bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2026–02–15
forty-four papers selected by
Grigor Varuzhanyan, UCLA
  1. SOX8/CPT2 axis regulates lipid metabolism to support enzalutamide resistance in prostate cancer.
  2. Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis.
  3. MBD3 increased expression by BRD4 and facilitated castration-resistant prostate cancer cell proliferation by inhibiting PTEN.
  4. Deciphering the eRNA landscape and revealing target aberrant pathways in prostate cancer.
  5. ADT and activation of HGF and WNT axes in double-null prostate cancer.
  6. ALKBH5 Orchestrates Ferroptosis-Driven Tumor Suppression: An LLM-Powered Discovery in Prostate Cancer.
  7. IL-6/STAT3 signaling in prostate cancer: CAF-driven immune evasion and therapeutic opportunities.
  8. Prostate Cancer-Associated Fibroblasts: A Review on CAF Functions, Heterogeneity, Resistance Mechanisms, and Future in a Chip.
  9. Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer.
  10. ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.
  11. Phytol Suppresses Androgen Receptor Nuclear Localization and Doubles Survival in Nude Mice Bearing Castration-Resistant Prostate Cancer Xenografts.
  12. Ectopic FGFR1 Increases Intracellular Pool of Cholesterol in Prostate Cancer Cells.
  13. A Combination of Xanthohumol and Ursolic Acid in the Diet Leads to Synergistic Inhibition of Prostate Cancer Progression.
  14. Dynamic Shifts in ER-Plasma Membrane Junctions Signaling Define Pro-Metastatic N-Glycosylation and Predict Prostate Cancer Progression.
  15. Palmitoylation-related gene expression and its prognostic value in prostate cancer: insights into immune infiltration and therapeutic potential.
  16. Tumor-responsive PEGylated mesoporous nanoparticles achieve enhanced chemotherapy and reduced toxicity in prostate cancer.
  17. Immunohistochemical Evidence of Telocytic Stroma Associated with Tumor Grade and Acinar Heterogeneity in Prostate Cancer.
  18. Cytosine Deaminase-TRAIL Expressing Human Adipose Stem Cells Inhibit Tumor Growth in Castration Resistant Prostate Cancer Bearing Mice with Less Toxicity.
  19. Snail1 Induced Suppression of Proliferation via EGR1, FOXO1, and CEPBγ Creates a Vulnerability for Targeting Apoptotic and Cellular Senescence Pathways.
  20. METTL3 facilitates the malignant progression of prostate cancer by inhibiting GDF15-mediated ferroptosis via a YTHDF1-dependent m6A mechanism.
  21. Mechanistic Language Modeling and Oxygenated 3D Screening Reveal Berberine and Enzalutamide Synergy in Resistant Prostate Cancer.
  22. SSTDhunter: a curated gene database for investigating androgen producing potential in microbiota species.
  23. Clinical implication of immune check point inhibitors in advanced prostate cancer: insight from the KEYNOTE-991 trial.
  24. Structure-guided design and evaluation of oxazolone-based PIM-1 kinase inhibitors with promising anticancer activity.
  25. A case report of small-cell carcinoma of the prostate with ectopic adrenocorticotropic-hormone (ACTH) syndrome and hypokalemia.
  26. Report of the Advanced Prostate Cancer Consensus Conference-JAPAN 2025 at the 112th Annual Meeting of the Japanese Urological Association.
  27. Prostate Cancer: Dissecting Novel Immunosuppressive Mechanisms Through Context-Specific Transcriptomic Programs and MDSC Cells.
  28. Targeting FANCD2 to overcome enzalutamide resistance in prostate cancer.
  29. A prostate-specific membrane antigen targeted small molecule-drug conjugate for efficient prostate cancer therapy at a low dosage.
  30. Tumor control probability analysis in carbon-ion radiotherapy for prostate cancer considering the oxygen effect.
  31. Cardiovascular and prostate cancer risk associated to testosterone replacement therapy - a systematic review and meta-analysis of 41 randomized controlled trials.
  32. Low Testosterone Levels and Grade Group Progression Among Localized Prostate Cancer Patients on Active Surveillance: A Retrospective Cohort Study.
  33. ProstNFound+: A Prospective Study using Medical Foundation Models for Prostate Cancer Detection.
  34. Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer.
  35. Retraction: Molecular mechanism of inhibitory effects of melatonin on prostate cancer cell proliferation, migration and invasion.
  36. RETRACTION: Combined Anticancer Effects of Simvastatin and Arsenic Trioxide on Prostate Cancer Cell Lines via Downregulation of the VEGF and OPN Isoforms Genes.
  37. Development of Prostate-Specific Lysosome-Targeting Degraders.
  38. Cardiac Function and Prostate Cancer Risk and Prognosis: The PROCA-Life Study.
  39. Patient awareness and perspectives regarding the value of focal therapy for localized prostate cancer: A cross-sectional study.
  40. Optimizing prostate cancer stereotactic body radiotherapy: margins, dose, or target volume-de-intensification?
  41. FAM64A Potentiates Bladder Carcinoma Tumorigenesis and Metastasis Through PI3K/mTORC2/AKT Pathway Activation.
  42. Integrative dual ctDNA 5mC/5hmC methylomics and clonal reconstruction infer tumor transcription and resistance phenotypes in metastatic prostate cancer.
  43. Epigenetic and Liquid Biopsy Biomarkers in Prostate Cancer: Bridging Tumor Heterogeneity and Clinical Implementation.
  44. A mechanical reprogramming: synergistic tumor microenvironment normalization improves nano-immunotherapy delivery in prostate cancer via multiphysics modeling.
  1. Cancer Cell Int. 2026 Feb 10.
    SOX8/CPT2 axis regulates lipid metabolism to support enzalutamide resistance in prostate cancer.
    Songsong Liu, Dingyong Zhang, Chao Jiang, Xin Chen, Liang Jin, Shiyong Xin, Xianchao Sun.
       BACKGROUND: Although androgen receptor (AR)-targeted therapies have shown notable clinical efficacy in prostate cancer (PCa), the emergence of drug resistance remains a critical factor driving the clinical prognosis in castration-resistant prostate cancer (CRPC). Aberrant tumor lipid metabolism not only fulfills the energetic and biosynthetic requirements of rapidly proliferating cancer cells but also contributes to the development of therapeutic resistance.
    METHODS: We examined SOX8 expression in enzalutamide resistance (EnzR) cell lines and validated its association with tumor progression and clinical outcome. The malignant phenotypes related to EnzR were assessed in vitro using PCa cell lines with stable SOX8 overexpression or knockdown. Tumor xenografts were subsequently generated by inoculating the corresponding cell lines into nude mice. To elucidate the underlying mechanisms, we conducted RNA-seq, CUT&Tag, non-targeted metabolomics, and a series of molecular and biochemical assays.
    RESULTS: SOX8 expression was elevated in EnzR prostate cancer cell lines and positively correlated with poor patient prognosis. Reduced SOX8 expression enhanced cellular sensitivity to enzalutamide, whereas elevated SOX8 expression decreased drug responsiveness. Chromatin immunoprecipitations (ChIP) assays revealed that AR was enriched at the SOX8 promoter region and transcriptionally repressed SOX8. In vivo, stable SOX8 knockdown markedly suppressed tumor growth in nude mouse xenografts. Mechanistically, SOX8 promotes the EnzR by reprograming lipid metabolism and we identified carnitine palmitoyltransferase 2 (CPT2), a key enzyme in lipid metabolism, as a novel downstream target of SOX8. SOX8-driven lipid metabolic reprogramming promoted enzalutamide resistance through the SOX8/CPT2 axis.
    CONCLUSIONS: High SOX8 expression promotes EnzR in PCa, suggesting SOX8 as a potential therapeutic target. Our findings demonstrate that SOX8 drives EnzR by activating the SOX8/CPT2 axis, thereby inducing lipid metabolic reprogramming in PCa cells.
    Keywords:  CPT2; Enzalutamide resistance; Lipid metabolism; Prostate cancer; SOX8
    DOI:  https://doi.org/10.1186/s12935-026-04215-4
  2. Prostate. 2026 Feb 10.
    Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis.
    Lai Wei, Ziwei Wang, Dajun Gao, Jianchao Ge, Xiaomin Chen, Huan Xu, Bin Xu.
       BACKGROUND: The progression of prostate cancer (PCa) to a castration-resistant state (CRPC) remains a major clinical challenge. Resistance to second-generation androgen receptor (AR) antagonists like enzalutamide often involves the reactivation of AR signaling, frequently through intratumoral androgen synthesis. The molecular drivers that regulate this adaptive resistance mechanism are not fully understood. GPR133 (also known as ADGRD1) is an adhesion G protein-coupled receptor with emerging roles in various cancers, but its function in prostate cancer is unknown. While androgen signaling is classically mediated by the nuclear AR, GPR133 has recently been identified as a novel membrane androgen receptor, though its functional relationship with the AR pathway in prostate cancer is unknown.
    METHODS: We analyzed GPR133 expression in patient-derived PCa tissues and its correlation with clinical outcomes using publicly available datasets and our patients' samples. We employed gain- and loss-of-function approaches in vitro to test whether GPR133 specifically mediates resistance to enzalutamide. RNA sequencing was used to identify downstream pathways regulated by GPR133. The role of the downstream effector HSD3B1 was assessed using siRNA-mediated silencing. The therapeutic implications of GPR133 expression were validated in vivo using xenograft mouse models.
    RESULTS: GPR133 expression is significantly downregulated in prostate cancer tissue compared to benign tissue and is further decreased in CRPC. Low GPR133 expression correlates with poorer disease-free survival. Silencing GPR133 conferred robust resistance to enzalutamide in vitro and in vivo. Conversely, overexpression of GPR133 could further sensitize cancer cells to enzalutamide. Mechanistically, loss of GPR133 transcriptionally upregulated key enzymes in the steroid hormone biosynthesis pathway, most notably HSD3B1. This upregulation led to elevated intracellular testosterone levels and sustained androgen receptor (AR) signaling, characterized by the persistent expression of AR target genes despite enzalutamide treatment. Silencing HSD3B1 reversed the enzalutamide resistance induced by GPR133 knockdown.
    CONCLUSIONS: Our findings identify GPR133 as a novel tumor suppressor in prostate cancer. Loss of GPR133 expression is a key event in the progression to CRPC that promotes therapeutic resistance by activating the intratumoral androgen synthesis pathway. GPR133 may serve as a valuable prognostic biomarker and a potential therapeutic target for advanced prostate cancer.
    Keywords:  GPR133; HSD3B1; castration resistant prostate cancer; enzalutamide resistance; intratumoral androgen synthesis
    DOI:  https://doi.org/10.1002/pros.70138
  3. Discov Oncol. 2026 Feb 09.
    MBD3 increased expression by BRD4 and facilitated castration-resistant prostate cancer cell proliferation by inhibiting PTEN.
    Liangming Pan, Jianliang Shen, Zhi Li, Guilin Xie, Cong Chen, Xi Chen.
      Prostate cancer (PCa) is the most prevalent malignancy among men with a rising mortality rate. Androgen deprivation therapy (ADT) effectively treats PCa. However, patients inevitably progress to castration-resistant prostate cancer (CRPC). There are still no effect methods for treating CRPC. The underlying mechanisms driving CRPC remain unclear. Methyl-CpG binding domain protein 3 (MBD3), a key member of the methyl-CpG binding protein family, exhibits high expression in lots of cancers. Here, we tried to find the mechanism of MBD3 in causing CRPC. We collected RNA-sequence data of PCa patients from public databases and collected CRPC samples from Tongji Hospital. Then, the expression of MBD3 in PCa samples was detected. By overexpression or knockdown MBD3, the role of MBD3 in affecting PCa cells proliferation was detected in vivo and vitro. Using public databases data, PCR, western blot and ChIP-qPCR experiments, the mechanism of MBD3 leading to PCa was analyzed. This study revealed that MBD3 is upregulated in both PCa and CRPC samples from public databases and clinical samples. Elevated MBD3 expression promotes CRPC cell proliferation by epigenetically silencing the tumor suppressor gene phosphatase and tensin homolog (PTEN). Furthermore, MBD3 is transcriptionally regulated by bromodomain-containing protein 4 (BRD4), and MBD3 knockdown enhances the sensitivity of CRPC cells to BET inhibitors. These findings suggest that the BRD4-MBD3-PTEN axis is a new pathway in CRPC, with MBD3 representing a potential therapeutic target, particularly in combination with BET inhibitors.
    Keywords:  BRD4; CRPC; Cell proliferation; MBD3; PTEN
    DOI:  https://doi.org/10.1007/s12672-026-04628-7
  4. BMC Cancer. 2026 Feb 10.
    Deciphering the eRNA landscape and revealing target aberrant pathways in prostate cancer.
    Chengling Yu, Yong Wen, Yanguo Li, Baiyang Song, Yiwei Hu, Zixing Meng, Zejun Yan, Wei Du, Hao Rong.
       BACKGROUND: Enhancer RNAs (eRNAs) have emerged as important regulators of gene expression and may reshape the therapeutic landscape of prostate cancer. However, their global landscape and clinical relevance in prostate cancer remain unclear.
    METHODS: We systematically integrated prostate cancer multi-omics and functional genomics datasets to characterize genome-wide eRNA transcription, construct eRNA-centered regulatory networks, and link eRNA-regulated genes to clinical outcomes. Representative eRNAs and their predicted target genes were further subjected to siRNA-mediated knockdown and functional validation in prostate cancer cell lines.
    RESULTS: We identified 13,595 eRNAs and 1,573 eRNA-regulated genes, including 266 transcription factors and 85 RNA-binding proteins. eRNA-regulated genes showed higher expression levels, lower variability, and enrichment in prostate cancer-related pathways. A five-gene eRNA-associated signature stratified patients into high- and low-risk groups with AUCs of 0.85, 0.77, and 0.89 for 1-, 3-, and 5-year survival and remained an independent prognostic factor. The two risk groups exhibited distinct genetic, transcriptomic, and epigenetic features. Functional validation further demonstrated that knockdown of representative eRNAs suppressed prostate cancer cell proliferation, migration, and invasion, accompanied by reduced expression of the target genes NUP93 and BICD1.
    CONCLUSION: These findings indicate that eRNAs may contribute to prostate cancer biology and could serve as useful markers for prognosis and pathway characterization.
    Keywords:  Enhancer RNA; Non-coding RNA; Prostate cancer; Regulated network
    DOI:  https://doi.org/10.1186/s12885-026-15675-2
  5. Nat Rev Urol. 2026 Feb 09.
    ADT and activation of HGF and WNT axes in double-null prostate cancer.
    Dexter Hoi Long Leung, Yao Mawulikplimi Adzavon, Gaeul Chu, Tae Ju Park, Kristoffer Nikias, Cheong-Wun Kim, Chenmiao Liu, Zijie Sun.
      Prostate cancer remains the most frequently diagnosed malignancy in men worldwide. Most primary prostate cancer cells express the androgen receptor (AR) and rely on androgens for oncogenic growth and progression. Thus, androgen deprivation therapy (ADT) that directly targets AR-expressing prostate cancer cells has been the frontline treatment for advanced prostate cancer. However, ADT inevitably fails in most patients, resulting in castration-resistant prostate cancer development. To inhibit reactivation of AR-promoted tumour progression via residual androgens and altered AR activation, next-generation AR antagonists and inhibitors of androgen biosynthesis were developed to improve clinical outcomes. However, these therapeutic advances also induce heterogeneous resistance phenotypes. Among them, double-null prostate cancer, featuring AR-null and neuroendocrine-null cell properties, occurs in patients treated with abiraterone and enzalutamide. Emerging clinical and experimental evidence demonstrates that current ADT induces HGF and canonical WNT signalling activation, which further elevates nuclear exporting and ribosomal biogenesis to foster tumour lineage plasticity and promote diverse castration-resistant prostate cancer phenotypes and double-null prostate cancer development. These mechanistic insights remain under active investigation, but they provide therapeutic prospects for co-targeting nuclear exporting, ribosomal biosynthesis and other oncogenic pathways in combination with current ADT to forestall the lethal disease.
    DOI:  https://doi.org/10.1038/s41585-026-01129-8
  6. Mol Ther. 2026 Feb 06. pii: S1525-0016(26)00088-2. [Epub ahead of print]
    ALKBH5 Orchestrates Ferroptosis-Driven Tumor Suppression: An LLM-Powered Discovery in Prostate Cancer.
    Xianyanling Yi, Zeyu Han, Dazhi Lu, Hang Xu, Xiaonan Zheng, Yaxiong Tang, Jin Li, Xuanji Li, Dazhou Liao, Hong Li, Qiang Wei, Lu Yang, Jiajie Peng, Jianzhong Ai.
      The treatment of prostate cancer (PCa) continues to pose substantial clinical challenges. The use of large language models (LLMs) to identify the key molecular determinants of PCa progression, followed by experimental biological validation, helps uncover novel therapeutic targets. We developed hierarchical knowledge-guided LLM for risk gene identification (HKLLM-RG), a PCa risk gene identification method. Among the candidate genes identified, ALKBH5 emerged as particularly noteworthy in the analysis. Reduced expression of ALKBH5 correlated with aggressive clinical features and significantly reduced survival in PCa. ALKBH5 inhibits PCa progression and promotes ferroptosis. CHRM3, which is the downstream molecule of ALKBH5, could promote PCa cell proliferation and migration. ALKBH5 regulates CHRM3 in an m6A-dependent manner. Mechanistically, the ALKBH5/CHRM3 axis suppresses AKT signaling, thereby inducing the upregulation of the transcriptional repressor ZNF281. This regulatory cascade subsequently downregulates the expression of SLC3A2 and GPX4, ultimately sensitizing cells to ferroptosis. Thus, AZD5363 and RSL3 targeting the ALKBH5/CHRM3/ZNF281 axis can effectively synergize to treat PCa by promoting ferroptosis. Taken together, this study leverages LLM-guided discovery to delineate a novel ALKBH5/CHRM3/ZNF281 regulatory axis controlling ferroptotic susceptibility in PCa. Importantly, a synergistic therapeutic strategy was identified by combining RSL3 with AZD5363, providing novel therapeutic targets and directions for PCa treatment.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.02.003
  7. Front Immunol. 2025 ;16 1736606
    IL-6/STAT3 signaling in prostate cancer: CAF-driven immune evasion and therapeutic opportunities.
    Tao Zhou, Yuqi Li, Zhiyu Liu, Zhiqiang Zeng, Tao Li, Li Chen, Huan Zhao, Xiaochun Wu, Yuxuan Shen, Haitao Fan, Xiaoxiao Zhu, Yubo Zhou, Lunhong Zou, Dan Zhao.
      Interleukin-6 (IL-6) plays a pivotal regulatory role in prostate cancer progression, contributing to therapy resistance and reshaping of the tumor microenvironment. This review outlines the clinical relevance of IL-6 as a potential prognostic biomarker and describes its mechanistic involvement in the development of castration resistance, with emphasis on its interplay with distinct cancer-associated fibroblast (CAF) subtypes. Elevated serum IL-6 levels in metastatic castration-resistant prostate cancer are associated with poor responses to docetaxel, enzalutamide, or abiraterone, and correlate with worse prognosis. Mechanistically, IL-6 promotes neuroendocrine differentiation and sustains cell survival under therapeutic stress through activation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and androgen receptor signaling pathways. Recent single-cell studies reveal that prostate CAFs are highly heterogeneous. Certain subtypes are linked to extracellular matrix remodeling and fibrosis, while others exhibit inflammatory or immune-modulatory characteristics, differentially influencing tumor evolution. Specific CAF subsets have been strongly implicated in promoting castration resistance and adverse outcomes. Therapeutic strategies targeting the IL-6/IL-6R axis-such as neutralizing antibodies, advanced chimeric antigen receptor (CAR)-T designs, and combination regimens-are under active investigation. Simultaneously, modulating CAF plasticity to convert tumor-promoting phenotypes into tumor-restraining ones represents a promising therapeutic avenue. A deeper understanding of IL-6 functions across CAF subtypes may unlock novel precision therapy opportunities for prostate cancer.
    Keywords:  cancer-associated fibroblasts; interleukin-6; prostate cancer; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1736606
  8. Int J Mol Sci. 2026 Feb 05. pii: 1585. [Epub ahead of print]27(3):
    Prostate Cancer-Associated Fibroblasts: A Review on CAF Functions, Heterogeneity, Resistance Mechanisms, and Future in a Chip.
    Nikolett Lupsa, Erika Heninger, Adeline B Ding, Cristina Sanchez De Diego, Katherine Vietor, Shannon R Reese, Aaron M LeBeau, David Kosoff, David J Beebe, Sheena C Kerr, Joshua M Lang.
      Cancer-associated fibroblasts (CAFs) are key regulators of the prostate tumor microenvironment (TME) with influence on disease progression and therapeutic response. CAFs originate from multiple precursors and retain remarkable plasticity while tumors evolve. Therefore, the CAF pool displays considerable functional heterogeneity, which is well-reflected in complex molecular signatures. However, overlapping biomarker patterns with other stromal subsets make it challenging to identify and assess the role of specific CAF subpopulations. Through reciprocal tumor-stroma interactions, CAFs promote extracellular matrix (ECM) remodeling, angiogenesis, metabolic reprogramming, and immune evasion, collectively fostering an adaptive niche that supports tumor survival, though some CAF subsets have been shown to support anti-tumor response. In prostate cancer (PCa), CAFs promote resistance to androgen receptor pathway inhibitor therapy, chemotherapy, and radiotherapy, emphasizing their potential value as therapeutic targets. However, CAF targeting has shown limited clinical benefit in PCa, due to complex, context-dependent CAF functions that make it challenging to exploit this unique stromal population for therapeutic gain. Recent advances in organ-on-a-chip (OOC) models offer new opportunities to investigate the mechanisms behind TME interactions and evaluate CAF-targeted strategies in physiologically relevant fully humanized environments. This review provides current insights into CAF heterogeneity and therapy resistance in PCa and highlights emerging translational OOC models to guide the development of more effective therapies to disrupt the TME.
    Keywords:  CAF heterogeneity; cancer associated fibroblasts; organ-on-a-chip models; prostate cancer; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27031585
  9. J Enzyme Inhib Med Chem. 2026 Dec;41(1): 2622725
    Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer.
    Shuai Liu, Yongfeng Lao, Long Cheng, Xi Xiao, Longtu Ma, Wenyun Wang, Kun Zhao, Wenxuan Li, Zhongze Zhou, Qingchao Li, Yan Tao, Shanhui Liu, Zhilong Dong.
      Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly expressed in various cancers and promotes malignant progression, yet its role in DTX resistance in prostate cancer remains unclear. In this study, bioinformatics analyses and in vitro/vivo experiments demonstrated that interfering with PYCR1 expression modulates the sensitivity of prostate cancer cells to DTX. Subsequently, via structure-based virtual screening, molecular dynamics simulations, and cellular thermal shift assay (CETSA), emodin-an anthraquinone compound-was identified as a PYCR1-targeting agent. Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through in vitro experiments.
    Keywords:  Docetaxel; PYCR1; emodin; prostate cancer; virtual screening
    DOI:  https://doi.org/10.1080/14756366.2026.2622725
  10. Cell Mol Life Sci. 2026 Feb 09. 83(1): 103
    ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.
    Ping Liu, Baozhen Wang, Hui Liu, Long Liu, Feifei Sun, Pinpin Sui, Jing Hu, Lin Gao, Bo Han.
      Although androgen receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Mechanistically, ZNF711 directly bound to the AR promoter, transcriptionally upregulating AR expression. ZNF711 knockdown markedly reduced AR chromatin occupancy at target loci. Additionally, ZNF711 formed a complex with BMI1 and AR, enhancing AR signaling pathway by suppressing CpG methylation at the promoter of AR and its downstream target genes (e.g., KLK3, TMPRSS2), thereby potentiating AR transcriptional activity. Notably, targeting ZNF711 with antagonistic chimeric siRNA restored enzalutamide sensitivity in vivo. Collectively, our findings establish ZNF711 as a critical regulator of ENZR that promotes resistance by dually modulating the AR signaling pathway via transcriptional activation and epigenetic demethylation. Targeting the ZNF711-AR axis represents a novel therapeutic strategy to overcome ENZR in prostate cancer.
    Keywords:  AR; BMI1; Enzalutamide resistance prostate cancer; Transcriptional regulation; ZNF711
    DOI:  https://doi.org/10.1007/s00018-026-06092-6
  11. Phytother Res. 2026 Feb 08.
    Phytol Suppresses Androgen Receptor Nuclear Localization and Doubles Survival in Nude Mice Bearing Castration-Resistant Prostate Cancer Xenografts.
    Wasia Showket, Dar Murtaza, Tasmeen J Parihar, Suhail Ashraf, Zahoor A Dar, Syed Inam-Ul-Haq, Imtiyaz A Bhat, Mohd Afsahul Kalam, Taha Mukhtar, Javeed A Mugloo, M Iqbal Yatoo, Nazir A Ganai, Khalid Z Masoodi.
      Androgen receptor (AR) plays a pivotal role in the development and progression of prostate cancer by regulating the expression of androgen-responsive genes. AR must translocate into the nucleus to exert its gene-regulatory functions. Disruption in AR nuclear localization or its cytoplasmic retention hampers its ability to activate target genes, thus impeding prostate cancer progression. Taraxacum officinale (dandelion) is a medicinal herb with potent anticancer properties, rich in antioxidants, flavonoids, and nutrients, dandelion serves as a promising herbal nutraceutical and superfood for cancer prevention. The study aimed to explore plant-based molecules from Taraxacum officinale (dandelion) capable of modulating AR nuclear localization in recurrent prostate cancer cells in vitro and in vivo. 400 plants were collected and 25,000 extracts were prepared using solvents of varying polarity (Indian Patent Grant No. 499495) and were screened for abrogation of Nuclear-cytoplasmic localization of AR. Phytochemical screening led to the isolation of Phytol (3,7,11,15-tetramethylhexadec-2-en-1-ol) (TaxO) from the hexane extract of Taraxacum officinale L leaves. The effects of TaxO was evaluated in vitro using the castration-resistant prostate cancer cell line C4-2, androgen-responsive cell line LNCaP, and AR-negative cell line PC3. Expression of AR and androgen-responsive genes, including EAF2, PSA, and CALR, were analyzed via RT-PCR. Inhibition of cellular proliferation and migration was assessed in vitro. Comparative transcriptomic analysis (RNA-Seq) was conducted to elucidate the mechanistic differences between treated and control groups. Molecular docking studies were conducted to evaluate interactions between TaxO and the AR ligand-binding domain. Finally, in vivo efficacy was examined using C4-2, LNCaP and PC3 xenograft mouse models, including immunohistochemistry (IHC) for AR, Ki67, CD31, and PSA. PK/PD analysis was carried out to assess the safety profile of TaxO. TaxO abrogated nuclear localization of GFP-tagged AR. TaxO significantly downregulated AR-responsive gene expression, EAF2, ELL2, PSA, and CALR and inhibited cell proliferation and migration of C4-2 and LNCaP cells. Transcriptomic profiling revealed major alterations in oncogenic signaling pathways post-TaxO treatment. Molecular docking confirmed strong binding between TaxO and the AR ligand-binding domain, driven by van der Waals forces and hydrogen bonding. In the xenograft model, TaxO markedly reduced tumor volume and doubled the life expectancy of mice harboring C4-2 and LNCaP prostate cancer cells. IHC revealed downregulation of AR and PSA levels and showed a reduction in Ki67 and CD31 index. However, PC3 cells were not affected by TaxO implicating that TaxO inhibits cancer cell growth through the AR-mediated pathway. The study demonstrates that TaxO, a phytochemical (Phytol) isolated from the hexane extract of Taraxacum officinale leaves, effectively modulates androgen receptor (AR) nuclear localization, thereby inhibiting prostate cancer progression. In vitro, TaxO significantly downregulated AR and androgen-responsive gene expression (EAF2, ELL2, PSA, CALR), reduced cell proliferation and migration in AR-positive C4-2 and LNCaP cell lines but showed no effect on AR-negative PC3 cells, indicating an AR-mediated mechanism. Transcriptomic analysis revealed disruptions in oncogenic signaling pathways, while molecular docking confirmed TaxO's strong binding to the AR ligand-binding domain. In vivo, TaxO reduced tumor volume, downregulated AR, PSA, Ki67, and CD31 protein expression, and doubled life expectancy in C4-2 and LNCaP xenograft mouse models. Pharmacokinetic and pharmacodynamic analyses further supported TaxO's favorable safety profile. These findings highlight TaxO as a promising plant-based therapeutic candidate for targeting AR-driven prostate cancer, warranting further clinical investigation.
    Keywords:  Taraxacum officinale L.; androgen responsive genes; castration resistant prostate cancer (CRPC); functional food; xenograft model
    DOI:  https://doi.org/10.1002/ptr.70115
  12. Int J Mol Sci. 2026 Jan 24. pii: 1190. [Epub ahead of print]27(3):
    Ectopic FGFR1 Increases Intracellular Pool of Cholesterol in Prostate Cancer Cells.
    Ziying Liu, Yuepeng Ke, Tingting Hong, Kennedy Smith, Peter Davies, Yun Huang, Dekai Zhang, Sanjukta Chakraborty, Yubin Zhou, Fen Wang.
      Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis.
    Keywords:  cholesterol; fibroblast growth factor; low-density lipoprotein; prostate cancer; sterol regulatory element-binding protein 2
    DOI:  https://doi.org/10.3390/ijms27031190
  13. Mol Carcinog. 2026 Feb 10.
    A Combination of Xanthohumol and Ursolic Acid in the Diet Leads to Synergistic Inhibition of Prostate Cancer Progression.
    Rachel Clark, Achinto Saha, G Lavender Hackman, Chelsea A Friedman, Ruggiero Gorgoglione, Stefano Tiziani, John DiGiovanni.
      Prostate cancer (PCa) is the second most common cancer and second leading cause of cancer death for American men. Chemoprevention by using phytochemicals offers a promising approach to improve outcomes due to their ability to act on cancer cell metabolism and growth while maintaining low toxicity profiles. The goal of this study was to assess the combination of xanthohumol (XAN) and ursolic acid (UA) given in the diet for synergistic efficacy against PCa progression and identify potential mechanisms of action. PCa cells were treated with the combination to evaluate cell survival and colony formation. Two mouse models of PCa were used to evaluate tolerability and efficacy of dietary administration of the combination and to further understand mechanism(s) of action. The combination of XAN + UA reduced PCa cell survival and colony formation. The combination given in the diet significantly and synergistically inhibited growth of HMVP2 PCa allograft tumors and also inhibited PCa progression in HiMyc mice. Mechanistically, inhibition of polyamine synthesis and epithelial-to-mesenchymal transition contributed to the inhibition of HMVP2 allograft tumor growth, while the inhibition of PCa progression in HiMyc mice was associated with activation of the unfolded protein response pathway and apoptosis. Further studies in cultured PCa cells revealed additional effects of the combination on several oncogenic signaling pathways (e.g, phospho-STAT3) and cell cycle regulatory proteins (e.g, cyclin D1, phospho-Rb).
    Keywords:  HiMyc mice; chemoprevention; oncogenic signaling; polyamine synthesis
    DOI:  https://doi.org/10.1002/mc.70087
  14. Adv Sci (Weinh). 2026 Feb 12. e22885
    Dynamic Shifts in ER-Plasma Membrane Junctions Signaling Define Pro-Metastatic N-Glycosylation and Predict Prostate Cancer Progression.
    Amanda J Macke, Tania Kamal, Taylor E Divita, Artem N Pachikov, Chad A LaGrange, Rajesh Ravichandran, Martha Morton, Robert Powers, Haowen Qiu, Jean-Jack M Riethoven, Colm Morrissey, Melinda Wojtkiewicz, Rebekah L Gundry, Carol A Casey, Armen Petrosyan.
      Prostate cancer (PCa) is the second most common and a leading cause of cancer-related deaths among men. Current screening methods lack precision in distinguishing aggressive cases, emphasizing a need for tissue-based biomarkers. Although Golgi disorganization, ER stress, and elevated high-mannose (Man) glycoproteins (e.g., Integrin αv, key metastatic player) are recognized features of metastatic prostate tumors, their interrelationships remain unexplored. It is observed that the growth of primary prostate tumors is linked to an increase in endoplasmic reticulum (ER)-plasma membrane (PM) junctions signaling, mediated by STIM1 and ORP5. However, transition to lymph node and tissue metastasis is associated with their downregulation, loss of ER-PM communications, significant Golgi dispersal, and rapid conversion of high-Man glycans in the Golgi to atypical MGAT5-modified sugars that facilitate Integrin αv clustering at the PM via Galectin-3 binding. Golgi dispersal is associated with increased organelle volume and surface area to accommodate heightened trafficking and processing. These findings position STIM1 and ORP5 as biomarkers of aggressive PCa and show that high-Man enrichment is not due to defective maturation but reflects a glycan pool that cancer cells actively utilize, suggesting that the concept of ER stress response in PCa should be redefined to include Golgi reorganization and altered ER-PM junctions.
    Keywords:  endoplasmic reticulum‐Plasma membrane junctions; golgi disorganization; high‐Mannose glycans; integrins; metastasis; prostate cancer
    DOI:  https://doi.org/10.1002/advs.202522885
  15. Transl Androl Urol. 2026 Jan 31. 15(1): 13
    Palmitoylation-related gene expression and its prognostic value in prostate cancer: insights into immune infiltration and therapeutic potential.
    Mingchao Wang, Yiming Ding, Lei Gao.
       Background: Prostate cancer (PRAD/PCa) is a leading malignancy in men, with high incidence and mortality rates globally. Although treatments like androgen deprivation therapy (ADT) and chemotherapy have advanced, the prognosis for advanced or metastatic PCa remains unfavorable. Post-translational modifications (PTMs), particularly protein palmitoylation, have emerged as critical regulators of cancer progression and potential therapeutic targets. This study investigates the features of palmitoylation-related genes (PRGs) in PRAD, their links to immune infiltration, and potential therapeutic applications.
    Methods: RNA-seq data and clinical information for PRAD were sourced from The Cancer Genome Atlas (TCGA), Deutsches Krebsforschungszentrum (DKFZ), Memorial Sloan Kettering Cancer Center (MSKCC), Gene Expression Omnibus (GEO), ArrayExpress, PCaProfiler, and PCaDB. Palmitoylation scores were calculated using the single-sample gene set enrichment analysis (ssGSEA) method. A prognostic model was developed based on characteristic genes from single-cell RNA sequencing (scRNA-seq) and validated in multiple external datasets. An integrative machine learning approach combining ten algorithms was used to construct a PRG signature. Potential drug sensitivity was analyzed using the oncoPredict R package, and experimental validation was performed on human prostate samples and PRAD cell lines.
    Results: Significant variations in palmitoylation scores were observed across different PRAD patient types and cell populations. Higher palmitoylation scores were associated with poorer biochemical recurrence (BCR)-free survival in the TCGA dataset. The developed prognostic signature demonstrated significant differences in BCR among patients stratified by risk score. Patients with elevated risk scores demonstrated advanced clinical features such as increased age, advanced tumor stage, lymph node metastasis, elevated prostate-specific antigen (PSA) levels, higher Gleason scores, and BCR. Transcriptomic analysis identified unique gene expression profiles and pathway activities between high- and low-risk groups, with the high-risk group exhibiting heightened activation of oncogenic and immune-related pathways. PRG risk scores significantly impacted the immune landscape, with the high-risk group showing elevated immune checkpoint expression [e.g., programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1)] and a more immunosuppressive microenvironment. Drug response analysis indicated that patients with different risk scores may respond differently to chemotherapy, with significant differences in the half-maximal inhibitory concentration (IC50) values for common chemotherapeutic agents. Functional importance and validation of hub genes, including cholinergic receptor nicotinic alpha 2 subunit (CHRNA2), supported their potential as therapeutic targets. Experimental validation of CHRNA2 knockdown in PRAD cells demonstrated significant inhibition of cell growth, migration, and invasion.
    Conclusions: This study underscores the prognostic importance of PRG expression in PRAD, linking it to tumor biology, immune infiltration, and treatment response. Targeting palmitoylation pathways may offer novel therapeutic opportunities for improving patient outcomes in PRAD. Future research should aim to clarify the molecular mechanisms of palmitoylation in PRAD and investigate its therapeutic potential through preclinical and clinical studies.
    Keywords:  Prostate cancer (PRAD/PCa); immune infiltration; palmitoylation; prognostic signature; therapeutic potential
    DOI:  https://doi.org/10.21037/tau-2025-477
  16. Int J Pharm X. 2026 Jun;11 100492
    Tumor-responsive PEGylated mesoporous nanoparticles achieve enhanced chemotherapy and reduced toxicity in prostate cancer.
    Yangyang Song, Xue Tan, Kai Yu, Yue Wang, Jixue Wang.
      Docetaxel (DTX) remains the first-line chemotherapeutic for advanced prostate cancer, however, its therapeutic efficacy remains limited by poor aqueous solubility, rapid systemic clearance, and severe dose-dependent toxicity. To overcome these constraints, we developed a PEGylated, disulfide-bridged hierarchical mesoporous silica nanocarrier (PEG-HMS) as a redox-sensitive delivery system for DTX (PEG-HMS-DTX). The nanostructure was fabricated by integrating disulfide-containing organosilanes into the silica framework and conjugating thiol-reactive PEG chains, thereby combining long circulation stability with tumor-selective release. Comprehensive physicochemical characterization confirmed uniform spherical morphology, an optimal hydrodynamic size (∼40-50 nm), attenuated surface charge following PEGylation, and high colloidal stability in physiological media, while disulfide linkages enabled responsive structural changes under reductive conditions. Drug release was minimal under physiological conditions (<30% at 72 h) but markedly accelerated in the presence of glutathione (∼60% at 72 h). Compared with free DTX or non-PEGylated carriers, PEG-HMS-DTX exhibited stronger cellular uptake and enhanced cytotoxicity in RM-1 prostate cancer cells. In tumor-bearing mice, PEG-HMS-DTX achieved superior tumor accumulation (peak at ∼12 h), pronounced tumor growth inhibition (>70%), minimal systemic toxicity, and elevated apoptosis characterized by increased cleaved caspase-3 and reduced PCNA/Bcl-2 expression. Collectively, this "stable-in-circulation, trigger-in-tumor" platform substantially improves intratumoral DTX delivery and apoptosis-driven antitumor efficacy, while maintaining systemic safety. These findings highlight PEG-HMS-DTX as a promising and generalizable strategy for prostate cancer chemotherapy, warranting further pharmacokinetic, immunogenicity, and GLP toxicology studies to support translational advancement.
    Keywords:  Disulfide-bridged nanocarriers; Docetaxel chemotherapy; PEGylated mesoporous silica nanoparticles; Prostate cancer therapy; Redox-responsive drug delivery
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100492
  17. Int J Mol Sci. 2026 Feb 04. pii: 1537. [Epub ahead of print]27(3):
    Immunohistochemical Evidence of Telocytic Stroma Associated with Tumor Grade and Acinar Heterogeneity in Prostate Cancer.
    Eduardo P Júnior, Mário F R Lima, Lúcia P F Castro, Pablo V N Ramos, Juan C M Onofre, Rafaela S Souza, Vivian Resende, Clémence Belleannée, Gabriel Campolina-Silva, Marcelo Mamede.
      Prostate cancer (PCa) progression involves dynamic interactions between neoplastic cells and the reactive stroma (RS). Although myofibroblasts are established components of the RS, the role of other stromal populations, such as telocytes, remains poorly understood. This study investigated the presence and distribution of a telocytic stromal phenotype (CD34+/Vimentin+) in PCa across different histological grades and acinar patterns. We used digital image analysis and standardized immunohistochemistry to assess biopsy samples from 120 patients with confirmed PCa. The telocytic phenotype showed a heterogeneous distribution and was significantly enriched in high-grade tumors and specific acinar architectures, particularly Patterns B and D. In contrast, well-differentiated regions exhibited lower telocyte density, resembling non-neoplastic prostate tissue. Although the myofibroblastic phenotype (α-SMA+/Vimentin+/CD34-) also increased overall with tumor grade and varied across acinar patterns, this association was comparatively weaker and less statistically robust than that observed for telocytes. These results suggest that stromal remodeling encompasses a spectrum of cellular phenotypes influenced by local architectural constraints. It is proposed that telocytes serve as key mediators of tissue organization and biomechanical signaling, contributing to a feedback loop that promotes tumor progression. Combining acinar architecture with stromal phenotyping provides a refined framework for understanding epithelial-stromal co-evolution in PCa.
    Keywords:  immunohistochemistry; myofibroblasts; prostate cancer; reactive stroma; telocytes; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27031537
  18. Int J Mol Sci. 2026 Feb 05. pii: 1563. [Epub ahead of print]27(3):
    Cytosine Deaminase-TRAIL Expressing Human Adipose Stem Cells Inhibit Tumor Growth in Castration Resistant Prostate Cancer Bearing Mice with Less Toxicity.
    Jae Heon Kim, Hyun Young Lee, In Seok Hong, Jeongkun Lee, Sang Hun Lee, Yun Seob Song.
      Stem cells can selectively migrate toward cancer cells, and therapeutic genes can be introduced into stem cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without harming normal cells. In this study, we evaluated the inhibition of tumor growth in castration-resistant prostate cancer (CRPC) using human adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) and soluble TRAIL (sTRAIL), combined with the prodrug 5-fluorocytosine (5-FC). An immortalized human ADSC line (hTERT-ADSC) was transduced with a lentiviral vector encoding CD and sTRAIL, generating ADSC.CD.sTRAIL cells. Expression of chemoattractant ligands and receptors was assessed by RT-PCR. The suicide gene effect was evaluated by 5-FC treatment, measuring cell viability and apoptosis markers in vitro. A subcutaneous CRPC mouse model was used for in vivo studies. ADSC.CD.sTRAIL cells showed enhanced migration toward prostate cancer cells. Treatment with 5-FC significantly reduced cell viability, and co-culture with PC3 cells plus 5-FC increased apoptosis marker expression. In vivo, mice treated with ADSC.CD.sTRAIL and 5-FC had significantly smaller tumor volumes than control groups, with no treatment-related toxicity observed. These findings suggest that ADSCs overexpressing CD and sTRAIL, combined with 5-FC, effectively inhibit CRPC tumor growth and represent a promising targeted therapeutic strategy.
    Keywords:  TRAIL; adipose stem cells; castration-resistant prostate cancer; cytosine deaminase; gene-directed enzyme prodrug therapy; hTERT-immortalization; suicide gene; tumor tropism
    DOI:  https://doi.org/10.3390/ijms27031563
  19. Cancers (Basel). 2026 Feb 04. pii: 510. [Epub ahead of print]18(3):
    Snail1 Induced Suppression of Proliferation via EGR1, FOXO1, and CEPBγ Creates a Vulnerability for Targeting Apoptotic and Cellular Senescence Pathways.
    Jack Tran, Samyukta Sundaram, Sukirti Shivpuri, Hunain Khawaja, Cynthia K Miranti.
       BACKGROUND/OBJECTIVES: The annual ~36,000 prostate cancer (PCa) deaths represent a large clinical unmet need and a call for deeper understanding of PCa metastasis. Epithelial-mesenchymal-transition (EMT) has been used to model metastatic behaviors in numerous cancers including PCa. One hallmark of EMT is cell cycle suppression, but how EMT impacts PCa proliferation remains unclear primarily due to the lack of appropriate models.
    METHODS: We transiently induced Snail1 (SNAI1) expression, an EMT driver expressed in PCa, at physiological levels in three PCa cells lines, C4-2B, 22Rv1, and DU145. We used RNA-seq, ChIP-Seq, bioinformatics, qRT-PCR, shRNA, and immunoblotting to identify mechanisms of Snail1-driven inhibition of proliferation.
    RESULTS: Snail1 suppressed proliferation and G2/M cell cycle progression, without affecting cell death. Mechanistically, Snail1 upregulated expression of CEBPγ, ERG1, FOXO1, cyclin G1, p21, stress genes SESN3 and SOD3, apoptotic programmers Puma, Bax, and Noxa, and senescence-related laminB1, and downregulated Ki67, cyclins A2 and B2. ChIP-Seq data identified Snail1 direct binding to p21, cyclin B2 and G1, EGR1, and CEPBγ promoters. EGR1 induced FOXO1, and EGR1 was required for Snail1-induced SOD3 and Puma, and suppression of Caspase 3 to prevent apoptosis. The EGR1/FOXO1 axis induced BAX, Noxa, and SESN3. CEBPγ was required for Snail1 induction of Lamin B1 to block Snail1-induced senescence.
    CONCLUSIONS: We identified three new major downstream targets of Snail1 that improve our understanding of the role of EMT in limiting stress signaling, apoptosis, and senescence during cell cycle suppression to create a vulnerability for therapeutic targeting.
    Keywords:  CEBPγ; ChIP-Seq; EGR1; FOXO1; RNA-Seq; Snail1 (SNAI1); apoptosis; cell cycle; epithelial mesenchymal transition (EMT); metastasis; p21; prostate cancer; senescence
    DOI:  https://doi.org/10.3390/cancers18030510
  20. Pathol Res Pract. 2026 Feb 07. pii: S0344-0338(26)00046-4. [Epub ahead of print]280 156395
    METTL3 facilitates the malignant progression of prostate cancer by inhibiting GDF15-mediated ferroptosis via a YTHDF1-dependent m6A mechanism.
    Jun Jiang, Jinming Li, Shaoxing Wang, Jiahao Liu, Shusen Zuo.
       BACKGROUND: Prostate cancer (PCa) represents one of the most common tumors in males. Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor β (TGF-β) family, exhibits elevated expression that correlates with cancer progression (including PCa). The RNA N6-methyladenosine (m6A) modification, an epigenetic regulatory mechanism, has been implicated in oncogenesis and tumor advancement. Therefore, this study aims to delineate the functional role of GDF15 in PCa progression.
    METHODS: Differentially expressed genes (DEGs) and GDF15 levels in tumor tissues were analyzed using Gene Expression Omnibus (GEO) and Tumor Immune Estimation Resource (TIMER) database. Gene levels were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration, and sphere-forming abilities were examined using colony formation, transwell, and spheroid formation assays. Reactive-oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and ferrous iron (Fe2 +) levels were examined using corresponding detection kits. Methylation sites of GDF15 were predicted by SRAMP database. Relationship between GDF15 and methyltransferase-like 3/YTH domain family member 1 (METTL3/YTHDF1) was detected using RNA immunoprecipitation (RIP). mRNA stability was analyzed using qRT-PCR. Effects of METTL3 and GDF15 in vivo were confirmed via animal experiment.
    RESULTS: GDF15 expression was highly expressed in PCa tissues and cells. Functionally, GDF15 knockdown repressed PCa cell proliferation, migration, and sphere-forming abilities and promoted ferroptosis. Mechanistically, METTL3 combined with YTHDF1 regulated the m6A methylation of GDF15. METTL3 silencing suppressed the malignant biological behaviors of PCa cells via regulating GDF15. In vivo, silencing METTL3 inhibited tumor growth and GDF15 expression.
    CONCLUSION: Silencing METTL3 inhibits the malignant biological progression of PCa by mediating GDF15 via a YTHDF1-dependent m6A mechanism. It is important to further research GDF15 and reveal its specific mechanism in PCa.
    Keywords:  Ferroptosis; Growth differentiation factor 15; Malignant progression; Methyltransferase-like 3; Prostate cancer
    DOI:  https://doi.org/10.1016/j.prp.2026.156395
  21. bioRxiv. 2026 Jan 26. pii: 2026.01.24.701539. [Epub ahead of print]
    Mechanistic Language Modeling and Oxygenated 3D Screening Reveal Berberine and Enzalutamide Synergy in Resistant Prostate Cancer.
    Chih-Hui Lo, Katie Shi, Lina Kafadarian, Alexandra Bermudez, Johnny Diaz, Liam Edwards, Yunqi Hong, Ziyi Chen, Hyeonji Hwang, Weihong Yan, Alan Levinson, Robert Damoiseaux, Cho-Jui Hsieh, Tanya Stoyanova, Andrew S Goldstein, Neil Y C Lin.
      Resistance to androgen receptor inhibitors remains a primary challenge in prostate cancer treatment, yet identifying synergis-tic co-therapies is hindered by immense combinatorial search spaces and the limited interpretability of predictive computation models. Here, we developed an integrated discovery-validation axis coupling knowledge-augmented large language models with oxygen-supplemented 3D spheroid assays. By leveraging inherent model stochasticity, our framework measures the degree of consensus across independent predictions to establish a formal metric for predictive accuracy. This principle enables high-throughput assessment of complex signaling crosstalk, yielding mechanistic rationales for all predictions and defining a high-confidence zone that minimizes experimental attrition. Utilizing this approach to screen 3,592 natural products, we identified a previously unrecognized synergy between berberine and enzalutamide that re-sensitizes resistant cells. Validation confirms that berberine perturbs the PI3K/AKT/mTOR and AMPK axes, a finding consistent with the mechanistic rationales computationally derived by the framework. Integrating interpretable AI with physiologically relevant 3D screening provides a scalable methodology for the rational discovery of synergistic therapies.
    Significance: Integrating mechanistic AI with oxygenated 3D screening, we identify a novel berberine-enzalutamide synergy. This framework resolves complex signaling dependencies, providing a scalable, transparent methodology for the rational discovery of effective combination therapies.
    DOI:  https://doi.org/10.64898/2026.01.24.701539
  22. Front Cell Infect Microbiol. 2026 ;16 1754671
    SSTDhunter: a curated gene database for investigating androgen producing potential in microbiota species.
    Shaojing Wang, Yifan Yang, Li Lei, Rongxin Wan, Zhaoying Su, Yan Liu, Huiqin Tang, Guoying Hu, Changlin Li, Changying Li, Jinhuan Meng, Kuo Yang.
      Androgens are critical for the growth of prostate cells, as well as prostate tumor cells. For prostate cancer patients under Androgen Deprivation Therapy (ADT) such as castration treatment, investigating the potential for androgen production by gut microbes is crucial. In microbe species, the side chain cleavage activity of steroid-17, 20-desmolase (SSTD) is responsible for 11-oxy-androgens production by biotransformation from cortisol, as well as from other endogenous steroids and pharmaceutical glucocorticoids. The side-chain cleavage product of prednisone could significantly promote the proliferation of prostate cancer cells. The SSTD is a complex formed by N-terminal and C-terminal transketolases encoded by desA and desB genes, whose activity has been well-characterized in Clostridium scindens ATCC 35704. While a void still existed in evaluating the androgen producing potential by gut microbiota owing to relatively low abundance of SSTD-carrying species and the lack of professional gene database. Meanwhile, mining SSTD encoding genes in explosion sequencing data has become computationally expensive and time-consuming using comprehensive database. Here, a professional database consisted of SSTD-coding genes, named SSTDhunter, was constructed using a large-scale genomic analysis along with homologous genes as background. These SSTD-coding genes were reconstruction through comprehensive characteristics consisted of operon structures, sequence identities, phylogenetic topologies and comparative analysis. To reduce false positives, protein sequences of homologous genes tktA, which encode component of sugar transketolase, were also included in SSTDhunter database as background noise. SSTDhunter is for rapid investigation of SSTD-coding genes in massive metagenomic data, which is freely available at http://www.orgene.net/SSTDhunter/.
    Keywords:  SSTDhunter database; androgens; gut microbiome; prostate cancer; steroid-17,20-desmolase
    DOI:  https://doi.org/10.3389/fcimb.2026.1754671
  23. Transl Androl Urol. 2026 Jan 31. 15(1): 7
    Clinical implication of immune check point inhibitors in advanced prostate cancer: insight from the KEYNOTE-991 trial.
    Yasutaka Yamada.
      
    Keywords:  Prostate cancer; androgen receptor pathway inhibitor (AR pathway inhibitor); immune checkpoint inhibitor (ICI)
    DOI:  https://doi.org/10.21037/tau-2025-703
  24. J Biomol Struct Dyn. 2026 Feb 11. 1-30
    Structure-guided design and evaluation of oxazolone-based PIM-1 kinase inhibitors with promising anticancer activity.
    Aanchal Rathi, Rajesh K Hadiya, Md Nayab Sulaimani, Shahbaz Ahmed, Gulam Mustafa Hasan, Namrata Goyal, Kaushik Shah, Mohammad Mahfuzul Haque, Bhaskar Datta, Md Imtaiyaz Hassan.
      PIM-1 kinase is a crucial modulator of cellular processes, including proliferation, survival and programmed cell death, positioning it as a compelling target for anticancer therapies. Using a structure-guided drug design strategy, we have designed novel oxazolone derivatives as potential PIM-1 inhibitors. Out of 42 designed oxazolone derivatives, molecular docking identified 30 candidates with favorable binding profiles. In this study, synthetic oxazolone derivatives (O20, O23 and O29) were evaluated for their inhibitory potential against PIM-1 through biochemical and biophysical approaches. Enzyme inhibition assays demonstrated consistent low-micromolar inhibition of PIM-1 with, 13.88 ± 1.8 µM for O20, 12.11 ± 2.5 µM for O23 and 15.04 ± 2.9 µM for O29. Fluorescence quenching confirmed potent ligand-protein interactions, with binding constants (Kₐ) in the order of 105-106 M-1. ITC measurements further validated these findings, revealing favorable binding enthalpy (ΔH = -5.3 × 105 kcal/mol for O29) and entropy-driven stabilization. Additionally, a cell proliferation assay was performed on a human prostate cancer cell line using compound O29, which showed promising anticancer potential with an IC50 of 8.46 µM. Collectively, these results indicate that O29 is the most promising candidate among the tested derivatives, offering high-affinity binding and efficient kinase inhibition. These findings suggest the therapeutic potential of oxazolone-based scaffolds as lead compounds for the development of potent PIM-1 inhibitors in prostate cancer treatment.
    Keywords:  Cancer therapy; PIM-1 kinase; drug development; kinase inhibitors; oxazolone derivatives
    DOI:  https://doi.org/10.1080/07391102.2026.2624059
  25. AME Case Rep. 2026 ;10 37
    A case report of small-cell carcinoma of the prostate with ectopic adrenocorticotropic-hormone (ACTH) syndrome and hypokalemia.
    Xin-Yi Cao, Hong-Bin Deng, Peng-Bo Jiang.
       Background: Small-cell prostate cancer is the most common type of treatment-related neuroendocrine prostate cancer. It typically originates from prostate adenocarcinoma following prolonged endocrine therapy, presenting as desmoplasia-resistant. At this stage, indicators such as prostate-specific antigen (PSA) and androgen receptor (AR) remain within normal ranges, conflicting with widespread metastatic lesions. Simultaneously, neuroendocrine indicators exhibit a significant elevation. Small-cell prostate cancer can secrete hormones, leading to ectopic endocrine syndrome.
    Case Description: In this context, we present a case wherein prostate adenocarcinoma transformed into small cell prostate cancer, accompanied by a rare paraneoplastic syndrome involving ectopic adrenocorticotropic-hormone (ACTH) production. The patient primarily presented with hypokalemia, edema, and hypertension. Following multi-line anti-tumor therapy and adrenal steroidogenesis inhibitors therapy, the patient's symptoms, including hypokalemia and edema, markedly improved. However, the patient ultimately succumbed to tumor progression. We present this case based on the CARE reporting checklist.
    Conclusions: Our case referred to the treatment regimen for small-cell lung cancer, suggesting that the treatment regimen for small-cell lung cancer is effective for small-cell prostate cancer, but tumors can quickly become resistant. The efficacy of adrenal steroidogenesis inhibitors in treating ectopic ACTH syndrome (EAS) is demonstrated, underscoring that judicious treatment decisions can effectively prolong patient survival and enhance their quality of life. We present this case series based on a list of AME case series reports.
    Keywords:  Case report; ectopic adrenocorticotropic-hormone syndrome (EAS); hypokalemia; small-cell prostate cancer; treatment of ectopic ACTH syndrome (treatment of EAS)
    DOI:  https://doi.org/10.21037/acr-24-271
  26. Transl Androl Urol. 2026 Jan 31. 15(1): 10
    Report of the Advanced Prostate Cancer Consensus Conference-JAPAN 2025 at the 112th Annual Meeting of the Japanese Urological Association.
    Takahiro Inoue, Takeo Kosaka, Masashi Kato, Akira Yokomizo, Masatoshi Eto, Isao Hara, Hiroyoshi Suzuki.
       Background: The Advanced Prostate Cancer Consensus Conference (APCCC) is a forum for discussing and debating current questions regarding the clinical management of patients with advanced prostate cancer, with a particular focus on these controversies. The aim of this study is to summarize and discuss the results of APCCC-JAPAN 2025 and APCCC 2024 to elucidate the current consensus for advanced prostate cancer in Japan.
    Methods: A total of 183 topics on advanced prostate cancer with substantial effects on daily practice but insufficient high-level evidence were addressed at APCCC 2024. From these, 16 questions were selected and presented by a panel of six prostate cancer experts at APCCC-JAPAN 2025 during the 112th Annual Meeting of the Japanese Urological Association. Japanese urologists attending the symposium cast their votes on questions on their smartphones using a web-based tool. The results were compared with those obtained at APCCC 2024.
    Results: Differences in voting results were observed between APCCC-JAPAN 2025 and APCCC 2024, particularly regarding treatment strategies for localized high-risk prostate cancer and metastatic hormone-sensitive prostate cancer.
    Conclusions: The APCCC-JAPAN 2025 highlighted critical aspects of the current issues surrounding the management of advanced prostate cancer in Japan. Both similarities and differences were observed in the treatment approaches employed by Japanese urologists and global prostate cancer experts.
    Keywords:  APCCC-JAPAN 2025; Advanced Prostate Cancer Consensus Conference 2024 (APCCC 2024); advanced prostate cancer
    DOI:  https://doi.org/10.21037/tau-2025-709
  27. Int J Mol Sci. 2026 Feb 03. pii: 1511. [Epub ahead of print]27(3):
    Prostate Cancer: Dissecting Novel Immunosuppressive Mechanisms Through Context-Specific Transcriptomic Programs and MDSC Cells.
    Pedro Reyes Martinez, Erick Sierra Diaz, Fabiola Solorzano Ibarra, Jorge Raul Vazquez Urrutia, José de Jesús Guerrero García, Martha Cecilia Téllez Bañuelos, Julio Enrique Castañeda Delgado, Karina Sanchez Reyes, Pablo Cesar Ortiz Lazareno.
      Prostate cancer remains largely refractory to immunotherapy, implying the existence of context-specific immune landscape programs that diverge between circulation and tumor. Here, we integrate bulk RNA sequencing from three cohorts (patient peripheral mononuclear cells, primary prostate tissue, and biochemical-recurrence tumors) with multiparameter flow cytometry, unsupervised UMAP/T-REX (Tracking Responders Expanding) mapping, and de novo discovery of long non-coding RNAs (lncRNAs) to characterize context-specific immunoregulation. Patient PBMCs revealed a coherent IL-1/TNF/IL-17 inflammatory architecture with strong chemotactic programs and an unexpected neutrophil-like signal despite density-gradient isolation, consistent with low-density PMN-MDSCs. In contrast, tumors broadly repressed chemokines and innate immune mediators, yet upregulated prostate cancer-associated lncRNAs, indicating local immune quiescence coupled with non-coding regulatory programs. Recurrent tumors acquired epithelial-mesenchymal transition and metabolic remodeling, accompanied by relapse-associated lncRNA signatures, whereas long-term nonrecurrent tumors preserved epithelial and stress-response networks. High-dimensional cytometry confirmed discrete, cancer-enriched myeloid clusters expressing CD47, SIRPα, PD-L1, CD73, and Galectin-9. Network analysis highlighted inflammatory hubs (CXCL2, PTGS2) in PBMCs and loss of mechanotransduction modules in tumors. Structural modeling uncovered a three-way junction and 3' triple helix in lncRNA. Collectively, these data suggest that circulating inflammatory rewiring is associated with checkpoint-rich suppressor expansion and tumor immune quiescence, outlining integrated myeloid- and RNA-directed strategies for cancer research.
    Keywords:  bulk RNA-seq; flow cytometry; immunosuppression; long non-coding RNAs (lncRNAs); myeloid-derived suppressor cells (MDSCs); prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27031511
  28. Cancer Metab. 2026 Feb 12.
    Targeting FANCD2 to overcome enzalutamide resistance in prostate cancer.
    Wenzhen Shi, Juliang Yang, Yue Xu, Huijie Yang, Junquan Hu, Shang Huang.
      
    Keywords:  Enzalutamide (ENZ); FANCD2; Ferroptosis; Nrf2; Prostate cancer
    DOI:  https://doi.org/10.1186/s40170-026-00419-4
  29. Int J Pharm X. 2026 Jun;11 100496
    A prostate-specific membrane antigen targeted small molecule-drug conjugate for efficient prostate cancer therapy at a low dosage.
    Jingjing Zhang, Fanchun Hu, Caiting Deng, Yuhan Ding, Yuchen Yang, Shupeng Han, Jun Liu, Feifei An, Mingsong Shi.
      Prostate-specific membrane antigen (PSMA), which is overexpressed in most prostate cancer cells, serves as an ideal target for precision therapy. The clinical utility of the potent chemotherapeutic agent SN38 is hindered by its poor water solubility and systemic toxicity. Herein, we present a novel, fully water-soluble small-molecule drug conjugate (SMDC), SN38-SS-3PEG24-3PSMA (SPP), designed for enhanced prostate cancer targeting and tumor-selective drug release. SPP integrates three PSMA-targeting ligands, a glutathione (GSH)-responsive disulfide linker, and three monodisperse polyethylene glycol (PEG) chains, achieving exceptional water solubility (>1 mM) and tumor-specific payload activation. In vivo fluorescence imaging revealed efficient tumor accumulation with minimal hepatic distribution, as evidenced by predominant renal clearance, thereby reducing hepatotoxicity risks. Remarkably, SPP demonstrated potent tumor growth inhibition at low doses (20 nmol) in PSMA-positive xenograft models, outperforming controls without PEG spacers or disulfide linkers. The GSH-triggered release of SN38 within the tumor cells ensured high cytotoxicity against cancer cells while maintaining stability in circulation, thereby minimizing off-target toxicity. Collectively, this study highlights SPP as a promising therapeutic candidate, combining enhanced water solubility, precise tumor targeting, and low-dose efficacy with an excellent safety profile, offering a transformative strategy for prostate cancer treatment.
    Keywords:  PEG; PSMA; Prostate cancer; SMDC; SN38
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100496
  30. Phys Med. 2026 Feb 10. pii: S1120-1797(26)00031-1. [Epub ahead of print]143 105744
    Tumor control probability analysis in carbon-ion radiotherapy for prostate cancer considering the oxygen effect.
    Yushi Wakisaka, Shuka Fukuda, Toshiro Tsubouchi, Noriaki Hamatani, Masashi Yagi, Mayu Nakata, Yuki Tominaga, Kazuhiko Hayashi, Masaaki Takashina, Kazumasa Minami, Teiji Nishio, Tatsuaki Kanai.
       PURPOSE: Carbon ion radiotherapy (CIRT) is expected to be effective against hypoxic tumors due to its lower oxygen enhancement ratio (OER) compared to X-ray radiotherapy (XRT). OER is expected to have a significant impact on therapeutic efficacy, especially for prostate cancer, which has low oxygen partial pressure. This study aimed to derive OERs for photon and carbon-ion spread-out Bragg peak (SOBP) irradiation through cellular experiments and incorporate them into the tumor control probability (TCP) function to test consistency with clinical outcomes.
    METHODS: To derive the OER for photons and the OERs at three depths (proximal, center, and distal) within the carbon-ion SOBP, the dose-dependent survival rate of the prostate cancer cell line PC3 was measured under both aerobic and hypoxic conditions. TCP functions incorporating dose-dependent OERs based on clinical prescription doses were fitted to clinical outcomes of prostate cancer treated with XRT and CIRT to test the clinical relevance of the obtained OERs.
    RESULTS: The OERs at 10% survival for PC3 cells were 2.12 ± 0.68 for photons, and 1.70 ± 0.13, 1.65 ± 0.19, and 1.56 ± 0.13 at the proximal, center, and distal depths of the carbon-ion SOBP, respectively. The TCP functions calculated using dose-dependent OERs were not inconsistent with the clinical outcomes for both XRT and CIRT, supporting the clinical relevance of the OERs derived from cell experiments.
    CONCLUSION: The carbon-ion SOBP used in prostate cancer treatment has a lower OER than photons, suggesting its potential effectiveness against hypoxic tumors.
    Keywords:  Carbon ion therapy; Oxygen enhancement ratio; Prostate cancer; Tumor control probability
    DOI:  https://doi.org/10.1016/j.ejmp.2026.105744
  31. Int J Impot Res. 2026 Feb 11.
    Cardiovascular and prostate cancer risk associated to testosterone replacement therapy - a systematic review and meta-analysis of 41 randomized controlled trials.
    Carlos A García-Becerra, Maria I Arias-Gallardo, Jesús E Juárez-García, Verónica Soltero-Molinar, Luis F Parra-Camaño, Mariabelen I Rivera-Rocha, Natalia García-Becerra, Carlos M García-Gutiérrez.
      Testosterone therapy (TTh) is widely used to treat late-onset hypogonadism, aiming to improve quality of life and alleviate symptoms of testosterone deficiency. However, concerns remain regarding its potential association with major adverse cardiovascular events (MACE) and prostate cancer events (PCaE). This systematic review and meta-analysis, registered in PROSPERO (CRD42024603054) and conducted in accordance with PRISMA guidelines, evaluated the risk of MACE, PCaE, and clinically significant prostate cancer (CsPcE) associated with TTh in randomized controlled trials (RCTs). A comprehensive search of PubMed, ClinicalTrials.gov, and Cochrane Central identified 3794 records, of which 41 RCTs (n = 11,161) met inclusion criteria. Pooled odds ratios (OR) were estimated using Mantel-Haenszel or restricted maximum likelihood methods under fixed or random-effects models, based on heterogeneity. Meta-regression explored sources of heterogeneity and effect modifiers, and sensitivity analyses were performed using continuity correction for zero-event trials. TTh was not associated with a statistically significant increase in MACE (OR 0.83; 95% CI: 0.52-1.32; I² = 53.2%), PCaE (OR 0.88; 95% CI: 0.52-1.51; I² = 0.0%), or CsPcE (OR 1.13; 95% CI: 0.39-3.26; I² = 0.0%). Comorbidities contributed to heterogeneity in MACE outcomes. Current evidence supports the short- to mid-term safety of TTh, though long-term data remain necessary. Registry and the Registration No. of the study/trial: CRD42024603054.
    DOI:  https://doi.org/10.1038/s41443-026-01237-4
  32. J Urol. 2026 Feb 09. 101097JU0000000000004986
    Low Testosterone Levels and Grade Group Progression Among Localized Prostate Cancer Patients on Active Surveillance: A Retrospective Cohort Study.
    Tarek Lawen, Rebekka S Garcia, Matthew T Smith, Jeissen Pyo, Noel M Higgason, Margaux Jm Robert, Brian F Chapin, Lisly S Chery, John W Davis, John F Ward, Louis L Pisters, Curtis A Pettaway, Andrew W Hahn, Daniel E Frigo, Peng Wei, Carrie R Daniel, Justin R Gregg.
       BACKGROUND: Active surveillance (AS) is an increasingly utilized strategy for managing localized prostate cancer, yet reliable biomarkers for predicting disease progression remain limited. Low testosterone has been associated with aggressive prostate cancer features at diagnosis, but its role in grade group progression during AS remains unclear.
    OBJECTIVE: To evaluate the association between baseline serum testosterone levels and grade group progression in men undergoing AS for localized prostate cancer.
    METHODS: We conducted a retrospective cohort study of 924 men enrolled in an AS program between 2001 and 2024, with a median follow-up of 46.1 months among those who did not progress. Serum testosterone levels were categorized as low if they met a threshold of ≤ 300 ng/dl based on guideline recommendations. Primary outcomes were biopsy progression to grade group 2 (GG2) or "extreme" progression to grade group 3 or higher (GG3) disease. Multivariable Cox proportional hazards models were used to assess associations between testosterone levels and progression, adjusting for age, PSA density and biopsy tumor volume. Potential clinically significant confounding by BMI, smoking status, and ethnicity was also considered.
    RESULTS: Among 924 men, the mean age was 63.6 years (SD 8.1), and the mean PSA density was 0.13 ng/mL2 (SD 0.14). The average baseline testosterone was 394 ng/dL (SD 160.4), with 29.4% (n=272) of men having a testosterone level ≤ 300 ng/dL. Low testosterone was associated with a statistically significant increased risk of GG3 progression (HR 1.61, 95% CI 1.03-2.51, p=0.04). Further, evidence suggested that low testosterone was not associated with risk of GG2 progression (HR 1.23, 95% CI 0.93-1.64, P=0.15). Findings were consistent when employing alternative cut-points for testosterone and when considering other potential confounders.
    CONCLUSION: These findings suggest that while low testosterone is not clearly associated with moderate progression (GG2), it may increase the risk of higher-grade "extreme" progression to GG3 or higher. Future studies should focus on prospective validation of our findings to elucidate the biological relationship between androgens and prostate cancer progression.
    Keywords:  Prostate cancer Active surveillance Hypogonadism
    DOI:  https://doi.org/10.1097/JU.0000000000004986
  33. Int J Comput Assist Radiol Surg. 2026 Feb 12.
    ProstNFound+: A Prospective Study using Medical Foundation Models for Prostate Cancer Detection.
    Paul F R Wilson, Mohamed Harmanani, Minh Nguyen Nhat To, Amoon Jamzad, Tarek Elghareb, Zhuoxin Guo, Adam Kinnaird, Brian Wodlinger, Purang Abolmaesumi, Parvin Mousavi.
       PURPOSE: Medical foundation models (FMs) offer a path to build high-performance diagnostic systems. However, their application to prostate cancer (PCa) detection from micro-ultrasound ( μ US) remains untested in clinical settings. We present ProstNFound+, an adaptation of FMs for PCa detection from μ US, along with its first prospective validation.
    METHODS: ProstNFound+ incorporates a medical FM, adapter tuning, and a custom prompt encoder that embeds PCa-specific clinical biomarkers. The model generates a cancer heatmap and a risk score for clinically significant PCa. Following training on multicenter retrospective data, the model is prospectively evaluated on data acquired five years later from a new clinical site. Model predictions are benchmarked against standard clinical scoring protocols (PRI-MUS and PI-RADS).
    RESULTS: ProstNFound+ shows strong generalization to the prospective data, with no performance degradation compared to retrospective evaluation. It aligns closely with clinical scores and produces interpretable heatmaps consistent with biopsy-confirmed lesions.
    CONCLUSION: The results highlight its potential for clinical deployment, offering a scalable and interpretable alternative to expert-driven protocols.
    Keywords:  Foundation models; Micro-ultrasound; Prospective data; Prostate cancer
    DOI:  https://doi.org/10.1007/s11548-025-03561-4
  34. Eur J Med Chem. 2026 Feb 09. pii: S0223-5234(26)00062-0. [Epub ahead of print]307 118617
    Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer.
    Lei Xu, Mengmeng Wang, Yanshuo Cheng, Hanhan Kuang, Yijing Zhu, Ning Liu, Qianqian Wang, Shicong Li, Jiefu Wang, Junfeng Wang, Ziqi Huang, Ranlu Liu, Shuangwei Liu, Kun Zhang, Guang Yang.
      Androgen receptor splice variant 7 (AR-V7) plays a crucial role in the malignant progression of castration-resistant prostate cancer (CRPC). Current research has demonstrated that the development of novel AR-V7 degraders holds broad prospects and is expected to serve as a clinical therapeutic regimen for this disease. In the present work, we utilized structural analogs of enzalutamide to conjugate a silicon-containing hydrophobic tag (SiHyT) moiety via Click chemistry, achieving the selective degradation of the androgen receptor (AR) and AR-V7. Mechanistic studies revealed that the degrader disrupted the interactions between AR/AR-V7 and HSP90. This disruption further prompted the E3 ubiquitin ligase helicase-like transcription factor (HLTF) to recognize AR and AR-V7, followed by their ubiquitination and degradation in CRPC cell lines. Additionally, the active compound exhibited favorable pharmacokinetic properties and metabolic profiles. In both in vitro and in vivo experiments, this degrader displayed more potent activity than enzalutamide in inhibiting the proliferation and migration of CRPC cells. This study expands the application scope of the silicon-containing hydrophobic tag (SiHyT) strategy and provides an alternative design concept for the development of drugs targeting the degradation of AR/AR-V7 in the treatment of CRPC.
    Keywords:  AR/AR-V7; Castration-resistant prostate cancer; HLTF; Silicon-based hydrophobic tags; Targeted protein degradation
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118617
  35. PLoS One. 2026 ;21(2): e0342720
    Retraction: Molecular mechanism of inhibitory effects of melatonin on prostate cancer cell proliferation, migration and invasion.
    PLOS One Editors
      
    DOI:  https://doi.org/10.1371/journal.pone.0342720
  36. J Cell Mol Med. 2026 Feb;30(3): e71059
    RETRACTION: Combined Anticancer Effects of Simvastatin and Arsenic Trioxide on Prostate Cancer Cell Lines via Downregulation of the VEGF and OPN Isoforms Genes.
       RETRACTION: A. Mirzaei, S. Rashedi, M. R. Akbari, F. Khatami, and S. M. K. Aghamir, "Combined Anticancer Effects of Simvastatin and Arsenic Trioxide on Prostate Cancer Cell Lines via Downregulation of the VEGF and OPN Isoforms Genes," Journal of Cellular and Molecular Medicine 26, no. 9 (2022): 2728-2740, https://doi.org/10.1111/jcmm.17286. The above article, published online on 02 April 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine, and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party. The investigation identified duplication of elements between Figures 3 and 4 in this article. Additional duplications were found between Figures 1, 3, and 4 of this article and figures in other articles published by some of the same authors. Not all authors of the article were involved in the later publications where the additional duplicated elements were found. Although those other articles were published later, some of the duplicated elements were used to represent different scientific contexts. The authors cooperated with the investigation and explained that these duplications were inadvertent errors resulting from figure mismanagement. However, they were unable to provide their original raw data. Due to the extent and nature of the concerns, the editors consider the results and conclusions to be unreliable.
    DOI:  https://doi.org/10.1111/jcmm.71059
  37. J Am Chem Soc. 2026 Feb 11.
    Development of Prostate-Specific Lysosome-Targeting Degraders.
    Deqin Cai, Xuankun Chen, Yaxian Zhou, Malick Bio Idrissou, Reinier Hernandez, Weiping Tang.
      Targeted protein degradation (TPD) technologies have emerged as transformative therapeutic modality for treating cancers and other diseases. While significant progress has been achieved in intracellular protein degradation, degradation of membrane proteins and extracellular targets remains in an early stage. In this study, we developed a prostate-specific lysosome-targeting degradation strategy using a prostate-specific membrane antigen (PSMA) as a lysosome-targeting receptor (LTR). We demonstrated that both extracellular and membrane proteins can be selectively degraded in prostate cancer cells via the lysosome pathway. These PSMA TArgeting Chimeras (PTACs) were shown to facilitate lysosomal degradation in a selective, potent, rapid, and sustained manner. Notably, Ctx-L3 and Atz-L5 exhibited exceptional degradation potencies in LNCaP cells, with DC50 values of 4.3 pM for EGFR and 2 pM for PD-L1, respectively─among the most potent degraders reported to date. Furthermore, the application of PTACs to degrade PD-L1, using both antibody- and small-molecule-based formats, highlights the versatility of this platform. Collectively, this work advances the application of TPD technology and offers promising avenues for precision medicine in prostate-related diseases.
    DOI:  https://doi.org/10.1021/jacs.5c18594
  38. Clin Genitourin Cancer. 2026 Jan 22. pii: S1558-7673(26)00008-X. [Epub ahead of print] 102508
    Cardiac Function and Prostate Cancer Risk and Prognosis: The PROCA-Life Study.
    Martin Støyten, Tore Knutsen, Inger Thune, Einar Stikbakke, Tom Wilsgaard, Anne-Elise Eggen, Elin Richardsen, Edward Giovannucci, Henrik Schirmer, Hege Sagstuen Haugnes.
       BACKGROUND AND OBJECTIVE: Prostate cancer (PCa) risk and the total cardiovascular disease (CVD) burden increases with age. The main objective was to evaluate the interplay between cardiac function and PCa risk and prognosis.
    METHODS: In the population-based cohort Prostate Cancer Study throughout life (PROCA-life), 2514 men participating in the Tromsø Study (1994-2016) had echocardiographic examinations. Overall, 235 were diagnosed with PCa during follow-up. Cox proportional hazard models were used to study associations between prediagnostic cardiac function and PCa risk and mortality.
    RESULTS: Mean time from echocardiography to PCa was 9.9 years for men with high risk/metastatic PCa, and the 10-year survival rate was 78.3 % among high risk/metastatic PCa. Men aged > 60.3 years at study entry with mitral peak E deceleration time (DT) < 140 ms or DT > 220 ms had a 1.66-3.37 times higher probability of high risk/metastatic PCa compared with men with normal DT (140-220 ms). Among men who developed PCa, low or high DT was associated with higher overall mortality compared to men with normal DT (HR 3.35, 95% CI, 1.35-8.33 and HR 2.00, 95% CI, 1.28-3.14, respectively). DT > 220 ms was associated with 2 times higher PCa-specific mortality (HR 2.09, 95% CI, 1.11-3.94).
    CONCLUSIONS AND CLINICAL IMPLICATIONS: Prediagnostic diastolic dysfunction may be associated with an increased risk of high risk/metastatic PCa, as well as higher overall mortality and PCa-specific mortality. These results support that cardiovascular follow-up among men with PCa is important.
    Keywords:  Cardio-oncology; Cardiovascular disease; Diastolic function; Echocardiography; Hypertension
    DOI:  https://doi.org/10.1016/j.clgc.2026.102508
  39. Urol Oncol. 2026 Feb 06. pii: S1078-1439(26)00003-7. [Epub ahead of print]44(4): 110993
    Patient awareness and perspectives regarding the value of focal therapy for localized prostate cancer: A cross-sectional study.
    Abdul-Qahar K Yasinzai, Jordan Smith, Amica Lertkitcharoenpo, Rafael A Bourricaudy, Jane J Chang, Thomas F Stringer, John Michael DiBianco, Jason P Joseph, Padraic O'Malley, Paul L Crispen, Li-Ming Su, Tarik Benidir.
       BACKGROUND: With the expanding therapeutic options for localized prostate cancer (PCa), little is known regarding patient values and perspectives that influence the selection process for focal therapy (FT) vs. conventional treatments. This study explores the socioeconomic and demographic factors that influence patients' decisions for FT.
    METHODS: This was a single-center cross-sectional study using a patient-centered survey of men with concerns about or a diagnosis of localized prostate cancer who were potential candidates for focal therapy. Information on patient demographics and clinical status was collected along with hypothetical scenarios to study the preferences of patients. Descriptives and univariate tests of associations were utilized for analysis.
    RESULTS: In total, 158 patients were enrolled; only 41.1% of patients had prior knowledge of FT. Among those with a diagnosis of PCa and endorsing prior FT knowledge, 44.3% did not understand its efficacy, while 27.9% did not know if FT has any potential side effects. Education and income significantly influenced FT knowledge. Specifically, 52.4% of patients with advanced education were familiar with FT compared to 20% of those with only a high school education (P < 0.01). Patients with income of >$75,000 were more likely to be aware of FT (60.7%, P = 0.010). Interestingly, neither disease stability nor treatment status influenced therapy preferences. Sexually active patients were more likely to be aware of FT as an option.
    CONCLUSIONS: A considerable proportion of PCa patients, specifically those in lower socioeconomic groups, remain unaware of FT's existence and its potential role in well-selected PCa management. Educated and higher-income patients had comparatively better knowledge about FT and also leaned towards functional outcomes. As FT demand continues to expand, addressing knowledge gaps is crucial to ensure informed and equitable healthcare delivery.
    Keywords:  Focal therapy; Health Disparities; Patient Preferences; Prostate cancer; Treatment Decision-Making
    DOI:  https://doi.org/10.1016/j.urolonc.2026.110993
  40. Radiother Oncol. 2026 Feb 11. pii: S0167-8140(26)00050-2. [Epub ahead of print] 111412
    Optimizing prostate cancer stereotactic body radiotherapy: margins, dose, or target volume-de-intensification?
    Jennifer Le Guevelou, Paul Sargos, Thomas Zilli.
      
    Keywords:  Bladder trigone; Genitourinary toxicity; Intraprostatic urethra; Prostate cancer; Stereotactic body radiotherapy
    DOI:  https://doi.org/10.1016/j.radonc.2026.111412
  41. Cancers (Basel). 2026 Feb 06. pii: 540. [Epub ahead of print]18(3):
    FAM64A Potentiates Bladder Carcinoma Tumorigenesis and Metastasis Through PI3K/mTORC2/AKT Pathway Activation.
    Tao Zhu, Cen Liufu, Cong Yin, Jinqing He, Junhua Luo, Bentao Shi, Yan Wang.
      Background: FAM64A is highly expressed in various cancers (e.g., breast cancer, ovarian cancer), indicating that it promotes tumorigenesis and progression by facilitating epithelial-mesenchymal transition. In the genitourinary system, dihydrotestosterone promotes the expression of FAM64A by binding of the androgen receptor to the FAM64A promoter, thereby enhancing the proliferation, migration, and cell cycle progression of androgen-dependent prostate cancer cell lines. However, its specific role in the initiation and progression of bladder cancer remains unclear. FAM64A overexpression has been observed in cancers such as breast and prostate; however, its role in bladder cancer (BLCA) is less understood. Muscle-invasive BLCA (MIBC) has a poor prognosis, with five-year survival rates below 50%. This study explores FAM64A's molecular mechanisms and therapeutic potential in BLCA. Methods: FAM64A expression was analyzed using TCGA data and clinical BLCA tissues. Functional assays (CCK-8, wound-healing, Transwell) assessed proliferation, migration, and invasion following FAM64A modulation. Western blotting was used to evaluate EMT markers (Vimentin, Slug) and proteins involved in the PI3K/AKT pathway. Bioinformatics (TCGA/GTEx) identified FAM64A-correlated genes, followed by KEGG pathway analysis. Taselisib (PI3K/AKT inhibitor) validated pathway involvement. Results: FAM64A was upregulated in BLCA and correlated with advanced tumor stage, T-stage, and grade. Knockdown suppressed proliferation, migration, and invasion, while overexpression exacerbated these effects. FAM64A promoted G2/M progression (via Cyclin B1/Ki67) and EMT (via Vimentin/Slug). KEGG analysis linked FAM64A to the PI3K/mTORC2/AKT signaling pathway. Taselisib reversed FAM64A-induced EMT and malignant phenotypes. Conclusions: FAM64A drives BLCA progression via PI3K/mTORC2/AKT-mediated EMT, serving as a potential prognostic biomarker and therapeutic target for metastatic BLCA.
    Keywords:  EMT; FAM64A; PI3K/mTORC2/AKT; bladder cancer
    DOI:  https://doi.org/10.3390/cancers18030540
  42. Res Sq. 2026 Feb 05. pii: rs.3.rs-8778762. [Epub ahead of print]
    Integrative dual ctDNA 5mC/5hmC methylomics and clonal reconstruction infer tumor transcription and resistance phenotypes in metastatic prostate cancer.
    Adam Sowalsky, Chennan Li, Anna Baj, Clara Seo, Nicholas Terrigino, Jack R Bright, S Hennigan, Isaiah King, Scott Wilkinson, Tzu-Ting Huang, Shana Trostel, William Figg, William L Dahut, David Takeda, Jung-Min Lee, Fatima Karzai.
      Liquid biopsies can detect actionable mutations and infer broad tumor states from genome-wide cfDNA measurements, but quantitative transcriptome-like phenotyping at single gene resolution still largely requires tissue. Here, we asked whether 6-base whole-genome sequencing that jointly quantifies 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) could infer gene expression directly from plasma. We applied this framework to plasma from patients enrolled in a phase 2 clinical trial of the PARP inhibitor olaparib plus the PD-L1 inhibitor durvalumab for metastatic castration-resistant prostate cancer. Inferred plasma transcriptomes distinguished adenocarcinoma vs. neuroendocrine phenotypes and identified a noncanonical WNT5A-associated signature linked to poor clinical response. Integrating longitudinal cfDNA methylomic profiles with phylogenetic reconstruction further revealed two resistance trajectories: one featuring high tumor heterogeneity with persistent AR signaling, and another marked by an AR-independent, stem-like program with metabolic reprogramming. These findings demonstrate that ctDNA can inform phenotype-driven tumor biology at gene-level resolution, integrating epigenetic modifications, inferred transcriptional programs, and clonal dynamics as a function of treatment response.
    DOI:  https://doi.org/10.21203/rs.3.rs-8778762/v1
  43. Cancers (Basel). 2026 Jan 27. pii: 389. [Epub ahead of print]18(3):
    Epigenetic and Liquid Biopsy Biomarkers in Prostate Cancer: Bridging Tumor Heterogeneity and Clinical Implementation.
    Joanna Robaczyńska, Maciej Maj, Adam Kiljańczyk, Bartosz Pastuszek, Emilia Reducha, Aleksandra Nurkiewicz, Milena Kiljańczyk.
      Prostate cancer (PCa) is the most common malignancy in men, characterized by significant genetic and epigenetic heterogeneity, which complicates both diagnosis and treatment processes. Epigenetic mechanisms-including DNA methylation, chromatin remodeling, and dysregulated non-coding RNAs (miRNAs, lncRNAs, circRNAs)-contribute to tumor initiation, progression, and therapy resistance, offering promising diagnostic and prognostic biomarker opportunities. Liquid biopsy technologies, such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes, allow minimally invasive, real-time monitoring of tumor evolution and resistance mechanisms, complementing traditional biomarkers like PSA and supporting precision oncology approaches. Clinically implemented assays, including PCA3, ConfirmMDx, and ExoDx Prostate, along with emerging multi-analyte panels, enhance risk stratification, reduce unnecessary biopsies, and guide therapeutic decisions. Integration of epigenetic and liquid biopsy biomarkers into multimodal diagnostic pathways has the potential to support personalized management of prostate cancer; however, many still require further validation and optimization.
    Keywords:  biomarkers; ctDNA; epigenetics; liquid biopsy; non-coding RNA; precision oncology; prostate cancer
    DOI:  https://doi.org/10.3390/cancers18030389
  44. Drug Deliv Transl Res. 2026 Feb 10.
    A mechanical reprogramming: synergistic tumor microenvironment normalization improves nano-immunotherapy delivery in prostate cancer via multiphysics modeling.
    Fatemeh Mirala, Madjid Soltani.
      There is a poor response of prostate cancer to immunotherapies because of dysfunctions in the tumor microenvironment (TME) characteristics, like abnormal vasculature structure, stiffened stroma, increased interstitial fluid pressure (IFP), and regions of hypoxia. However, the existing computational modelings are unable to tackle this issue, as they are based on two-dimensional (2D) geometry that ignores TME properties (like TME biphasic composition) and interaction between cancer and immune cells. To address this knowledge gap, this paper offers a patient-specific multiphysics model for prostate cancer. The proposed model is based on three-dimensional (3D) geometry obtained from magnetic resonance imaging (MRI) and combines three complementary approaches to normalizing the tumor microenvironment: vascular normalization via anti-angiogenic therapy, stromal normalization via extracellular matrix softening, and immune checkpoint blockade. One important new aspect of this work is that new nanoparticle delivery models have been developed for 20-100 nm nanoparticles (NP) delivering immunotherapy agents. These equations explicitly incorporate interactions between the components of the TME and directly account for mechanical stress induced by tumor growth, enabling mathematical modeling of physical TME changes and their subsequent impact on the dynamics of immune cells (such as cytotoxic T cells (CD8 + T cells), regulatory T cells (Treg), and pro-inflammatory macrophages (M1-like)/anti-inflammatory macrophages (M2-like) and cancer cells. This capability is absent in previous models. The other important novelty is that for the first time in a prostate cancer model, factors for vascular and stromal normalization and immunotherapy have been incorporated in a 3D geometry. The parameters of this model have been optimized based on literature and preclinical trial data related to immunology and tumors. The sensitivity analysis has confirmed that all therapeutic factors, optimized vascular function (functional vessel density increases from 43 to 112 cm2/cm3), reduced stromal solid stress (decrease in shear modulus from 10.4 to 6.1 kPa), as well as a 70% reduction in IFP (from 1471 to 441 Pa), in combination contribute to a 30% increase in accumulation of nanoparticles in the tumor, 60% increase in the ratio of CD8 + /Tregs, a 45% decrease in the ratio of M1/M2 macrophages, a 15% reduction in the tumor hypoxia gradient, and a 40% decrease in the size of the tumor within 50 days. This model can thus provide a clinically applicable tool for predicting the efficacy of nano-immunotherapy in prostate cancer. Experimental confirmation is required to better evaluate NP toxicity.
    Keywords:  COMSOL Multiphysics; Computational modeling; Drug delivery; Immune response; Immunotherapy; Nanomedicine; Prostate cancer; Stromal normalization; Tumor microenvironment; Vascular normalization
    DOI:  https://doi.org/10.1007/s13346-026-02051-7
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