bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2026–02–01
forty-one papers selected by
Grigor Varuzhanyan, UCLA
  1. Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.
  2. OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.
  3. Remodeling of androgen metabolism network mediated by UGT2B: a new perspective on treatment resistance in prostate cancer.
  4. E2F1-driven cholesterol synthesis via the SND1/ACLY axis potentiates malignant progression in prostate cancer.
  5. Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.
  6. Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent Stem-like/Mesenchymal Prostate Cancer.
  7. C21orf2 as a potential regulator of JAK2/STAT3 signaling in prostate cancer cell proliferation and apoptosis: an exploratory study.
  8. Inhibition of the RORC/GPX4 mediated ferroptosis regulatory axis suppresses tumor growth and alleviates enzalutamide resistance in prostate cancer.
  9. Myeloid-derived suppressor cells promote therapy-induced resistance in prostate cancer.
  10. Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.
  11. Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
  12. Constitutive NF-kB Activation Is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells That Resist Viral Oncolysis.
  13. Polydopamine-Coated Surfaces Promote Adhesion, Migration, Proliferation, Chemoresistance, Stemness, and Epithelial-Mesenchymal Transition of Human Prostate Cancer Cell Lines In Vitro via Integrin α2β1-FAK-JNK Signaling.
  14. Cuproptosis-related gene PROK1 predicts the diagnosis and prognosis of prostate cancer based on multiple machine learning.
  15. Non-Coding RNA Biomarkers in Prostate Cancer: Evidence Mapping and In Silico Characterization.
  16. Clonal selection of pre-existing neuroendocrine component in prostate cancer during androgen receptor signaling inhibitor therapy: A case report.
  17. HSP90α and KLK6 Coregulate Stress-Induced Prostate Cancer Cell Motility.
  18. FOSL2 regulates PD-L1 and modulates hormone therapy response heterogeneity.
  19. PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer.
  20. Machine-Learning-Based Prediction of Biochemical Recurrence in Prostate Cancer Integrating Fatty-Acid Metabolism and Stemness.
  21. GSTA1 deficiency drives neuroendocrine differentiation via TNFRSF13B/c-FOS/CHGA axis in prostate cancer.
  22. High RMI1 expression is associated with cancer cell progression and poor prognosis in prostate cancer.
  23. Adipokine Metabolic Drivers, Gut Dysbiosis, and the Prostate Microbiome: Novel Pathway Enrichment Analysis of the Adiposity-Based Chronic Disease-Prostate Cancer Network.
  24. Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer.
  25. Predicting HER2 overexpression in prostate cancer using machine learning: implications for personalized therapy.
  26. Current update on toll-like receptors and prostate cancer: a decade of progress and emerging insights.
  27. Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA.
  28. Research advances on the risk of prostate cancer from phthalates exposure: from epidemiological evidence to multidimensional prevention and control.
  29. Metformin Sensitizes PTEN-deficient Prostate Cancer to PARP Inhibitors by Rebuilding NADP+ Homeostasis.
  30. Advances in the identification of novel cell signatures in benign prostatic hyperplasia and prostate cancer using single-cell RNA sequencing.
  31. Histone-modifying enzymes as drivers and therapeutic targets in androgen-resistant prostate cancer.
  32. Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.
  33. Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer.
  34. Comprehensive Biochemical Insights into Prostate-Specific Antigen: From Biomarker to Functional Mediator in Prostate Cancer Pathophysiology.
  35. Methyl Protodioscin Promotes Ferroptosis of Prostate Cancer Cells by Facilitating Dissociation of RB1CC1 from the Detergent-Resistant Membranes and Its Nuclear Translocation.
  36. Talin1 Mediates Tumor-Nerve Interactions in Prostate and Breast Cancer Cells.
  37. De Novo high-volume metastatic prostate cancer with primary resistance to standard systemic therapy and exceptional response to PSMA-Lu177: A case report.
  38. Cancer Cell-Intrinsic Cholesterol Induces Lipid-Associated Macrophage Differentiation via SP1 Palmitoylation to Promote Prostate Cancer Progression.
  39. Missense and Intronic Variants in HNF1A Affect Prostate Cancer Aggressiveness in Patients with Biochemical Recurrence.
  40. The castration-resistant prostate cancer-associated SNP rs11067228 facilitates neuroendocrine differentiation through an enhancer-mediated chromatin interaction with SRRM4.
  41. Emerging Therapeutic Strategies in Prostate Cancer: Targeted Approaches Using PARP Inhibition, PSMA-Directed Therapy, and Androgen Receptor Blockade with Olaparib, Lutetium (177Lu)Vipivotide Tetraxetan, and Abiraterone.
  1. Cell Death Dis. 2026 Jan 28.
    Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.
    Lei Chen, Jingyan Zhang, Yanshuo Hu, Xufeng Peng, Hong Wang, Binghua Chen, Jun Xia, Wei Xue, Chun-Wu Pan.
      Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide.GNG4 interacts with GNB1 to stabilize GNAI3 via the ubiquitination-proteasome pathway, thereby activating autophagy. This process promotes prostate cancer progression and resistance to androgen receptor signaling inhibitors (ARSis). In contrast, GNG4 knockdown or pharmacological inhibition of autophagy restores ARSI sensitivity and suppresses tumor growth.
    DOI:  https://doi.org/10.1038/s41419-026-08421-w
  2. Mol Cancer Res. 2026 Jan 27.
    OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.
    Matthew J Bernard, Andrea Gallardo, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Shile Zhang, Ernie Lee, Kylie Y Heering, Grigor Varuzhanyan, Sachi Bopardikar, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Sandy Che-Eun S Lee, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Owen N Witte, Michael C Haffner, David B Shackelford, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.
      As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0913
  3. Eur J Pharmacol. 2026 Jan 23. pii: S0014-2999(26)00078-6. [Epub ahead of print] 178596
    Remodeling of androgen metabolism network mediated by UGT2B: a new perspective on treatment resistance in prostate cancer.
    YuanYuan Wang, Chenxi Tu, Hao Qin, Yingying Ma, Yukai Yang, Yinhua Xiong, Liang Peng, Lin Zhang.
      Prostate cancer (PCa) is the most common and aggressive malignancy in males worldwide, with its progression influenced by multiple factors. Androgens, the primary regulators of prostate cell growth and physiology, play a pivotal role in PCa pathogenesis through the androgen receptor (AR) signaling pathway, thus earning PCa designations as a hormone-sensitive or hormone-dependent cancer. Current anti-androgen therapies (e.g., androgen deprivation therapy, ADT) have demonstrated initial effectiveness but ultimately failed to prevent progression to castration-resistant prostate cancer (CRPC). Previous research has predominantly focused on AR and its associated signaling pathways. However, UGT2B15 and UGT2B17, as key members of the human UDP-glucuronosyltransferase (UGT) family, serve as critical catalytic enzymes in androgen metabolism. They both efficiently convert androgens into more excretable glucuronidated metabolites, thereby modulating systemic hormone levels, primarily affecting the activation of AR. This article systematically explores the association between the UGT2B subfamily and hormone-dependent prostate cancer, covering various aspects such as gene function, regulatory mechanisms, disease progression, and diagnosis. It elucidates the different roles of UGT2B genes and reveals their significant potential in being developed into biomarkers and therapeutic targets, paving the way for improvements in precision medicine for prostate cancer.
    Keywords:  UGT2B; androgen metabolism; biomarker; expression regulation; prostate cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178596
  4. Epigenomics. 2026 Jan 26. 1-14
    E2F1-driven cholesterol synthesis via the SND1/ACLY axis potentiates malignant progression in prostate cancer.
    Xiaopeng Zheng, Chengru Yang, Deqiang Bian, Guoxin Shi, Li Wang, Xiaohan Li, Yufei Chen, Hua Xin, Liming Wang.
       AIM: This study aimed to clarify the mechanisms of E2F transcription factor 1 (E2F1) in the Cholesterol (CHOL) synthesis of Prostate cancer (PCa).
    METHODS: CHOL component content was detected using a commercial test kit. The interaction between E2F1 and staphylococcal nuclease domain-containing protein 1 (SND1) promoter was confirmed employing dual luciferase and chromatin immunoprecipitation assay. RNA immunoprecipitation and RNA pull-down analysis were utilized to validate the interaction between SND1 and ATP citrate lyase (ACLY) mRNA. A xenograft tumor model was used to confirm these mechanisms in vivo.
    RESULTS: E2F1, SND1, ACLY protein levels, along with CHOL concentrations, were up-regulated in human PCa tumor tissues. E2F1 enhanced cell proliferation, invasion, and CHOL synthesis in PCa cells. E2F1 could transcriptionally activate SND1, which subsequently bound to ACLY mRNA, stabilizing its expression. E2F1 induced CHOL synthesis via the enhancement of SND1/ACLY axis. E2F1 promoted CHOL synthesis and PCa tumor growth in vivo.
    CONCLUSION: E2F1 enhanced cell proliferation, invasion, and tumor growth by enhancing CHOL synthesis via the SND1/ACLY axis in PCa models.
    Keywords:  ACLY; CHOL synthesis; E2F1; Pca; SND1
    DOI:  https://doi.org/10.1080/17501911.2026.2617186
  5. Front Oncol. 2025 ;15 1748527
    Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.
    Ephraim J Gardner, Sasikumar Ponnusamy, Remi Adelaiye-Ogala.
      Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in the treatment of castration-resistant prostate cancer (CRPC). Emerging evidence suggests that Enzalutamide resistance is not solely due to the loss of AR dependency but can also arise from epigenomic reprogramming of the AR cistrome toward noncanonical gene networks. Recent studies have revealed that this reprogramming is mediated by previously unrecognized coactivators, including CXXC5, TET2, and EZH2, which cooperate with AR to establish a transcriptional landscape that supports lineage plasticity and therapeutic evasion. These noncanonical AR transcriptional programs enable CRPC cells to survive under continued AR blockade, acting as a transitional state towards neuroendocrine differentiation. Pharmacologic disruption of these coactivators abrogates noncanonical AR activity and suppresses tumor growth, highlighting a tractable vulnerability. These findings redefine AR signaling in advanced disease, suggesting that targeting noncanonical AR coactivators could offer a novel therapeutic paradigm to overcome resistance. Advances in single-cell and epigenomic profiling are poised to delineate further the heterogeneity and dynamics of AR cistrome remodeling in treatment-refractory prostate cancer.
    Keywords:  AR cistrome; advanced prostate cancer; androgen receptor; canonical and noncanonical AR cistrome; enzalutamide resistance; lineage plasticity; noncanonical AR coactivator; therapeutic strategies
    DOI:  https://doi.org/10.3389/fonc.2025.1748527
  6. Int J Biol Sci. 2026 ;22(3): 1126-1141
    Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent Stem-like/Mesenchymal Prostate Cancer.
    Ágata Sofia Assunção Carreira, Marianna Ciuffreda, Nathakan Thongon, Charles M Haughey, Adam Pickard, Sharon L Eddie, Rebecca E Steele, Elena Cerri, Romina Belli, Daniele Peroni, Elisa Facen, Irene Caffa, Moustafa Ghanem, Alessio Nencioni, Andrea Lunardi, Toma Tebaldi, Ian G Mills, Alessandro Provenzani.
      Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux, and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is crucial for identifying patient subgroups that are most likely to benefit from NAMPT-targeted therapies. Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is characterized by independence from androgen receptor (AR) signaling, dependency on YAP/TAZ, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key regulator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells. Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues PC3 cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) depletion. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC-SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes. Murine prostate cancer cells with mesenchymal/stemness phenotypes (DVL3-SCM), that exhibit NNMT overexpression and high aggressiveness in vivo, also show increased sensitivity to FK866 compared with their parental counterparts (DVL3-PAR). In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers.
    Keywords:  CRPC; EMT; FK866; NAMPT; NNMT; Stemness; YAP
    DOI:  https://doi.org/10.7150/ijbs.120532
  7. BMC Cancer. 2026 Jan 29.
    C21orf2 as a potential regulator of JAK2/STAT3 signaling in prostate cancer cell proliferation and apoptosis: an exploratory study.
    ShiHao Jiang, Shuai Su, Delin Wang.
       BACKGROUND: Prostate cancer (PCa) is a major health concern for men worldwide, and its incidence is rising rapidly, so identifying key molecules that regulate the malignant biological behavior of PCa is crucial for early diagnosis and targeted therapy. This study aimed to elucidate the regulatory role of chromosome 21 open reading frame 2 (C21orf2) in the biological functions of prostate cancer cells and further explore the molecular mechanisms by which C21orf2 regulates cell proliferation and apoptosis via the JAK2/STAT3 signaling pathway.
    MATERIALS AND METHODS: In vitro, C21orf2's effects on cell proliferation, migration, invasion, and apoptosis were tested using CCK-8, scratch assays, Transwell assays, TUNEL staining, and electron microscopy. Western blotting assessed the impact of C21orf2 on JAK2/STAT3 proteins and related markers. Co-immunoprecipitation and immunofluorescence explored interactions with downstream targets. In vivo, a subcutaneous xenograft model in nude mice validated C21orf2's role in tumor growth and apoptosis.
    RESULTS: C21orf2 was upregulated in prostate cancer tissues and regulated the malignant biological behavior of prostate cancer cells, and C21orf2 showed a negative correlation with KCTD5. High expression of C21orf2 promoted the activation of the JAK2/STAT3 signaling pathway and upregulated its downstream target genes, including c-MYC, Cyclin A1, Bcl-2, and Cleaved caspase-3, thereby promoting cell proliferation and inhibiting apoptosis.
    CONCLUSIONS: Our study indicates that C21orf2 is a potential biomarker for the diagnosis and treatment of prostate cancer and highlights its potential as a therapeutic target through the JAK2/STAT3 signaling pathway in prostate cancer.
    Keywords:  Apoptosis; C21orf2; JAK2/STAT3 signaling pathway; Proliferation; Prostate cancer
    DOI:  https://doi.org/10.1186/s12885-026-15637-8
  8. Cell Mol Biol Lett. 2026 Jan 24. 31(1): 11
    Inhibition of the RORC/GPX4 mediated ferroptosis regulatory axis suppresses tumor growth and alleviates enzalutamide resistance in prostate cancer.
    Yan Li, Bingqi Zhang, Zhongmin Zhang, Wei Yan, Haoyu Wang, Xun Xu, Anqi Lv, Zhengming Liao, Lang Guo.
       BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) often develop resistance following long-term enzalutamide treatment. Building upon previous research, we aims to further explore the effect of ilicicolin A (ili-A) on enzalutamide resistance and to elucidate the underlying resistance mechanisms.
    METHODS: Proliferation, migration, and invasion of prostate cancer (PCa) cells were evaluated by 5-ethynyl-2'-deoxyuridine (EdU) assays, colony formation, scratch, and Transwell. Cell Counting Kit 8 (CCK-8) was used to assess the efficacy of drug inhibition in CRPC cells. The expression of tumor cell apoptotic proteins and ferroptosis was assessed using western blot (WB) analysis. Coimmunoprecipitation (Co-IP) and proximity ligation assay (PLA) were used to identify the mechanism of interaction between ilicicolin A and ferroptosis. Tumor transplantation experiments with mice were conducted to confirm findings.
    RESULTS: Ili-A showed dose-dependent inhibition of PCa cells including C4-2B and 22Rv1 cell lines. The overexpression of the RORC gene activated the expression of ferroptosis-related proteins, such as FTH1, GPX4 and SLC7A11, and enhanced proliferation of PCa cells. WB experiments indicated that RORC upregulated AR and AR-V7. An enzalutamide-resistant C4-2B cell line revealed that RORC serves as a gene target for enzalutamide resistance. Finally, it was observed that ili-A could suppress CRPC cells proliferation by downregulating RORC expression, thereby promoting ferroptosis and enhancing the sensitivity to enzalutamide.
    CONCLUSIONS: Ili-A inhibited RORC expression, increased malondialdehyde (MDA) content, suppressed glutathione (GSH) production, released free Fe2+, increased reactive oxygen species (ROS), activated the ferroptosis pathway, enhanced enzalutamide sensitivity, and inhibited CRPC cell proliferation. Furthermore, ili-A enhances the interaction between ROR-γ and GPX4.
    Keywords:  Castration-resistant prostate cancer; Drug resistance; Enzalutamide; Ferroptosis; Ilicicolin A; Orphan nuclear receptor
    DOI:  https://doi.org/10.1186/s11658-025-00846-z
  9. Int J Surg. 2026 Jan 28.
    Myeloid-derived suppressor cells promote therapy-induced resistance in prostate cancer.
    Anlin Liu, Pan Song, Zhenghuan Liu, Manuel Colucci, Ping Lai, Luchen Yang, Xin Yan, Haiyun Qiu, Qiang Dong.
      Androgen deprivation therapy (ADT) is the standard treatment for prostate cancer (PCa), but it is often followed by the development of resistance, leading to the progression of castration-resistant prostate cancer. A key factor influencing treatment response, disease progression, and prognosis is the tumor immune microenvironment. Notably, the accumulation of myeloid-derived suppressor cells (MDSCs) within the tumor creates an immunosuppressive milieu, contributing to treatment failure. Interactions between MDSCs and tumor cells in PCa have been shown to drive castration resistance and facilitate tumor progression. Targeting this immunosuppressive microenvironment holds significant promise for improving therapeutic outcomes. Strategies to target MDSCs include modulating their immunosuppressive activity, promoting their maturation, or inducing their apoptosis. While monotherapy with immunotherapy has shown limited survival benefits in PCa, combining MDSC-targeted therapies with immunotherapy may significantly enhance treatment efficacy and patient outcomes. This review aims to examine the role of MDSCs in therapy resistance and explore potential strategies for targeting them in PCa.
    Keywords:  androgen deprivation therapy; castration-resistant; myeloid-derived suppressor cells; prostate cancer
    DOI:  https://doi.org/10.1097/JS9.0000000000004227
  10. FEBS Lett. 2026 Jan 28.
    Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.
    Alexis Wilson, Mackenzie K Herroon, Shane Mecca, Laimar C Garmo, Jacob Lindquist, Shrila Rajendran, Steve M Patrick, Izabela Podgorski.
      The mechanisms supporting progression of metastatic prostate cancer (PCa) in adipocyte-rich bone marrow remain unclear. We hypothesized that stearoyl-coenzyme A desaturase (SCD) promotes PCa survival in bone by modulating stress responses and regulating lipid peroxidation. We show that SCD-high PCa cells are sensitive to SCD loss, showing smaller spheroids, reduced mTOR signaling, and elevated endoplasmic reticulum (ER) stress. SCD expression is further augmented by adipocytes, and SCD loss induces DNA damage and repair activation only with adipocyte exposure. In vivo, pharmacological SCD inhibition reduces tumor size and increases ER stress and DNA damage in SCD-high-expressing bone tumors. These findings suggest SCD plays a role in redox regulation and DNA repair sensitivity, with therapeutic potential for targeting DNA repair pathways in combination with SCD inhibition. Impact statement This study reveals that stearoyl-CoA desaturase (SCD) supports prostate cancer growth in adipocyte-rich bone by regulating redox balance and DNA repair responses, uncovering a metabolic mechanism linking lipid metabolism to genomic stability and suggesting therapeutic potential for combining SCD and DNA repair pathway inhibition.
    Keywords:  DNA damage; ER stress; bone marrow adipocytes; bone metastasis; lipid desaturation; prostate cancer; stearoyl CoA desaturase
    DOI:  https://doi.org/10.1002/1873-3468.70290
  11. Oncol Res. 2026 ;34(2): 10
    Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
    Yang Wu, Dong Xu, Run Shi, Mingwei Zhan, Shaohui Xu, Xin Wang, Jianpeng Zhang, Zhaokai Zhou, Weizhuo Wang, Yongjie Wang, Minglun Li, Zihao Xu, Kaifeng Su.
      Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, largely due to therapy resistance and metastatic progression. Increasing evidence highlights the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), as a critical determinant of disease behavior. CAFs constitute a heterogeneous population originating from fibroblasts, mesenchymal stem cells, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), and adipose tissue. Through dynamic crosstalk with tumor, immune, endothelial, and adipocyte compartments, CAFs orchestrate oncogenic processes including tumor proliferation, invasion, immune evasion, extracellular matrix remodeling, angiogenesis, and metabolic reprogramming. This review comprehensively summarizes the cellular origins, phenotypic and functional heterogeneity, and spatial distribution of CAFs within the prostate TME. We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance, and critically evaluate emerging strategies to therapeutically target CAF-mediated signaling, metabolic, and immune pathways. By integrating recent advances from single-cell and spatial transcriptomics (ST), our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
    Keywords:  Prostate cancer; cancer-associated fibroblasts; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2025.073265
  12. Viruses. 2026 Jan 01. pii: 67. [Epub ahead of print]18(1):
    Constitutive NF-kB Activation Is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells That Resist Viral Oncolysis.
    Alaa A Abdelmageed, Jack F Smerczynski, Mukul Kandwal, Lute J Douglas, Tori L Russell, Matthew C Morris, Stephen Dewhurst, Maureen C Ferran.
      Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF-κB activation and NF-κB-dependent antiviral signaling contribute to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF-κB localized to the nucleus in VSV-infected PC3 cells, but not in the VSV-susceptible LNCaP PrCa cell line. Analysis of the upstream NF-κB inhibitor IκB-α revealed higher levels of both total and phosphorylated IκB-α in PC3 cells compared to LNCaP cells, indicating constitutive activation of the NF-κB pathway via an IκB-α-dependent mechanism. Notably, VSV infection did not alter IκB-α phosphorylation in PC3 cells, suggesting that VSV may amplify NF-κB signaling through an IκB-α-independent pathway. Furthermore, PC3 cells displayed elevated levels of the NF-κB p65 protein subunit compared to LNCaP cells, with its phosphorylated form significantly increased upon VSV infection. These results from phosphorylation assays confirm that multiple steps in the NF-κB pathway are differentially activated in PC3 and LNCaP cells. Finally, the expression of several NF-κB-dependent cytokines and proinflammatory genes, including IL12 and IL6, was upregulated following VSV infection in PC3 cells, as compared to LNCaP cells. Collectively, these findings suggest that enhanced NF-κB signaling may underlie the resistance of PC3 cells to VSV oncolysis, potentially offering new insights into therapeutic strategies targeting NF-κB in resistant prostate cancers.
    Keywords:  IkB-a; NF-kB; VSV; apoptosis; cytokines; cytolysis; interferon; oncolytic resistance; p65
    DOI:  https://doi.org/10.3390/v18010067
  13. Int J Mol Sci. 2026 Jan 08. pii: 655. [Epub ahead of print]27(2):
    Polydopamine-Coated Surfaces Promote Adhesion, Migration, Proliferation, Chemoresistance, Stemness, and Epithelial-Mesenchymal Transition of Human Prostate Cancer Cell Lines In Vitro via Integrin α2β1-FAK-JNK Signaling.
    Won Hoon Song, Ji-Eun Kim, Lata Rajbongshi, Su-Rin Lee, Yuna Kim, Seon Yeong Hwang, Sae-Ock Oh, Byoung Soo Kim, Dongjun Lee, Sik Yoon.
      Polydopamine (PDA) surface coatings are widely used in biomedical engineering to enhance cell-substrate interactions; however, their effects on cancer-cell behavior remain unclear. In this study, we investigated how PDA-coated two-dimensional (2D) culture surfaces influence oncogenic traits of human prostate cancer (PC) cells in vitro. Using LNCaP, DU145, and PC3 cell lines, we found that PDA-coated substrates markedly increased the adhesion, migration, invasion, proliferation, and colony formation in a dose- and time-dependent manner. PDA exposure also induced epithelial-mesenchymal transition (EMT), upregulated cancer stem cell markers (CD44, CD117, CD133, Sox2, Oct4, and Nanog), and elevated expression of metastasis- and chemoresistance-associated molecules (MMP-2, MMP-9, MDR1, and MRP1). Mechanistically, PDA coatings enhanced integrin α2β1-associated cell adhesion, accompanied by increased focal adhesion kinase (FAK) phosphorylation and downstream activation of JNK signaling. Pharmacological inhibition of integrin α2β1 (BTT-3033), FAK (PF573228) and JNK (SP600125) effectively abrogated PDA-induced malignant phenotypes and restored chemosensitivity to cabazitaxel, cisplatin, docetaxel, curcumin, and enzalutamide. Collectively, these findings identify PDA-coated surfaces as a simple, efficient, and reductionist in vitro platform for studying adhesion-mediated signaling and phenotypic plasticity in PC cells, while acknowledging that further validation in three-dimensional (3D) and patient-derived models will be required to establish in vivo relevance.
    Keywords:  FAK–JNK signaling; adhesion; chemoresistance; epithelial–mesenchymal transition; migration; polydopamine; proliferation; prostate cancer; stemness
    DOI:  https://doi.org/10.3390/ijms27020655
  14. J Cancer. 2026 ;17(2): 268-289
    Cuproptosis-related gene PROK1 predicts the diagnosis and prognosis of prostate cancer based on multiple machine learning.
    Xin Qin, Qinghua Wang, Wei Jiang, Yan Zhao, Haopeng Li, Tong Zi, Yaru Zhu, Xilei Li, Chengdang Xu, Tao Yang, Xinan Wang, Yicong Yao, Xi Chen, Juan Zhou, Gang Wu.
      Cuproptosis, a newly identified form of cell death, influences the development, progression, and prognosis of prostate cancer (PCa). Identifying key genes associated with cuproptosis and developing robust predictive models through machine learning approaches are crucial for personalized PCa treatment. In our study, multiple machine learning methods and their combinations were employed for the construction of diagnostic and prognostic models for PCa, which were then validated in multiple external independent cohorts. The model key gene, PROK1, was selected for further analysis, and its expression was compared in clinical samples and cell lines. Additionally, the anticancer effect of PROK1 was explored through regulating the expression of PROK1. Most cuproptosis-related genes (CRGs) showed differential expression between PCa and normal prostate tissues. The two clusters derived from the Consensus Clustering method, based on cuproptosis gene expression characteristics, exhibit distinct clinical features and immune microenvironment infiltration patterns. Models constructed based on machine learning methods showed promising diagnostic capabilities for PCa and were associated with the prediction of biochemical recurrence-free survival and disease-free survival of patients. Inhibiting PROK1 expression promoted PCa cell proliferation and invasion, while its overexpression had the opposite effect. Furthermore, pathway exploration revealed that PROK1 inhibits tumor growth by mediating apoptosis under copper ion stress. Its association with cuproptosis warrants further investigation to elucidate the precise mechanism.
    Keywords:  PROK1; cuproptosis; diagnosis; machine learning; prognosis; prostate cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.7150/jca.113505
  15. Life (Basel). 2026 Jan 08. pii: 95. [Epub ahead of print]16(1):
    Non-Coding RNA Biomarkers in Prostate Cancer: Evidence Mapping and In Silico Characterization.
    Lorena Albarracín-Navas, Nicolás I Lara-Salas, Javier H Alarcon-Roa, Maylin Almonte-Becerril, Enmanuel Guerrero, Ángela L Riffo-Campos.
      Non-coding RNAs (ncRNAs) have emerged as promising biomarkers for prostate cancer (PCa), yet evidence remains dispersed across heterogeneous studies and their regulatory context is seldom analyzed in an integrated manner. This study systematically maps ncRNAs reported as diagnostic biomarkers for PCa and characterizes their molecular interactions through in silico analyses. A comprehensive evidence-mapping strategy across major bibliographic databases identified 693 studies, of which 58 met eligibility criteria. Differentially expressed ncRNAs were extracted and classified by RNA type. Subsequently, miRNA-target prediction, miRNA-protein interaction network construction, and functional enrichment analyses were performed to explore the regulatory landscape of miRNA-associated proteins. Results: The final dataset included 4500 participants (2871 PCa cases and 2093 controls) and reported 94 differentially expressed miRNAs, eight lncRNAs, and several circRNAs, snoRNAs, snRNAs, and piRNAs. In silico analyses predicted 13,493 miRNA-mRNA interactions converging on 4916 unique target genes, with an additional 2481 prostate tissue-specific targets. The miRNA-protein network comprised 845 nodes and 2335 edges, revealing highly connected miRNAs (e.g., hsa-miR-16-5p, hsa-miR-20a-5p) and protein hubs (QKI, YOD1, TBL1XR1; prostate-specific CDK6, ACVR2B). Enrichment analysis showed strong overrepresentation of metabolic process-related GO terms and cancer-associated KEGG pathways. Conclusions: These findings refine the list of promising ncRNA biomarkers and highlight candidates for future clinical validation.
    Keywords:  circRNA; diagnostic biomarkers; in silico analysis; lncRNA; miRNA; miRNA–protein interaction network; non-coding RNA; piRNA; prostate cancer; snoRNA
    DOI:  https://doi.org/10.3390/life16010095
  16. Urol Case Rep. 2026 Mar;65 103347
    Clonal selection of pre-existing neuroendocrine component in prostate cancer during androgen receptor signaling inhibitor therapy: A case report.
    Haruka Kubota, Toshiki Kijima, Hadzki Matsuda, Toshitaka Uematsu, Kohei Takei, Masahiro Yashi, Kazuyuki Ishida, Takao Kamai.
      Neuroendocrine prostate cancer (NEPC) is often considered treatment-induced. We report a case with pre-existing neuroendocrine differentiation that became evident during androgen receptor signaling inhibitor (ARSI) therapy. A 79-year-old man with metastatic prostate cancer received degarelix plus apalutamide. Prostate-specific antigen (PSA) decreased to <0.01 ng/mL. Subsequently, lung and liver metastases developed while PSA remained low, with neuron-specific enolase rising to 584 ng/mL. Liver biopsy revealed PSA-negative, neuroendocrine marker-positive carcinoma. Re-evaluation of initial biopsy demonstrated positivity for both PSA and neuroendocrine markers, indicating pre-existing neuroendocrine differentiation.
    Keywords:  Androgen receptor signaling inhibitor; Clonal selection; Neuroendocrine prostate cancer; PSA-imaging discordance
    DOI:  https://doi.org/10.1016/j.eucr.2026.103347
  17. Cells. 2026 Jan 16. pii: 166. [Epub ahead of print]15(2):
    HSP90α and KLK6 Coregulate Stress-Induced Prostate Cancer Cell Motility.
    Katelyn L O'Neill, Johnny W Zigmond, Raymond Bergan.
      Prostate cancer (PCa) metastasis is reliant on the activity of proteases, such as matrix metalloproteinase-2 (MMP-2). While increased extracellular heat shock protein 90α (eHSP90α) has been linked to increased MMP-2 activity, this has not been examined in the context of cellular stress. We examined stress-induced eHSP90α in human prostate cell lines by immunoblot. Fluorometric gelatin dequenching and zymography assays measured MMP activity. Wound healing and Matrigel drop invasion assays were used to quantify cell motility. HSP90α knockout (KO) cells were established with CRISPR/Cas9. Proteases were profiled with molecular inhibitors and protein arrays and validated by siRNA knockdown, immunoblot, and motility assays. Stress increased eHSP90 in four out of four human prostate cell lines examined. Surprisingly, it concurrently decreased MMP-2 activity. The functional relevance of this was demonstrated when conditioned media from stressed cells decreased the motility of non-stressed cells. Screening for protease inhibitors that would rescue stress-induced decreases in MMP-2 activity identified a single serine protease inhibitor: aprotinin. Yet rescue with aprotinin was lost in HSP90α KO cells. A protease array identified stress-induced increases in kallikrein-related peptidase 6 (KLK6). Knockdown of KLK6 rescued stress-induced MMP-2 activity and cell motility. In conclusion, we identify a novel stress-induced extracellular network that regulates MMP-2 activity and cell motility. We identified KLK6 as a stress-induced extracellular protease leading to decreased MMP-2 activity and cellular invasion, while eHSP90α is required for the rescue of MMP-2 activity once KLK6 is neutralized.
    Keywords:  HSP90α; KLK6; MMP-2; cell motility; prostate cancer; stress
    DOI:  https://doi.org/10.3390/cells15020166
  18. Mol Cancer Res. 2026 Jan 30.
    FOSL2 regulates PD-L1 and modulates hormone therapy response heterogeneity.
    Feifei Sun, Baozhen Wang, Shuyu Mei, Lin Zhang, Xinpei Wang, Hui Liu, Wenyao Liu, Jiajia Wang, Qianqian Zhou, Bo Han, Jing Hu, Lin Gao, Xueli Wang.
      The response to androgen-targeted therapy in prostate cancer (PCa) is highly heterogeneous. While previous studies have primarily concentrated on tumor cell-intrinsic signaling changes, the tumor microenvironment, particularly the interactions between tumor-infiltrating lymphocytes (TILs) and tumor cells, is equally critical in shaping treatment responses. Building on our previous observations linking TILs to treatment efficacy in the context of neoadjuvant androgen deprivation therapy (NADT), we employed publicly available clinical datasets, in vitro T cell-PCa cell co-culture systems, and murine xenograft models to investigate this interplay. We found treatment-related dynamic change in TILs populations, accompanied by a concordant expression pattern of FOSL2 and PD-L1. Mechanistically, FOSL2 directly bound to the PD-L1 promoter to transcriptionally upregulate PD-L1, thereby modulating T cell infiltration and function. Importantly, in vivo results demonstrated that targeting FOSL2 enhanced the antitumor effect when it combined with hormone therapy and anti-PD-L1 treatment. These findings suggest that FOSL2 may contribute to treatment response heterogeneity by shaping the tumor immune microenvironment, offering novel insights into resistance mechanisms and uncovering potential strategies to enhance the efficacy of hormone therapy in PCa. Implications: Targeting FOSL2-mediated PD-L1 regulation offers a promising strategy to overcome immune microenvironment-mediated resistance and improve the therapeutic efficacy of androgen-targeted therapy in PCa.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0611
  19. J Clin Invest. 2026 Jan 27. pii: e197157. [Epub ahead of print]
    PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer.
    Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang.
      Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARP inhibitors (PARPi) may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restore natural killer (NK) cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlates with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells binds to ANXA6 and activates the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocks the FPR1-AKT signaling and diminishes the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolongs survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.
    Keywords:  Cancer immunotherapy; Immunology; NK cells; Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI197157
  20. Int J Mol Sci. 2026 Jan 12. pii: 750. [Epub ahead of print]27(2):
    Machine-Learning-Based Prediction of Biochemical Recurrence in Prostate Cancer Integrating Fatty-Acid Metabolism and Stemness.
    Zao Dai, Ningrui Wang, Mengyao Liu, Zhenguo Wang, Guanyun Wei.
      Prostate cancer (PCa) is a common malignancy among men worldwide. After radical prostatectomy (RP) and radical radiotherapy (RT), patients may experience biochemical recurrence (BCR) of prostate cancer, indicating disease progression. Therefore, it is meaningful to predict and accurately assess the risk of BCR, and a machine-learning-based-model for BCR prediction in PCa based on fatty-acid metabolism and cancer-cell stemness was developed. A stemness prediction model and ssGSEA (single-sample gene set enrichment analysis) empirical cumulative distribution function algorithm were used to score the stemness scoring (mRNAsi) and fatty-acid metabolism of prostate-cancer samples, respectively, and further analysis showed that the two scores of the samples were positively correlated. Based on WGCNA (weighted correlation network analysis), we discovered modules significantly associated with both stemness and fatty-acid metabolism and obtained the genes within them. Then, based on this gene set, 101 algorithm combinations of 10 machine-learning methods were used for training and prediction BCR of PCa, and the model with the best prediction effect was named fat_stemness_BCR. Compared with 23 published PCa BCR models, the fat_stemness_BCR model performs better in TCGA and CPGEA data. To facilitate the use of the model, the trained model was encapsulated into an R package and an online service tool (PCaMLmodel, Version 1.0) was built. The newly developed fat_stemness_SCR model enriches the prognostic research of biochemical recurrence in PCa and provides a new reference for the study of other diseases.
    Keywords:  machine learning; prostate cancer
    DOI:  https://doi.org/10.3390/ijms27020750
  21. Int J Biol Sci. 2026 ;22(3): 1632-1647
    GSTA1 deficiency drives neuroendocrine differentiation via TNFRSF13B/c-FOS/CHGA axis in prostate cancer.
    Jiajun Qian, Yang Luo, Yao Fu, Wenli Diao, Qiubo Ding, Wei Chen, Xuefeng Qiu, Hongqian Guo.
      Rationale: Androgen deprivation therapy (ADT) is the cornerstone of prostate cancer (PCa) treatment. Prolonged ADT inevitably increases the risk of neuroendocrine differentiation, which leads to the development of hormone-refractory subtypes. In this study, we explored the molecular mechanisms underlying the neuroendocrine differentiation of PCa cells under ADT. Methods: We performed digital spatial profiling (DSP) sequencing using tissue microarrays from five patients with PCa who underwent neoadjuvant therapy before radical prostatectomy at the Nanjing Drum Tower Hospital. Results: Glutathione S-transferase alpha 1 (GSTA1) was identified as a driver of neuroendocrine differentiation in PCa cells using DSP sequencing of tissue microarrays prepared from clinical samples. Following enzalutamide (ENZ) treatment, GSTA1 expression is inhibited. Decreased GSTA1 levels have also been reported in patients with neuroendocrine PCa (NEPC). GSTA1 knockdown leads to increased intracellular reactive oxygen species (ROS), which can activate the inflammatory gene, tumor necrosis factor receptor superfamily member 13B (TNFRSF13B). TNFRSF13B induces c-Fos expression, forming a transcriptional complex with c-Jun, thereby regulating chromogranin A (CHGA) and promoting the neuroendocrine phenotype. Conclusion: Our study suggested that GSTA1 deficiency leads to elevated ROS levels and activation of TNFRSF13B and c-FOS, which subsequently transcriptionally regulate CHGA and ultimately drive neuroendocrine differentiation in PCa.
    Keywords:  androgen deprivation therapy; glutathione S-transferase alpha 1; neuroendocrine differentiation; prostate cancer
    DOI:  https://doi.org/10.7150/ijbs.120497
  22. Oncol Rep. 2026 Apr;pii: 55. [Epub ahead of print]55(4):
    High RMI1 expression is associated with cancer cell progression and poor prognosis in prostate cancer.
    Pengliang Shen, Xiaosong Wang, Xiaoting Yan, Hongyang Du, Bo Wu, Xiaoming Cao.
      DNA replication stress and energy homeostasis are critical yet underexplored pathways in prostate cancer (PCa). Identifying PCa prognostic biomarkers associated with these pathways are essential for advancing diagnostics and treatment. The present study aimed to analyze transcriptomic and clinical data from public datasets to identify DNA replication stress and energy homeostasis‑related genes associated with PCa. Biomarkers were assessed using reverse transcription‑quantitative (RT‑q) PCR, western blotting and consistent expression trends across datasets. Survival analyses evaluated the effect of biomarkers on clinical outcomes, while immune microenvironment changes and immunotherapy responses were evaluated. Mutation and drug sensitivity analyses explored genetic variations and chemotherapy efficacy. Functional assays, including cell proliferation, migration, RT‑qPCR and western blotting, confirmed biomarker roles in PCa progression. RecQ mediated genome instability 1 (RMI1) was identified as a novel biomarker, consistently upregulated in PCa tissues across datasets and experiments (P<0.05). High RMI1 expression was associated with worse survival outcomes, advanced clinical stages, immune escape and TP53 mutations. Enrichment analysis linked RMI1 to cell cycle, DNA replication and metabolic pathways. Functional assays revealed that RMI1 knockdown inhibited PCa cell proliferation and migration, suggesting its role in tumor progression. Additionally, high RMI1 expression was associated with resistance to certain chemotherapeutic agents, such as irinotecan. These results underscored RMI1 as a promising prognostic biomarker and a potential therapeutic target for the management of PCa. In conclusion, the present study identified RMI1 as a biomarker for the detection of PCa and may promote cancer cell progression by promoting proliferation and migration.
    Keywords:  DNA replication stress; RecQ mediated genome instability 1; biomarker; energy homeostasis; prostate cancer
    DOI:  https://doi.org/10.3892/or.2026.9060
  23. Cancers (Basel). 2026 Jan 08. pii: 206. [Epub ahead of print]18(2):
    Adipokine Metabolic Drivers, Gut Dysbiosis, and the Prostate Microbiome: Novel Pathway Enrichment Analysis of the Adiposity-Based Chronic Disease-Prostate Cancer Network.
    Zachary Dovey, Elena Tomas Bort, Jeffrey I Mechanick.
      Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man's life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa.
    Keywords:  adiposity-based chronic disease; gut dysbiosis; inflammatory pathways; pathway enrichment analysis; prostate cancer; prostatitis
    DOI:  https://doi.org/10.3390/cancers18020206
  24. Biochem Pharmacol. 2026 Jan 27. pii: S0006-2952(26)00091-2. [Epub ahead of print] 117760
    Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer.
    Jun Yan, Long Cheng, Qing-Qing Ma, Qiao-Xuan Zhang, Shu Gan, Hai-Biao Lin, Li-Qiao Han, Peng-Wei Zhang, Fen Ouyang, Pei-Feng Ke, Xian-Zhang Huang.
      Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound CD-15, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, CD-15 displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of CD-15. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of CD-15 in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that CD-15 covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, CD-15 exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, CD-15 emerges as a promising candidate for the treatment of PCa and deserves further investigation.
    Keywords:  Chalcone derivative; Drug development; Ferroptosis; Prostate cancer; Thioredoxin reductase
    DOI:  https://doi.org/10.1016/j.bcp.2026.117760
  25. Front Oncol. 2025 ;15 1707946
    Predicting HER2 overexpression in prostate cancer using machine learning: implications for personalized therapy.
    Xuantong Huang, Zhen Jiang, Xun Wang, Jie Gao, Danyan Li, Qing Zhang, Xiaozhi Zhao, Hongqian Guo.
       Background: Human Epidermal Growth Factor Receptor 2 (HER2), a component of the epidermal growth factor receptor family, is thought to be related to advanced prostate cancer (PCa) when overexpressed. Currently, most research on HER2 is limited to molecular pathology, with relatively few studies focused on imaging aspects.
    Objectives: To develop a predictive model by extracting high-throughput radiomics features from magnetic resonance imaging and combining them with clinical characteristics for predicting HER2 overexpression.
    Materials and methods: A total of 201 patients who underwent radical prostatectomy and HER2 immunohistochemistry were retrospectively enrolled. These patients were randomly divided into a training set (n=160) and a test set (n=41). Multimodal radiomics features extracted from T2-weighted imaging (T2WI) and apparent diffusion coefficient maps (ADC) were selected using Mann-Whitney U test and least absolute shrinkage and selection operator (LASSO) with ten-fold cross-validation. Predictive models were developed and evaluated based on discrimination and clinical utility.
    Results: The combined model integrating ISUP Grade, PSA and Radscore achieved an area under the curve (AUC) of 0.841 (95% CI: 0.697-0.955) in the test set, significantly outperforming the clinical model (AUC = 0.580; p = 0.02, DeLong test) and demonstrating a modest improvement over the Radscore model (AUC = 0.838 (0.693-0.951). Evaluation results showed consistent discriminatory power: 0.78 accuracy, 0.77 sensitivity, and 0.79 specificity, indicating well-balanced performance between positive and negative classes. Decision curve analysis and Waterfall plot demonstrated strong clinical applicability.
    Conclusion: The combined model effectively predicts HER2 overexpression in prostate cancer, with potential to inform more personalized treatment strategies for HER2-overexpressing PCa patients.
    Keywords:  HER2; machine learning; magnetic resonance imaging; prostate cancer; radiomics
    DOI:  https://doi.org/10.3389/fonc.2025.1707946
  26. Front Immunol. 2025 ;16 1711815
    Current update on toll-like receptors and prostate cancer: a decade of progress and emerging insights.
    Jahnavi Janjirala, Matthew Blanton, Kenneth S Ramos, Dekai Zhang.
      Prostate cancer remains the most common cancer and the second leading cause of cancer-related mortality among men in the United States. Despite advances in therapy, relapses and progression of disease continue to pose major clinical challenges, underscoring the need for innovative strategies. A decade ago, we reviewed the emerging evidence linking Toll-like receptors (TLRs), a family of innate immune sensors, to prostate cancer initiation and progression. Since then, substantial advances have deepened our understanding of TLR biology in prostate cancer, revealing their role in either promoting tumor growth or activating anti-tumor immunity depending on cellular context and signaling pathways. Recent studies have expanded knowledge of TLR expression on both immune and tumor cells, identified key endogenous ligands driving chronic inflammation, and uncovered microRNA-mediated regulation of TLR signaling. Moreover, new insights into TLR polymorphisms and their potential association with cancer risk, as well as preclinical and clinical progress in TLR-targeted immunotherapies, highlight both opportunities and challenges in translating TLR biology into therapeutic applications. In this review, we update the field by summarizing the latest discoveries, evaluating the complexities of TLR signaling in prostate cancer, and discussing how this evolving knowledge may inform future biomarker development and immunotherapeutic strategies.
    Keywords:  cancer immunity; immune checkpoint inhibitor; immunotherapy; innate immunity; prostate cancer; toll-like receptors
    DOI:  https://doi.org/10.3389/fimmu.2025.1711815
  27. Int J Biol Sci. 2026 ;22(3): 1306-1321
    Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA.
    Xu Wu, Hui Gao, Qianfeng Zhuang, Feng Li, Xingliang Feng, Naiyuan Shao, Wei Zhang, Yuyang Zhang, Xiansheng Zhang.
      Enzalutamide (ENZ), a next-generation androgen receptor (AR) inhibitor, is a cornerstone treatment for metastatic prostate cancer. However, resistance to ENZ inevitably develops in these patients, and the mechanisms underlying this resistance remain poorly understood. This study reveals that UFL1 is dysregulated in ENZ-resistant cells, xenograft models, and prostate tumors. UFL1 deficiency enhances prostate cancer cell resistance to ENZ both in vitro and in vivo. Mechanistically, UFL1 loss decreases METTL16 UFMylation, thereby reducing its ubiquitination level and increasing its protein stability. Additionally, METTL16-mediated m6A modification of EEF1A1 mRNA activates the m6A-IGF2BP1 axis, resulting in increased EEF1A1 protein levels and enhanced resistance to ENZ-induced apoptosis. These findings uncover a novel UFL1-METTL16-EEF1A1 signaling pathway that drives ENZ resistance, suggesting that targeting this cascade may offer a promising therapeutic strategy for overcoming ENZ resistance in prostate cancer.
    Keywords:  EEF1A1; METTL16; UFL1; enzalutamide resistance
    DOI:  https://doi.org/10.7150/ijbs.124214
  28. Front Cell Dev Biol. 2025 ;13 1740894
    Research advances on the risk of prostate cancer from phthalates exposure: from epidemiological evidence to multidimensional prevention and control.
    Binbin Wang, Hongliang Cao, Shuxin Li, Zhijun Tang, Gengchen Huang, Zhanhao Li, Yutao Ma, Wei Wei, Mo Chen.
      Prostate cancer (PCa) poses a significant threat to men's health worldwide, with persistently high incidence and mortality rates. Phthalates (PAEs), typical environmental endocrine disruptors (EDCs), are ubiquitous in the environment and readily accumulate in the human body due to their widespread use in plastics and consumer products. Their potential role in PCa development has drawn considerable attention. This review systematically summarizes the epidemiological associations between PAEs and PCa, their potential mechanisms of action, long-term risks, and corresponding prevention and control strategies. Epidemiological studies confirm that high-molecular-weight PAEs (e.g., di(2-ethylhexyl) phthalate [DEHP], dibutyl phthalate [DBP]) are significantly associated with increased PCa risk, with abdominally obese men identified as a susceptible population. Urinary PAE metabolites (e.g., mono(2-ethylhexyl) phthalate [MEHP], mono-n-butyl phthalate [MnBP]) serve as non-invasive biomarkers for assessing PAE exposure in prostate tissue. Mechanistically, PAEs may regulate PCa progression through multiple pathways, including disrupting the androgen/estrogen signaling balance, inducing epigenetic abnormalities (DNA hypomethylation, microRNA dysregulation), activating pro-proliferative/invasive signaling pathways (MAPK/AP-1, Wnt/β-catenin pathways), and inducing oxidative stress and facilitating epithelial-mesenchymal transition (EMT). Concurrently, PAEs may pose long-term carcinogenic risks through developmental programming and synergistic interactions with obesity to exacerbate PCa risk. Furthermore, this review proposes a multi-tiered prevention and control system comprising industrial source control, targeted protection of susceptible populations, occupational safeguards, and clinical integration. Future research should focus on core scientific questions, such as identifying key PAE subtypes that may be carcinogenic to the prostate, elucidating transgenerational epigenetic mechanisms underlying PAE-induced PCa susceptibility, and verifying the reversibility of PAE-obesity interactions in PCa development, to provide more substantial evidence for mitigating PAE-associated PCa risk.
    Keywords:  biomarkers; endocrine disruption; epidemiological association; mechanism of action; phthalate esters (paes); prevention and control strategies; prostate cancer (PCa)
    DOI:  https://doi.org/10.3389/fcell.2025.1740894
  29. Int J Biol Sci. 2026 ;22(3): 1346-1368
    Metformin Sensitizes PTEN-deficient Prostate Cancer to PARP Inhibitors by Rebuilding NADP+ Homeostasis.
    Xiaodong Hao, Zheng Chao, Hao Peng, Xiangdong Guo, Shuo Zheng, Chunyu Zhang, Hao Ding, Yanan Wang, Zirui Xi, Yuan Gao, Guanyu Qu, Yao Zhu, Zhiqiang Chen, Peixiang Lan, Le Li, Zhihua Wang.
      Purpose: DNA repair and DNA damage responses in cancer cells are regulated by metabolic reprogramming, which is increasingly recognized as a key factor contributing to PARP inhibitor (PARPi) treatment failure. This study aims to explore the metabolic mechanisms underlying PARPi resistance in PTEN-deficient prostate cancer and identify clinically viable metabolic interventions to overcome therapy failure. Experimental Design: A multicenter retrospective cohort was analyzed to evaluate the efficacy of combined metformin-PARPi therapy. Mechanistic studies utilized molecular assays to elucidate PARPi resistance and its critical determinants. Machine learning models predicting PARPi response were developed using clinical datasets and interpreted via SHAP analysis. Results: In PTEN-deficient cancer cells, lactate accumulation activated the NHE1/PKC/NOX1 axis, sustaining elevated NADP+ levels. NADP+ competitively inhibited the formation of PARPi-PARP-DNA complexes, leading to PARPi resistance. However, metformin administration significantly elevated NADP+ levels, inducing allosteric effects on PARP structures and enhancing PARPi efficacy. Based on these findings, we developed and validated a predictive machine learning model for PARPi response, which was interpreted using SHAP and deployed on a web platform. Conclusions: Metformin modulates NADP+ levels to influence PARPi sensitivity in PTEN-deficient prostate cancer. Additionally, we developed a machine learning model to provide clinicians with personalized predictions for PARPi response.
    Keywords:  NADP+; PARP inhibitor; PTEN-deficient PCa; machine learning model; metformin
    DOI:  https://doi.org/10.7150/ijbs.121033
  30. Front Immunol. 2025 ;16 1684895
    Advances in the identification of novel cell signatures in benign prostatic hyperplasia and prostate cancer using single-cell RNA sequencing.
    Yu Pan, Qingqing Song, Bingjie Lai, He Ma.
      Nowadays, chronic benign and malignant prostatic diseases are prevalent, costly, and impose a significant burden. Benign prostatic hyperplasia (BPH), a common condition in the aging population, often coexists with localized prostate cancer (PCa). These diseases likely share underlying molecular mechanisms, which remain poorly understood. The exploration of novel cell subpopulations and specific biomarkers for accurate diagnosis and treatment of prostatic diseases is ongoing and holds great clinical promise. Prostate cell proliferation and immune inflammation are key contributors to the progression of BPH and PCa, involving various prostate and immune cell subpopulations. This raises important questions about how specific cell types drive phenotypic heterogeneity. Advanced single-cell RNA sequencing (scRNA-seq), a cutting-edge technology, offers unparalleled insights at the single-cell level. Similar to a microscope that identifies cell types within tissue samples, scRNA-seq elucidates cellular heterogeneity and diversity within single cell populations, positioning itself as a future-leading sequencing technology. Considering that BPH and PCa share androgen-dependent growth, chronic inflammation and specific microenvironmental changes, this review discusses recent discoveries of novel cell subpopulations and molecular signatures in BPH and PCa that can be dissected by scRNA-seq. It aims to help researchers better understand the molecular pathogenesis of these conditions while offering new therapeutic possibilities for clinical management of benign and malignant prostatic disorders.
    Keywords:  benign prostatic hyperplasia; cell subpopulations; chronic prostatic diseases; molecular signatures; prostate cancer; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2025.1684895
  31. Front Endocrinol (Lausanne). 2025 ;16 1730397
    Histone-modifying enzymes as drivers and therapeutic targets in androgen-resistant prostate cancer.
    Tanaya A Purohit, Kayla Bahr, Bing Yang, Zachery Schultz, Peter W Lewis, John M Denu, David F Jarrard.
      Androgen deprivation therapy (ADT) remains the cornerstone of treatment for advanced, hormone-sensitive prostate cancer (HSPC), but responses are transient, and most patients ultimately develop castration-resistant prostate cancer (CRPC), a largely incurable stage of disease. The mechanisms driving resistance are not yet fully understood. Recent data suggest epigenetic dysregulation driven by alterations in chromatin remodelers and histone-modifying enzymes (HMEs) contributes significantly to prostate cancer (PC) progression and resistance to androgen-directed therapies. HMEs control chromatin structure and transcriptional programs, and their altered activity contributes to androgen resistance and tumor progression. HME inhibitors offer promising therapeutic potential, yet their effects are highly context-dependent, emphasizing the importance of biomarker-guided precision strategies and rational combination therapies. This review highlights the contribution of histone PTMs and HMEs to CRPC progression and discusses their potential as novel strategies to improve clinical outcomes.
    Keywords:  EZH2 overexpression; NSD2; androgen resistance; castration-resistant prostate cancer; epigenetics (chromatin remodeling); histone acetylation; histone methylation; prostate cancer
    DOI:  https://doi.org/10.3389/fendo.2025.1730397
  32. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2515790122
    Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.
    Nicole A Traphagen, Esmé Wheeler, Rong Li, Tara Akhshi, Ramya Ravindranathan, Christian Alfieri, Feng Lu, Buraq Ahmed, Alok K Tewari, Steven P Balk, Peter S Nelson, Eva Corey, Henry Long, Alan D D'Andrea, Xintao Qiu, Myles Brown.
      Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination-proficient prostate cancer.
    Keywords:  PARP inhibitor; androgen receptor; castration-resistant; prostate cancer
    DOI:  https://doi.org/10.1073/pnas.2515790122
  33. J Med Chem. 2026 Jan 29.
    Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer.
    James S Scott, Laura Evans, Peter C Astles, Argyrides Argyrou, Sharan K Bagal, David Beattie, Erin L Braybrooke, Doyle J Cassar, Claire Crafter, Coura Diène, Gary Fairley, Charlene Fallan, Graham Fraser, Nuria Galeano-Dalmau, Thomas G Hammond, Andreas K Hock, Thomas Jones, Jasper Komen, Gillian M Lamont, Chrysiis Michaloglou, Michael J Niedbala, Antonio Ramos-Montoya, Monica C Rodrigo-Brenni, Martin J Packer, Stuart Pearson, Andy Pike, Markus Schade, Joseph Shaw, Ziyanda Shologu, Oliver Steward.
      Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an in vitro mitotoxicity signal to give 3n. This compound inhibited AR signaling in vitro and was able to inhibit tumor growth in vivo in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03138
  34. Anticancer Agents Med Chem. 2026 Jan 21.
    Comprehensive Biochemical Insights into Prostate-Specific Antigen: From Biomarker to Functional Mediator in Prostate Cancer Pathophysiology.
    Laxmidhar Das.
      Prostate-Specific Antigen (PSA) is a glycoprotein produced in the prostate and is widely used as a biomarker for the diagnosis of prostate cancer (PCa). Although elevated PSA levels are often associated with PCa, several noncancerous conditions can also lead to increased PSA. In addition to total PSA, various PSA isoforms are detectable in the blood of patients, and their levels may differ depending on the underlying pathophysiological condition, whether benign or malignant. Measuring serum PSA levels alone is not sufficient to detect PCa, leading to widespread overdiagnosis and overtreatment. Therefore, comprehensive biochemical insights into PSA and its isoforms, of normal, benign, and malignant origin, may improve PSA assays for PCa diagnosis. Apart from its role as a biomarker, PSA plays multiple roles in the pathophysiology of PCa by activating the Epithelial-Mesenchymal Transition (EMT) and promoting tumor progression, as well as regulating the invasion and metastasis of PCa cells. In PCa, elevated PSA levels are associated with immunosuppression, antiapoptotic properties, and inhibition of angiogenesis. A comprehensive review of numerous important research findings on PSA and its isoforms was conducted to elucidate the role of PSA as a biomarker and functional mediator in PCa pathophysiology. Thus, the use of PSA as a biomarker for the diagnosis of PCa can minimize unnecessary and inappropriate biopsies, identify suitable patients for prostate biopsy, ensure early diagnosis, and initiate treatment at an early stage of PCa. Furthermore, the role of PSA as a functional mediator will enable us to study the pathophysiology of patients with prostate cancer (PCa).
    Keywords:  Prostate cancer; benign prostatic hyperplasia; biomarker; diagnosis; functions of PSA.; isoforms of PSA; prostate-specific antigen
    DOI:  https://doi.org/10.2174/0118715206420493251029064813
  35. Biomolecules. 2025 Dec 25. pii: 38. [Epub ahead of print]16(1):
    Methyl Protodioscin Promotes Ferroptosis of Prostate Cancer Cells by Facilitating Dissociation of RB1CC1 from the Detergent-Resistant Membranes and Its Nuclear Translocation.
    Ruonan Wang, Chaoyu Hu, Yi Zhao, Shuhan Wu, Shujuan Cao, Leiming Xu, Dengke Yin, Song Tan.
      Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscorea plants, has been shown to effectively inhibit proliferation of prostate cancer cells in vitro and in vivo. However, the mechanism underlying this inhibitory action remains unclear. To elucidate the mechanism, we used mass spectrometry to analyze protein rearrangements in detergent-resistant membranes (DRMs). Ferroptosis-related factors were identified in cells in vitro and in vivo. MPD induced the expression of acyl-CoA synthetase long chain family member 4 and reduced expression levels of glutathione peroxidase 4 and solute carrier family 7 member 11. Following MPD treatment, RB1-inducible coiled-coil 1 (RB1CC1) dissociated from DRMs and translocated from the cytoplasm to the nucleus. This translocation induced the expression of ferroptosis-related protein coiled-coil-helix-coiled-coil-helix domain containing 3, promoting ferroptosis in prostate cancer cells. As the nuclear translocation of RB1CC1 was promoted by the JNK signaling pathway, SP600125, a JNK inhibitor, prevented the MPD-induced RB1CC1 nuclear translocation. In summary, MPD induced the dissociation of RB1CC1 from DRMs and its subsequent nuclear translocation, contributing to ferroptosis of prostate cancer cells.
    Keywords:  RB1CC1; detergent-resistant membranes; ferroptosis; methyl protodioscin; mitochondria; prostate cancer
    DOI:  https://doi.org/10.3390/biom16010038
  36. J Cancer. 2026 ;17(2): 359-371
    Talin1 Mediates Tumor-Nerve Interactions in Prostate and Breast Cancer Cells.
    Bor-Jang Hwang, Gloria Polanco, Sanam Sane, Igor C Almeida, Kensei Tsuzaka, Frank Denaro, Khosrow Rezvani, Valerie A Odero-Marah.
      Prostate cancer (PCa) and breast cancer (BCa) are the leading causes of death in men and women in the US. Neurite outgrowth is a fundamental process in differentiating neurons and contributes to cancer progression. Snail transcription factor promotes cancer progression and regulates neurite outgrowth in PCa cells, but their molecular mechanisms are not fully understood. We hypothesize that Snail can stimulate neurite outgrowth through the secretion of extracellular vesicles. To test this hypothesis, we isolated exosomes from PCa (C4-2 non-silencing (NS) control and C4-2 Snail knockdown) and BCa (MCF7 Neo control and MCF7 Snail overexpressing) cells, which were confirmed by western blot analysis and Transmission Electron Microscopy. Proteomics of isolated exosomes from Snail-expressing C4-2 cancer cells shows predominantly Talin1 proteolyzed C-terminal rod domain and N-terminal head domain within exosomes, while full-length Talin1 is found in whole cell lysates. A significantly higher percentage of NPC (Neural Progenitor Cells) with neurite outgrowth is observed when cultured with conditioned medium or exosomes collected from C4-2 NS PCa or MCF7 Snail BCa cells expressing high levels of Snail compared to C4-2 Snail knockdown or MCF7 Neo, respectively. A similar trend is observed for increased average neurite length due to Snail expression. Furthermore, we find that mH4, a specific inhibitor of proteolyzed Talin1, reduces Snail-induced neurite outgrowth and AKT activation within neurons. Overall, Snail may promote cancer-nerve interactions via Talin1, indicating that Talin1 inhibitors can be a potent targeted therapy in malignant tumors with neurite outgrowth.
    Keywords:  Snail; Talin1; exosome; mH4; neurite outgrowth
    DOI:  https://doi.org/10.7150/jca.127292
  37. Int Cancer Conf J. 2026 Jan;15(1): 154-159
    De Novo high-volume metastatic prostate cancer with primary resistance to standard systemic therapy and exceptional response to PSMA-Lu177: A case report.
    Desiree Rafizadeh, D Kaakour, S Sun, J Herman, T Kain, A Rezazadeh Kalebasty.
      Prostate specific membrane antigen (PSMA) Lutetium-177 (Lu-177) therapy is a relatively new theranostic treatment using a targeted radioligand therapy in the treatment of metastatic prostate cancer. PSMA-Lu177 has been approved by the FDA for treatment of prostate cancer in the metastatic castrate resistant setting. Here, we present the case of a 90-year-old man with metastatic castrate resistant prostate cancer (mCRPC) and primary resistance to androgen deprivation, second-generation androgen receptor inhibitors, and docetaxel chemotherapy. Despite the lack of response to prior lines of therapy, the patient demonstrated a rapid response to PSMA-Lu177 therapy with a substantial drop in PSA level, starting from the first cycle.
    Keywords:  PSA; PSMA-Lu177; mCRPC
    DOI:  https://doi.org/10.1007/s13691-025-00834-2
  38. Adv Sci (Weinh). 2026 Jan 28. e08588
    Cancer Cell-Intrinsic Cholesterol Induces Lipid-Associated Macrophage Differentiation via SP1 Palmitoylation to Promote Prostate Cancer Progression.
    Shirong Peng, Weilong Lin, Zean Li, Ruilin Zhuang, Shengmeng Peng, Bingheng Li, Bingliang Chen, Yong Luo, Yuan Ou, Wei Zhuang, Tao Du, Kaiwen Li, Hai Huang.
      Cholesterol metabolism influences prostate cancer (PCa) progression, especially by affecting the tumor microenvironment. The present study demonstrated that cancer cell-intrinsic cholesterol promoted the S-palmitoylation of specificity protein 1 (SP1), enhancing SP1 nuclear translocation and driving the transcription and secretion of midkine (MDK), which in turn facilitated the differentiation of macrophages into a lipid-associated phenotype. Furthermore, targeting cholesterol metabolism with simvastatin significantly reduced MDK levels, inhibited immunosuppressive macrophage polarization, and enhanced the efficacy of enzalutamide in vivo. These findings suggested that targeting the cancer cell-intrinsic cholesterol-induced immunosuppressive tumor microenvironment could be an effective strategy to improve therapeutic outcomes in prostate cancer patients.
    Keywords:  Lipid‐associated macrophages; Specificity protein 1; S‐palmitoylation; cholesterol; midkine
    DOI:  https://doi.org/10.1002/advs.202508588
  39. Int J Med Sci. 2026 ;23(2): 510-519
    Missense and Intronic Variants in HNF1A Affect Prostate Cancer Aggressiveness in Patients with Biochemical Recurrence.
    Min-Che Tung, Yung-Wei Lin, Chung-Howe Lai, Chia-Yen Lin, Lun-Ching Chang, Yu-Ching Wen, Shun-Fa Yang, Ming-Hsien Chien.
      Prostate cancer (PCa) is a genetically and phenotypically heterogeneous disease, and further advancements in PCa biomarker discovery are urgently required. Hepatocyte nuclear factor 1 A (HNF1A), a transcription factor, plays a critical role in PCa progression after biochemical recurrence (BCR). However, studies investigating the impact of HNF1A genetic variants on PCa are scarce. Therefore, in this study, we explored the associations of HNF1A single-nucleotide polymorphisms (SNPs) with susceptibility to BCR in PCa and its clinicopathological development. Two nonsynonymous (missense) SNPs [rs2464196 (S487N) and rs1169288 (I27L)] and two intronic SNPs [rs1169286 and rs735396] were analyzed using a TaqMan allelic discrimination assay for genotyping in a cohort of 690 Taiwanese patients with PCa. The results demonstrated that patients with PCa carrying the HNF1A rs735396 (TC+CC), rs2464196 (GA+AA), or rs1169288 (AC+CC) had a higher risk of developing tumors with higher pathological Gleason grades (3-5). These associations were particularly evident in the BCR subpopulation. Moreover, analysis of data from The Cancer Genome Atlas revealed that HNF1A expression was higher in PCa tissues than in normal tissues. Moreover, higher HNF1A expression was correlated with higher Gleason scores, more advanced pathological T stages, and metastasis. Taken together, our findings indicated that elevated HNF1A expression promotes PCa progression and that the missense SNPs rs2464196 and rs1169288, as well as the intronic SNP rs735396, may influence HNF1A expression, thereby influencing PCa aggressiveness, particularly in patients with BCR.
    Keywords:  biochemical recurrence; clinicopathologic progression; hepatocyte nuclear factor 1 alpha; prostate cancer; single-nucleotide polymorphism
    DOI:  https://doi.org/10.7150/ijms.127638
  40. Int J Biol Sci. 2026 ;22(3): 1440-1460
    The castration-resistant prostate cancer-associated SNP rs11067228 facilitates neuroendocrine differentiation through an enhancer-mediated chromatin interaction with SRRM4.
    Yuan Jiang, Zhenhao Zhao, Peng Li, Guangsong Su, Yuyang Qian, Yuting Zhao, Bo Wang, Yunlong Bai, Lei Zhang, Zhongfang Zhao, Jiandang Shi, Wange Lu.
      Neuroendocrine prostate cancer is an aggressive disease characterized by early metastasis, drug resistance and poor prognosis. Genome-wide association studies (GWAS) previously identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer. SNP rs11067228 as a significant variant associated with castration-resistant metastasis (CM) in prostate cancer (PCa). However, mechanisms underlying activity of the rs11067228 risk variant remain unclear. Here, we demonstrated that risk SNP rs11067228 is located in an H3K27ac-enriched active enhancer, and that activity of that region affects castration-resistance and neuroendocrine differentiation in PCa cells. We identified the RNA-splicing factor SRRM4 as a functional target gene as shown in both cell line and xenograft model. In addition, overexpression of SRRM4 is sufficient to induce PCa cell drug resistance and neuroendocrine differentiation. Moreover, site-directed mutation of the rs11067228 non-risk G to the risk A allele enabled binding of the transcription factor SOX4, activating candidate target gene expression. Taken together, our findings indicated that the rs11067228-associated enhancer modulates expression of SRRM4 via allele-specific long-range chromatin interactions, thereby governing PCa drug resistance and neuroendocrine differentiation.
    Keywords:  SNP rs11067228; enhancer; long-range chromatin interaction; neuroendocrine differentiation; prostate cancer
    DOI:  https://doi.org/10.7150/ijbs.124731
  41. J Clin Med. 2026 Jan 14. pii: 685. [Epub ahead of print]15(2):
    Emerging Therapeutic Strategies in Prostate Cancer: Targeted Approaches Using PARP Inhibition, PSMA-Directed Therapy, and Androgen Receptor Blockade with Olaparib, Lutetium (177Lu)Vipivotide Tetraxetan, and Abiraterone.
    Piotr Kawczak, Tomasz Bączek.
      Prostate cancer is one of the most common malignancies in men, and advanced or metastatic disease remains associated with substantial morbidity and mortality. Therapeutic progress in recent years has been driven by the introduction of targeted treatment strategies, notably poly (ADP-ribose) polymerase (PARP) inhibitors, prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT), and androgen receptor pathway inhibitors (ARPIs). This review summarizes evidence from phase II and III clinical trials, meta-analyses, and real-world studies evaluating the efficacy, safety, and clinical integration of olaparib, lutetium (177Lu) vipivotide tetraxetan, and abiraterone in advanced prostate cancer. Emphasis is placed on the practical clinical application of these agents, including patient selection, treatment sequencing, and combination strategies. PARP inhibition with olaparib has demonstrated clear benefits in metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) mutations, particularly BRCA1/2 alterations. PSMA-directed RLT offers a survival advantage in PSMA-positive mCRPC following AR pathway inhibition, with distinct toxicity considerations that influence patient selection. Abiraterone remains a cornerstone therapy across disease stages and plays an important role both as monotherapy and as a combination partner. Emerging data suggest a potential synergy between PARP inhibitors and AR-targeted agents, while also highlighting the limitations of biomarker-unselected approaches. We conclude that the optimal use of PARP inhibitors, PSMA-targeted RLT, and ARPIs requires a personalized strategy guided by molecular profiling, functional imaging, prior treatment exposure, and safety considerations. This clinically focused overview aims to support evidence-based decision-making in an increasingly complex treatment landscape.
    Keywords:  PARP inhibitor; PSMA-targeted therapy; abiraterone; androgen receptor blockade; lutetium Lu 177 vipivotide tetraxetan; mCRPC; olaparib; precision oncology; prostate cancer; targeted therapy
    DOI:  https://doi.org/10.3390/jcm15020685
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