bims-meproc 2026-02-22 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–02–22
28 papers selected by
Grigor Varuzhanyan, UCLA

B4GALNT4-Mediated Glycosylation of PDK1 Activates the PI3K-AKT Signaling Pathway to Promote Prostate Cancer Progression.
Hypoxia‑induced miR‑135b‑5p promotes neuroendocrine differentiation of prostate cancer cells through HIF1AN‑HIF1α axis.
p300-mediated acetylation of KCNN4 drives enzalutamide resistance in prostate cancer.
A Novel Peptide, HS1002, Enhances Antitumor Activity via Dual Targeting of the GnRH Receptor and Human Telomerase Reverse Transcriptase in Prostate Cancer Cells.
Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1.
Delineating the roles of HOXB13 X285K variant in prostate cancer.
TRPV1 Downregulation Impairs Prostate Cancer Growth: Functional and Translational Insights from Cellular and In Vivo Models.
A novel aurora kinase molecular glue-based degrader sp-2-067 inhibits prostate cancer cell growth and alters immune profile.
A conserved eIF1A+ luminal cell-centered hypoxic and "cold" tumor microenvironment promotes pan-subtype prostate cancer progression.
Reversing-or Rewiring-Lineage Plasticity? Lessons from EZH2 Loss in Prostate Cancer.
Genetic loss of CHD1 regulates distinct histone post-translational modifications in the development of castration-resistant prostate cancer.
Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.
SeSA-HCPT: A dual-targeting agent that induces DNA damage and inhibits repair for castration-resistant prostate cancer therapy.
Marine trichodermamide B inhibits prostate cancer progression via catalase inhibition-induced apoptosis.
Integrative bulk and single-cell transcriptomics link EZH2 to immunosuppressive programs and tumor-Treg crosstalk in castration-resistant prostate cancer.
The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth.
YEATS2 promotes DNA repair and induces anoikis resistance by enhancing chromatin accessibility to drive prostate cancer metastasis.
Modulation of the intestinal microbiome and reversal of the immunosuppressive microenvironment by nanoparticles for chemoimmunotherapy in prostate cancer.
Continuous, Preclinical Activity Reconstruction in 177Lu-based Radiopharmaceutical Therapy Using a Sparse Uncollimated γ-Sensor Network.
Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.
M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells.
Suppression of PARP1 enhances PTEN mRNA therapy in castration-resistant prostate cancer by glycolysis disruption.
Distinct prognostic value of [18F]FDG PET and [68Ga]Ga-PSMA-11 PET in advanced hormone-sensitive prostate cancer.
Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.
Thrombosis-related gene signature predicts prostate cancer recurrence and immune therapy: insights from retrospective cohorts, bioinformatics, and experimental validation.
Gut Microbiome as a Lifestyle Risk Factor Associated with Prostate Cancer.
FOXJ1 mediates taxane resistance through regulation of microtubule dynamics.
ERBB2 as a Prognostic Biomarker in Prostate Cancer: Integration of Single-Cell Transcriptomics, Deep Learning, and Immunohistochemical Validation.

Adv Sci (Weinh). 2026 Feb 16. e11293

B4GALNT4-Mediated Glycosylation of PDK1 Activates the PI3K-AKT Signaling Pathway to Promote Prostate Cancer Progression.

Shaoqin Jiang, Mengqiang Li, Qingfu Su, Ruiling Dou, Shaoshan Lin, Jili Zhang, Xiaochen Sun, Haolan Yu, Wei Bao, Min Qu, Yan Wang, Chenghua Yang, Xu Gao.

  Abnormal glycosylation is a hallmark of cancer cells and plays a crucial role in tumor invasion and metastasis. However, the relationship between glycogenes and prostate cancer (PCa) remains poorly understood. This study aims to identify glycogenes involved in the onset and progression of PCa and to investigate the molecular mechanisms underlying their role. By integrating RNA-seq data from multiple clinical cohorts (TCGA and CPGEA) and performing biochemical validation, we identified beta-1,4-N-acetylgalactosaminyltransferase 4 (B4GALNT4) as a glycogene significantly associated with advanced pathological stages, higher Gleason scores, and poor prognosis in PCa patients. Furthermore, multivariate Cox regression analysis confirmed B4GALNT4 as an independent prognostic factor for survival. Mechanistically, we discovered that B4GALNT4 interacts with PDK1 and glycosylates it at residue N531. This N-glycosylation stabilizes PDK1 by blocking its degradation, thereby activating the PI3K-AKT signaling pathway. This signaling axis promotes PCa cell proliferation, migration, and invasion in vitro. Moreover, B4GALNT4 knockdown suppresses tumor growth in xenograft models and correlates with decreased PDK1 and p-AKT levels in vivo. Our findings establish B4GALNT4 as a critical regulator of PCa progression through PDK1 glycosylation and PI3K-AKT activation, suggesting that B4GALNT4 serves as both a prognostic biomarker and a potential therapeutic target for PCa.

Keywords:  B4GALNT4; PDK1; PI3K‐AKT signaling pathway; glycosylation; prostate cancer

DOI:  https://doi.org/10.1002/advs.202511293
Oncol Rep. 2026 Apr;pii: 74. [Epub ahead of print]55(4):

Hypoxia‑induced miR‑135b‑5p promotes neuroendocrine differentiation of prostate cancer cells through HIF1AN‑HIF1α axis.

Pampana Sandhya Venkata Lakshmi, Jagrati Parashar, Biswajit Biswas, Ramesh Ummanni.

  Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa), associated with poor prognosis and resistance to androgen receptor (AR)‑targeted therapies. Hypoxia is a well‑established driver of lineage plasticity and has been implicated in promoting NE differentiation (NED) of tumors. However, the underlying molecular mechanisms linking hypoxia to NED remain unclear. In the present study, miR‑135b‑5p was identified as a critical regulator of hypoxia‑induced NED through modulation of the hypoxia‑inducible factor alpha‑1 subunit alpha inhibitor (HIF1AN)‑HIF1α axis. Exposure of androgen‑dependent PCa cell lines (LNCaP and VCaP) to hypoxia induced neurite outgrowth and increased expression of NE markers, concurrent with upregulation of miR‑135b‑5p. Target prediction followed by experimental validation in luciferase reporter assays confirmed that HIF1AN is a direct target of miR‑135b‑5p. Suppression of HIF1AN results in the stabilization of HIF1α, which in turn activates the AKT/mTOR signaling pathway, facilitating NE trans differentiation. Functional studies demonstrated that overexpression of miR‑135b‑5p by mimics promotes NED in LNCaP cells, while inhibition of miR‑135b‑5p reverses the NE features in NE‑LNCaP and NCI‑H660, NE cells. Furthermore, pharmacological inhibition of HIF1α using PX‑478 abrogated hypoxia‑induced NED and attenuated activation of AKT/mTOR signaling, further underscoring the significance of the miR‑135b‑5p‑HIF1AN‑HIF1α axis in NED of PCa cells. Collectively, the findings of the present study reveal a novel miR‑135b‑5p‑HIF1AN‑HIF1α signaling axis that is involved in hypoxia‑induced NED via AKT/mTOR activation and identify miR‑135b‑5p and HIF1α as potential therapeutic targets for NEPC.

Keywords:  NCI‑H660; NE‑LNCaP; anti‑miR‑135b‑5p; hypoxia; miRNA; miR‑135b‑5pmimic

DOI:  https://doi.org/10.3892/or.2026.9079
Exp Cell Res. 2026 Feb 12. pii: S0014-4827(26)00058-3. [Epub ahead of print]457(1): 114941

p300-mediated acetylation of KCNN4 drives enzalutamide resistance in prostate cancer.

Weiqiang Song, Jiankun Zhang, Zekun Xin.

  Enzalutamide resistance remains a critical obstacle in the treatment of castration-resistant prostate cancer (CRPC), with potassium calcium-activated channel subfamily N member 4 (KCNN4) emerging as a key mediator of therapeutic failure. Here, we demonstrate that KCNN4 is significantly upregulated in enzalutamide-resistant PCa cells and clinical tissues, correlating with poor prognosis. Mechanistically, p300, a histone acetyltransferase, directly binds to KCNN4 and mediates its acetylation at lysine 16, which competitively inhibits ubiquitination-mediated degradation, thereby stabilizing KCNN4 protein. Notably, p300 inhibition disrupts KCNN4 acetylation, restores its proteasomal degradation, and resensitizes resistant cells to enzalutamide both in vitro and in vivo. Moreover, KCNN4 knockdown suppresses tumor growth and synergizes with enzalutamide in xenograft models, underscoring the therapeutic potential of targeting the p300-KCNN4 axis. Collectively, our findings reveal a previously unrecognized epigenetic regulatory mechanism coupling p300-mediated acetylation to potassium channel stability, providing a promising therapeutic strategy to overcome chemoresistance in advanced prostate cancer.

Keywords:  Acetylation; Chemoresistance; KCNN4; Prostate cancer; Ubiquitination

DOI:  https://doi.org/10.1016/j.yexcr.2026.114941
MedComm (2020). 2026 Mar;7(3): e70630

A Novel Peptide, HS1002, Enhances Antitumor Activity via Dual Targeting of the GnRH Receptor and Human Telomerase Reverse Transcriptase in Prostate Cancer Cells.

Jae Hyeon Park, Joo Chan Lee, Swati Sharma, Chunxue Jiang, Haeun Lee, Hyun-Ju Park, Hyung Sik Kim.

  Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and is an important target for cancer therapy. In this study, HS1002 was synthesized based on the amino acid sequences of gonadotropin-releasing hormone (GnRH) and hTERT. This study aimed to evaluate HS1002's anticancer activity and its effects on the gonadotropin-releasing hormone receptor (GnRHR) and hTERT in prostate cancer cells. HS1002 increased cytosolic calcium influx in GnRHR-overexpressing HEK293 cells and showed specific molecular docking interactions with GnRHR. Compared with prostate cancer cell lines, HS1002 exhibited the highest cytotoxicity against LNCaP cells. The hTERT expression correlated with telomerase activity was suppressed by HS1002, resulting in reduced metastasis and increased apoptosis and autophagy. Additionally, HS1002 suppressed c-Myc and ERK protein expressions in LNCaP cells. Furthermore, HS1002 inhibited tumor growth and downregulated hTERT expression in the xenograft model tumor tissues. HS1002/IL-2-pretreated PBMCs also exhibited potent cytotoxicity toward LNCaP cells. In addition, HS1002 increased the production of granzyme B and IFN-γ in CD8+ T cells in MC38 syngeneic mice. These findings demonstrate that HS1002 suppresses prostate cancer cell growth and induces anticancer immunity, suggesting its potential as a novel therapeutic agent against prostate cancer.

Keywords:  GnRHR; HS1002; hTERT; immune response; prostate cancer

DOI:  https://doi.org/10.1002/mco2.70630
Front Immunol. 2026 ;17 1744197

Multi-omics analyses related to unfolded protein response in prostate cancer implicate pro-tumor role of IFRD1.

Yifeng Xue, Enyao Huang, Caichen Luo, Yanrong Qian, Tiange Wu, Chunyan Chu, Fan Shi, Shengrong Chen, Dakun Zhang, Weijun Chen, Weihua Huang, Ping Wang, Huixing Chen, Yifei Cheng, Yunxia Fan.

   Introduction: The unfolded protein response (UPR) promotes prostate cancer (PCa) progression, yet its multi-omics landscape and clinical utility remain undefined.
Methods: We integrated single-cell and bulk transcriptomic datasets, and identified UPR-related genes (UPRRGs) through a combination of differential expression analysis and weighted gene co-expression network analysis (WGCNA), based on which we further developed a consensus UPR-related signature (UPRRS) using a machine learning framework. The UPRRGs were further characterized by functional enrichment, cell-cell communication, and survival analyses. A clinically applicable nomogram integrating UPR-related prognostic genes was constructed for prognostic prediction. Through in silico and in vitro analyses, we validated the clinical relevance between the hub UPRRGs and PCa progression.
Results: Single-cell analyses revealed elevated UPR activity in prostate epithelial cells, most prominently within the LE-KLK3 subpopulation. These cells exhibited enhanced ligand-receptor interactions in TNF, VEGF and NOTCH signaling axes. A seven-UPRRG signature (including IFRD1, DDIT3, HSPA5) demonstrated robust prognostic performance in the TCGA training set and three external validation cohorts (C-index > 0.82; AUC > 0.80). Multivariate Cox analysis confirmed UPRRS as an independent prognostic factor beyond clinical stage and Gleason score. Mechanistically, the UPRRS-high subgroup displayed an immunosuppressive microenvironment and reduced sensitivity to multiple chemotherapeutics. In vitro knock-down of IFRD1 markedly attenuated PCa cell proliferation and migration.
Conclusion: We provide the first systematic single-cell atlas of UPR heterogeneity in PCa and develop a clinically translatable UPRRS prognostic model. IFRD1, a key driver, emerges as a dual diagnostic and therapeutic target, offering both theoretical and experimental foundations for precision stratification and individualized management of PCa.

Keywords:  IFRD1; UPR; prognostic biomarker; prostate cancer; scRNA-seq; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1744197
Serican J Med. 2025 Jan 14. pii: 23160. [Epub ahead of print]2(1):

Delineating the roles of HOXB13 X285K variant in prostate cancer.

Xiaodong Lu, Samantha Ye, Mingyang Liu, Jindan Yu.

  HOXB13 X285K is a frameshift mutant caused by the deletion of one nucleotide, c.853delT, within the HOXB13 stop codon, resulting in an extension of HOXB13 protein by 96 amino acids on the C terminus. It was found primarily in men of West African ancestry and associated with early-onset prostate cancer (PCa) and more advanced stage. Whether and how X285K contributes to PCa progression remains largely unknown. Here, we established isogenic 22Rv1 cell lines with heterozygous wildtype/X285K HOXB13, which recapitulates the genotypes of X285K in PCa patients. In addition, using the unique C-terminal region of X285K as an antigen, we developed an antibody that specifically recognizes the HOXB13 X285K protein. Lastly, we demonstrated that X285K, similar to wildtype HOXB13, was able to rescue the effects of HOXB13 knockdown on both induced and repressed genes, such as FASN and PSA, in PCa cells. In summary, our study reports that X285K retained the transcriptional regulation ability of wildtype HOXB13 and provides isogenic PCa cell lines with wildtype and/or X285K HOXB13 expression and an X285K-specific antibody for a comprehensive investigation of X285K function in PCa.

Keywords:  HOXB13; X285K; prostate cancer

DOI:  https://doi.org/10.17161/sjm.v2i1.23160
Int J Biol Sci. 2026 ;22(4): 2101-2120

TRPV1 Downregulation Impairs Prostate Cancer Growth: Functional and Translational Insights from Cellular and In Vivo Models.

Belén G Sánchez, José M Mora-Rodríguez, Alicia Bort, Ana Palacín, Carlos Sánchez-Rodríguez, Manuel Sánchez-Chapado, Julie Courraud, Jerome Zoidakis, Inés Díaz-Laviada.

  The transient receptor potential vanilloid 1 (TRPV1), the canonical capsaicin (CAP) receptor, has been implicated across diverse pathologies, yet its role in prostate cancer (PCa) remains elusive. Here, we uncover TRPV1 as a key regulator of PCa progression and a mediator of CAP's antiproliferative effects. Through a comprehensive strategy combining proteomic profiling, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse modeling, and validation in human prostate biopsies, we assessed TRPV1 expression, its functional role, and its association with tumor markers. Both proteomic analysis and Western blotting of TRPV1-silenced cells revealed reduced expression of PCNA, Cyclin B1, and AURKA, along with elevated levels of the cell cycle inhibitor p21. Similarly, CAP treatment resulted in comparable changes in the proteomic profile. Functional assays demonstrated that both TRPV1 knockdown and CAP exposure significantly impaired cell cycle progression and mitosis. Moreover, sustained CAP treatment led to a reduction in TRPV1 expression, further supporting its oncogenic role. In TRAMP mice, a high-fat diet feeding elevated plasma PSA levels and TRPV1 expression in the prostate, whereas CAP supplementation reversed these effects. Importantly, TRPV1 expression correlated positively with cancer stem cell markers in both murine models and human samples. Collectively, our results reveal that TRPV1 is not only overexpressed in PCa but also contributes to proliferation regulation and stemness features, positioning it as a potential diagnostic and prognostic biomarker for prostate cancer.

Keywords:  TRPV1; biomarker; capsaicin; cell cycle; proliferation; prostate cancer; proteomics; stemness

DOI:  https://doi.org/10.7150/ijbs.125429
Invest New Drugs. 2026 Feb 21.

A novel aurora kinase molecular glue-based degrader sp-2-067 inhibits prostate cancer cell growth and alters immune profile.

Sanjeev Shukla, Sarah Pogash, Arjun Venkatesh, Joseph McGrath, Reynier D Rodriguez Rosales, Jean-Pierre Kanumuambidi, Mohammed Al-Toubat, Steven Fletcher, K C Balaji.

  Aurora Kinase A (AKA) is overexpressed in prostate cancer and promotes disease progression through oncogenic pathways and immune modulation. AKA inhibition faces challenges in clinical trials, and alternate methods, such as degradation, may overcome some of these barriers. We evaluated SP-2-067, a novel selective AKA degrader, in C4-2 prostate cancer cells using viability assays, Western blot analysis, and siRNA knockdown. SP-2-067's dose- and time-dependent effects on AKA, related proteins (AUNIP and NINEIN) and immune checkpoint (IC) proteins (PD-L1 and LAG3) were quantified. In silico analysis of TCGA datasets examined the clinical link of the AKA axis and its correlation with immune cell infiltration in prostate cancer. SP-2-067 demonstrated potent dose-dependent anti-proliferative effects. The compound selectively degraded AKA over Aurora Kinase B (AKB) with sustained effects at 72 h. Treatment induced marked PD-L1 upregulation (~ 20-fold at 3 h) and concurrent LAG3 downregulation. siRNA experiments confirmed these effects were AKA-dependent. TCGA analysis revealed AKA, AUNIP, and NINEIN overexpression in prostate cancer correlates with distinct immune-cell infiltration. SP-2-067 is a novel, selective AKA degrader that modulates IC expression by upregulating PD-L1 and downregulating LAG3, indicating its potential for immunomodulation through AUNIP- and NINEIN-mediated mechanisms. Additionally, AKA, AUNIP, and NINEIN are linked to a distinct immune cell profile, presenting an opportunity to reshape the tumor immune microenvironment and support combinatorial strategies with IC inhibitors in prostate cancer.

Keywords:  Aurora kinase A; Drug discovery; Immune checkpoint proteins; Immunotherapy; Prostatic neoplasms

DOI:  https://doi.org/10.1007/s10637-026-01603-5
Cell Rep Med. 2026 Feb 17. pii: S2666-3791(26)00036-4. [Epub ahead of print]7(2): 102619

A conserved eIF1A+ luminal cell-centered hypoxic and "cold" tumor microenvironment promotes pan-subtype prostate cancer progression.

Yifei Cheng, Lilin Wan, Enyao Huang, Bing Zheng, Xuefei Ding, Song Tan, Gaoxiang Ma, Wenchao Li, Chunyan Chu, Tiange Wu, Shengrong Chen, Junyong Zhuang, Rong Na, Zhan Chen, Gaojun Teng, Dingxiao Zhang, Shenghong Ju, Ming Chen, Bin Xu.

  Prostate cancer (PCa) is a malignancy with high heterogeneity arising from tumor microenvironment and histological subtypes. Identifying conserved progression drivers within such heterogeneity is essential for improving clinical outcomes. Using imaging mass cytometry, this study analyzes 38 proteins across paracancerous tissue and four histological subtypes: low-grade prostate acinar adenocarcinoma (LgPAC), high-grade PAC (HgPAC), intraductal carcinoma (IDC), and ductal adenocarcinoma (DAC). Results reveal that eIF1A is overexpressed in high-risk subtypes including HgPAC, IDC, and DAC and correlates with poor prognosis. In luminal cells, EIF1A knockdown and the translation inhibitor homoharringtonine (HHT) both suppress HIF-1α translation and tumor growth, while promoting infiltration of anticancer immune cells including PD-1- T cells and CD163- macrophages. Clinically, neoadjuvant HHT combined with androgen deprivation therapy reduces hypoxia and enhances immune cell infiltration, as shown by single-cell RNA sequencing. Collectively, this work defines conserved molecular features across PCa subtypes, providing promising insights for clinical management. This study was registered at Clinicaltrials.gov (NCT06834321).

Keywords:  ductal adenocarcinoma; eIF1A; homoharringtonine; hypoxia; imaging mass cytometry; intraductal carcinoma; prostate cancer; translation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2026.102619
Cancer Res. 2026 Feb 16. 86(4): 827-829

Reversing-or Rewiring-Lineage Plasticity? Lessons from EZH2 Loss in Prostate Cancer.

Phillip Thienger, Dilara Akhoundova, Mark A Rubin.

Enhancer of zeste homolog 2 (EZH2) inhibitors have been proposed to counteract lineage plasticity (LP) in prostate cancer and thereby resensitize tumors to androgen receptor (AR) inhibition. In this issue of Cancer Research, Jacobi and colleagues provide new mechanistic insights into EZH2 biology across prostate cancer progression using a genetically engineered mouse model that recapitulates the transition toward a neuroendocrine (NE) phenotype. Unexpectedly, genetic deletion of Ezh2 did not reverse LP but instead promoted the diversification of transcription factor (TF) programs driving NE differentiation. In particular, the loss of EZH2 activated members of the KLF TF family, which contributed to this transcriptional diversification. Moreover, EZH2 deletion altered the chromatin-binding landscape of AR, redirecting it toward KLF-associated genomic sites. Collectively, these results refine our understanding of EZH2 function in prostate cancer: Rather than simply reversing LP, EZH2 loss rewires transcriptional networks and reshapes the AR cistrome. These findings are timely given the growing number of clinical trials testing EZH2 inhibitors in metastatic prostate cancer and highlight the need to define when and how to deploy EZH2 inhibition to exploit its effects on tumor lineage dynamics. See related article by Jacobi et al., p. 889.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5407
Neoplasia. 2026 Feb 19. pii: S1476-5586(26)00018-7. [Epub ahead of print]73 101289

Genetic loss of CHD1 regulates distinct histone post-translational modifications in the development of castration-resistant prostate cancer.

Tanaya A Purohit, Joseph Gawdzik, Eric A Armstrong, Bing Yang, Zachery Schultz, Kayla Bahr, Truman J Do, Rehaan Machhi, Sean Sardeson, Mohammad Rizvi, Sarah A Nakada, Anupama Singh, Karla Esbona, Wei Huang, Marjorie L Roskes, Ekta Khurana, Peter W Lewis, John M Denu, David F Jarrard.

  Epigenetic alterations accumulate with the development of castration resistance in prostate cancer (PC), yet an understanding of how these patterns arise remains incompletely defined. Through histone post-translational modification (PTMs) profiling in paired hormone-sensitive (HS) and castration-resistant (CR) patient-derived xenografts, we identified a novel chromatin state characterized by CHD1 deficiency and global reductions in H3.3K27 and H3.3K36 methylation, which occurred with castration resistance development. Compared to wildtype, CHD1-deficient tumors exhibited lower expression and enzymatic activity of the histone-modifying enzymes (HMEs) NSD2 and EZH2-key regulators of the altered histone PTM landscape. Gene expression analysis of human CRPC samples revealed strong positive correlations among CHD1, NSD2, and EZH2. CHD1 knockout (KO) in CRPC cell lines confirms reduced H3.3K27K36 methylation and downregulation of NSD2 and EZH2. Results from mechanistic studies support a process in which CHD1 occupancy at the promoter regions of NSD2 and EZH2 facilitates transcription via enhanced chromatin accessibility and increased deposition of the activating histone mark H3K4me3. In contrast, CHD1-KO led to promoter accumulation of repressive H3K27me3 modifications. CHD1-KO downregulates interferon (IFN) signaling, including viral mimicry and IFN-stimulated genes. Bulk RNA-sequencing and ChIP-qPCR analyses confirmed co-regulation of these genes by CHD1 and NSD2, coinciding with reduced H3K36me2 enrichment. Notably, this CHD1-deficient epigenetic state confers resistance to NSD2 inhibition. These findings highlight a previously unrecognized role in tumor resistance for CHD1 in modulating HMEs that may influence lineage plasticity as well as suggest new avenues for personalized therapeutic strategies targeting CHD1-specific epigenetic vulnerabilities.

Keywords:  CHD1; Castration resistant prostate cancer (CRPC); EZH2; Epigenetics; Histone methylation; NSD2

DOI:  https://doi.org/10.1016/j.neo.2026.101289
Nat Commun. 2026 Feb 21.

Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.

Richa Singh, Varadha Balaji Venkadakrishnan, Eddie Imada, Yasutaka Yamada, Nicholas J Brady, Kate E Dunmore, Richard Garner, Matthew A Booker, Brian Hanratty, Michael C Haffner, Michael Y Tolstorukov, Luigi Marchionni, Brian D Robinson, David S Rickman, Himisha Beltran.

Prostate cancer lineage plasticity is associated with changes in DNA methylation and enhancer of zeste homolog 2 (EZH2) activity. How these epigenetic programs functionally interact to modulate transcriptional reprogramming in neuroendocrine prostate cancer (NEPC) is not well understood. In this study, we demonstrate that hypomethylated regions of DNA preferentially accumulate the repressive mark, H3K27me3. We established an NEPC mouse model with deletion of Ezh2 in the background of Pten and Rb1 loss plus human MYCN overexpression. Deletion or pharmacological inhibition of EZH2 in NEPC murine or patient-derived models leads to a genome-wide rewiring of DNA methylation, characterized by hypomethylation and upregulation of neuroendocrine-lineage genes along with hypermethylation and repression of polycomb repressive complex 2 (PRC2) targets. On the other hand, deletion of DNA methyltransferase 1 (DNMT1) results in significant changes in H3K27me3 distribution, particularly affecting bivalent promoters bearing both H3K27me3 and active H3K4me3 marks. In NEPC models, neuroendocrine-lineage genes are repressed upon DNMT1 deletion associated with increased H3K27me3. Conversely, in prostate adenocarcinoma models, DNMT1 deletion leads to de-repression of neuroendocrine lineage genes with a loss of H3K27me3 marks. Our findings reveal a functional interplay between two repressive epigenetic machineries that mediates lineage plasticity in prostate cancer.

DOI: https://doi.org/10.1038/s41467-026-69308-0
iScience. 2026 Feb 20. 29(2): 114824

SeSA-HCPT: A dual-targeting agent that induces DNA damage and inhibits repair for castration-resistant prostate cancer therapy.

Yajie Wang, Qiuyu Wang, Li Meng, Xiaoying Lian, Xinyue Wu, Yuqing Wang, Tianyu Zhang, ShiLin Wei, Yanming Wang, Changjun Zhu.

  Castration-resistant prostate cancer (CRPC) remains difficult to treat due to tumor heterogeneity and resistance. We developed SeSA-HCPT, a dual-targeting compound that links the topoisomerase I inhibitor hydroxycamptothecin (HCPT) with a selenium analog of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid. SeSA-HCPT showed markedly higher cytotoxicity in prostate cancer (PCa) cells than single or combined treatments, while sparing normal keratinocytes. At effective concentrations, it triggered pronounced S-phase arrest and apoptosis, driven by Topo I inhibition and extensive DNA double-strand breaks; concurrently, SeSA-HCPT suppressed homologous recombination through downregulation of KIF4A and impaired RAD51 recruitment. In a PC-3 xenograft model, SeSA-HCPT significantly inhibited tumor growth relative to the combination treatment without observable systemic toxicity. These results nominate SeSA-HCPT as a promising dual-mechanism therapeutic candidate for advanced PCa.

Keywords:  Biotechnology; Cancer; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.114824
Cell Commun Signal. 2026 Feb 16.

Marine trichodermamide B inhibits prostate cancer progression via catalase inhibition-induced apoptosis.

Wenxuan Fang, Chunmei Chen, Mingyi Nie, Qiuyu Liu, Tianwen Huang, Chenghai Gao, Yonghong Liu, Xuefeng Zhou, Xueni Wang.

   BACKGROUND: Prostate cancer, a leading cause of cancer-related mortality in men, often develops resistance to conventional therapies, necessitating the discovery of novel therapeutic targets. Catalase plays a critical role in maintaining cellular redox homeostasis. Its inhibition disrupts oxidative balance, leading to oxidative stress and cell death, which positions catalase as a promising therapeutic target for cancer treatment. This study explores the anti-cancer effects and mechanisms of action of trichodermamide B in targeting catalase-induced apoptosis in prostate cancer cells.
METHODS: The anti-prostate cancer activity of trichodermamide B was evaluated using multiple prostate cancer cell lines, including LNCaP, 22Rv1, PC-3, and DU145. Cytotoxicity was assessed through cell viability assays, while clonogenic assays were employed to measure the compound's ability to inhibit colony formation. The impact on 3D cell sphere growth was examined using LNCaP-3D models. Flow cytometry was utilized to analyze cell cycle arrest and apoptosis induction. Molecular docking studies were conducted to predict the interaction between trichodermamide B and catalase. The cell-free catalase enzymatic activity assay was employed to detect the inhibitory effect of trichodermamide B on catalase activity in vitro. Proteome profiler human apoptosis array kits and immunoblotting were used to validate the suppression of catalase expression. Additionally, the effects on androgen receptor (AR) activity and AR target genes (KLK3 and TMPRSS2) were investigated by western blot and qPCR. In vivo efficacy was confirmed using zebrafish and mouse xenograft tumor models.
RESULTS: Trichodermamide B demonstrated potent cytotoxicity against all tested prostate cancer cell lines, with significant inhibition of clonal colony formation in 22Rv1 and PC-3 cells. It also impaired the growth of LNCaP-3D cell spheres, indicating its ability to target both 2D and 3D cancer models. Flow cytometry revealed that trichodermamide B induced cell cycle arrest and apoptosis. Molecular docking studies predicted a strong binding affinity between trichodermamide B and catalase. This was corroborated by experimental data showing that trichodermamide B inhibits the enzymatic activity of catalase in a dose-dependent manner in vitro. This inhibition led to disrupted redox homeostasis, accumulation of reactive oxygen species (ROS), and intense oxidative stress. In AR-dependent LNCaP cells, trichodermamide B suppressed AR activity and downregulated the expression of AR target genes. In vivo studies using zebrafish and mouse xenograft models further validated its anti-prostate cancer efficacy.
CONCLUSION: Trichodermamide B targets catalase while mediating crosstalk between the catalase axis and the AR signalling axis to induce oxidative stress and apoptosis in prostate cancer cells. Its efficacy in both in vitro and in vivo models underscore its viability as a novel drug candidate for prostate cancer treatment.

Keywords:  Apoptosis; Catalase; Prostate cancer; Redox homeostasis; Trichodermamide B

DOI:  https://doi.org/10.1186/s12964-026-02737-y
Front Immunol. 2026 ;17 1725097

Integrative bulk and single-cell transcriptomics link EZH2 to immunosuppressive programs and tumor-Treg crosstalk in castration-resistant prostate cancer.

Xing Xiong, Jianhu Xie, Ping Dai, Chao Cheng, Jiani Liu, Guixiao Huang.

   Background: Enhancer of zeste homolog 2 (EZH2) is frequently upregulated in prostate cancer (PCa) and further increased in castration-resistant prostate cancer (CRPC), a lethal state characterized by profound immune dysfunction. However, EZH2-associated immune programs in bulk cohorts and their corresponding cell-type-specific features in single-cell RNA sequencing (scRNA-seq) data have not been systematically delineated in advanced PCa.
Methods: We integrated bulk RNA-seq and scRNA-seq to map EZH2-associated transcriptional and immune features in PCa. In bulk cohorts (TCGA-PRAD and an independent metastatic CRPC cohort), we quantified EZH2 expression, clinical outcomes, and immune-signature enrichment. Immune-modulated differentially expressed genes (IMDEGs) were defined by intersecting EZH2-associated differential expression with correlations to Treg/TAM-related signature scores, and were used for NMF-based immune subtyping and penalized Cox modeling with validation. In scRNA-seq cohorts (GSE264573 and an independent CRPC cohort), malignant epithelial cells were inferred by copy-number alteration profiles, EZH2^high versus EZH2^low malignant programs were characterized, T-cell subsets were quantified, and tumor-Treg communication was inferred using CellPhoneDB as hypothesis-generating predictions. For perturbation, the EZH2 inhibitor tazemetostat was evaluated in the CRPC-relevant C42 cell line with H3K27me3 readouts and transcriptomic profiling, with key changes validated by RT-qPCR.
Results: Across bulk cohorts, higher EZH2 expression was associated with adverse clinical outcomes and increased enrichment of immunosuppressive signatures, including Treg- and TAM-related programs. IMDEG-based NMF subtyping identified patient groups with distinct immune states, and an IMDEG-derived risk score stratified prognosis. Single-cell profiling revealed elevated EZH2 in CRPC malignant cells and Tregs; EZH2^high malignant cells exhibited a proliferative transcriptional state accompanied by reduced expression of immune-related programs. Predicted tumor-Treg interaction patterns were stronger in CRPC and positively associated with EZH2 expression. In C42 cells, tazemetostat reduced H3K27me3 and induced coordinated transcriptional changes, including upregulation of immune- and inflammation-associated genes such as TIMP3, PLCG2, and SOCS3, validated by RT-qPCR.
Conclusion: This multi-layer integrative analysis suggests that EZH2 is associated with proliferative malignant states and immunosuppressive microenvironment features in advanced PCa, including Treg-linked crosstalk. Transcriptomic profiling following EZH2 inhibition supports modulation of these programs by EZH2-targeted perturbation, while functional and causal mechanisms warrant further investigation.

Keywords:  CRPC; EZH2; Treg; immunosuppressive; prostate cancer; single-cell RNA-seq

DOI:  https://doi.org/10.3389/fimmu.2026.1725097
Cancer Gene Ther. 2026 Feb 17.

The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth.

Jun Huang, Sheng-Dong Ge, Ling-Lan Zhao, Xian-Lu Song, Qu Li, Xiao-Feng Liu, Wen-Jun Tang, Qing Li, Tao Wang, Shan-Chao Zhao.

While the functions of activator protein-1 (AP-1) family transcription factors in prostate cancer (PCa) have been well researched, the specific role and mechanisms of FOSB in PCa progression are poorly understood. Here, we aimed to elucidate the precise role of FOSB in PCa and its underlying molecular mechanisms. A comprehensive investigation involving bioinformatics analysis of the TCGA and GEO datasets, validation in clinical PCa samples and cell lines, functional studies in vitro and in vivo, and RNA sequencing coupled with targeted validation (dual-luciferase reporter assays, ChIP‒qPCR, RT‒qPCR, Western blotting, and immunohistochemistry) was performed. FOSB is downregulated in PCa, and its high expression in tumours may reduce the risk of PCa progression by influencing characteristic growth-related cancer pathways. FOSB overexpression significantly inhibited PCa cell proliferation, increased apoptosis in vitro, and attenuated tumour growth in vivo, whereas FOSB knockdown resulted in the opposite effects. Mechanistically, FOSB transcripts were enriched in cell nuclei, where they upregulated the expression of IGFBP5, a gene that modulates the cellular response to IGF-1. This FOSB-mediated upregulation of IGFBP5 expression subsequently weakened the susceptibility of IGF1R to IGF-1 stimulation and suppressed the downstream PI3K/Akt and Ras/Raf/ERK oncogenic pathways. Our findings identify the novel FOSB-IGFBP5-IGF-1 axis upstream of PI3K/Akt and Ras/Raf/ERK signalling as a key regulator of PCa progression.

DOI: https://doi.org/10.1038/s41417-026-01012-z
Oncogene. 2026 Feb 18.

YEATS2 promotes DNA repair and induces anoikis resistance by enhancing chromatin accessibility to drive prostate cancer metastasis.

Haoran Li, Yarong Song, Yukun Cong, Chuxiong Wang, Kang Chen, Chunyu Liu, Menghao Zhou, Yunjie Ju, Jinyu Chen, Liang Chen, Yifei Xing.

Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their survival in the vascular system and plays a key role in metastasis. Therefore, investigating the molecular mechanisms of metastasis and anoikis resistance is essential for identifying novel therapeutic targets and strategies. In this study, we found that YEATS domain-containing 2 (YEATS2) plays a critical role in promoting PCa metastasis by suppressing anoikis. We observed that YEATS2 expression was elevated in mPCa and associated with poor clinical outcomes. Knockdown of YEATS2 reduced the metastatic potential of PCa cells both in vivo and in vitro, whereas its overexpression inhibited anoikis and promoted metastasis by upregulating the expression of the DNA damage repair gene RAD50. Mechanistically, YEATS2 increases chromatin accessibility at the RAD50 promoter region by recognizing H3K27ac and subsequently recruits the transcription factor NR2C2. Mirin suppressed lymph node metastasis of PCa cells in vivo. Our study demonstrated a novel function of the YEATS2/NR2C2/RAD50 axis in regulating DNA damage responses and anoikis resistance in PCa metastasis, highlighting an important pathway that drives metastatic progression and offering potential new strategies for treating mPCa.

DOI: https://doi.org/10.1038/s41388-026-03696-x
J Adv Res. 2026 Feb 17. pii: S2090-1232(26)00159-1. [Epub ahead of print]

Modulation of the intestinal microbiome and reversal of the immunosuppressive microenvironment by nanoparticles for chemoimmunotherapy in prostate cancer.

Jie Xu, Ruimin Hu, Jun Zheng, Qian Ju, Youxin Liu, Saipeng Chen, Zhicheng Liu, Yuhao Lei, Jing Yang, Dinglin Zhang, Wenhao Shen.

   INTRODUCTION: Prostate cancer (PCa), a "cold" tumor with an immunosuppressive microenvironment, exhibits poor sensitivity to immunotherapies, limiting treatment efficacy. Chemotherapeutics often cause intestinal injury and disrupt gut microbiota, further impairing chemoimmunotherapy outcomes. Modulating gut microbiota to reverse immunosuppression represents a potential strategy to enhance PCa treatment.
OBJECTIVES: To develop a novel therapeutic strategy using nanomedicine to regulate intestinal flora, thereby reversing the immunosuppressive microenvironment and improving chemoimmunotherapy efficacy in PCa.
METHODS: Cabazitaxel (CBZ)-loaded, folic acid (FA)-modified pH/ROS dual-responsive nanoparticles (CBZ/FA-CA-OCD NPs) were fabricated. In vitro and in vivo experiments evaluated NPs accumulation, cellular internalization (via FA-mediated endocytosis), drug release, intestinal mucosal injury, and tumor growth inhibition. Gut microbiota modulation (e.g., Lachnospiraceae, Firmicutes, Muribaculaceae, Bacteroidota) and CD4+/CD8+ T-cell infiltration were assessed. Fecal microbiota transplantation (FMT) validated microbiota-mediated immune effects.
RESULTS: The CBZ/FA-CA-OCD NPs accumulated in PCa tissues were internalized by PC-3/LNCaP cells and released CBZ in acidic/ROS microenvironments to inhibit tumor growth. Compared to free CBZ, NPs attenuated intestinal injury, modulated microbiota (increased Lachnospiraceae/Firmicutes, decreased Muribaculaceae/Bacteroidota), and enhanced anti-PD-1 efficacy by increasing CD4+/CD8+ T-cell infiltration. FMT confirmed that microbiota from NP-treated mice promoted T-cell infiltration in tumors.
CONCLUSION: CBZ/FA-CA-OCD NPs improve PCa chemoimmunotherapy by regulating gut microbiota, reversing immunosuppression, and enhancing T-cell infiltration. This nanomedicine-based strategy provides a promising approach to boost PCa treatment outcomes.

Keywords:  Cabazitaxel; Chemoimmunotherapy; Fecal microbiota transplantation; Immunosuppressive microenvironment; Intestinal microbiome; Prostate cancer; pH/ROS dual-responsive drug delivery system

DOI:  https://doi.org/10.1016/j.jare.2026.02.027
Int J Radiat Oncol Biol Phys. 2026 Feb 17. pii: S0360-3016(26)00403-7. [Epub ahead of print]

Continuous, Preclinical Activity Reconstruction in 177Lu-based Radiopharmaceutical Therapy Using a Sparse Uncollimated γ-Sensor Network.

Rahul Lall, Michael Evans, Youngho Seo, Ali Niknejad, Mekhail Anwar.

   PURPOSE: 177Lu-based radiopharmaceutical therapy (RPT) has shown increasing promise in the treatment of neuroendocrine and metastatic prostate cancer. Delivering optimal radiation dose to tumors while minimizing dose to organs-at-risk (OAR) remains an unmet need due to significant patient-to-patient heterogeneity in treatment response, necessitating multiple snapshots of the in vivo activity distribution. Towards this goal, here we present a high temporal-resolution activity reconstruction method demonstrated on preclinical prostate cancer models.
METHODS: Utilizing a priori knowledge of tumor locations from a pretherapy scan (e.g. PET/CT), we have developed a low-cost, sparse sensor network to reconstruct the real-time tumor and OAR activity in preclinical cancer models. The proposed system was successfully validated1 with a small custom phantom filled with [177Lu]Lu-PSMA-617 and (2) with 4 mice models, bearing varying numbers of tumors from two human prostate cancer cell lines (PC3-PIP, PC3-flu), to which [177Lu]Lu-PSMA-617 RPT was administered. Uncollimated γ counts using the developed network were acquired outside of the mouse at 10 minutes post-injection (m.p.i), 6 hours, 12 hours, 24 hours, and 48 hours post-injection (h.p.i).
RESULTS: The developed system's total tumor activity and percent injected activity per milliliter of tissue (%IA/mL) reconstruction in tumors, kidneys, and bladders is highly linear with the total tumor activity (R2=0.991) and %IA/mL (R2=0.994) from state-of-art small-animal SPECT. Acquisition and reconstruction were performed at a 1-minute temporal resolution, greater than 30 times faster than conventional small-animal SPECT imaging, allowing for the ability to capture fast kinetics at early timepoints and create close-to continuous time-activity curves at a fraction of the cost of small-animal SPECT systems.
CONCLUSIONS: The system can be used for high temporal resolution preclinical activity reconstruction, and motivates clinical adaptation in order to improve 177Lu-based RPT quality and safety through frequent activity distribution measurements of multiple tumors and OAR.

Keywords:  activity reconstruction; continuous dosimetry; radiopharmaceutical therapy; sparse network

DOI:  https://doi.org/10.1016/j.ijrobp.2026.02.224
Front Oncol. 2026 ;16 1659869

Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.

Zhongze Zhou, Yongfeng Lao, Kun Zhao, Long Cheng, Xi Xiao, Wenxuan Li, Shuai Liu, Xiangbin Kong, Zhilong Dong.

   Background: Prostate cancer (PCa) is one of the most common malignancies in men, and metastatic castration-resistant PCa (mCRPC) has limited treatment options. While chimeric antigen receptor T (CAR-T) therapy has revolutionized treatment of hematologic cancers, its efficacy in PCa is constrained by factors such as scarce tumor-specific antigens, an immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and safety issues (e.g., cytokine release syndrome).
Methods: We performed a comprehensive literature review of CAR-T therapy in PCa. We summarized known PCa-specific CAR targets, identified major TME-related and technical barriers, and highlighted recent advances in CAR engineering (including armored CAR-T cells, gene editing, and metabolic reprogramming) as well as combination approaches with other therapies.
Results: Emerging strategies show promise for overcoming these obstacles. Next-generation CAR designs, such as cytokine-armed CAR-T cells, may enhance T cell infiltration and persistence despite the suppressive TME. Modulating tumor metabolism and immune checkpoints can reverse T cell exhaustion. Multi-antigen CARs and targeted gene edits (for example, PD-1 disruption) may limit antigen escape. Early clinical trials in PCa have demonstrated CAR-T cells specifically recognizing prostate-associated antigens and eliciting antitumor immune responses, although durable remissions remain rare.
Conclusion: CAR-T therapy for prostate cancer is a rapidly advancing field. This review provides an updated perspective on CAR-T targets, engineering strategies, and combination approaches in PCa. Ongoing innovations in CAR design and therapeutic combinations offer the potential to develop more effective and durable CAR-T treatments for advanced prostate cancer.

Keywords:  CAR design; chimeric antigen receptor T-cell; immunotherapy; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1659869
Cancer Lett. 2026 Feb 12. pii: S0304-3835(26)00083-2. [Epub ahead of print]644 218320

M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells.

Keisuke Shigeta, Shinkichi Takamori, Hiroki Ozawa, Naoki Haratake, Mai Onishi, Tatsuaki Daimon, Tomohiro Kitano, Atrayee Bhattacharya, Atsushi Fushimi, Mototsugu Oya, Mark D Long, Donald Kufe.

  Advanced castration-resistant prostate cancer (CRPC) is responsive to PARP inhibitors, but only in settings of defects in homologous recombination (HR). The oncogenic M1C protein drives CRPC progression; however, it is not known if M1C plays a role in the response to PARP inhibition. The present work demonstrates that M1C is induced by olaparib treatment of HR-competent CRPC cells. As a result, M1C drives (i) ATM expression, (ii) phosphorylation of KAP1(S824) and (iii) activation of STING, which have been linked to derepression of the LINE-1 (L1) retrotransposon. In this way, M1C is necessary for induction of (i) L1-5'UTR, L1-ORF1 and L1-ORF2 transcripts and (ii) the encoded ORF1p RNA binding protein. Activation of retrotransposons induces genomic instability and drug resistance. By extension, we show that M1C also activates HERV-K102/108 gag, pol and env genes and expression of the HERV-K ENV protein. Our work further demonstrates that M1C integrates L1 and HERV-K activation with induction of APOBEC3 (A3) genes that evolved to restrain genomic instability induced by these retrotransposons. Of translational relevance, these findings demonstrate that M1C (i) is essential for inducing L1, HERV-K and A3 expression and resistance of CRPC cells to olaparib, and (ii) is a target for advancing the treatment of HR-competent CRPC with PARP inhibitors.

Keywords:  APOBEC3; Castration-resistant prostate cancer; HERV-K; Homologous recombination; LINE-1; M1C; Olaparib; Retrotransposons

DOI:  https://doi.org/10.1016/j.canlet.2026.218320
Mol Ther Oncol. 2026 Mar 19. 34(1): 201133

Suppression of PARP1 enhances PTEN mRNA therapy in castration-resistant prostate cancer by glycolysis disruption.

Bo Hu, Pengfei Wu, Lulu Zheng, Haiyin Yang, Yuchuan Fan, Jun Yang, Lu Tang, Sudong Kong, Chao Zhu, Minghui Yang, Jiatao Zhang, Qing Liu, Yuanyu Huang.

  Current treatments for prostate cancer (PC) inevitably lead to the development of resistance to androgen deprivation therapy, resulting in the emergence of castration-resistant prostate cancer (CRPC), which is currently considered incurable. In this study, we discovered that the loss of phosphatase and tensin homolog (PTEN) function, in combination with elevated poly(ADP-ribose) polymerase 1 (PARP1) expression, significantly shortens the survival of PC patients. Motivated by this finding, we developed an RNA-based therapeutic agent consisting of PARP1-targeting small interfering RNA (siRNA) (siPARP1) and PTEN-expressing mRNA (mPTEN), which were co-encapsulated in an ionizable lipid nanoparticle, named mPsiP@miLAND. Both siPARP1 and mPTEN were shown to individually attenuate tumor cell growth. Moreover, the simultaneous regulation of these two targets nearly completely suppressed proliferation and robustly induced apoptosis and necrosis in CRPC both in vitro and in vivo. Mechanistically, the restoration of PTEN inhibited glycolysis via the PI3K-Akt signaling pathway in CRPC cells, and the silencing of PARP1 further enhanced this effect. Overall, the mPsiP@miLAND developed in this study effectively inhibited the growth of PTEN-deficient prostate tumors, providing a promising strategy to overcome CRPC by exploiting the synergistic effects of PI3K-Akt and PARP inhibition.

Keywords:  MT: Regular Issue; PARP1; PTEN; castration-resistant prostate cancer; lipid nanoparticle; mRNA; siRNA

DOI:  https://doi.org/10.1016/j.omton.2026.201133
Commun Med (Lond). 2026 Feb 17.

Distinct prognostic value of [18F]FDG PET and [68Ga]Ga-PSMA-11 PET in advanced hormone-sensitive prostate cancer.

Ang Li, Haotian Wu, Xiang Zhou, Yinjie Zhu, Weiwei Zhang, Kai Shen, Linglin Tang, Jiayan Yi, Bo Liu, Ruopeng Su, Xinyu Liu, Xinyu Chai, Qi Wang, Jiahua Pan, Wei Xue.

BACKGROUND: This study aimed to evaluate the distinct prognostic value of [18F]FDG and [68Ga]Ga-PSMA-11 PET imaging in advanced hormone-sensitive prostate cancer, highlighting their complementary roles at both patient and lesion levels.
METHODS: This study retrospectively included 298 patients with newly diagnosed prostate cancer who underwent baseline dual-tracer PET imaging. Quantitative PET parameters for both [18F]FDG and [68Ga]Ga-PSMA-11 were extracted. Clinical outcomes, including progression-free survival, biochemical response, and radiographic response, were collected during follow-up. Lesion-based analysis was performed in 267 measurable lesions to evaluate the association between tracer uptake and local radiographic response, as determined by changes in lesion diameter following systemic therapy.
RESULTS: Here we show that higher whole-body [18F]FDG uptake, including total lesion glycolysis (HR = 3.525, p < 0.001) and metabolic tumor volume (HR = 2.757, p < 0.001), is significantly associated with shorter progression-free survival. In contrast, only PSMA-derived tumor volume (HR = 2.019, p = 0.018), but not total lesion PSMA uptake (HR = 1.438, p = 0.221), demonstrates prognostic value. Moreover, patients with higher whole-body [18F]FDG burden receive greater benefit from chemotherapy (HR = 2.936, p = 0.004). At the lesion level, higher [68Ga]Ga-PSMA-11 uptake is significantly correlated with more favorable radiographic response (p < 0.001), while lesion-level [18F]FDG uptake does not demonstrate predictive value.
CONCLUSIONS: [18F]FDG PET and [68Ga]Ga-PSMA-11 PET provide distinct but complementary prognostic value in advanced hormone-sensitive prostate cancer. Dual-tracer PET imaging enhances prognostic accuracy and provides comprehensive guidance for individualized treatment strategies.

DOI: https://doi.org/10.1038/s43856-026-01444-6
Eur J Med Chem. 2026 Feb 16. pii: S0223-5234(26)00126-1. [Epub ahead of print]308 118681

Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.

Kaiyuan Ma, Weiqin Jin, Yan Zhang, Zhifang Lu, Xiaoxi Zhuang, Junhua Li, Xinyi Jing, Jun Wang, Liang Li, Yanan Zhou, Xin Li, Tingting Xu, Jinxin Xu, Jinming Ma, Junjie Deng, Xin Zhai, Bin Lin, Yong Xu, Hui Shen.

  Liver receptor homolog-1 (LRH-1) is a key regulator in multiple cancers, including prostate cancer, making its antagonists a promising therapeutic strategy. However, the development of potent LRH-1 antagonists remains largely inadequate, underscoring an urgent unmet need for novel candidates with therapeutic potential. Herein, we report the discovery and characterization of a novel class of indole-based LRH-1 antagonists. Starting from high-throughput virtual screening, we employed structure-based drug design strategy to optimize lead compounds, yielding 26 (XY25026) and 28 (XY25028), which exhibit potent LRH-1inhibition with IC50 values of 280 nM and 300 nM, respectively. In cellular assays, 26 and 28 inhibited the cell proliferation across a panel of androgen receptor (AR)-positive prostate cancer cell lines with distinct androgen responsiveness and AR signaling profiles and suppressed AR target genes (KLK2 and KLK3). Importantly, oral administration of 26 and 28 elicited significant in vivo antitumor efficacy in a 22Rv1 xenograft model, with no detectable systemic toxicity observed in treated mice. These results identify 26 and 28 as promising orally bioavailable LRH-1 antagonists, validating them as attractive lead molecules for further structural optimization and development for castration-resistant prostate cancer (CRPC) therapy.

Keywords:  Antagonist; Castration-resistant prostate cancer; LRH-1; Nuclear receptor

DOI:  https://doi.org/10.1016/j.ejmech.2026.118681
Inflamm Res. 2026 Feb 19. 75(1): 41

Thrombosis-related gene signature predicts prostate cancer recurrence and immune therapy: insights from retrospective cohorts, bioinformatics, and experimental validation.

Yong Luo, Peixian Chen, Minyi Situ, Wei Zhuang, Jinxing Huang, Baojun Wang, Qiong Wang, Shengmeng Peng, Hai Huang.

   BACKGROUND: Thrombosis was recognized as a significant cause of morbidity and mortality for prostate cancer (PCa). The potential mechanisms underlying the effect of thrombosis on PCa remain elusive.
METHODS: Retrospective analysis of dual-center clinical data identified thrombosis-PCa correlations. Bioinformatics integration of TCGA-PRAD transcriptomics and thrombosis-related genes enabled construction of a prognostic signature, validated externally. Functional, immune, and drug sensitivity analyses were performed. Experimental validation included IHC, qPCR, IF, in vitro functional assays, and in vivo models.
RESULTS: Elevated thrombosis risk strongly correlated with PCa aggressiveness and adverse clinical features. A five-gene risk model stratified PCa patients into distinct survival groups (low-risk: superior outcomes), validated by ROC/Cox analyses as an independent prognostic tool. Findings from functional enrichment, alongside evaluations of immune cell infiltration, immunotherapy responsiveness, and drug sensitivity, reinforced the capacity to accurately forecast the clinical efficacy of precision therapies, as validated by clinical relevance analysis and nomogram development. Immunohistochemistry and qPCR of signature genes revealed marked differences between PCa and adjacent tissues. Importantly, experimental knockdown of VAV2 in 22RV1 cells downregulated prothrombotic inflammatory factors (CXCL8, IL-6, and VEGF). Conditioned media from VAV2-knockdown cells markedly inhibited tube formation in HUVECs and suppressed NETs formation. In vivo, mice administered with conditioned media from VAV2-deficient cells exhibited prolonged PT and APTT, and reduced fibrinogen levels, indicating attenuated coagulation potential.
CONCLUSION: We successfully developed and validated an innovative and robust five-gene signature, seamlessly integrating clinical prognostic parameters for the precise prediction of PCa patients outcomes. This dissertation offers an in-depth exploration of thrombosis, elucidating potential biological mechanisms underpinning therapeutic strategies related to tumor immunity in PCa.

Keywords:  Gene signature; Immune microenvironment; Prostate cancer; Thrombosis; VAV2

DOI:  https://doi.org/10.1007/s00011-025-02138-w
Eur Urol Focus. 2026 Feb 17. pii: S2405-4569(26)00001-5. [Epub ahead of print]

Gut Microbiome as a Lifestyle Risk Factor Associated with Prostate Cancer.

Michael A Liss, James R White, Molly Doris, Zhao Lai, Teresa L Johnson-Pais, Robin J Leach, Martin Goros, Jonathan Gelfond, Brian Wickes.

   BACKGROUND AND OBJECTIVE: Most prostate cancer prevention strategies suggest lifestyle modifications, which lack personalization. Gut microbiome is increasingly recognized as an influencing factor in nongastrointestinal cancers, including prostate cancer. The use of gut microbiome as a lifestyle biomarker could help identify individuals with lifestyle more prone to prostate cancer and allow for modification. We aimed to develop a gut microbiome-based biomarker derived from patients undergoing prostate cancer screening.
METHODS: We assessed whether the future cancer risk can be evaluated based on a microbiome risk analysis. After extracting DNA, sequencing, and performing a bioinformatics analysis, we identified 39 unique microbial genera of importance. We utilized an artificial intelligence model to calculate their presence, abundance, and weighted significance, generating a microbiome score (Prostate Cancer Risk Insight using Microbiome UnderStanding [PRIMUS]) that ranges from 0 to 1.
KEY FINDINGS AND LIMITATIONS: Men with an increasing PRIMUS signature showed a sequential increase in prostate cancer risk. The prostate cancer risk persisted after a median follow-up of 4.5 yr. As a risk-assessment tool, the microbiome score compared favorably with prostate cancer risk calculators. Study limitations include the use of two patient groups to diversify the population for both a screening and a prebiopsy scenario; however, the cohorts used different collection methods, including stool, rectal swabs, and glove tip samples, but the same DNA isolation and sequencing. We relied on the longitudinal approach to help reduce these initial differences.
CONCLUSIONS AND CLINICAL IMPLICATIONS: The gut microbiome may serve as a lifestyle risk factor for prostate cancer, but it is not intended to guide biopsy decisions. The implications of this study hinge on the potential for modifiability of the microbiome that could be tested in future clinical trials on prostate cancer risk reduction.

Keywords:  Biomarker; Cancer risk prediction; Fecal microbiota transplantation; Gut microbiome; Inflammatory bowel disease; Machine learning; Microbiome analysis; Personalized medicine; Prostate Cancer Risk Insight using Microbiome UnderStanding signature; Prostate cancer

DOI:  https://doi.org/10.1016/j.euf.2026.01.001
Nat Commun. 2026 Feb 14.

FOXJ1 mediates taxane resistance through regulation of microtubule dynamics.

Fang Xie, Ada Gjyrezi, Daniel Fein, Maryam Labaf, Larysa Poluben, Betul Ersoy-Fazlioglu, Christopher M Dennehy, Olga Voznesensky, Aniket Gad, Eva Corey, Andreas Varkaris, David J Einstein, Rupal S Bhatt, Paraskevi Giannakakou, Steven P Balk.

Docetaxel is the first-line chemotherapy for metastatic prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. Here we show, in an in vivo model of docetaxel resistant PC patient-derived xenografts, increased expression of genes that drive development of multiciliated cells including FOXJ1 and its effectors, many of which regulate microtubules (MTs). Mechanistically, FOXJ1 overexpression confers docetaxel resistance in vitro and in vivo, which is associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) has similar effects. Conversely, FOXJ1 knockdown impairs basal MT function, enhances taxane binding to MTs, and increases docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification is increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 is predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together, these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients who will not benefit from taxane treatment.

DOI: https://doi.org/10.1038/s41467-026-69556-0
Biochem Genet. 2026 Feb 17.

ERBB2 as a Prognostic Biomarker in Prostate Cancer: Integration of Single-Cell Transcriptomics, Deep Learning, and Immunohistochemical Validation.

Chen Wang, Li-Jing Zhu, Wei-Bo Mao, Ting Chen, Teng-Fei Gu, Sheng-Ping Hu, Yong-Tao Pan, Guo-Lin Yan, Yun-Peng Dong, Jie Li.

  Biochemical recurrence (BCR) is a critical factor affecting the prognosis of prostate cancer (PCa) patients, while T cell exhaustion and metastatic prostate cancer (mPC)-related genes play significant roles in tumor progression. This study aims to identify key genes associated with BCR by integrating single-cell transcriptomics and deep learning techniques, and to validate their clinical significance. First, we identified highly expressed genes in CD8+ T cell exhaustion clusters from single-cell RNA sequencing data (scRNA-seq) of PCa and intersected them with mPC-related genes. Based on these genes, significant prognostic factors were screened using Cox regression analysis, and a deep learning neural network model was constructed to predict the risk of biochemical recurrence in prostate cancer patients. The tumor-infiltrating lymphocyte (TILs) infiltration was predicted by stratifying patients into high- and low-risk groups. ERBB2 was identified as the most predictive gene through model analysis. Subsequently, ERBB2 expression was validated in an independent PCa cohort using immunohistochemistry (IHC), and its association with biochemical recurrence and clinicopathological features was evaluated through survival analysis and statistical methods. The deep learning model demonstrated excellent performance in predicting BCR, with ERBB2 identified as the most important predictive factor. IHC results revealed that patients with high ERBB2 expression had significantly shorter biochemical recurrence-free survival (bRFS) (P < 0.05). Moreover, high ERBB2 expression was significantly associated with higher prostate-specific antigen (PSA) levels, Node-Metastasis (NM) stage, and International Society of Urological Pathology (ISUP) grade (P < 0.05). This study, for the first time, integrates single-cell transcriptomics, deep learning, and IHC to reveal the critical role of ERBB2 in biochemical recurrence of PCa. High ERBB2 expression is not only a potential biomarker for poor prognosis in PCa patients but may also provide a novel target for personalized therapy.

Keywords:  Biochemical recurrence; Deep learning; ERBB2; Immunohistochemistry; Prostate cancer; Single-cell RNA sequencing

DOI:  https://doi.org/10.1007/s10528-026-11333-1