bims-meproc 2026-03-01 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–03–01
twenty-one papers selected by
Grigor Varuzhanyan, UCLA

UHRF1 regulates AR ubiquitination to promote the loss of AR signaling and enzalutamide resistance in progression of prostate cancer.
Androgen Metabolism in Prostate Cancer: Recent Advances.
Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.
Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance.
Ginsenoside Rg3 synergizes with near-infrared photothermal therapy to suppress prostate cancer progression by inhibiting RAS signaling and enhancing ARL11-mediated macrophage reprogramming.
Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features.
From clinical evidence to biological mechanisms: GPRC5B as a key mediator of metabolic syndrome-associated prostate cancer.
Biomechanical Forces in Prostate Cancer: Current Insights and Future Directions.
PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2.
Genetic and epigenetic mechanisms underlying treatment-induced neuroendocrine prostate cancer.
Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.
Obesogens in Prostate Cancer: An Endocrine and Metabolic Threat.
Androgen Signaling Represses Homeobox C9, an Inhibitor of Androgen Receptor, in Prostate Cancer Cells.
A ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop promotes the malignant behaviors and glycolysis of prostate cancer cell.
Histone lactatation-related genes GPR19 and SLC22A16 are important diagnostic markers and drug treatment targets for prostate cancer.
Prostate specific membrane antigen-targeted multimodal imaging nanobubbles with ultrasound irradiation inhibit prostate cancer growth via autophagy activation.
The dual roles of exosomes in prostate cancer: mechanisms in tumorigenesis and avenues for clinical translation.
Advances in spatial omics for the analysis of prostate cancer.
PDHA1-acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer.
Causal relationships between plasma metabolites and prostate cancer: A Mendelian randomization study exploring immune and inflammatory mediators.
PARP Inhibitors Combined with Abiraterone Overcome Resistance in Metastatic Castration-Resistant Prostate Cancer Independently of Androgen Receptor.

Cell Death Dis. 2026 Feb 27.

UHRF1 regulates AR ubiquitination to promote the loss of AR signaling and enzalutamide resistance in progression of prostate cancer.

Yifan Zhang, Zhaojun Yu, Yadong Li, Mayao Luo, Wenli Hou, Sangsang Li, Jiapeng He, Shidong Lv, Qiang Wei, Hailiang Hu.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, increasingly associated with loss of androgen receptor (AR) signaling, and in many cases induction of stemness phenotypes and neuroendocrine features. However, targeted therapies for this stage of the disease are currently lacking. In this study, we demonstrated the critical role of the epigenetic regulator UHRF1 in the enzalutamide resistance development of prostate cancer. We have shown that UHRF1 is highly expressed in enzalutamide-resistant prostate cancer cells and its expression correlates with the loss of AR-dependent glandular features. Knocking down UHRF1 led to increased AR expression and enhanced the activity of canonical AR signaling pathway in prostate cancer cells. The combination of UHRF1 knockdown with enzalutamide treatment demonstrated synergistic tumor inhibitory effects both in vitro and in vivo. Mechanistically, UHRF1 was found to bind to AR and promote its ubiquitination and degradation. Furthermore, inhibition of UHRF1 restored AR pathway activity and re-sensitized resistant prostate cancer cells to enzalutamide. Therefore, our findings elucidate an intracellular molecular mechanism that promotes prostate cancer lineage plasticity and suggest that UHRF1 may serve as a potential therapeutic target for overcoming resistance to AR-targeted therapies.

DOI: https://doi.org/10.1038/s41419-026-08511-9
Endocrinology. 2026 Feb 24. pii: bqag021. [Epub ahead of print]

Androgen Metabolism in Prostate Cancer: Recent Advances.

Nima Sharifi.

  Androgen biosynthesis is physiologically necessary for generating the principal stimulus for androgen receptor (AR) signaling and thus plays an essential role for development of the normal prostate, prostate cancer growth and the development of resistance to hormonal therapies. Testosterone and dihydrotestosterone are both potent endogenous androgens that stimulate AR signaling. While the role of gonadal androgens has been recognized in stimulating prostate cancer progression for over 80 years, the appreciation for non-gonadal precursor steroids in prostate cancer has been more limited in duration of time, attention and focus in the field. Nevertheless, the very clearly established role of non-gonadal androgens in enabling prostate cancer progression, especially in the absence of gonadal testosterone, frames the essentiality of androgen metabolic processes for dictating prostate cancer clinical behavior. Here, the role of androgen metabolism in prostate cancer is reviewed, particularly within the context of hormonal therapy, hormone therapy resistance and with emphasis on recent advances.

Keywords:  androgens; enzymes; metabolism; prostate cancer; steroids

DOI:  https://doi.org/10.1210/endocr/bqag021
Antioxidants (Basel). 2026 Jan 28. pii: 171. [Epub ahead of print]15(2):

Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.

Dominga Manfredelli, Camilla Torcoli, Veronica Ceccarelli, Tatiana Armeni, Guido Bellezza, Vincenzo N Talesa, Angelo Sidoni, Cinzia Antognelli.

  Glyoxalase 2 (Glo2) is a key enzyme of the glyoxalase system that catalyzes the conversion of S-lactoylglutathione (LSG) into glutathione (GSH) and D-lactate. In prostate cancer (PCa), we previously demonstrated that the oncogenic PTEN-PI3K-AKT-mTOR-ERα signaling pathway upregulates Glo2, leading to intracellular D-lactate accumulation and enhanced cell migration, invasiveness, and expression of epithelial-to-mesenchymal transition (EMT)-associated markers. However, whether D-lactate acts as a bioactive metabolic signal contributing to tumor aggressiveness remains unclear. Here, after confirming our previous findings, we demonstrate-using Glo2 silencing, ectopic expression, pharmacological inhibitors, and exogenous D-lactate supplementation-that Glo2-dependent D-lactate accumulation promotes EMT-like plasticity, migration, and invasion in PTEN-deficient PCa cells via a functional link with FAK/Src signaling. Collectively, these results suggest that the Glo2-D-lactate axis may contribute to metabolic rewiring associated with aggressive behavior in PTEN-deficient PCa, warranting further in vivo studies to evaluate its potential as a therapeutic target to limit tumor progression.

Keywords:  D-lactate; EMT; FAK/Src; Glo2; PTEN; invasion; migration; prostate cancer

DOI:  https://doi.org/10.3390/antiox15020171
J Natl Cancer Cent. 2026 Feb;6(1): 58-72

Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance.

Shuai Gao, Nolan D Patten, Changmeng Cai.

  The androgen receptor (AR) is instrumental in the onset and progression of prostate cancer (PCa), establishing androgen deprivation therapy (ADT) as the first-line treatment for metastatic disease. However, the effectiveness of ADT is commonly short-lived. Many patients eventually relapse and develop castration-resistant prostate cancer (CRPC), commonly marked by reactivated AR signaling. Although next-generation AR signaling inhibitors (ARSi) provide temporary control, resistance inevitably emerges. While a small subset of CRPC cases may evolve through AR-independent pathways, most regain partial AR function through multiple mechanisms. A key regulator of AR activity is the pioneer transcription factor FOXA1, which governs AR binding to chromatin. The AR-FOXA1 axis is essential for prostate luminal epithelial cell lineage determination and drives the development of prostate adenocarcinoma. Emerging evidence shows profound alterations in this axis in CRPC and in tumors resistant to ARSi therapies. In this review, we highlight the genetic, epigenetic, transcriptional, and posttranscriptional changes within the AR-FOXA1 axis in PCa following ADT and ARSi treatments.

Keywords:  Androgen receptor; Castration-resistant prostate cancer; FOXA1; Prostate cancer; Transcriptional reprogramming

DOI:  https://doi.org/10.1016/j.jncc.2025.05.003
Int Immunopharmacol. 2026 Feb 23. pii: S1567-5769(26)00261-4. [Epub ahead of print]175 116417

Ginsenoside Rg3 synergizes with near-infrared photothermal therapy to suppress prostate cancer progression by inhibiting RAS signaling and enhancing ARL11-mediated macrophage reprogramming.

Haiping Zhang, Ying Chang, Qiang Fu, Tiefeng Jin, Songnan Zhang, Meihua Zhang.

  Prostate cancer (PCa) progression and therapeutic resistance are largely driven by aberrant oncogenic signaling and an immunosuppressive microenvironment. Ginsenoside Rg3, a natural saponin from Panax ginseng, exhibits antitumor and immunomodulatory activity, but its therapeutic efficacy is limited when used as a monotherapy. Here, we investigated the synergistic potential of combining Rg3 with near-infrared (NIR) exposure in PCa. In PC-3 and DU145 cells, co-treatment with Rg3 and NIR synergistically inhibited proliferation, migration, and angiogenesis, while promoting apoptosis and reversal of epithelial-mesenchymal transition. Bioinformatic and molecular analyses identified the RAS/RAF/ERK pathway as a key target, with Rg3 showing a strong potential to interact with RAS and suppressing downstream phosphorylation of RAF and ERK; pharmacologic RAS activation partially reversed these effects. Beyond direct tumor inhibition, the combination also enhanced macrophage ARL11 expression and reprogrammed tumor-associated macrophages from an M2 to M1 phenotype through suppression of tumor RAS signaling. In xenograft models, Rg3 and NIR co-treatment markedly reduced tumor growth without systemic toxicity and increased M1 infiltration within tumor tissues. Collectively, these findings demonstrate that Rg3 combined with NIR exerts potent and safe antitumor activity by concurrently targeting tumor-intrinsic RAS/RAF/ERK signaling and ARL11-mediated immune reprogramming, offering a promising multimodal strategy for PCa therapy.

Keywords:  ARL11; Ginsenoside Rg3; Near-infrared photothermal therapy; Prostate cancer; RAS/RAF/ERK signaling pathway; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.intimp.2026.116417
Curr Urol. 2026 Jan;20(1): 1-14

Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features.

Yuan Shao, Zihao Liu, Jialu Ma, Yuankang Feng, Jianpeng Yu, Hua Huang, Yang Liu, Yuanjie Niu, Yong Wang.

  Castration-resistant prostate cancer (CRPC) is a considerable clinical challenge, driven by complex molecular mechanisms that enable tumors to evade androgen deprivation therapy. This review explores the molecular mechanisms driving CRPC progression, focusing on androgen receptor (AR) signaling, cancer stem cells (CSCs), and neuroendocrine differentiation (NED). In AR-dependent CRPC, AR signaling remains pivotal in disease progression. Mutations, splice variants, alternative pathways, and transcriptional regulation facilitate sustained AR activation despite androgen deprivation therapy. In addition, CSCs promote tumor recurrence and treatment resistance by maintaining cellular heterogeneity and evading conventional therapies. Furthermore, castration-resistant neuroendocrine prostate cancer, an aggressive subtype of CRPC, is characterized by AR independence and NED, making treatment challenging. These findings underscore the need for therapeutic strategies targeting AR-, CSC-, and NED-specific mechanisms. Crucially, the molecular classification of CRPC into AR-dependent CRPC, stem cell-like CRPC, and castration-resistant neuroendocrine prostate cancer subtypes-based on the interplay between AR signaling, CSCs, and neuroendocrine features-is essential for advancing precision medicine. Tailoring treatments to the molecular subtype and characteristics of each patient offers the potential to substantially improve prognosis and survival in CRPC.

Keywords:  Androgen receptor signaling; Biomarker; Cancer stem cell; Castration-resistant prostate cancer; Molecular subtype; Neuroendocrine prostate cancer

DOI:  https://doi.org/10.1097/CU9.0000000000000312
Int J Biol Macromol. 2026 Feb 22. pii: S0141-8130(26)00978-5. [Epub ahead of print]350 151052

From clinical evidence to biological mechanisms: GPRC5B as a key mediator of metabolic syndrome-associated prostate cancer.

Weilong Lin, Peixian Chen, Yuan Ou, Shanhe Huang, Zonglin Li, Jinxing Huang, Baojun Wang, Ruihui Xie, Hai Huang.

  Metabolic syndrome (MetS) is a recognized risk factor for prostate cancer (PCa), yet the precise biological mechanisms driving this association remain poorly understood. Unraveling these molecular pathways is essential for developing targeted interventions to improve patient outcomes. In this study, we analyzed NHANES (2005-2014) data to examine associations between MetS and PCa outcomes, finding that MetS was significantly associated with higher PCa risk (OR = 1.52), all-cause mortality (HR = 1.53), and cancer-specific mortality (HR = 2.17). Through integrated multi-omics, weighted gene co-expression network analysis, and machine learning, we identified the orphan receptor GPRC5B as a critical hub gene downregulated in both conditions. Single-cell transcriptomic analysis further confirmed that GPRC5B is predominantly expressed in endothelial cells. Mechanistically, GPRC5B loss was found to hyperactivate p38 MAPK signaling through a specific dual mechanism: increasing phosphorylation of upstream MKK3/6 kinases while concurrently suppressing the negative feedback phosphatase DUSP1. This synergistic dysregulation drove enhanced endothelial proliferation, migration, and tube formation in vitro. In vivo, endothelial GPRC5B deficiency significantly accelerated tumor growth and neovascularization, phenotypes that were effectively reversed by the p38 inhibitor SB202190. Clinical specimens corroborated reduced GPRC5B expression and increased microvessel density in MetS-associated PCa. Collectively, our findings establish endothelial GPRC5B downregulation as a key molecular driver promoting pathological angiogenesis via the MKK3/6-DUSP1-p38 axis, suggesting that targeting this signaling cascade offers a promising therapeutic strategy for managing MetS-associated PCa aggression.

Keywords:  Endothelial cells; GPRC5B; Metabolic syndrome (MetS); P38 MAPK pathway; Prostate cancer (PCa)

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151052
Cancers (Basel). 2026 Feb 12. pii: 608. [Epub ahead of print]18(4):

Biomechanical Forces in Prostate Cancer: Current Insights and Future Directions.

Yunjie Ju, Dong Ni, Shimin Zou, Ping Dai, Jianhu Xie, Kangnan He, Yarong Song, Yifei Xing, Liang Chen.

  Over the past decade, research in tumor biomechanics has increasingly shown that cancer cells adapt to changing physical microenvironments by rewiring adhesion, cytoskeletal organization, and force-responsive signaling pathways, thereby shaping survival, invasion, and responses to therapy. Prostate cancer (PCa), like other solid tumors, resides in a highly dynamic mechanical milieu molded by extracellular matrix (ECM) remodeling, solid stress, and fluid shear forces. Available evidence generally supports that malignant prostate tissue is stiffer than benign tissue. During metastatic progression, however, the mechanical phenotype of PCa cells appears to undergo context-dependent remodeling. Such mechanical adaptations may help tumor cells withstand the physical challenges associated with circulation, adhesion switching, and colonization, and may intersect with the development of therapy resistance. Here, we synthesize recent advances in PCa biomechanics, highlight the intricate interplay between mechanical cues and tumor biology, and discuss opportunities to incorporate a mechanical perspective into diagnostic and therapeutic strategies. A deeper understanding of these processes may ultimately enable the development of emerging "mechanotherapies" for prostate cancer.

Keywords:  extracellular matrix remodeling; fluid shear stress; mechanotransduction; prostate cancer; solid stress; tissue stiffness; tumor biomechanics

DOI:  https://doi.org/10.3390/cancers18040608
Cell Death Discov. 2026 Feb 23. pii: 105. [Epub ahead of print]12(1):

PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2.

Yukun Cong, Kang Chen, Yunjie Ju, Qingliu He, Chunyu Liu, Jiawei Chen, Fang Lv, Jinyu Chen, Haoran Li, Liang Chen, Yarong Song.

Cells that detach from the extracellular matrix (ECM) undergo various forms of cell death, including ferroptosis. Previous studies have demonstrated that prostate cancer (PCa) cells undergo ferroptosis following ECM detachment, and resistance to ferroptosis may facilitate tumor metastasis. Pyruvate dehydrogenase E1 alpha 1 (PDHA1) has been identified as a key regulator in the progression of several malignancies; however, its role in ferroptosis and prostate cancer metastasis remains unclear. In this study, anoikis resistance (AnoR) prostate cancer cells exhibited a substantial increase in PDHA1 expression, which enhanced their survival and metastatic potential by increasing resistance to ferroptosis. Mechanistically, nuclear PDHA1 in AnoR cells facilitated histone H3 lysine 9 acetylation (H3K9Ac) that significantly accumulated at the promoter region of peroxisome proliferator-activated receptor alpha (PPARA), thereby upregulating its expression. PPARA, in turn, activated the transcription of apoptosis-inducing factor mitochondria-associated 2 (AIFM2), whose upregulation inhibited ferroptosis in AnoR prostate cancer cells. This study demonstrates that PDHA1 expression is found to be elevated in primary tumors from patients with metastatic prostate cancer. Additionally, the aberrant overexpression of PDHA1 in AnoR prostate cancer cells upregulates PPARA and AIFM2 expression through nuclear translocation, collectively suppressing ferroptosis and promoting metastasis. These findings reveal a novel role for PDHA1 in mediating ferroptosis resistance during ECM detachment and provide a potential therapeutic target for prostate cancer treatment.

DOI: https://doi.org/10.1038/s41420-026-02958-7
J Natl Cancer Cent. 2026 Feb;6(1): 88-97

Genetic and epigenetic mechanisms underlying treatment-induced neuroendocrine prostate cancer.

Viriya Keo, Xiaodong Lu, Jonathan C Zhao, Jindan Yu.

  Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC) characterized by unique pathological features and molecular changes, including the loss of androgen receptor (AR) activities and the gain of neuroendocrine gene expression. The incidence of t-NEPC has increased substantially in the last decade, in up to 20 % of CRPC cases, largely due to intensive treatment of advanced prostate cancer (PCa) with AR pathway inhibitors (ARPi). While genomic alterations between CRPC and t-NEPC are largely conserved, their epigenetic programs are markedly distinct. The molecular mechanisms underlying the neuroendocrine transformation (NET) of PCa are rapidly emerging. Here, we first briefly summarize the genetic drivers of t-NEPC and then comprehensively review 2D and 3D chromatin alterations, including changes in DNA methylation, histone modifications, chromatin accessibility, and 3D chromatin organization, during NET of PCa. We then review key molecular regulators, including lineage-specific transcription factors and chromatin modifiers, of such epigenetic programs. Lastly, we discuss evidence that suggests a mixed model of clonal selection and transformation that underlies NEPC progression.

Keywords:  Chromatin; Clonal Selection; Epigenetics; Lineage Plasticity; Methylation; Neuroendocrine Prostate Cancer; Transcription Factors

DOI:  https://doi.org/10.1016/j.jncc.2025.11.001
Research (Wash D C). 2026 ;2026 1128

Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer.

Junjiang Ye, Yandong Xie, Jie Wang, Ruicheng Wu, Dengxiong Li, Koo Han Yoo, Dilinaer Wusiman, William C Cho, Zhaojie Lyu, Dechao Feng.

The persistence of castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy and androgen receptor (AR) signaling inhibition underscores the need to elucidate resistance mechanisms. The AR signaling pathway plays a central role in the development of prostate cancer. Metabolic reprogramming of androgen synthesis and aberrant activation of AR signaling collectively drive CRPC development. Under therapeutic pressure, AR signaling adapts through AR amplification, ligand-binding domain mutations, splice variants, and alternative activation by cytokines/growth factors, maintaining AR transcriptional activity in low-androgen environments. Concurrently, somatic alterations (like PTEN loss) and crosstalk with key pathways such as PI3K/AKT, coupled with the evolving multifocal spatial heterogeneity, further complicate the role of AR signaling in CRPC treatment resistance. Innovations in single-cell and spatial technologies reveal tumor heterogeneity and lineage plasticity governed by genetic and epigenetic alterations. Current therapeutic innovations, including approaches such as CYP11A1 inhibition, targeting of the AR N-terminal domain, and bipolar androgen therapy, are showing promise in clinical trials. Overcoming CRPC effectively requires cotargeting androgen/AR-associated pathways and suppressing lineage plasticity through dynamic monitoring and precision interventions.

DOI: https://doi.org/10.34133/research.1128
Curr Obes Rep. 2026 Feb 25. pii: 14. [Epub ahead of print]15(1):

Obesogens in Prostate Cancer: An Endocrine and Metabolic Threat.

Mariana Feijó, Lara R S Fonseca, Endre Kiss-Toth, Sílvia Socorro, Sara Correia.



Keywords:  Adipose tissue; Endocrine-disrupting chemicals; Obesity; Obesogens; Prostate cancer

DOI:  https://doi.org/10.1007/s13679-026-00690-y
Int J Mol Sci. 2026 Feb 18. pii: 1962. [Epub ahead of print]27(4):

Androgen Signaling Represses Homeobox C9, an Inhibitor of Androgen Receptor, in Prostate Cancer Cells.

Takao Susa, Eiki Tsuboi, Tomoko Okada, Miho Akimoto, Noriyuki Okudaira, Hiroko Okinaga, Masayoshi Iizuka, Tomoki Okazaki, Mimi Tamamori-Adachi.

  Because prostate cancer proliferates in an androgen-dependent manner, various inhibitors of androgen production and antagonists of the androgen receptor (AR) are used as therapeutic agents. However, the emergence of castration-resistant prostate cancer has prompted the development of additional treatment strategies. In this study, we focused on the antiprostate cancer effects of vitamin D3 and examined novel antiproliferative effects through the crosstalk with androgen signaling. In human prostate cancer LNCaP cells, homeobox C9 (HOXC9) was identified as a common regulated target gene by dihydroxytestosterone and 1α,25-dihydroxyvitamin D3, but in opposite directions. Ligand-stimulated AR and vitamin D receptor competitively shared binding sites in the HOXC9 regulatory region, but dihydroxytestosterone stimulation preferentially suppressed HOXC9 expression due to the stronger binding properties of AR and the induction of DNA methylation. Forced expression of HOXC9 inhibited androgen signaling to eliminate the androgen-dependent proliferation by associating with the AR transcription complex, in part due to interference with AR binding to some of its targets in LNCaP cells. In summary, this study provides evidence for the involvement of HOXC9 in antiproliferative effects through a regulatory mechanism mediated by a crosstalk between vitamin D receptor and AR.

Keywords:  AR; HOXC9; LNCaP; VDR; androgen; prostate cancer; vitamin D3

DOI:  https://doi.org/10.3390/ijms27041962
Exp Mol Med. 2026 Feb 27.

A ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop promotes the malignant behaviors and glycolysis of prostate cancer cell.

Xiang Wang, Limei Yu, Xiaoling Qian, Zhenfei Yu.

Circular RNAs are implicated in the pathogenesis of prostate cancer (PCa). However, their functions, biogenesis and molecular mechanisms remain largely elusive. Here we aimed to investigate the role of circPHGDH in PCa. Cellular behaviors were assessed by the colony formation assay, Transwell analysis, western blotting and Seahorse assay. The underlying mechanisms were investigated using a luciferase reporter assay, RNA pull-down and real-time quantitative PCR. The lactylation of ESRP1 was examined by RNA immunoprecipitation, immunoprecipitation and western blotting. Our results revealed that circPHGDH expression was upregulated in PCa tissues and cells. Furthermore, the knockdown of circPHGDH inhibited PCa cell proliferation, migration, invasion, epithelial-mesenchymal transition and glycolysis. Mechanistically, circPHGDH functioned as a sponge for miR-149, which in turn directly targeted RAP1B. The biogenesis of circPHGDH was regulated by the splicing factor ESRP1. The glycolytic product lactate stabilized ESRP1 by promoting its lactylation at the K43 site; conversely, circPHGDH knockdown suppressed ESRP1 lactylation. Moreover, the silencing of circPHGDH inhibited tumor growth and metastasis in vivo via the miR-149/RAP1B axis, whereas circPHGDH facilitated tumor progression. In conclusion, the lactylation-modified ESRP1/circPHGDH/miR-149/RAP1B axis drives the progression of PCa. These findings provide novel insights into the pathogenesis of PCa and suggest promising therapeutic targets for its treatment.

DOI: https://doi.org/10.1038/s12276-026-01646-x
Genes Genomics. 2026 Feb 24.

Histone lactatation-related genes GPR19 and SLC22A16 are important diagnostic markers and drug treatment targets for prostate cancer.

Yunkun Yan, Zhuo Li, Mushi Ye, Jianchang Li.

   BACKGROUND: Histone lactylation is an emerging epigenetic modification involved in tumor progression, but its transcriptional characteristics and clinical relevance in prostate cancer (PCa) remain poorly understood.
PURPOSE: To preliminarily explore histone lactylation-related transcriptional features in prostate cancer and identify potential diagnostic biomarkers.
METHODS: The TCGA-PRAD dataset was used as the training cohort and the GSE46602 dataset as the validation cohort. Based on histone lactylation-related genes (HLRGs) reported in the literature, single-sample gene set enrichment analysis (ssGSEA) scores were calculated to characterize histone lactylation-related transcriptional states. Differentially expressed genes were identified between tumor and normal tissues, as well as between highand low-ssGSEA score groups, and overlapping genes were selected for further analysis. Mendelian randomization (MR) analysis was then applied to identify genes significantly associated with PCa, and receiver operating characteristic (ROC) curves were used to evaluate their discriminatory performance. Functional enrichment and regulatory network analyses were also performed. In addition, gene expression was examined in prostate-related cell lines, and gene knockdown experiments were conducted to preliminarily assess the effects on prostate cancer cell viability and proliferation.
RESULTS: GPR19 and SLC22A16 were ultimately identified as candidate biomarkers. Both genes were significantly upregulated in prostate cancer tissues and cell lines. Functional analyses indicated that GPR19 and SLC22A16 were associated with the "cell cycle" and "aminoacyl-tRNA biosynthesis" pathways, respectively. In vitro experiments showed that knockdown of SLC22A16 significantly suppressed the viability and proliferation of PC-3 cells.
CONCLUSION: Based on histone lactylation-related transcriptional features, this study preliminarily identified GPR19 and SLC22A16 as genes associated with prostate cancer and provided supportive evidence for their potential biological relevance. Further studies are required to elucidate their regulatory mechanisms and clinical significance.

Keywords:  Causality; Histone lactylation; Mendelian randomization; Prognosis; Prostate cancer

DOI:  https://doi.org/10.1007/s13258-026-01740-4
Acta Biomater. 2026 Feb 20. pii: S1742-7061(26)00121-2. [Epub ahead of print]

Prostate specific membrane antigen-targeted multimodal imaging nanobubbles with ultrasound irradiation inhibit prostate cancer growth via autophagy activation.

Yi Ling, Xunhu Dong, Jun Zhang, Deng Liu, Xin Li, Li Dong, Xuemei Chen, Luofu Wang, Jun Deng, Yanli Guo.

  Ultrasound-targeted nanobubble destruction (UTND) is a promising noninvasive strategy for cancer treatment. However, off-target effects significantly influence UTND-mediated therapeutic efficacy and compromise accurate evaluation of tumors. Prostate-specific membrane antigen (PSMA) is overexpressed on the membranes of prostate cancer (PCa) cells, making it a key therapeutic target. In this study, we constructed theranostic-targeted nanobubbles (PSMA-617-ICG NBs) incorporating PSMA-617, a clinical small-molecule inhibitor of PSMA, and indocyanine green (ICG) employing mechanical vibration in conjunction with a biotin-avidin coupling strategy. PSMA-617-ICG NBs were selectively extravasated across the tumor vascular endothelium, bound to PSMA-positive cells and accumulated effectively within the tumor tissue. Under ultrasound irradiation, sufficient number of PSMA-617-ICG NBs adhered to the cell surface and generated close-range shock waves and cavitation, significantly destroying tumor cells and inhibiting PCa growth. Meanwhile, ultrasound, photoacoustic, and fluorescence imaging enabled monitoring of PSMA expression in tumor tissues, potentially providing imaging evidence to support UTND-mediated targeted therapy and assisting in tumor localization. Notably, mechanistic investigations revealed enhanced autophagosome formation and increased autophagosome-lysosome fusion in treated cells, indicating that UTND successfully activated autophagy and exerted an anti-tumor effect by inducing autophagy-related cell death. Therefore, this study demonstrates that the feasibility of using targeted multimodal imaging nanobubbles in combination with ultrasound irradiation as a potential therapeutic strategy for PCa. STATEMENT OF SIGNIFICANCE: This work presents prostate specific membrane antigen (PSMA)-targeted nanobubbles (PSMA-617-ICG NBs) that integrate multimodal imaging with ultrasound-triggered therapy for prostate cancer. Its significance lies in overcoming the off-target effects of conventional ultrasound targeted nanobubble destruction (UTND) through precise molecular targeting, and realizing ultrasound/photoacoustic/fluorescence imaging-guided therapy. Under ultrasound irradiation, the targeted nanobubbles successfully activate autophagy and exert an anti-tumor effect through inducing autophagy-related cell death. The targeted nanobubbles demonstrate specific accumulation in PSMA-positive tumors, monitoring therapy, and significantly amplified therapeutic efficacy against prostate cancer, bringing a non-invasive, promising approach for prostate cancer therapy.

Keywords:  Autophagy; Multimodal imaging; Prostate cancer; Targeted nanobubbles; Ultrasound-targeted nanobubble destruction (UTND)

DOI:  https://doi.org/10.1016/j.actbio.2026.02.036
Front Immunol. 2026 ;17 1748272

The dual roles of exosomes in prostate cancer: mechanisms in tumorigenesis and avenues for clinical translation.

Mingyun Yu, Dan Zhou, Huijie Wei, Tong Wu, Jiahong Fan, Guanghe Ran, Chong Zhang.

  Prostate cancer (PCa) management remains challenged by tumor heterogeneity, unpredictable progression, and limitations in early detection, driving demand for innovative biological insights. As pivotal mediators of intercellular communication, exosomes exhibit dualistic roles in PCa pathogenesis and therapy. While acting as 'foes' by facilitating epithelial-mesenchymal transition (EMT), angiogenesis, tumor microenvironment formation, metastasis, immune evasion, and therapy resistance, they concurrently serve as 'friends' through their diagnostic and therapeutic potential. Exosome-derived biomarkers enable non-invasive liquid biopsy for early diagnosis, risk stratification, and treatment monitoring. Moreover, engineered exosomes function as targeted drug carriers, delivering precision therapeutics to overcome treatment barriers. This review systematically examines exosomal biogenesis, isolation methodologies, and their bidirectional regulation in PCa progression, while exploring emerging diagnostic and therapeutic applications to advance exosome-mediated precision oncology.

Keywords:  cancer; clinical application; exosomes; mechanism; prostate cancer

DOI:  https://doi.org/10.3389/fimmu.2026.1748272
Anal Bioanal Chem. 2026 Feb 21.

Advances in spatial omics for the analysis of prostate cancer.

Junyi Xu, Dejiang Wang, Xiangjun Di, Yang Liu.

  Prostate cancer is one of the most common malignancies in men and is marked by extensive clinical and molecular heterogeneity. Although genomic and transcriptomic studies have revealed recurrent alterations and lineage plasticity, these approaches lack spatial resolution and therefore cannot capture the microenvironmental context that underpins tumor progression and therapeutic resistance. Spatial omics technologies have emerged as transformative tools by integrating high-dimensional molecular profiling with preserved tissue architecture. Advances in spatial transcriptomics, proteomics, epigenomics, and metabolomics now permit the mapping of gene expression, protein signaling, chromatin accessibility, modifications, and folding, along with metabolic gradients at cellular to subcellular resolution. Spatial analysis of prostate cancer has revealed key features of disease progression, including stromal remodeling, immune evasion, lipid metabolic rewiring, and therapy-resistant niches. This review highlights recent spatial omics technologies, their emerging integrative and clinical applications in prostate cancer, and the future challenges in standardization, data integration, and clinical translation.

Keywords:  Epigenomics; Prostate cancer; Proteomics; Spatial transcriptomics

DOI:  https://doi.org/10.1007/s00216-026-06396-3
Cell Death Dis. 2026 Feb 23.

PDHA1-acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer.

Ruilin Zhuang, Qianghua Zhou, Bisheng Cheng, Shirong Peng, Zhi Xiong, Zhaoxiang Xie, Weilong Lin, Tong Su, Zean Li, Kai Yao, Zhiming Wu, Hai Huang, Kaiwen Li.

Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating cuproptosis, offering a promising therapeutic approach for treating refractory prostate cancer.

DOI: https://doi.org/10.1038/s41419-026-08462-1
Curr Urol. 2026 Jan;20(1): 15-22

Causal relationships between plasma metabolites and prostate cancer: A Mendelian randomization study exploring immune and inflammatory mediators.

Mengjun Huang, Dong Ning, Tongyu Tong, Qiliang Teng, Fei Cao, Yupeng Guan, Yiting Wang, Hanqi Lei, Jun Pang.

   Background: Metabolic alterations and inflammatory processes contribute substantially to the pathogenesis of prostate cancer (PCa). This study used Mendelian randomization (MR) to investigate the causal relationships between plasma metabolites and PCa and to identify potential mediators, including immune cell traits and circulating inflammatory proteins.
Materials and methods: A 2-sample MR analysis was conducted using data from the Canadian Longitudinal Study on Aging and a diverse genome-wide association study of PCa. A total of 1400 plasma metabolites were analyzed. Single-nucleotide polymorphisms were carefully selected and refined using linkage disequilibrium clumping. The inverse variance weighting method was used for primary analysis, supplemented by sensitivity analyses, including MR-Egger, weighted median, and MR-Pleiotropy RESidual Sum and Outlier, to ensure the robustness of the results.
Results: Eight metabolites were significantly associated with PCa. Specifically, a higher phosphate-to-uridine ratio was associated with a decreased risk of PCa, whereas higher levels of N-acetyl-arginine were linked to an increased risk. Other significant metabolites included the phosphate-to-2'-deoxyuridine ratio; N6-methyl-lysine, N-acetyl-leucine, N-succinyl-phenylalanine, and cysteinylglycine disulfide levels; and the α-ketoglutarate-to-ornithine ratio. Sensitivity analyses and the MR-Steiger test confirmed the robustness and causal direction of these associations. In addition, further analysis indicated that certain metabolites may influence PCa risk by modulating the expression of inflammatory markers, such as leukemia inhibitory factor receptor, interleukin-8, and CD33-related markers.
Conclusions: This study identified plasma metabolites that exert causal effects on the risk of PCa and highlighted the mediating role of immune traits and inflammatory proteins. These findings underscore the complexity of the biological pathways involved and suggest potential targets for therapeutic interventions.

Keywords:  Causal inference; Immune cell traits; Inflammation; Mendelian randomization; Plasma metabolites; Prostate cancer

DOI:  https://doi.org/10.1097/CU9.0000000000000307
Cancers (Basel). 2026 Feb 09. pii: 560. [Epub ahead of print]18(4):

PARP Inhibitors Combined with Abiraterone Overcome Resistance in Metastatic Castration-Resistant Prostate Cancer Independently of Androgen Receptor.

Hamza Mallah, Sina Soultani, Zania Diabasana, Véronique Lindner, Philippe Barthélémy, Ysia Idoux-Gillet, Thierry Massfelder.

   BACKGROUND: PC is the second most common malignancy in men, and progression to metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) remains incurable. Current treatments for mCRPC include chemotherapy, immunotherapy, radiopharmaceuticals, and second-line androgen receptor signaling inhibitors (ARSIs) such as Abiraterone. PARP inhibitors (PARPis) have recently shown clinical benefits in tumors with homologous recombination repair (HRR) deficiencies, particularly BRCA1/2 mutations. Combining PARPi with ARSIs has improved progression-free (PFS) and overall survival (OS), especially in ARSI-naïve patients, but limited data exist for resistant disease.
OBJECTIVES: This work focuses on intrinsically hormone-insensitive, AR-negative, BRCA-wildtype models, representing a clinically distinct population with limited therapeutic options. We thus investigated the therapeutic potential of combining Abiraterone with PARPis (Niraparib or Olaparib) in Abiraterone-resistant prostate cancer.
METHODS: Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models.
RESULTS: Cytotoxicity assays revealed significantly reduced cell viability with combination therapy compared to single agents. These findings were supported by RT-qPCR, Western blot, and immunofluorescence analyses of xenograft tumors, demonstrating enhanced antitumor activity with the combination.
CONCLUSIONS AND SIGNIFICANCE: Overall, the results indicate that maintaining Abiraterone treatment in combination with PARPis after resistance develops provides superior therapeutic efficacy compared to PARP inhibition alone, offering a promising strategy for managing Abiraterone-resistant prostate cancer. Combining Abiraterone with PARPis enhances therapeutic efficacy and overcomes the acquired insensitivity in mCRPC with BRCA1/2 or HRR mutations. These results support continued use of PARPis with Abiraterone to improve clinical outcomes.

Keywords:  BRCA/HRR deficiency; PARP inhibitors; abiraterone resistance; combination therapy; mCRPC; prostate cancer

DOI:  https://doi.org/10.3390/cancers18040560