bims-meproc 2026-01-11 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–01–11
34 papers selected by
Grigor Varuzhanyan, UCLA

A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer.
Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
Unraveling the microbial landscape in prostate cancer: pathogenesis to therapy.
Targeting Cancer-Associated Fibroblasts in Prostate Cancer: Recent Advances and Therapeutic Opportunities.
Study on the Role of Long Non-Coding RNA GAS5 in Promoting the Malignant Progression of Prostate Cancer by Regulating miR-12/GPRC5B Signaling Axis.
Multimode MALDI-MSI deciphers matrine-induced metabolic reprogramming in prostate cancer xenografts: spatial mapping of low-molecular-weight compound alterations.
Targeting YAP1-CD70 axis potentiates the efficacy of anti-PD-1 therapy in prostate cancer.
EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2.
CircFAM120B promotes prostate cancer progression through miR-1182 inhibition and FBXO17-mediated AKT activation.
Integrative single-cell and spatial transcriptomics with explainable AI reveal lethal prognostic axis in prostate cancer.
PEAK1 promotes prostate cancer progression and docetaxel resistance by mediating the polarization of tumor-associated macrophages.
Imperatorin induces ferroptosis via mediating lipid peroxidation and SLC7A11/ACSL4/GPX4 signaling for inhibition and therapeutics of prostate cancer.
Tributyltin Protumorigenic Effects Targeting Prostate Cancer Cell Metabolism, Proliferation, Migration, and Invasion.
Integrative high-throughput studies to develop novel targets and drugs for the treatment of advanced prostate cancer.
The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of EPHA3-Centered Oncogenic Network.
Elevated Tumor-Associated Androgen Receptor Activity Correlates with Poor Immune Infiltration and Immunotherapy Response across Cancer Types.
Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD.
The Zeb1/system Xc- axis safeguards iron-loaded cancer-associated fibroblasts against ferroptosis and promotes immunosuppression in prostate cancer.
Inhibition of PREX1 Reverses Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
Deciphering the role of zinc in prostate health: From mechanism to therapeutic application.
miR-146b-5p promotes prostate cancer progression by targeting and negatively regulating FOXO3 and its mechanism.
CD24 and Mutant p53: Emerging Therapeutic Targets in Prostate Cancer Progression.
HSP90α and KLK6 Co-Regulate Stress-Induced Prostate Cancer Cell Motility.
New Insights into Prostate Cancer Susceptibility in European Caucasians: A Systematic Review and Meta-Analysis of CYP3A4 Pharmacogene.
Mechanical Stimuli-Induced Manipulation of Malignant Behavior in Bioprinted Cancer Microtissues via PI3K/NF-κB Activation.
Targeting CAMK1D-engineered nanoactivator suppresses cancer stem cell maintenance and immune evasion in enzalutamide-resistant prostate cancer.
Green tea catechins and prostate cancer: mechanisms, clinical evidence, and safety: a narrative review.
Daidzein-engineered high-accumulation self-therapeutic nanoplatform drives androgen receptor degradation via ubiquitination-proteasome system to overcome enzalutamide resistance in castration-resistant prostate cancer.
APOBEC3C Suppresses Prostate Cancer by Regulating Key Molecules Involved in Cellular Inflammation, Cell Cycle Arrest, and DNA Damage Response.
NOTIFICATION: RhoGDIα Downregulates Androgen Receptor Signaling in Prostate Cancer Cells.
3'-Hydroxypterostilbene suppresses prostate cancer via apoptosis and autophagy in vitro and potent tumor growth inhibition in vivo.
Sodium-Glucose Cotransporter 2 Inhibitors for Patients With Prostate Cancer Undergoing Hormone Therapy.
Integrative analysis of DEHP exposure and prostate cancer: Mechanistic insights and predictive modeling.
CRISPR-Cas9-Loaded Theranostic Liposomes for Enhancing Radiosensitization of Prostate Cancer through POLD4 Gene Editing under Real-Time MRI Monitoring.

bioRxiv. 2025 Dec 26. pii: 2025.12.25.696507. [Epub ahead of print]

A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer.

Jeyaluxmy Sivalingam, Kyung Hyun Cho, Yingli Shi, Preston Barron, Michael Lan, Omar Franco, Xiuping Yu.

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor (AR) pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained unclear. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and cell line models, whereas MYC is downregulated and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Mechanistically, MYCL activation is not driven by genomic amplification but reflects a permissive epigenetic landscape. Functionally, MYCL overexpression suppresses AR signaling and induces neuroendocrine-like transcriptional reprogramming, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. We further identify ASCL1 and INSM1 as upstream regulators of MYCL, establishing a conserved neuroendocrine transcriptional axis. Together, these findings define MYCL as a lineage-specific regulator that drives neuroendocrine identity and plasticity in advanced prostate cancer.

DOI: https://doi.org/10.64898/2025.12.25.696507
Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
NPJ Biofilms Microbiomes. 2026 Jan 06.

Unraveling the microbial landscape in prostate cancer: pathogenesis to therapy.

Xiancai Du, Jing Wu, Siyuan Xia, Hao Zheng, Baotong Zhang.

Emerging evidence suggests a role of microbiota in prostate cancer, yet this association remains poorly understood. This review systematically examines microbes from the skin, oral cavity, gut, urinary tract, and the prostate cancer microenvironment, summarizing how these communities affect prostate cancer initiation, progression, and therapeutic response. We highlight key molecular pathways and metabolic reprogramming events underlying host-microbiota interactions and outline current findings and knowledge gaps to guide microorganism-based therapeutic strategies.

DOI: https://doi.org/10.1038/s41522-025-00900-w
Cancers (Basel). 2025 Dec 31. pii: 151. [Epub ahead of print]18(1):

Targeting Cancer-Associated Fibroblasts in Prostate Cancer: Recent Advances and Therapeutic Opportunities.

Peng Chen, Junhao Chen, Peiqin Zhan, Xinni Ye, Li Zhao, Zhongsong Zhang, Jieming Zuo, Hongjin Shi, Xiangyun Li, Songhong Wu, Yuanzhi Fu, Haifeng Wang, Shi Fu.

  Advanced prostate cancer, particularly castration-resistant disease, remains challenging to treat due to intratumoral heterogeneity, immune exclusion, and a suppressive tumor microenvironment. Within this ecosystem, cancer-associated fibroblasts shape tumor-stroma communication, but their marked heterogeneity and plasticity complicate classification and make indiscriminate fibroblast depletion potentially ineffective or even harmful. This review summarizes recent progress in fibroblast origins, functional subtypes, and fibroblast-driven mechanisms that promote tumor progression and therapy resistance, as well as emerging therapeutic opportunities in prostate cancer. We conducted a structured literature search of PubMed, ScienceDirect, and major publisher platforms (including Nature and SpringerLink) from database inception to 15 February 2025, supplemented by targeted manual screening of reference lists. Evidence from single-cell/spatial-omics and mechanistic studies indicates that prostate tumors contain multiple fibroblast programs that occupy distinct niches yet can interconvert. Across these studies, it was found that these fibroblasts contribute to immune suppression, extracellular matrix remodeling and stromal barrier formation, angiogenesis, and metabolic support, collectively limiting drug penetration and reinforcing immune evasion; therapeutic pressure can further rewire fibroblast states and resistance-associated signaling. Overall, the literature supports a shift toward function- and subtype-directed intervention rather than "one-size-fits-all" targeting, with promising directions including precision targeting and reversible reprogramming, rational combination strategies, and localized delivery approaches that reduce stromal barriers while preserving tissue homeostasis in high-risk and treatment-refractory prostate cancer.

Keywords:  cancer-associated fibroblasts; castration-resistant prostate cancer; prostate cancer; stromal heterogeneity; targeted therapy; therapeutic resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18010151
Bull Exp Biol Med. 2026 Jan 08.

Study on the Role of Long Non-Coding RNA GAS5 in Promoting the Malignant Progression of Prostate Cancer by Regulating miR-12/GPRC5B Signaling Axis.

Cang Li.

  The paper is aimed to screen the target molecules of miR-12 and to further explore the mechanism of GAS5 action in prostate cancer. The expression of GPRC5B in prostate cancer cell lines LNCaP, VCaP, 22RV1, DU145, and PC3 was measured by quantitative real-time PCR with reverse transcription (RT-qPCR) and variations in GPRC5B expression were analyzed after down-regulating GAS5 or silencing miR-12. CCK8 and plate clone experiments were performed to detect changes in proliferative activity and colony-forming capacity of prostate cancer cells after down-regulating GPRC5B. After transfection of prostate cancer cells with sh-GAS5 and/or miR-12 inhibitor, the changes in GPRC5B expression were evaluated with RT-qPCR and Western blotting. Our results showed that GPRC5B was highly expressed in prostate cancer cell lines. Down-regulating of GAS5 decreased GPRC5B expression, while silencing miR-12 increased it. CCK8 and plate clone experiments showed that expression of GPRC5B increased proliferative activity and clone formation ability of prostate cancer cells. RT-qPCR and Western blotting revealed that miR-12 inhibited the promoting effect of GAS5 on GPRC5B expression. Thus, GPRC5B is directly bound to miR-12. GAS5 promotes proliferation, migration, and invasion of prostate cancer cells and participates in malignant progression of tumors by suppressing miR-12-mediated regulation of GPRC5B expression.

Keywords:  cultivated cells of prostate cancer; long non-coding RNA GAS5; miR-12 microRNA; migration; proliferation

DOI:  https://doi.org/10.1007/s10517-026-06539-7
Front Pharmacol. 2025 ;16 1627864

Multimode MALDI-MSI deciphers matrine-induced metabolic reprogramming in prostate cancer xenografts: spatial mapping of low-molecular-weight compound alterations.

Jia Xu, Liang Qin, Xiao Liang, Lulu Chen, Juexin Wang, Hua Guo, Fengmei Wang, Ran Wu, Xiaojing An, Wenjuan Liu, Xiaodong Wang, Qi Li.

   Background: Matrine, a bioactive isoquinoline alkaloid, exhibits antitumor efficacy by modulating multiple signaling pathways to suppress cancer cell proliferation, migration and invasion. However, its metabolic regulatory mechanisms in prostate cancer intervention require systematic characterization.
Methods: We implemented matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) for spatial metabolomic profiling of prostate tissues, integrated with multivariate analytical approaches including principal component analysis, Pearson correlation-based clustering heatmap, partial least squares-discriminant analysis, and hierarchical clustering heatmap analysis. This multimodal strategy enabled comparative evaluation of low-molecular-weight metabolite distributions across normal control, prostate cancer, and matrine-treated prostate cancer cohorts.
Results: Multi-omics integration identified 19 discriminant metabolites (VIP >1.0) spanning lipid signaling mediators (choline, glycerophosphoglycerol, sphinganine, glycerophosphoinositol, linoleic acid, oleic acid, N,N-Dimethylsphingosine), amino acid network regulators (cysteic acid, 5-Hydroxylysine, glutamine-glutamate axis components), nucleotide biosynthesis (adenine, Ribose 1,5-bisphosphate, uracil, dihydrouracil, deoxyinosine, adenosine), markers of oxidative damage (8-Hydroxyguanine) and cofactor of nitric oxide synthases and aromatic amino acid hydroxylases (tetrahydropteridine). Linoleic acid, oleic acid, and N,N-Dimethylsphingosine exhibited the highest levels in the NC group; these metabolites were significantly downregulated in the PCa group and partially restored in the PCa+MAT group. In addition, the results revealed a progressive depletion of tetrahydropteridine across experimental groups, with the PCa+MAT group exhibiting significantly lower tetrahydropteridine levels compared to both NC and PCa groups (PCa+MAT < NC < PCa). Notably, the expression levels of other compounds were the lowest in the NC group, while they were significantly upregulated in the PCa group and with intermediate levels observed in the PCa+MAT group. Spatial metabolomics delineated dynamic metabolic reprogramming during prostate cancer progression, with matrine treatment demonstrating partial reversal of cancer-associated metabolic shifts, particularly in lipid pathways, underscoring its potential as a modulator of oncogenic metabolism.
Conclusion: This study establishes MALDI-MSI as a powerful platform for pharmacometabolomic evaluation, while elucidating matrine's therapeutic potential through coordinated regulation of lipid metabolic remodeling, amino acid/nucleotide biosynthesis pathways and oxidative stress responses. Our findings provide mechanistic insights into matrine's anticancer action and validate metabolomic approaches for natural product evaluation.

Keywords:  low-molecular-weight compound; matrine; matrix-assisted laser desorption/ionization mass spectrometry imaging; metabolic reprogramming; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2025.1627864
Biomark Res. 2026 Jan 07. 14(1): 6

Targeting YAP1-CD70 axis potentiates the efficacy of anti-PD-1 therapy in prostate cancer.

Tongyu Tong, Yupeng Guan, Juan Luo, Binyuan Yan, Xiangwei Yang, Junfu Zhang, Zheng Yang, Fei Cao, Guangxi Sun, Hao Zeng, Peng Li, Jun Pang.

  The mechanisms by which prostate cancer (PCa) evades anti-tumor immunity and the immune checkpoint blockade (ICB) response are poorly understood. Yes-associated protein 1 (YAP1) activation is a common feature in PCa. However, to date, there is no direct evidence regarding the effect of YAP1 activity on anti-tumor immunity in PCa patients. In this study, we discovered that YAP1 expression is usually abundant in PCa tissues. Transcriptome analysis revealed that PD-L1 and the immune costimulatory molecule CD70 were consistently upregulated in YAP1-activated PCa cells. Meanwhile, CD70 is also abundantly exhibited in ICB non-responder patients, but absent in ICB responders, who usually show high cytotoxic T cell infiltration. More importantly, CD70 inhibition restores the sensitivity to anti-PD-1 immunotherapy in YAP1-activated PCa cells. Mechanistically, YAP1 directly regulates the transcription of CD70 through cooperation with DNA-binding factor RUNX1. The upregulation of CD70 thus suppresses immune cell infiltration into malignant lesions and promotes the exhaustion of CD8 + T cells to facilitate evasion from immunosurveillance. Taken together, our findings define the YAP1-CD70 signaling axis as a novel immunosuppressive mechanism in PCa, which provides new insights into the potential of targeting the CD70 pathway to help further subdivide the population of PCa patients who can benefit from immunotherapy.

Keywords:  Anti-tumor immunity; Biomarker; CD70; Hippo signaling pathway; Prostate cancer

DOI:  https://doi.org/10.1186/s40364-025-00880-1
Oncogene. 2026 Jan 07.

EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2.

Wanqing Xie, Qi Chu, Lourdes Brea, Guihua Zeng, Yuan Wang, Xiaodong Lu, Mohan Zheng, Corinne R Ley, Zhiquan Lei, Hongshun Shi, Joshua L Zhu, Lihu Gong, M Cynthia Martin, Xianglin Shi, Galina Gritsina, Arabela A Grigorescu, Hana Chandonnet, Xin Liu, Jonathan C Zhao, Gary E Schiltz, Jindan Yu.

Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It catalyzes H3K27 methylation for epigenetic silencing of tumor suppressors and critically drives prostate cancer (PCa) progression. However, inhibitors of EZH2 catalytic function (EZH2i), such as EPZ-6438, showed limited efficacy in PCa. Here, we designed and developed a series of VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2 using EPZ-6438 as a ligand and identified PROTAC-6272 as a lead compound. PROTAC-6272 effectively degraded EZH2 and other PRC2 subunits across diverse PCa cell lines. However, PROTAC-6272 and other similar EZH2i-based PROTACs were consistently unable to decrease androgen receptor (AR), a gene that is directly activated by solo EZH2. Mechanistically, EZH2 PROTACs failed to degrade EZH2 coactivators, such as p300, due to their inability to engage EZH2 outside of the PRC2 complex. Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.

DOI: https://doi.org/10.1038/s41388-025-03662-z
3 Biotech. 2026 Jan;16(1): 65

CircFAM120B promotes prostate cancer progression through miR-1182 inhibition and FBXO17-mediated AKT activation.

Zijin Wan, Gang Liu.

  Circular RNAs (circRNAs) have emerged as key post-transcriptional regulators in cancer progression through their ability to modulate microRNA (miRNA) activity. However, the functional role and regulatory mechanisms of many circRNAs in prostate cancer (PCa) remain poorly understood. This study investigates the oncogenic potential of circFAM120B (hsa_circ_0001666) and its regulatory interaction with miR-1182 and FBXO17 in PCa. CircFAM120B expression was assessed in PCa tissues and cell lines using qRT-PCR and confirmed by Sanger sequencing and RNase R digestion. Functional assays, including CCK-8, EdU, colony formation, wound healing, Transwell, and flow cytometry, were performed to evaluate the effects of circFAM120B knockdown. RNA pull-down, dual-luciferase reporter, and rescue assays were conducted to investigate the molecular interaction between circFAM120B, miR-1182, and FBXO17. Additionally, a xenograft tumor model was used to validate in vivo tumorigenic effects. CircFAM120B was significantly upregulated in PCa tissues and cells and exhibited high cytoplasmic stability. Knockdown of circFAM120B suppressed PCa cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) while promoting apoptosis. Mechanistically, circFAM120B functioned as a sponge for miR-1182, thereby relieving its suppression of FBXO17. This axis led to activation of the AKT signaling pathway, which was attenuated following circFAM120B knockdown. Rescue experiments with a miR-1182 inhibitor confirmed that circFAM120B exerts its oncogenic effects via the miR-1182/FBXO17/AKT axis. In vivo, circFAM120B knockdown reduced tumor growth and metastatic potential in a PCa xenograft model. CircFAM120B promotes PCa progression by sponging miR-1182 and upregulating FBXO17 expression. Targeting the circFAM120B/miR-1182/FBXO17 axis may represent a novel therapeutic strategy for PCa.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04677-9.

Keywords:  AKT; FBXO17; MiR-1182; Prostate cancer; circFAM120B

DOI:  https://doi.org/10.1007/s13205-025-04677-9
NPJ Digit Med. 2026 Jan 06.

Integrative single-cell and spatial transcriptomics with explainable AI reveal lethal prognostic axis in prostate cancer.

Qintao Ge, Zhenda Wang, Yangyun Wang, Tonghui Chu, Zhongyuan Wang, Wenkai Zhu, Youzhao Zhang, Yonghao Chen, Dingwei Ye, Wenhao Xu, Zhong Wang, Mierxiati Abudurexiti.

Prostate cancer (PCa) remains clinically heterogeneous. We integrated single-cell and spatial transcriptomics with explainable machine learning to define a lethal tumor axis and establish an interpretable prognostic model. From 141,986 high-quality single cells spanning localized, hormone-sensitive, and castration-resistant PCa, we identified a malignant C4 epithelial subpopulation characterized by high chromosomal instability, androgen receptor and cell-cycle activation, and stemness potential. Spatial mapping further revealed immune-enriched yet suppressive niches, where fibroblasts and myeloid cells coexisted with exhausted lymphocytes, reflecting functional immune imbalance. We benchmarked 101 machine learning pipelines, selecting a Lasso plus PLS-Cox model that achieved strong concordance across independent cohorts. The C4-based risk score independently predicted recurrence-free survival after adjustment for age, Gleason score and T stage, and a nomogram combining this score with clinical variables showed good discrimination. SHAP interpretation highlighted MT1M, PCSK1N, and ACSL3 as major risk-driving features. PCSK1N was progressively upregulated from normal prostate to castration-resistant disease and promoted proliferation, clonogenicity, migration and enzalutamide resistance, while its inhibition sensitized organoids and xenografts to AR-targeted therapy. These findings define a C4-centered lethal tumor axis and provide an explainable, experimentally supported framework for prognostic stratification in PCa.

DOI: https://doi.org/10.1038/s41746-025-02297-4
Eur J Med Res. 2026 Jan 06. 31(1): 41

PEAK1 promotes prostate cancer progression and docetaxel resistance by mediating the polarization of tumor-associated macrophages.

Jianxin Ni, Xuelian Li, Zhengqi Shi, Boxin Guo, Yongfei Duan, Yongpan An, Ruixiao Li.

   BACKGROUND: Pseudopodium-enriched atypical kinase 1 (PEAK1) expression is altered in multiple human malignancies and promotes tumor proliferation, metastasis, and chemical therapy resistance. Here, we aimed to investigate the role and mechanisms of PEAKs in prostate cancer (PCa) progression and docetaxel resistance.
METHODS: The expression of PEAKs in PCa cells (LNCaP, PC3, DU145, and VCaP) was analyzed. PEAK1 knockdown or overexpression models were established in DU145, LNCaP, and PC3 cells. Functional assays were conducted to measure cell proliferation via CCK-8, EdU staining, and colony formation assays; cell migration was tested via transwell assays; and epithelial-to-mesenchymal transition (EMT) was detected via Western blotting. The sensitivity of PCa cells to docetaxel (DTX) or enzalutamide was tested via the CCK8 assay. A coculture model of PCa cells and THP-1 cells was used to test the interaction between PCa cells and THP-1 macrophages. Furthermore, the effects of PEAK1 on PCa cell growth were investigated in a xenograft model in nude mice. Western blot analysis was used to validate the expression levels of HIF-1α, PD-L1, STAT3, and NF-κB p65. Immunohistochemistry was used to detect infiltration of macrophages and T cells in the tumors.
RESULTS: PEAK1 expression was significantly elevated in DU145 and PC3 cells after long-term treatment with DTX. PEAK1 upregulation promoted cell proliferation, migration, EMT, and growth in nude mice, whereas PEAK1 knockdown reversed these effects. PEAK1 overexpression attenuated PCa cell sensitivity to DTX and enzalutamide, as evidenced by enhanced cell proliferation and reduced apoptosis. Furthermore, PEAK1-overexpressing PCa cells induced CCL2 and IL-6 production and promoted "M2" polarization of macrophages (M2-Mφ). M2-Mφs enhanced PCa cell proliferation and migration and attenuated DTX sensitivity. In vivo assays revealed that PEAK1 upregulation enhanced PCa cell growth and M2-Mφ infiltration but reduced CD8 + T-cell infiltration. Mechanistically, TGF-β, possibly produced by "M2" macrophages, induced PEAK1 upregulation. PEAK1 overexpression led to increased expression of HIF-1α and increased STAT3 and NF-κB pathway activation in PCa cells.
CONCLUSIONS: PEAK1 plays an oncogenic role in prostate cancer by promoting cell metastasis, reducing docetaxel and enzalutamide sensitivity, and mediating "M2" polarization of macrophages by activating the HIF-1α/STAT3/NF-κB pathway.

Keywords:  Docetaxel; Macrophage; Metastasis; PEAK1; Prostate cancer

DOI:  https://doi.org/10.1186/s40001-025-03568-2
Biochem Pharmacol. 2026 Jan 06. pii: S0006-2952(26)00014-6. [Epub ahead of print]245 117683

Imperatorin induces ferroptosis via mediating lipid peroxidation and SLC7A11/ACSL4/GPX4 signaling for inhibition and therapeutics of prostate cancer.

Jingang Jian, Haodong Xu, Xiaofeng Shi, Jun Zhang, He Wang, Yuefan Xu, Yuhua Huang, Jianquan Hou, Xuedong Wei, Yuxin Lin.

  Prostate cancer (PCa) remains a leading cause of cancer-related death among males worldwide. Targeting ferroptosis has now emerged as a promising strategy against cancer. This study aims to deciphering the anti-tumor role of imperatorin, a natural furanocoumarin, in mediating ferroptosis-induced mechanisms for PCa inhibition and treatment. Cell-based assays, including CCK-8, EdU, colony formation, migration, and invasion assays, were used to evaluate the effects of imperatorin on cellular malignant phenotypes. RNA sequencing and bioinformatics analyses identified ferroptosis-related marker signatures, i.e., SLC7A11, ACSL4 and GPX4, were key targets of imperatorin, which were functionally validated using experimental approaches to establish its binding role of ferroptosis, clarify drug specificity, and support translational relevance. It is showed that imperatorin inhibited proliferation, migration, and invasion of PCa cells in a dose-dependent manner by triggering ferroptosis with a potential mechanism of inducing lipid peroxidation via downregulating SLC7A11/GPX4 and upregulating ACSL4. In particular, a significant decreased level of TRIM21-mediated ubiquitination was detected in ACSL4 after imperatorin treatment. Moreover, imperatorin exhibited a synergistic effect with Enzalutamide in vitro, highlighting it as a latent medication strategy for combination therapy. In vivo characterization further demonstrated that imperatorin reduced tumor growth and altered the expression of ferroptosis marker signatures with favorable safety on vital organs from toxicity. This study revealed the ferroptosis-induced power of imperatorin, indicating it as a novel therapeutic candidate against PCa resistance. Future pharmacological and clinical analyses will be conducted for translational understanding of the findings to personalized PCa management.

Keywords:  Ferroptosis; Imperatorin; Personalized therapeutics; Prostate cancer; SLC7A11/ACSL4/GPX4 axis

DOI:  https://doi.org/10.1016/j.bcp.2026.117683
Environ Toxicol. 2026 Jan 06.

Tributyltin Protumorigenic Effects Targeting Prostate Cancer Cell Metabolism, Proliferation, Migration, and Invasion.

Mariana Feijó, Luís P Brás, Catarina M D Serra, Lara R S Fonseca, Sara Correia, Bruno J Pereira, Ana P Duarte, Henrique J Cardoso, Cátia V Vaz, Sílvia Socorro.

  Prostate cancer (PCa) is an endocrine-related cancer highly dependent on androgenic signaling. Beyond hormone dependence, extrinsic factors play a significant role in the risk of developing PCa, which raises concern about the influence of environmental compounds such as endocrine-disrupting chemicals (EDCs). Tributyltin (TBT) is an EDC used in antifouling paints, and its androgenic (and obesogenic) actions have been described. This study investigated the effect of TBT on various cancer hallmarks, specifically its impact on the viability, metabolism, proliferation, migration, and invasion of prostate cells, using in vitro and in vivo models. Androgen-sensitive (LNCaP) and androgen-insensitive (PC3) PCa cells were exposed to 1-100 nM TBT for 24 and 48 h. Additionally, LNCaP cells were treated with 100 nM TBT in the presence of the androgen receptor antagonist bicalutamide (1-40 μM) or 10 nM TBT and/or low-density lipoprotein (LDL, 100 μg/mL) and 5α-dihydrotestosterone (DHT, 10 nM, 48 h). Wistar rats were administered TBT (50 μg/kg) every 3 days for 45 days. TBT disrupted glycolytic flux and lipid handling in prostate cells, enhancing their proliferative activity. Moreover, 100 nM TBT stimulated migration and invasion of LNCaP cells. Bicalutamide attenuated the effect of TBT in inducing glucose consumption and LNCaP cell proliferation. A 10× lower TBT concentration maintained the stimulatory effects on LNCaP cells' viability, proliferation, and migration/invasion, sustained by high LDL-cholesterol availability and DHT. Our results show TBT as a potential inducer of PCa progression and aggressiveness and contribute to increasing awareness about the roles of EDCs in the prostate carcinogenic process.

Keywords:  5α‐dihydrotestosterone; endocrine‐disrupting‐chemicals; low‐density lipoprotein; prostate cancer; tributyltin

DOI:  https://doi.org/10.1002/tox.70029
Genes Dis. 2026 Mar;13(2): 101732

Integrative high-throughput studies to develop novel targets and drugs for the treatment of advanced prostate cancer.

Xuehui Li, Yanting Shen, Na Zhang, Dong Lu, Shuhua Ding, Fanchen Wu, Xiaowei Song, Xiangru Zhou, Shan Lin, Huan Xu, Zhong Wang, Fuwen Yuan.

  Androgen deprivation therapies targeting the androgen receptor (AR) signaling pathway are the primary treatment strategy for prostate cancer. However, these therapies often lead to castration resistance. Developing novel agents targeting AR-independent oncogenes is critical to address this challenge, particularly for advanced castration-resistant prostate cancer. This study identified three potential tumor drivers of advanced prostate cancer, including CDC20, DTL, and RRM2, through integrative bioinformatic screening that considered gene dependency using CRISPRi/RNAi database, clinical relevance, and experimental validation with CRISPR-Cas13-mediated gene ablation. Further mechanistic studies revealed that CDC20, DTL, and RRM2 were transcriptionally regulated by the RB1/E2F1 axis, mediating cell cycle progression in prostate cancer. Additionally, we identified novel agents targeting these candidates through virtual screening and drug-sensitive tests, utilizing our established small-molecule library. These agents exhibited superior anti-tumor efficacy compared with AR antagonists in vitro. Our study identified novel prostate cancer therapeutic targets independent of the AR signaling pathway and established a research paradigm for developing anti-tumor agents through integrative cancer bioinformatics and network pharmacology analysis.

Keywords:  Advanced prostate cancer; CDC20; DTL; RB1/E2F1 axis; RRM2; Structure-based virtual screening

DOI:  https://doi.org/10.1016/j.gendis.2025.101732
Cancers (Basel). 2025 Dec 21. pii: 26. [Epub ahead of print]18(1):

The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of EPHA3-Centered Oncogenic Network.

Md Towhidul Islam Tarun, Hassan Y Ebrahim, Khalid A El Sayed.

  Background/Objectives. Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men in the United States. Treatment with second-generation androgen receptor (AR) inhibitors, such as enzalutamide, can trigger lineage plasticity, promoting the transdifferentiation of PCa cells into an AR-independent, poorly differentiated neuroendocrine phenotype (NEPC). The receptor tyrosine kinase EPHA3 is a critical driver for NEPC. It is overexpressed in PCa, particularly in androgen-independent and neuroendocrine subtypes. EPHA3 activates c-Myc signaling to enhance EZH2 expression, promoting histone H3K27 trimethylation. The neural transcription factor BRN2 functions upstream of both EZH2 and ASCL1. The latter regulates the Notch pathway ligand DLL3, thereby orchestrating neuroendocrine differentiation. Elevated expression of classical neuroendocrine markers CHGA and SYP is characteristic of the NEPC phenotype. This study reports the novel usage of the olive phenolic S-(-)-hydroxyoleocanthal (HOC, oleacein) to effectively control NEPC by targeting the EPHA3-BRN2-EZH2-ASCL1-DLL3-SYP-CHGA oncogenic network. Methods. Cell viability assays were conducted to assess in vitro effects. To model NEPC progression and recurrence, NCI-H660-Luc cells were xenografted into male athymic nude mice. RNA-sequencing was performed to compare the differentially expressed genes between placebo control and treated tumors. Results. HOC significantly attenuated the proliferation of NEPC NCI-H660 cells in vitro. Daily oral administration of HOC at 10 mg/kg body weight markedly suppressed the progression of NEPC NCI-H660-Luc tumors. Continued HOC treatments after surgical excision of the primary tumors substantially reduced locoregional recurrence. HOC significantly downregulated the expression of EPHA3, BRN2, EZH2, ASCL1, DLL3, SYP, and CHGA in treated primary and recurrence tumors versus placebo control. Conclusions. These findings establish HOC as a multifaceted therapeutic entity capable of disrupting key NEPC oncogenic networks, highlighting its potential as a novel lead intervention for aggressive NEPC.

Keywords:  EPHA3–BRN2–EZH2–ASCL1–DLL3–SYP–CHGA axis; RNA-sequencing; S-(-)-hydroxyoleocanthal; neuroendocrine prostate cancer; olive phenolics; progression; recurrence

DOI:  https://doi.org/10.3390/cancers18010026
Cancer Res Commun. 2026 01 01. 6(1): 17-35

Elevated Tumor-Associated Androgen Receptor Activity Correlates with Poor Immune Infiltration and Immunotherapy Response across Cancer Types.

Ya-Mei Hu, Faming Zhao, Julie N Graff, Canping Chen, Yi Zhang, Jayne M Stommel, Jinho Lee, Gabriel M Zangirolani, Joshua Rose, George V Thomas, Hui Wu, Adel Kardosh, Gordon B Mills, Joshi J Alumkal, Amy E Moran, Zheng Xia.

The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. In this study, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA sequencing [RNA-seq; The Cancer Genome Atlas (TCGA)], single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and single-sample gene set enrichment analysis. Key findings were validated using digital spatial profiling and IHC. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, with highest observed in prostate adenocarcinoma. Genes significantly correlated with AR activity showed negative associations and were enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFNγ pathway activity across tumors and sexes-unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed that AR inhibition enhanced immune cell and IFNγ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.
SIGNIFICANCE: Tumor-associated AR activity negatively correlates with immune infiltration and immunotherapy response across cancers, independent of sex, suggesting that combining AR inhibitors with checkpoint blockade may benefit patients with immunotherapy-refractory tumors.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0409
bioRxiv. 2025 Dec 31. pii: 2025.12.30.697072. [Epub ahead of print]

Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD.

Teng Han, Zhen Sun, Matthew Lange, Y Zoe Cho, Patrick Mcgillivray, Maren Büttner, Nathaniel R Kastan, Subhiksha Nandakumar, Huiyong Zhao, Sanyukta Oak, Linda Fong, Wenfei Kang, Ning Fan, Jimmy Zhao, Nazifa Salsabeel, Harmanpreet Kaur, Ninghui Mao, Qing Chang, Eric Rosiek, Eric Chan, Murray Tipping, Nikolaus Schultz, Pierre-Jacques Hamard, Elisa DeStanchina, Dana Pe'er, Richard Koche, Zhenghao Chen, A James Hudspeth, Charles L Sawyers.

Treatment-related neuroendocrine prostate cancer (NEPC) is an increasingly frequent mechanism of resistance to androgen receptor pathway inhibitor (ARPI) therapy in prostate adenocarcinoma (PRAD). This lineage transition is dependent on upregulation of the NE-specifying transcription factor ASCL1, typically in a genetic background of RB1 and TP53 loss. Here we identify extracellular matrix-integrin-YAP1/TEAD signaling as a critical brake on NEPC lineage transition. Deletion of Itgb1 , the shared B1 subunit required for collagen and laminin-mediated integrin activation, is sufficient to induce ASCL1 and NE lineage gene expression, by activating LATS1/2 kinases with subsequent inactivation of YAP1/TEAD signaling. Conversely, restoration of YAP1/TEAD signaling by pharmacological LATS1/2 inhibition, or by expression of constitutively active YAP1/TAZ mutants, prevents or reverts NEPC lineage transition. NOTCH and AR cooperate with YAP/TEAD to repress ASCL1, such that combined inhibition leads to complete reprograming of PRAD into NEPC in vitro , providing a dynamic platform to dissect the molecular events responsible for lineage transition over time. We find that lineage transition is accompanied by a redistribution of FOXA1 and TEAD cistromes from PRAD to NEPC-specific enhancers and requires the pioneering activity of FOXA1. Thus, extracellular matrix/integrin signaling in the PRAD tumor microenvironment restrains NE lineage plasticity, highlighting a potential path for pharmacological inhibitors in modulating treatment-induced lineage change.

DOI: https://doi.org/10.64898/2025.12.30.697072
Cancer Lett. 2026 Jan 02. pii: S0304-3835(26)00006-6. [Epub ahead of print]639 218243

The Zeb1/system Xc- axis safeguards iron-loaded cancer-associated fibroblasts against ferroptosis and promotes immunosuppression in prostate cancer.

Yingchao Zhang, Huifang Zhao, Penghui Xu, Kaiyuan Liu, Genyu Du, Xinyu Chen, Na Jing, Wei Bao, Chaping Cheng, Jinming Wang, Mingyue Wang, Nan Wang, Xialian Xi, Yiyun Liu, Yujiao Sun, Wei-Qiang Gao, Helen He Zhu, Kai Zhang.

  A subset of iron-loaded cancer-associated fibroblasts is unraveled in the tumor microenvironment of prostate cancer (PCa) and termed as the ferrum iron CAFs (FerroCAFs) in our previous study. Importantly, FerroCAFs have been identified as a source of C-C motif ligand 2 (CCL2), C-X-C motif ligand chemokines 1/2 (CXCL1/2), and colony-stimulating factor 1 (CSF1) to induce immunosuppression. However, the iron-loaded phenotype of FerroCAFs also elicits high amounts of lethal oxygen radicals, lipid peroxides and reactive oxygen species (ROS) due to iron excess. Consequently, the mechanism by which FerroCAFs resist ferroptosis, a form of cell death induced by iron-dependent lipid peroxidation, remains to be elucidated. Here, we find that the upregulation of cystine/glutamate antiporter System Xc-, specifically Slc7a11, functions as a protective mechanism that preserves FerroCAFs against ferroptosis. The zinc finger E-box binding homeobox 1 (Zeb1) occupies the Slc7a11 gene promoter region and activates Slc7a11 transcription. Knockdown of FerroCAF-specific Slc7a11 suppresses tumor growth and subverts immunosuppression. Collectively, this study demonstrates that Zeb1/System Xc- axis protects FerroCAFs against ferroptosis. Targeting this vulnerability of FerroCAFs by blockade of Zeb1/System Xc- axis provokes anti-tumor immunity in PCa, implying a promising CAF-centric immunotherapeutic strategy.

Keywords:  Cancer-associated fibroblast (CAF); Ferroptosis; Immunosuppression; Iron metabolism; Prostate cancer (PCa)

DOI:  https://doi.org/10.1016/j.canlet.2026.218243
World J Mens Health. 2025 Nov 17.

Inhibition of PREX1 Reverses Enzalutamide Resistance in Castration-Resistant Prostate Cancer.

Chung Un Lee, Seon-Yong Yeom, Wan Song, Minyong Kang, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Soo Jeon, Seong Il Seo.

   PURPOSE: Castration-resistant prostate cancer (CRPC) often progresses despite initial responses to enzalutamide owing to the development of resistance. Our study explored the mechanisms underlying resistance in enzalutamide-resistant prostate cancer cell lines, along with the role of phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (PREX1) in CRPC resistance.
MATERIALS AND METHODS: The sequencing of total RNA was performed to analyze the microarray gene expression profiles. In our colony formation assay, 1,000 cells per well were seeded into six-well plates to evaluate clonogenic survival. Phosphoprotein profiling was conducted to assess specific signaling pathways and estimate cell proliferation rates. Protein expression was analyzed by western blotting, and Rac GTPase activity was measured to evaluate the cellular responses to enzalutamide. Cell invasion was examined using Transwell migration assays. An in vivo model involving the subcutaneous implantation of tumor cells into mice was used to study tumorigenic potential under resistant conditions.
RESULTS: RNA sequencing revealed activation of the cancer migration pathway in enzalutamide-resistant prostate cancer cells with significant upregulation of PREX1. PREX1 knockdown reduced the proliferation and colony formation rates of resistant cell lines. Mechanistically, PREX1 suppression inhibited both epidermal growth factor receptor and its downstream signaling pathways, including signal transducers and activators of transcription 5, thereby reducing cell migration and epithelial-mesenchymal transition, independent of Rac activation. In vivo, tumors derived from PREX1-knockdown cells exhibited significantly lower weights than those derived from control cells.
CONCLUSIONS: This study provides compelling evidence on the pivotal role of PREX1 in mediating enzalutamide resistance in CRPC. Our findings suggest that PREX1 is a promising therapeutic target that may modulate treatment efficacy and drug resistance in CRPC.

Keywords:  Enzalutamide; Prostatic neoplasms, castration-resistant; Signal transduction

DOI:  https://doi.org/10.5534/wjmh.250135
Biochem Pharmacol. 2026 Jan 07. pii: S0006-2952(26)00020-1. [Epub ahead of print] 117689

Deciphering the role of zinc in prostate health: From mechanism to therapeutic application.

Ziang Li, Yifan Hou, Zhenhua Zhao, Wenbo Zhang, Jianhua Zhang, Song Li, Xiaobo Nie, Junqing Hou.

  Zinc is an essential trace element crucial for human health. The prostate contains the highest concentration of zinc in the male body, making it the organ most affected by zinc disturbances. Zinc plays a critical role in maintaining normal prostate structure and function by modulating energy metabolism and secretory processes in prostate cells, regulating androgen balance, and exerting antibacterial effects. Disturbances in zinc homeostasis are closely associated with the pathogenesis of common prostatic diseases, including prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Consequently, zinc supplementation has emerged as a potential strategy for managing certain prostatic diseases. However, its efficacy and safety remain controversial. This review presents a comprehensive overview of zinc metabolism and mechanisms of action, with a focus on its role in the pathogenesis of common prostatic diseases, and analyzes recent advancements and current challenges in the clinical application of zinc supplementations.

Keywords:  Benign prostatic hyperplasia; Bioavailability; Mechanism of action; Prostate cancer; Prostatitis; Zinc

DOI:  https://doi.org/10.1016/j.bcp.2026.117689
World J Surg Oncol. 2026 Jan 06.

miR-146b-5p promotes prostate cancer progression by targeting and negatively regulating FOXO3 and its mechanism.

Baoji Xing, Meini Cen, Yin Yu, Feng Feng, Zhao Wang.

   AIMS: To investigate the expression and potential mechanism of action of miR-146b-5p in prostate cancer (PCa).
METHODS: Quantification of miR-146b-5p and FOXO3 expression by RT-qPCR was performed on 140 paired PCa and normal adjacent tissues. Kaplan-Meier curves and Cox regression models were used to analyze the relationship between miR-146b-5p expression and 5-year survival outcomes. In vitro experiments were performed in PC-3 and 22RV1 cells to explore the regulatory relationship between miR-146b-5p and FOXO3.
RESULTS: miR-146b-5p is markedly upregulated in PCa tissues and cell lines, exhibiting a significant correlation with tumor stage, Gleason score, lymph node metastasis, and unfavorable prognosis. miR-146b-5p overexpression promoted PCa cell proliferation, migration, and invasion, while inhibition exerted opposite effects. Bioinformatics prediction and dual-luciferase assay confirmed that miR-146b-5p directly targeted the 3'UTR of FOXO3, negatively regulating its expression. Rescue experiments demonstrated that silencing FOXO3 reversed the inhibitory effects of miR-146b-5p inhibitor on PCa cell malignancy.
CONCLUSIONS: miR-146b-5p drives PCa progression through the targeted downregulation of FOXO3, implicating it as a promising prognostic marker and therapeutic target.

Keywords:  FOXO3; Prognosis; Prostate cancer; miR-146b-5p

DOI:  https://doi.org/10.1186/s12957-025-04161-x
Anticancer Agents Med Chem. 2026 Jan 05.

CD24 and Mutant p53: Emerging Therapeutic Targets in Prostate Cancer Progression.

Yin Qinzhamusu, Lan Xintian, Gan Zhihao, Han Tiezheng, Zhu Ming, Xie Ruishi, Guo Yi, Wang Yong.

   INTRODUCTION: Prostate cancer is a leading cause of cancer-related mortality in men worldwide, and the treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. CD24, a glycosylated cell surface protein, plays a critical role in tumor progression and immune evasion. This review focuses on the role of CD24 in prostate cancer pathogenesis, particularly its interaction with mutant p53, and explores potential therapeutic implications.
METHODS: Through a systematic search of the PubMed, Web of Science, and Embase databases (2015-2025), using the following structured search terms: (CD24 OR "CD24 antigen") AND ("prostate cancer" OR "prostatic neoplasms") AND ("mutant p53" OR "TP53 mutation") AND ("targeted therapy" OR immunotherapy), relevant studies were identified and screened according to PRISMA guidelines.
RESULTS: CD24 overexpression was significantly associated with high Gleason scores, metastasis, and poor prognosis. Mechanistically, CD24 promotes tumor progression by destabilizing p53 through the disruption of ARF-NPM interactions and by synergizing with mutant p53. Preclinical studies indicate that therapies targeting CD24, such as CAR-T cells and nanoparticle-based drug delivery systems, demonstrate potent anti-tumor effects.
DISCUSSION: The CD24-p53 axis is amplified in mCRPC and interacts with androgen receptor signaling, while tumor microenvironment factors further enhance treatment resistance.
CONCLUSION: CD24 and mutant p53 represent promising therapeutic targets in metastatic castration-resistant prostate cancer (mCRPC). Translating these targeting strategies into clinical practice may help overcome current therapeutic challenges and improve patient outcomes.

Keywords:  CD24; immunotherapy; mutant p53; prostate cancer; targeted therapy.

DOI:  https://doi.org/10.2174/0118715206405420251117053720
bioRxiv. 2025 Dec 29. pii: 2025.12.19.695259. [Epub ahead of print]

HSP90α and KLK6 Co-Regulate Stress-Induced Prostate Cancer Cell Motility.

Katelyn L O'Neill, Johnny W Zigmond, Raymond Bergan.

Background: 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.
Methods: 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.
Results: Stress increased eHSP90 in 4 of 4 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.
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.

DOI: https://doi.org/10.64898/2025.12.19.695259
Cancers (Basel). 2025 Dec 24. pii: 58. [Epub ahead of print]18(1):

New Insights into Prostate Cancer Susceptibility in European Caucasians: A Systematic Review and Meta-Analysis of CYP3A4 Pharmacogene.

Maria Pagoni, Claudia Cava, George T Tsangaris, Fotios Siannis, Nikolaos Drakoulis.

   BACKGROUND/OBJECTIVES: Prostate cancer is the most frequent male malignancy. The incidence of disease varies among different ethnic groups. CYP3A polymorphisms are candidates for prostate cancer susceptibility studies. The aim of the present study is to investigate the ethnicity-related clinical impact of CYP3A4 variants on prostate cancer risk.
METHODS: A systematic literature search and meta-analysis were conducted according to PRISMA guidelines. A total of 10 eligible studies, including 3116 prostate cancer cases and 3008 healthy controls, were analyzed. We evaluated the association between the CYP3A4*1B (rs2740574, -392 A > G) variant and prostate cancer risk in European Caucasians. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using six genetic models. Data were analyzed using fixed and random-effects models based on the I2 value of heterogeneity magnitude. Funnel plots and Egger's linear regression tests were used to assess publication bias.
RESULTS: CYP3A4*1B was associated with prostate cancer susceptibility in the allele (G vs. A: OR = 1.32, CI = 0.91-1.93), dominant (AG + GG vs. AA OR = 1.41, CI = 0.95-2.09), recessive (GG vs. AA + AG, OR = 1.82, CI = 1.26-2.63), homozygous (GG vs. AA, OR = 1.92, CI = 1.32-2.77), heterozygous model (AG vs. AA, OR = 1.31, CI = 0.89-1.93) and co-dominant model (AG vs. AA + GG; OR = 1.27, CI = 0.88-1.85). Significant heterogeneity characterized the allele, as well as the dominant model (I2 = 84.1%, I2 = 80.0%). Egger's tests (p < 0.05) and funnel plots did not identify publication bias.
CONCLUSIONS: The present meta-analysis indicates that the G allele and GG genotype might affect prostate cancer susceptibility in European Caucasians; however, the validity and reliability of the results need to be examined in future research.

Keywords:  CYP3A4; European Caucasians; SNPs; meta-analysis; pharmacogene; prostate cancer

DOI:  https://doi.org/10.3390/cancers18010058
Adv Sci (Weinh). 2026 Jan 04. e18295

Mechanical Stimuli-Induced Manipulation of Malignant Behavior in Bioprinted Cancer Microtissues via PI3K/NF-κB Activation.

Seok-Hyeon Lee, Jeongho Lee, Min-Seo Choi, Minjun Ahn, Sik Yoon, Dongjun Lee, Sae-Ock Oh, Won-Woo Cho, Byoung Soo Kim.

  Increased matrix stiffness within tumor microenvironments (TMEs) significantly influences cancer progression and gene expression, contributing to drug resistance and poor clinical outcomes. Studies demonstrate a strong correlation between nuclear factor kappa B (NF-κB) upregulation and prostate cancer malignancy. However, the mechanisms by which the mechanical stress within the TME activates NF-κB remain underexplored. This study developed a prostate cancer spheroid model using an in-bath 3D bioprinting technique. Cancer spheroids were printed within a bespoke hydrogel bath with tunable stiffness, facilitating the investigation of the relationship between mechanical cues and oncogenic behavior. Increased hydrogel stiffness promoted spheroid compaction, induction of epithelial-mesenchymal transition (EMT) and stemness programs, and elevated drug resistance. Transcriptomic analysis revealed that the phosphoinositide 3-kinase (PI3K) pathway is most enriched under mechanical stress. Findings demonstrated that increased extracellular matrix stiffness activated PI3K/NF-κB signaling through mechanotransduction. Pharmacological inhibition of PI3K suppressed NF-κB nuclear translocation and enhanced chemotherapy efficacy. The bespoke hydrogel effectively recapitulated the mechanical environment of prostate cancer, indicating the pivotal role of PI3K/NF-κB signaling in regulating prostate cancer malignancy under mechanical stimulation. This suggests a promising therapeutic avenue for improving treatment outcomes.

Keywords:  in‐bath 3D bioprinting; matrix stiffness; prostate cancer

DOI:  https://doi.org/10.1002/advs.202518295
Theranostics. 2026 ;16(6): 2918-2935

Targeting CAMK1D-engineered nanoactivator suppresses cancer stem cell maintenance and immune evasion in enzalutamide-resistant prostate cancer.

Feifei Sun, Yuchuan Yan, Deqing Sun, Shijia Liu, Zhaoru Dong, Guoqiang Pan, Lin Zhang, Xianhao Shao, Yuliang Xu, Ying Qu, Tao Li.

  Rationale: Hormonal therapy is fundamental to prostate cancer (PCa) management; however, its long-term efficacy is compromised by enzalutamide resistance (ENZR), which is fuelled by prostate cancer stem-like cells (PCaSCs) and an immunosuppressive microenvironment. Methods: A CD44-targeted nanoactivator (EC@HNA) was engineered to co-deliver ENZ and siCAMK1D. Its physicochemical properties, cellular uptake and gene-silencing efficiency were characterized in vitro. Functional and mechanistic assays were used to assess PCaSCs expansion, cytokine modulation, immune cell dynamics, and CREB-dependent regulation of stemness genes. Therapeutic efficacy and safety were validated in ENZR cell cultures, murine tumor models, and patient-derived organoids. Results: EC@HNA efficiently delivered siCAMK1D and achieved potent CAMK1D silencing, thereby significantly suppressing the expansion and self-renewal of PCaSCs. This treatment downregulated the immunosuppressive cytokines IL-10 and TGF-β, decreased regulatory T cell (Treg) infiltration, promoted M1-like polarization of tumor-associated macrophages, and enhanced CD8⁺ T cell infiltration and cytotoxicity in ENZR prostate tumors, thereby reprogramming the tumor immune microenvironment. Mechanistically, EC@HNA suppressed CREB phosphorylation at Ser133, which transcriptionally repressed key stemness regulators, including CD44, CD133, and NR4A1, thereby attenuating tumor stemness and immune evasion. These effects have been validated using in vitro cell models, ENZR xenografts, and patient-derived organoids. Collectively, EC@HNA dismantled the stemness-immunity axis sustaining ENZR and restored robust anti-tumor immunity with minimal systemic toxicity. Conclusions: Overall, the CD44-targeted EC@HNA nanoplatform disrupted stemness programs and restored tumor-immune surveillance, representing a promising strategy to reverse ENZR and potentiate immunotherapy in clinical ENZR PCa patients.

Keywords:  CAMK1D; engineered lipid-based nanoactivator; enzalutamide-resistant prostate cancer; immune evasion; stemness

DOI:  https://doi.org/10.7150/thno.120826
BMC Cancer. 2026 Jan 08.

Green tea catechins and prostate cancer: mechanisms, clinical evidence, and safety: a narrative review.

Hatice Berin Altinoz, Nevin Sanlier.

  Prostate cancer (PCa) is the second most common malignancy among men and the fifth leading cause of cancer-related mortality worldwide. In this study, a review of the literature was conducted in an attempt to clarify the relationship between green tea catechins (GTCs) and PCa. Published articles were searched using PubMed, Web of Science, Google Scholar, and Scopus databases. The study analysed the studies, which were mainly conducted between 2016 and 2025. Polyphenolic compounds are attracting increasing attention for their potential roles in cancer prevention and treatment, and many in vitro, animal, and clinical studies have explored the roles of polyphenols in cancer. Epigallocatechin gallate (EGCG), the predominant flavanol in green tea (GT), exerts significant therapeutic potential by inhibiting cell cycle progression, modulating oncogenic signalling, and interacting with nuclear transcription factors. These mechanisms suggest that EGCG may aid in PCa prevention and management, with evidence indicating that EGCG suppresses PCa cell proliferation by regulating androgen receptor activity and inducing apoptosis, potentially inhibiting tumour growth and metastasis. However, conclusive evidence supporting the use of EGCG as a therapeutic agent for PCa is still lacking. As detailed in this review, preclinical studies have demonstrated this compound's promising anticancer activity, but clinical evidence on the effects of GTCs remains limited due to the small number of human trials and low sample sizes of studies conducted to date, as well as variability in GT formulations.

Keywords:  Epigallocatechin gallate; Green tea; Green tea catechins; Polyphenol; Prostate cancer

DOI:  https://doi.org/10.1186/s12885-025-15516-8
Mater Today Bio. 2026 Feb;36 102655

Daidzein-engineered high-accumulation self-therapeutic nanoplatform drives androgen receptor degradation via ubiquitination-proteasome system to overcome enzalutamide resistance in castration-resistant prostate cancer.

Zhaoxiang Xie, Chunlei Dai, Zhi Xiong, Minghui Li, Liying Wang, Junjia Xie, Xinyin Li, Yi Zhao, Kaiwen Li, Jun Wu, Hai Huang.

  High levels of androgen receptor (AR) are associated with poor prognosis and drug resistance in castration-resistant prostate cancer (CRPC), and monotherapy with AR antagonists such as enzalutamide (Enz) is currently inadequate to meet the clinical needs. Dual-targeted therapeutic strategy of AR degradation combined with AR inhibition is a promising strategy to improve the efficacy and to address the problem of drug resistance in CRPC, thus the development of safer, stable, and effective agents with AR-degrading activity is urgent. In our study, we found that daidzein, a phytoestrogen, could reduce the risk of prostate cancer, exhibited a good affinity for AR and down-regulated AR levels. Consequently, we developed daidzein-based, redox-responsive self-therapeutic nanocarriers to deliver Enz (D44DA@Enz NPs) to realize the dual-targeted therapeutic strategy against AR in CRPC. The results showed that D44DA NPs facilitated AR degradation via the ubiquitin-proteasome pathway, which combined with the inhibitory effect of Enz on AR nuclear translocation greatly improved the efficacy against CRPC. In vivo studies, D44DA NPs demonstrated approximately 40-fold increased enrichment at the tumor site, exhibited excellent self-antitumor activity and synergistically enhanced the therapeutic effects of Enz with minimal toxic side effects. In summary, this study provides a highly promising AR-degrading active nanoplatform and dual-targeted AR therapeutic strategy for the treatment of CRPC.

Keywords:  Androgen receptor; Castration-resistant prostate cancer; Daidzein; Enzalutamide; Phytoestrogens

DOI:  https://doi.org/10.1016/j.mtbio.2025.102655
Cancers (Basel). 2026 Jan 03. pii: 170. [Epub ahead of print]18(1):

APOBEC3C Suppresses Prostate Cancer by Regulating Key Molecules Involved in Cellular Inflammation, Cell Cycle Arrest, and DNA Damage Response.

Zhongqi Pang, Jianshe Wang, Yidan Xu, Bo Ji, Minghua Ren, Beichen Ding.

  Background: Prostate cancer (PCa) is a prevalent malignancy with a rising incidence. Advanced PCa, often resistant to therapy, remains a major clinical challenge, underscoring the need to identify novel molecular drivers. Methods: Utilizing transcriptomic data from the TCGA and GEO databases, we identified APOBEC3C (A3C) as a key candidate through WGCNA, differential expression analysis, and LASSO regression. Its clinical relevance was assessed via Kaplan-Meier survival analysis. Then, we validated A3C expression patterns using immunohistochemistry and Western blot in normal and malignant prostate cell lines. The functional effects of A3C on proliferation, migration, and invasion and mechanisms of such were evaluated through in vitro gain- and loss-of-function assays (CCK-8, Ki67 staining, wound healing, Transwell, Western blot, etc.). Results:A3C was significantly downregulated in PCa, and this low expression strongly correlated with adverse clinicopathological features, including advanced T stage, higher Gleason scores, and worse survival. Bioinformatically, high A3C expression was associated with an activated anti-tumor immune microenvironment, characterized by enhanced CD8+ T cell infiltration, reduced M2 macrophage abundance, and upregulation of the immune checkpoint CD40. In vitro, A3C overexpression effectively suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, A3C enhances the expression of the STING1 and its downstream related molecules Caspase-1, IL-18, and IL-1β; upregulates DNA damage-protective genes (GSTP1 and GPX3); and enhances the expression of cell cycle regulator GAS1. Conclusions: This study establishes A3C as a suppressor in PCa, which impedes tumor progression by regulating key molecules involved in cellular inflammation, cell cycle arrest, and DNA damage response.

Keywords:  APOBEC3C; immune microenvironment; inflammation; prognosis; prostate cancer

DOI:  https://doi.org/10.3390/cancers18010170
Prostate. 2026 Jan 05.

NOTIFICATION: RhoGDIα Downregulates Androgen Receptor Signaling in Prostate Cancer Cells.

NOTIFICATION: "RhoGDIα Downregulates Androgen Receptor Signaling in Prostate Cancer Cells," by Y. Zhu, C. Liu, R. Tummala, N. Nadiminty, W. Lou, and A. C. Gao, The Prostate 73, no. 15 (2013): 1614-1622, https://doi.org/10.1002/pros.22615. This Notification is for the above article, published online on 06 August 2013 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Dr. Samuel Denmeade; and Wiley Periodicals LLC. A third party reported that the cytoplasmic Pol II band and nuclear tubulin bands in Figure 4C had been duplicated. An investigation by the publisher also found that the RhoGDIα and Tubulin bands were duplicated between Figure 2D and Figure 2E. The authors responded to an inquiry by the publisher and reported that the authors used the same images in Figure 2D and 2E to show that RhoGDIa expression was knocked down by shGDI, as the same materials were used for Fig. 2E and 2D. The editors agreed with this statement and confirmed that the Pol II and tubulin bands in Figure 4C were intentionally marked with blank images and that the same blank image had been used to illustrate that Pol II and tubulin were used as loading controls for nuclear and cytoplasmic proteins, respectively. As such, the journal's investigation has determined that there are no concerns regarding the duplicated bands in Figures 2 and 4. This Notification has been agreed to in order to inform and alert readers of the investigation.

DOI: https://doi.org/10.1002/pros.70121
Food Funct. 2026 Jan 08.

3'-Hydroxypterostilbene suppresses prostate cancer via apoptosis and autophagy in vitro and potent tumor growth inhibition in vivo.

Hui-Yun Tsai, Zhi-Ling Liu, Ching-Yi Kuan, Chi-Tang Ho, Yu-Kuo Chen.

3'-Hydroxypterostilbene (OHPt), a hydroxylated derivative of pterostilbene (Pt) naturally occurring in dietary plant sources, was evaluated for its anti-prostate cancer potential. In PC-3 cells, OHPt markedly reduced viability in a dose- and time-dependent manner, exhibiting stronger growth inhibition than Pt, implying that hydroxyl substitution at the 3' position enhances anti-proliferative activity. Mechanistic studies revealed that OHPt triggered both intrinsic and extrinsic apoptosis, evidenced by mitochondrial membrane depolarization, activation of caspase-8, -9, and -3, and an increased Bax/Bcl-xL ratio. Additionally, OHPt promoted autophagic cell death, upregulating Beclin-1, LC3-II expression, and autophagosome formation. In a PC-3 xenograft nude mouse model, OHPt administration significantly suppressed tumor growth without apparent toxicity, accompanied by reduced COX-2 and MMP-9 protein levels and increased LC3-II expression. These findings suggest that OHPt displays strong anti-tumor activity in vitro and in vivo, achieved via coordinated activation of apoptotic and autophagic mechanisms, thereby supporting its potential as a therapeutic candidate for prostate cancer.

DOI: https://doi.org/10.1039/d5fo04237b
JAMA Oncol. 2026 Jan 08.

Sodium-Glucose Cotransporter 2 Inhibitors for Patients With Prostate Cancer Undergoing Hormone Therapy.

Ruofan Shi, Yongle Zhan, Ruochen Ma, Salida Ali, Chi Yao, Tsun Tsun Stacia Chun, Ada Tsui-Lin Ng, Matthew Kin-Liang Chiu, Bryan Cho Wing Li, Rong Na.

Importance: While preliminary evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors for diabetes may have antitumorigenic effects, their potential benefits in prostate cancer remain unexplored. Understanding their association with outcomes among patients undergoing hormone therapy could inform future adjunct treatment strategies.
Objective: To evaluate whether the use of SGLT2 inhibitors is associated with clinical outcomes in patients with prostate cancer receiving hormone therapy.
Design, Setting, and Participants: This population-based, sequential target trial emulation of monthly cohorts used territory-wide electronic health records (January 1, 1993, to April 30, 2025) from the Hong Kong Hospital Authority, covering a population of approximately 7.5 million. Adult men diagnosed with prostate cancer who initiated androgen deprivation therapy (ADT) were included. Follow-up extended through April 2025, and data were analyzed from June to October 2025.
Exposures: Use of SGLT2 inhibitors (primarily dapagliflozin and empagliflozin) initiated during hormone therapy and maintained for at least 1 month. Comparator groups included nonusers of SGLT2 inhibitors.
Main Outcomes and Measures: The primary outcome was time to ADT failure. Secondary outcomes include time to next-generation hormonal agent failure, disease-specific survival, and overall survival. Both intention-to-treat and per-protocol analyses were conducted using complementary log-log model regression to provide the hazard ratio (HR) estimate.
Results: Among 14 223 eligible patients (median [IQR] age at enrollment, 74 [68-80] years) with a median follow-up of 66 months (95% CI, 65-67 months), intention-to-treat SGLT2 inhibitor use was associated with reduced risk of ADT failure (HR, 0.63; 95% CI, 0.41-0.95; P = .03) and next-generation hormonal agent failure (HR, 0.44; 95% CI, 0.20-0.97; P = .04). Sensitivity analyses confirmed robustness of these findings across different comparator subgroups. Metformin monotherapy was not associated with disease progression but was associated with improved overall survival (HR, 0.59; 95% CI, 0.42-0.83; P = .002). No statistically significant outcome differences were observed between dapagliflozin and empagliflozin.
Conclusions and Relevance: In this cohort study with a target trial emulation design, SGLT2 inhibitor use was associated with delayed hormone therapy failure in patients with prostate cancer, suggesting a potential oncologic benefit beyond glucose lowering. These findings support the potential of SGLT2 inhibitors in treatment for prostate cancer.

DOI: https://doi.org/10.1001/jamaoncol.2025.5869
Environ Pollut. 2026 Jan 01. pii: S0269-7491(25)02002-0. [Epub ahead of print]392 127628

Integrative analysis of DEHP exposure and prostate cancer: Mechanistic insights and predictive modeling.

Wen-Cai Zheng, Wen-Tao Xu, Chao-Ran Chen, Fei Lin, Shao-Hao Chen, Xiao-Dong Li, Xiong-Lin Sun, Qing-Shui Zheng, Yong Wei, Xue-Yi Xue, Zhi-Bin Ke, Ning Xu.

   OBJECTIVE: Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer of significant health concern due to its endocrine disrupting effects. The study aims to elucidate underlying molecular mechanisms between DEHP exposure and prostate cancer (PCa).
METHODS: In vitro and in vivo experiments were undertaken to validate the effects of DEHP on the biological function of prostate cancer, and RNA sequencing was performed to elucidate the underlying mechanism. We integrated in silico toxicological assessments and bioinformatics methodologies was employed to investigate the key targets and associated downstream pathways in DEHP-induced PCa progression.
RESULTS: In vitro and in vivo experiments showed that MEHP promoted the proliferation, migration, and invasion of PCa cells and tumorigenicity, and RNA sequencing revealed that the metabolic pathways, pathways in cancer, PI3K-Akt signaling pathway, MAPK signaling pathway might be potential mechanisms involved in this process. Additionally, six DEHP-related genes were identified and a DEHP-related model was constructed. The data of scRNA indicated that these six DEHP-related genes may contribute in the tumor microenvironment of PCa. The molecular docking analysis revealed DEHP's ability to bind to crucial DEHP -related proteins.
CONCLUSIONS: Our study unveils a novel insight into the function for DEHP in PCa, shedding new light on prediction, assessment, and mitigation of DEHP exposure and PCa progression.

Keywords:  Biochemical recurrence; Di-(2-ethylhexyl) phthalate; Molecular docking; Progression; Prostate cancer

DOI:  https://doi.org/10.1016/j.envpol.2025.127628
Adv Sci (Weinh). 2026 Jan 07. e19704

CRISPR-Cas9-Loaded Theranostic Liposomes for Enhancing Radiosensitization of Prostate Cancer through POLD4 Gene Editing under Real-Time MRI Monitoring.

Xuhui Fan, Ruru Zhang, Linjun Yang, Shixiong Chen, Meijuan He, Yongqiang Wang, Linjie Huang, Jianfeng Zeng, Shuwang Wu, Mingyuan Gao, Han Wang.

  Radiotherapy is a fundamental treatment for prostate cancer; however, its therapeutic efficacy is frequently limited by radioresistance mediated through DNA repair mechanisms and other biological factors. Although gene therapy holds promise for overcoming such resistance, identifying effective radiosensitization targets and developing efficient gene delivery systems remain practically challenging. In this study, transcriptomic analysis of radiotherapy-treated prostate cancer cells revealed a marked upregulation of DNA polymerase delta subunit 4 (POLD4), a target that has not been systematically studied. To evaluate the potential of POLD4 for overcoming radioresistance, CRISPR-Cas9-based plasmids along with ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) were encapsulated within cationic liposomes for achieving an MRI-trackable gene delivery platform (plasmid and iron oxide co-loaded liposomes, termed PIO@Lipo). Comprehensive in vitro and in vivo studies demonstrated that PIO@Lipo enabled efficient POLD4 knockdown. Furthermore, PIO@Lipo synergized with radiotherapy to induce extensive DNA damage, promote tumor cell apoptosis, and remodel the immunosuppressive microenvironment. Notably, PIO@Lipo displayed superior MRI contrast enhancement capability and passive tumor targeting ability. In conclusion, this study has identified POLD4 as a potent target for radiosensitization, capable of disrupting DNA damage-repair homeostasis through MRI-monitored gene editing, thereby offering a promising strategy to enhance the efficacy of radiotherapy in prostate cancer.

Keywords:  DNA repair; lipid nanoparticles; magnetic resonance imaging; prostate cancer; radiosensitization

DOI:  https://doi.org/10.1002/advs.202519704