Ludwig, Ali T Arafa, Saasha Vinoo, Jason C Jones, Abderrahman Day, Hannah E Bergom, Zoi Sychev, Alec Horrmann, Nicholas M Levinson, Scott M Dehm, Emmanuel S Antonarakis, Justin Hwang, Justin M Drake.
      Prostate cancer is the most common non-cutaneous cancer among men in the United States. Most prostate cancers are driven by androgen receptor (AR) signalling, but there are an increasing number of cases that lose AR and gain neuroendocrine (NE) features (AR-/NE+) or lack both (AR-/NE-). These latter subtypes are particularly aggressive and lethal. Extracellular vesicles (EVs) have shown great potential as biomarkers for non-invasive liquid biopsy assays, as EVs contain biomolecules from their cells of origin. Here, we used a shotgun proteomics approach with mass spectrometry to interrogate the global proteome of EVs isolated from prostate cancer cell lines reflecting diverse clinical subtypes, including AR-/NE+ and AR-/NE- models. We identified 3952 EV proteins, which clustered largely by tumour subtype and provided enough proteomic coverage to derive classic gene signatures of AR or NE identity that are of high relevance for prostate cancer prognostication. EVs isolated from AR+ cells displayed high levels of proteins regulated by AR and mTOR signalling. EVs isolated from AR-/NE+ cells contained known NE markers such as SYP and CHGA, whereas EVs from AR-/NE- models were enriched in basal cell markers and proteins that regulate epithelial-to-mesenchymal transition (EMT). We integrated our cell line data with recently published EV proteomics data from 27 advanced prostate cancer patients and found 2733 overlapping proteins, including cell surface markers relevant to prostate cancer, AR activity indicators, and proteins enriched in specific subtypes (AR+, AR-/NE-, AR-/NE+). This approach may be useful for rare cancer subtypes, such as prostate cancers that lose AR-related features and gain NE features, to optimise the use of these liquid biopsy samples for clinical decision making.
    DOI:  https://doi.org/10.1002/jev2.70176
  4. Expert Opin Investig Drugs. 2025 Oct 09.
    Androgen receptor pathway signaling inhibitors in development for prostate cancer therapy.
    Sara Bleve, Pier Vitale Nuzzo, Abdul Baseet Arham, Aaron Holmes, Scott T Tagawa.
       INTRODUCTION: Prostate cancer (PC), including castration-resistant disease (CRPC), remains largely driven by dysregulated androgen receptor (AR) signaling. While androgen deprivation therapy (ADT) combined with next-generation AR inhibitors improves survival, resistance inevitably arises through mechanisms such as AR amplification, mutations, and splice variants. Additionally, chronic AR suppression induces significant metabolic, musculoskeletal, and cardiovascular toxicities, highlighting the need for novel therapies that overcome resistance while minimizing systemic adverse effects.
    AREAS COVERED: This review outlines the pivotal role of AR signaling in PC pathogenesis and evaluates the clinical impact and limitations of current AR-targeted therapies. In addition, it examines emerging therapeutic strategies aimed at modulating AR activity, disrupting androgen biosynthesis, and degrading the AR protein itself. Finally, we explore novel approaches targeting alternative oncogenic pathways involved in resistance and lineage plasticity, with the goal of advancing more effective and durable treatment paradigms.
    EXPERT OPINION: Novel strategies such as bipolar androgen therapy (BAT), selective androgen receptor modulators (SARMs), and AR degraders like PROTACs offer context-specific or mechanistically distinct ways to overcome resistance to traditional AR antagonism in prostate cancer. These approaches, along with CYP11A1 inhibitors and resistance pathway targeting (e.g. PI3K/AKT, EZH2), mark a shift toward more personalized therapies aimed at improving efficacy while minimizing toxicity.
    Keywords:  AR antagonists; Androgen receptor (AR); Bipolar androgen therapy (BAT); PROTACs; Prostate cancer; Selective androgen receptor modulators (SARMs)
    DOI:  https://doi.org/10.1080/13543784.2025.2573647
  5. Oncogene. 2025 Oct 04.
    Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation.
    Jiaqi Chen, Mu-En Wang, Alyssa R Bawcom, Yi Lu, John M Asara, Lei Li, Ming Chen.
      Lipid metabolism is among the most frequently dysregulated metabolic processes in human cancer, yet how cellular lipids, the end products of lipogenesis, and their composition are altered to support various aspects of cancer remains poorly understood. Here, we show that targeting SREBP-dependent lipogenesis via FGH10019, an orally available SREBP inhibitor, enhances docetaxel-induced cytotoxicity in human prostate cancer cells in vitro and in vivo. Mechanistically, suppression of lipid biosynthesis leads to a shift in cellular lipid composition toward polyunsaturated lipids, resulting in increased membrane permeability and intracellular docetaxel accumulation. Thus, our findings reveal a critical role of de novo lipogenesis in protecting cancer cells from chemotherapeutics and suggest that treatment with lipogenesis inhibitors could improve the efficacy of chemotherapy against human prostate cancer.
    DOI:  https://doi.org/10.1038/s41388-025-03588-6
  6. Biol Trace Elem Res. 2025 Oct 07.
    Borax Triggers Ferroptosis by Modulating the TfR1/GPX4/ACSL4 Pathway in Prostate Cancer Cells with Differential Androgen Sensitivity.
    Ekrem Basaran, Ceyhan Hacioglu, Dursun Baba, Arda Taşkın Taşkıran, Ahmet Yıldırım Balık.
      Prostate carcinoma remains a predominant contributor to cancer-associated morbidity in males, with rising prevalence and therapeutic resistance highlighting unmet clinical needs. Ferroptosis-a non-apoptotic cell death mechanism mediated through iron-catalyzed phospholipid peroxidation-has emerged as a promising strategy to circumvent drug-resistant malignancies. We investigated the mechanistic interplay between transferrin receptor 1 (TfR1) and borax-mediated ferroptotic activation in androgen-responsive and androgen-independent prostate adenocarcinoma models. Cytotoxic effects of borax on LNCaP and DU-145 cells were assessed using CCK-8 and BrdU assays across 2.5 μM to 320 μM concentrations over 24-72 h. Expression and levels of TfR1, GPX4, ACSL4, GSH, MDA, total ROS, and intracellular Fe2⁺ were evaluated through ELISA, Western blotting, and RT-PCR. Ferroptosis specificity was confirmed using ferrostatin-1 inhibition studies and exclusion of apoptosis/necroptosis/autophagy by pharmacological inhibitors. Nuclear alterations and superoxide anion production were examined using DAPI staining. IC₅₀ values were 138 μM (95% CI: 115-153 μM) for LNCaP cells and 92.1 μM (95% CI: 83.4-102 μM) for DU-145 cells, with DU-145 demonstrating higher sensitivity. Borax exposure in DU-145 cells decreased GSH and GPX4 levels while increasing MDA, ROS, Fe2⁺, ACSL4, and TfR1 expression. Ferrostatin-1 pretreatment effectively attenuated these effects, confirming ferroptosis-dependent mechanisms. Nuclear abnormalities and elevated superoxide production were observed. These findings demonstrate that borax induces cytotoxicity in prostate cancer cells through ferroptosis via TfR1/GPX4/ACSL4 cascade modulation, suggesting a potential role for TfR1 in governing ferroptotic vulnerability. While high concentrations limit immediate clinical application, these results establish mechanistic foundations for ferroptosis-targeted therapy development in prostate cancer.
    Keywords:  Borax; Ferroptosis; Prostate cancer; TfR1
    DOI:  https://doi.org/10.1007/s12011-025-04843-3
  7. J Pathol. 2025 Oct 06.
    Androgen receptor-mediated regulation of BRCA1 modulates the antioxidant defense in prostate cancer.
    Saiganesh Sriraman, Verneri Virtanen, Antti Kukkula, Mervi Toriseva, Anni Lumiainen, Gun West, Matti Poutanen, Pekka Taimen, Maria Sundvall.
      Lethal prostate cancer (PCa) is a genetically heterogeneous disease characterized by evolving androgen receptor (AR) signaling, eventually culminating in castration resistance. The tumor suppressor gene BRCA1 has multiple functions that include secondary processes cooperating with its main function as a caretaker of genomic integrity. BRCA1 is often mutated in breast and ovarian cancer, but BRCA1 mutations are also associated with PCa, although they are less frequently observed. Most PCa patients do not, however, carry BRCA1 mutations, and interestingly, it has been shown that BRCA1 expression is enriched in castration-resistant PCa. In this study we elucidated the prostate tissue-specific role of the BRCA1 protein. Although the regulation of DNA damage response genes has been studied in PCa, comprehensive analyses of BRCA1 regulation in the context of androgen signaling are lacking. Our results indicate that BRCA1 is dynamically regulated by AR signaling and that activation of AR via its natural ligand, dihydrotestosterone, represses BRCA1 expression. Our analyses both in vitro and of patient samples and mouse xenografts showed that BRCA1 expression was induced and sustained after androgen deprivation. Moreover, we observed that oxidative stress-related pathways were regulated by BRCA1 in PCa cells and that androgen deprivation therapy-induced activation of BRCA1 supported the function of NRF2, the master regulator of antioxidant defense, and a known interactor of BRCA1. Impaired NRF2 activity, in the absence of BRCA1, decreased growth in a 3D environment. Our findings shed light on the functional role of BRCA1 protein in PCa and suggest that BRCA1 is regulated by the evolving AR signaling state during PCa progression. Thus, AR-mediated suppression of BRCA1 accumulates oncogenic alterations in the early phases of PCa tumor progression and safeguards from excessive reactive oxygen species (ROS) when upregulated during androgen deprivation therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  BRCA1; DNA damage; NRF2; androgen deprivation therapy; androgen receptor; castration‐resistant prostate cancer; oxidative stress
    DOI:  https://doi.org/10.1002/path.6468
  8. Oncol Lett. 2025 Dec;30(6): 549
    Protein arginine methyltransferase 7 regulates the cell cycle and promotes the progression of prostate cancer.
    Hongyuan Wan, Hangshen Zhou, Jiandong Gui, Dongjie Yang, Rong Wang, Jiang Ni, Sheng Wu, Yan Qin, Qiaowei Qi, Lijie Zhu, Ninghan Feng, Yuanyuan Mi.
      Prostate cancer (PCa) is the second most common cancer in men worldwide. Protein arginine methyltransferase 7 (PRMT7) expression is associated with tumor growth, as it can drive tumor cell proliferation and promote its invasiveness in several types of cancer. However, its mechanism in PCa remains to be elucidated. In the present study, the function and associated mechanism of PRMT7 in PCa cells were investigated. The relationship between PRMT7 and PCa was analyzed using The Cancer Genome Atlas online database. Tissue chip techniques were used to identify the clinical relevance of PRMT7 expression. PRMT7 expression levels in PCa tissues and cells were verified using reverse transcription-quantitative PCR (RT-qPCR). Cell cycle, migration, proliferation and apoptosis of PC3 and DU145 cells were observed using flow cytometry, Cell Counting Kit-8, wound healing, plate cloning and cell invasion assays. Gene set enrichment analysis and chip expression profiles were used to predict the potential signaling pathway involved in the action of PRMT7 in PCa. First, The Cancer Genome Atlas database, tissue microarray analysis and RT-qPCR revealed that PRMT7 expression was increased in PCa tissues and cells. Furthermore, small interfering RNA-mediated PRMT7 knockdown led to a notable reduction in the proliferation of cells, increased apoptosis, affected the cell cycle and decreased cell migration and invasion. Furthermore, PRMT7 regulated the functions of Yin Yang 1 (YY1), tumor protein p53 (TP53), cyclin D2 (CCND2), CDK6 and retinoblastoma 1 (RB1) in PCa. PRMT7 may promote proliferation, migration and metastasis in PCa cells by regulating the activity of YY1, TP53, CCND2, CDK6 and RB1 in the cell cycle signaling pathway.
    Keywords:  cell cycle; progression; prostate cancer; protein arginine methyltransferase 7; tumor marker
    DOI:  https://doi.org/10.3892/ol.2025.15295
  9. J Steroid Biochem Mol Biol. 2025 Oct 02. pii: S0960-0760(25)00200-6. [Epub ahead of print] 106872
    Androgen receptor inhibitory activity of dihydrocapsaicin: Insights from in vitro, in vivo and in silico studies.
    Jingqi Zhao, Xue Liu, Yong Pang, Haoge Luo, Jie Zhang, Chen Shao.
      As a natural capsaicinoid from Capsicum annuum L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and disease in humans and is the main focus for prostate cancer treatment. This study seeks to explore how dihydrocapsaicin inhibits the AR in human prostate cancer cell lines, aiming to offer a new natural product-derived AR inhibitor for the clinical management of prostate-related conditions. At first, it was observed that dihydrocapsaicin can induce proliferation suppression in human prostate cancer cells by hindering the cell cycle at the G0/G1 phase. In addition, dihydrocapsaicin probably inhibited AR activity by blocking its movement from the cytoplasm to the nucleus through binding to the AR-LBD, highlighting its potential as an effective inhibitor. From a mechanistic perspective, dihydrocapsaicin facilitated AR release from a stabilizing chaperone complex and enhanced its ubiquitination by E3 ligases, resulting in AR partial degradation via the ubiquitin-proteasome pathway. Our study on the molecular mechanisms behind dihydrocapsaicin's inhibitory effects on the AR revealed that it not only hindered the growth of prostate cancer cells but also reduced tumor growth in vivo. These results offer both experimental evidence and a theoretical basis for the thorough development of AR inhibitors, emphasizing dihydrocapsaicin's potential for application in functional foods or nutritional supplements targeting prostatic disorders.
    Keywords:  Androgen receptor; Dihydrocapsaicin; Inhibitory activity; Prostatic disorders
    DOI:  https://doi.org/10.1016/j.jsbmb.2025.106872
  10. iScience. 2025 Oct 17. 28(10): 113520
    ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA.
    Yutong Chen, Yang Li, Zongzhu Liang, Zhao Yang, Haotian Ren, Wanqing Wei, Yuanjie Niu, Zhiqun Shang.
      Prostate cancer (PCa) often progresses to castration-resistant PCa (CRPC), where docetaxel (DTX) resistance is a major challenge. We investigated the role of the m6A demethylase ALKBH5 in this resistance. ALKBH5 expression was significantly reduced in CRPC clinical samples. Functionally, overexpressing ALKBH5 inhibited PCa cell proliferation and migration, while its knockdown enhanced these effects and increased DTX resistance. Conversely, restoring ALKBH5 or knocking down the m6A reader IGF2BP2 reversed resistance. Multi-omics analysis identified CLSPN, a DNA replication stress regulator, as a key downstream target. Mechanistically, ALKBH5-mediated m6A demethylation reduces CLSPN mRNA stability in an IGF2BP2-dependent manner. Low ALKBH5, therefore, stabilizes CLSPN via IGF2BP2, promoting resistance. These findings, validated in clinical samples and organoid models, demonstrate that the ALKBH5-IGF2BP2 axis modulates DTX resistance in metastatic CRPC through m6A-dependent regulation of CLSPN. Targeting this pathway represents a promising therapeutic strategy to overcome DTX resistance.
    Keywords:  Cancer; Molecular interaction; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2025.113520
  11. Cell Signal. 2025 Oct 09. pii: S0898-6568(25)00578-9. [Epub ahead of print]136 112163
    PPP1R14B promotes the progression of prostate cancer by regulating the JAK2/STAT3/AR pathway and alters the sensitivity and resistance to enzalutamide.
    Long Cheng, Chengyu You, Longtu Ma, Shuai Liu, Yongfeng Lao, Xin Guan, Wenyun Wang, Xi Xiao, Yan Tao, Zhilong Dong.
      Prostate cancer (PCa) is the tumor with the highest incidence rate among men worldwide. There is still a lack of effective treatment options for metastatic PCa and castration-resistant prostate cancer (CRPC). Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) has been found to be associated with the occurrence and development of various cancers. However, the role and mechanism of PPP1R14B in PCa have not yet been deeply explored. Here, we found that PPP1R14B was highly expressed in PCa tissues and was significantly associated with a higher Gleason score and clinical T stage. Knockdown of PPP1R14B significantly inhibited the proliferation, migration and invasion abilities of PCa cells, while overexpression of PPP1R14B produced the opposite effect. Mechanistic investigations revealed that PPP1R14B mainly regulates the expression of AR through the JAK2/STAT3 pathway and forms a positive feedback loop with STAT3 to promote the progression of PCa, reduce the sensitivity of tumors to enzalutamide, and accelerate the formation of drug resistance. In addition, genistein, a drug screened through virtual drug prediction and molecular alignment, mainly inhibits the expression of STAT3 by targeting PPP1R14B. Moreover, when combined with STAT3-IN-13, it can more effectively curb the malignant ability of PCa and enhance the sensitivity of tumor cells to enzalutamide. In conclusion, these findings reveal the function and mechanism of PPP1R14B in the progression of PCa and the resistance of enzalutamide, indicating that PPP1R14B is a potential target for the treatment of PCa and the prospect of genistein as a therapeutic drug.
    Keywords:  Enzalutamide resistance; Genistein; JAK2/STAT3; PPP1R14B; Prostate cancer
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112163
  12. J Cancer. 2025 ;16(13): 3928-3941
    Disulfidptosis-Associated CCNB2: A Prognostic Biomarker and Immune Microenvironment Modulator in Prostate Cancer.
    Wei Jiang, Qinghua Wang, Juan Zhou, Yan Zhao, Xin Qin, Xilei Li, Haopeng Li, Licheng Wang, Gang Wu.
      Background Disulfidptosis, a newly recognized form of cell death activated by disulfide bond stress, differs from apoptosis, ferroptosis, cuproptosis, and pyroptosis. Understanding its role in prostate cancer is essential for developing tailored therapeutic approaches for managing this condition. Here, we establish the first disulfidptosis-based molecular subtyping framework for prostate cancer (PCa) and identify CCNB2 as a novel regulator of disulfidptosis, revealing its dual role in apoptosis activation and immune microenvironment remodeling. Methods We used consensus clustering to classify disulfidptosis into different subtypes and to study the unique characteristics linked to each one. We also developed a Dis score to measure the severity of each patient's subtype. We compared immune infiltration, pathway enrichment, and survival differences among the subtypes and revealed that the level of the score is significantly associated with the prognosis of PCa.Subsequently, we used Cytoscape software to further filter out hub genes and investigated how these genes influence the progression of PCa and their potential mechanisms through in vitro and in vivo experiments. Results We identified three molecular subtypes associated with disulfidptosis (Cluster A, B, C) and three gene subtypes (GeneCluster A, B, C). Each subtype exhibited a distinct prognosis, level of immune cell infiltration, and biological pathway activation. Notably, Cluster B and GeneCluster B, characterized by elevated disulfidptosis gene expression, were correlated with favorable prognosis. Additionally, we discovered that patients with higher scores exhibited lower tumor mutational burden (TMB) and improved prognosis. Finally, our experimental results confirmed that downregulation of CCNB2 expression promoted disulfidptosis in prostate cancer cells, thereby inhibiting their migration and proliferation capacities. Conclusion This study demonstrates that disulfidptosis can be utilized to stratify risk in patients with PCa. Furthermore, the CCNB2 gene emerges as a potential therapeutic target for prostate cancer by regulating disulfidptosis, thereby influencing the biological behaviors of PCa cells, including their proliferation and migration.
    Keywords:  CCNB2; Disulfidptosis; Prognosis; Prostate cancer
    DOI:  https://doi.org/10.7150/jca.112791
  13. Bioorg Chem. 2025 Oct 04. pii: S0045-2068(25)00940-X. [Epub ahead of print]165 109060
    Oxadiazole derivatives as potent androgen receptor inhibitors: Design, synthesis, and anticancer evaluation.
    Shubham Kumar, Pankaj Wadhwa.
      Prostate cancer remains one of the most prevalent malignancies worldwide, necessitating the continuous development of novel therapeutic agents. In this study, a series of novel oxadiazole-based compounds (MS01-MS15) were synthesized and evaluated for their anticancer potential against PC-3 prostate cancer cell lines. The MTT assay revealed significant cytotoxic effects, with percentage inhibition reaching up to 97.32 % and IC50 values ranging from 370.37 nM to 838.14 nM. In comparison, the standard drug bicalutamide exhibited an IC50 value of 158.03 nM. Molecular docking studies using Autodock Vina demonstrated strong interactions between the synthesized compounds and the androgen receptor (PDB ID: 1Z95), with binding affinities ranging from -6.5 to -9.0 kcal/mol. Notably, MS14, featuring a fluorine substituent at the para position, emerged as the most potent compound, exhibiting the highest binding affinity (-9.0 kcal/mol) and the lowest IC50 value (370.37 nM). Moreover, ROS production assay and androgen receptor inhibition assay has shown promising results for MS-14 as compared to standard drug. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents, particularly fluorine and chlorine, enhanced the anticancer efficacy, whereas bulkier and electron-donating groups diminished activity. Importantly, validation in androgen-sensitive LNCaP cells confirmed that MS14 retained significant antiproliferative activity, achieving up to 78.2 % inhibition at 1000 nM, thereby supporting its dual AR-dependent and AR-independent modes of action. These findings underscore the potential of oxadiazole derivatives as promising androgen receptor inhibitors for prostate cancer therapy.
    Keywords:  Androgen receptor inhibitors; Cytotoxicity; Molecular docking; Oxadiazole derivatives; Prostate cancer; Structure-activity relationship (SAR)
    DOI:  https://doi.org/10.1016/j.bioorg.2025.109060
  14. Gene. 2025 Oct 06. pii: S0378-1119(25)00608-0. [Epub ahead of print] 149819
    Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.
    Yuelian Fan, Yuping Suo.
      Ovarian cancer (OVCA) is a highly malignant gynecological tumor characterized by a dismal 5-year survival rate that is closely linked to aberrant ferroptosis regulation and lipid metabolic reprogramming. This study integrated bioinformatics analyses of TCGA and The Human Protein Atlas datasets, clinical validation in 30 pairs of OVCA tissues, in vitro functional assays using HO8910 and HEYT30 cell lines, and nude mouse xenograft models to explore the role of suppressor of cytokine signaling 6 (SOCS6) in OVCA prognosis. The results revealed that SOCS6 was significantly downregulated in OVCA tissues and cell lines, and low expression was strongly correlated with poor patient prognosis. Mechanistically, SOCS6 overexpression inhibited cellular proliferation, migration, and invasion and enhanced sensitivity to the ferroptosis inducer erastin. This effect occurs by promoting the ubiquitin-proteasomal degradation of the ferroptosis antagonist SLC7A11, reducing intracellular glutathione (GSH) levels, and augmenting reactive oxygen species (ROS) and Fe2+ accumulation. Additionally, SOCS6 suppressed de novo fatty acid synthesis by downregulating the key enzymes FASN and ACC, leading to decreased triglyceride and phospholipid production. In vivo xenograft experiments confirmed that SOCS6 overexpression inhibited tumor growth and reduced the expression of SLC7A11 and lipid metabolism-related molecules. Collectively, these results establish SOCS6 as a critical molecular hub linking ferroptosis and lipid metabolism in OVCA, highlighting its potential as both a prognostic biomarker and a therapeutic target for improving clinical outcomes in OVCA.
    Keywords:  Ferroptosis; Lipid metabolism; OVCA; SLC7A11; SOCS6
    DOI:  https://doi.org/10.1016/j.gene.2025.149819
  15. Biochem Biophys Res Commun. 2025 Sep 30. pii: S0006-291X(25)01434-2. [Epub ahead of print]786 152718
    A novel Rhein derivative AQ-NC inhibits prostate cancer by suppressing the PI3K/AKT pathway.
    Tingting Yang, Mulan Li, Limei Yang, Mingyu Ji, Zhihong Zhou, Yerong Liu, Dong Ran, Wei Tian, Peilin Yang.
       OBJECTIVE: This research endeavors to explore the anti-prostate cancer (PCa) activity and potential molecular mechanisms of the newly synthesized Rhein derivative AQ-NC.
    METHODS: The CCK-8 test was employed to evaluate the anti-PCa activity of AQ-NC and its lead compound, Rhein. The EdU assay was utilized to assess how AQ-NC impacts the proliferation of PCa cells. The scratch and Transwell assays were carried out to detect the influence of AQ-NC on the migratory capacity of DU-145 and C4-2 cells. Western blot analysis was used to measure the expression of proteins associated with migration. Flow cytometry was applied to detect the effect of AQ-NC on apoptosis in DU-145 and C4-2 cells. Additionally, the expression levels of apoptosis-associated proteins were assessed using Western blot. Mechanistically, potential signaling pathways were predicted by molecular docking and the expression of relevant proteins were verified using Western Blot.
    RESULTS: AQ-NC demonstrated significantly superior cellular activity to Rhein, as determined by the CCK-8 assay. Observations of cell morphology and EdU assays further demonstrated that AQ-NC could suppress the proliferation of PCa cells. Scratch and Transwell assays revealed that AQ-NC effectively hindered the migration of PCa cells. Flow cytometry and Western blot analyses indicated that AQ-NC could trigger apoptosis in PCa cells. Additionally, molecular docking and Western blot results indicated that AQ-NC could suppress the expression of proteins related to p-EGFR, p-PI3K, and p-AKT.
    CONCLUSION: AQ-NC inhibits the proliferation and migration of PCa cells and induces apoptosis, potentially through the inhibition of the PI3K/AKT signaling pathway.
    Keywords:  PI3K/AKT pathway; Prostate cancer; Rhein derivatives
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152718
  16. Cancer Epidemiol Biomarkers Prev. 2025 Oct 10.
    Statin and other antilipemic use and prostate cancer : Results from the EPICAP study.
    Emilie Cordina-Duverger, Pierre-Jean Lamy, Brigitte Trétarre, Florence Menegaux.
       BACKGROUND: Antilipemic drugs have been hypothesized to decrease the risk of several cancers, however results are still conflicting for prostate cancer.
    METHODS: We used data from the EPICAP study, a French population-based case-control study including 819 incident prostate cancer cases and 879 population-based controls frequency matched by age. Detailed information on the use of antilipemic drugs have been collected.
    RESULTS: The use of overall antilipemic drugs was not associated with prostate cancer risk, while the use of statins, and particularly lipophilic statins was inversely associated with high-grade prostate cancer with an ISUP score ≥ 4 (OR=0.52, 95%CI 0.27-1.00, OR=0.30, 95%CI 0.12-0.77, respectively). When taking into account the duration of use, long duration (≥ 10 years) of statin and lipophilic statin were inversely associated to prostate cancer overall (OR=0.69, 95%CI 0.47-1.01, OR=0.54, 95%CI 0.35-0.85, respectively) and to high-grade prostate cancer (OR=0.49, 95% CI 0.24-1.01, OR=0.26, 95%CI 0.09-0.72, respectively).
    CONCLUSIONS: Our results showed an inverse association between high-grade prostate cancer and statins, particularly lipophilic statins and indicated that these associations were more pronounced for long duration.
    IMPACT: In a context of overdiagnosis and overtreatment, identifying factors associated with aggressive prostate cancers is important and could help improving targeted screening strategies.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-25-0919
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