bims-meproc 2026-01-18 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–01–18
29 papers selected by
Grigor Varuzhanyan, UCLA

Molecular characterization of palmitoylation in prostate cancer reveals KIFC2 as a prognostic biomarker and potential therapeutic target.
TESTOSTERONE DOES NOT DRIVE PROSTATE CANCER: PRESENTING THE NEW FRAMEWORK OF ANDROGEN ADEQUACY VERSUS INADEQUACY.
Chondroitin sulfate E activates IL-6/STAT3 signaling to drive androgen-independent growth in castration-resistant prostate cancer.
Spatial and single-cell multi-omics reveal pro-angiogenic THY1⁺ fibroblast subtypes predicting prognosis in prostate cancer.
Inhibition of Growth and Induction of Apoptosis of Human Prostate Cancer Cells by Enzymatic Blockage of Kallikreins.
[Overexpression of lncRNA SNHG12 promotes docetaxel resistance of prostate cancer cells by activating PI3K/AKT signaling via interacting with ELAVL1].
Theranostic Nanoparticles in Prostate Cancer: Disrupting Hypoxia-Induced Glycolysis by Targeting Hypoxia-Inducible Factor-1 Alpha and Downstream Metabolites.
Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.
MECOM Function is Critical for AR-Driven Treatment-Resistant Prostate Cancer.
ZDHHC14 enhances P16 stability via palmitoylation to inhibit prostate cancer progression.
A Double-Negative Prostate Cancer Subtype is Vulnerable to SWI/SNF-Targeting Degrader Molecules.
The Role of Nutrition in Prostate Cancer Risk, Progression, and Mortality: A Comprehensive Review.
Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions.
Targeting the HSP60/p53 Axis with Extracellular Vesicle-Delivered siRNA Reprograms Glycolysis in Prostate Cancer.
Pre-diagnostic circulating untargeted metabolomics and risk of overall and clinically significant prostate cancer: a systematic review and meta-analysis.
Landscape of allele-specific expression in prostate cancer reveals recurrent, stage-specific events in AR signaling and resistance pathways.
Comparative miRNA Expression Profiling Reveals Candidates Involved in Prostate Cancer Radioresistance.
Editorial Comment on (Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer).
Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer.
Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models.
Screening anticancer peptides performance in organotypic prostate tumor-stroma 3D models.
DIAPH3 is a multifaceted prognostic biomarker that links immunotherapy response to tumor microenvironment in prostate cancer.
Cooperative interaction between YAP1 and EphA3 receptor tyrosine kinase regulates cellular plasticity and treatment response in prostate cancer.
FASN targeting by G28UCM impairs mitochondrial fatty acid synthesis and reveals a FASN-SDHB Synthetic Interaction.
PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer.
Cross-omics interpretable neural network for discovery of molecular markers in prostate cancer.
Downregulation of ANPEP Is Associated with Aggressive Prostate Cancer and Poor Disease-specific Outcomes.
Genetic relationships between the gut microbiota and prostate cancer: Mendelian randomization combined with bioinformatics analysis.
Methylation-induced silencing of AZGP1 enhances prostate cancer metastasis by stimulating tumoral glycolysis.

Comput Biol Med. 2026 Jan 10. pii: S0010-4825(26)00010-7. [Epub ahead of print]202 111450

Molecular characterization of palmitoylation in prostate cancer reveals KIFC2 as a prognostic biomarker and potential therapeutic target.

Liang Huang, Shusuan Jiang, Fuhua Zeng, Gongqian Zeng, Hong Shan.

  Protein palmitoylation, a reversible post-translational lipid modification, has been implicated in regulating cancer cell signaling and progression; however, its role in prostate cancer (PCa) remains unclear. In this study, we comprehensively analyzed palmitoylation-related genes (PRGs) in PCa by integrating bulk transcriptomic, single-cell RNA sequencing, and spatial transcriptomic datasets. Unsupervised consensus clustering based on PRG expression identified two molecular subtypes with distinct prognoses, immune infiltration profiles, and pathway activities. Differential expression and weighted gene co-expression network analyses revealed five key feature genes, among which KIFC2 was highly expressed in tumor cells and correlated with poor clinical outcomes. The KIFC2 was predominantly enriched in high-grade adenocarcinoma regions. Functional experiments demonstrated that silencing KIFC2 significantly inhibited proliferation and promoted apoptosis in PC3 and DU145 prostate cancer cell lines. Additionally, high KIFC2 expression was associated with increased cell cycle progression and oncogenic signaling pathways, including KRAS and PI3K-AKT. Collectively, these results suggest that palmitoylation and KIFC2 play critical roles in PCa progression and may serve as promising biomarkers and therapeutic targets.

Keywords:  Immune infiltration; KIFC2; Palmitoylation; Prognostic biomarker; Prostate cancer

DOI:  https://doi.org/10.1016/j.compbiomed.2026.111450
J Urol. 2026 Jan 13. 101097JU0000000000004936

TESTOSTERONE DOES NOT DRIVE PROSTATE CANCER: PRESENTING THE NEW FRAMEWORK OF ANDROGEN ADEQUACY VERSUS INADEQUACY.

Abraham Morgentaler, Abdulmaged M Traish.

   PURPOSE: 1) To review the evidence whether "testosterone drives prostate cancer"; 2) to dissect the arguments supporting this belief; and 3) to present the new framework of androgen adequacy versus inadequacy to explain the relationship of testosterone and prostate cancer.
MATERIALS AND METHODS: A MEDLINE review of the literature was performed.
RESULTS: The belief that testosterone (T) drives prostate cancer (PCa) originated with Charles Huggins in 1941, led to a near-complete prohibition against T therapy (TTh) for 60 years, and persists today in regulatory warnings, guideline restrictions, and widespread clinical concerns. However, the evidence is now overwhelming that T does not drive PCa. Biopsy studies show PCa risk is unrelated to endogenous androgen concentrations. Large RCTs reveal identical PCa rates in men receiving TTh versus placebo. TTh in men with known PCa has not shown increased rates of recurrence or progression. While androgens are required for PCa growth, PCa growth also requires other chemicals, e.g., calcium. What is unique to androgens is it is the only required chemical that does not cause loss of life with severe deprivation. The key concept to understand the relationship of androgens and PCa is adequacy versus inadequacy. Adequate T concentrations for optimal PCa growth occur at a low concentration called the saturation point. Below this, cellular metabolism is compromised and cell death may occur depending on degree of deprivation.
CONCLUSIONS: Testosterone does not drive prostate cancer. Androgen adequacy versus inadequacy provides a scientifically sound framework to understand the relationship of testosterone and prostate pathophysiology.

Keywords:  dihydrotestosterone; prostate; prostate cancer; testosterone; testosterone therapy

DOI:  https://doi.org/10.1097/JU.0000000000004936
Cell Commun Signal. 2026 Jan 13.

Chondroitin sulfate E activates IL-6/STAT3 signaling to drive androgen-independent growth in castration-resistant prostate cancer.

Hayato Ota, Kazuo Yamamoto, Shoko Nishihara.

   BACKGROUND: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, as tumor growth persists despite androgen receptor (AR) pathway inhibition. Glycosaminoglycans, particularly chondroitin sulfate (CS), are increasingly recognized as modulators of oncogenic signaling. However, the contribution of distinct sulfation motifs to therapeutic resistance is poorly understood. Here, we identify the CS-E motif as a critical regulator of IL-6/STAT3 signaling and a driver of hormone-independent growth in CRPC.
METHODS: Transcriptomic profiling (RNA-seq), real-time PCR, and flow cytometry were employed to assess CS sulfation changes in C4-2 prostate cancer cells under androgen-deprived conditions. Because reliable tools to detect CS-E have been lacking, we engineered a novel mutant lectin (Cochlin B8) with selective affinity for CS-E. This innovation enabled precise monitoring and functional characterization of CS-E on the surface of cancer cells. Functional studies combined GALNAC4S-6ST knockdown, pharmacological inhibition with Chst15-IN-1, and signaling assays to examine effects on IL-6/STAT3 activation and cell proliferation.
RESULTS: Androgen deprivation induced upregulation of GALNAC4S-6ST and enhanced CS-E biosynthesis on the cell surface. Elevated CS-E facilitated IL-6 binding to the cell surface, potentiated STAT3 phosphorylation, and sustained androgen-independent proliferation. Genetic or pharmacological inhibition of GALNAC4S-6ST significantly reduced CS-E levels, impaired IL-6 binding, attenuated STAT3 activation, and selectively suppressed proliferation under hormone-depleted conditions (IC₅₀ = 1.39 µM under androgen-deprived conditions vs. 4.46 µM under androgen-replete conditions). These effects were specific to IL-6/STAT3, with no detectable impact on AR-independent EGFR or WNT signaling pathways.
CONCLUSIONS: This study reveals a previously unrecognized mechanism whereby CS-E sustains CRPC progression by selectively enhancing IL-6/STAT3 signaling when AR signaling is suppressed. Importantly, the development of Cochlin B8 overcomes a major technical barrier in CS-E research, providing a novel tool for its specific detection and functional analysis. Targeting CS-E biosynthesis represents a promising therapeutic strategy to counter resistance and improve prostate cancer treatment.

Keywords:  Castration-resistant prostate cancer; Chondroitin sulfate E; GALNAC4S-6ST; Glycosaminoglycan; IL-6/STAT3 signaling

DOI:  https://doi.org/10.1186/s12964-026-02657-x
Transl Oncol. 2026 Jan 12. pii: S1936-5233(26)00001-X. [Epub ahead of print]65 102664

Spatial and single-cell multi-omics reveal pro-angiogenic THY1⁺ fibroblast subtypes predicting prognosis in prostate cancer.

Yongqiang Huang, Chunping Xiang, Yu Wang, Wei Zhang, Leilei Du, Wenfeng Wang, Guohai Shi, Jianhua Wang.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) play a key role in prostate cancer (PCa) progression, though their heterogeneity and specific protumorigenic subsets remain poorly characterized. This study aimed to identify and validate a distinct THY1⁺ CAF subset associated with aggressive PCa.
METHODS: Multiomics data from public (TCGA-PRAD, GEO) and prospective (FUSCC, n = 84) cohorts were analyzed. An 8-gene CAF-derived prognostic signature was constructed using LASSO Cox regression. THY1⁺ CAF clusters were identified via scRNA-seq. Primary CAFs were isolated from patient tissues, and THY1⁺/THY1⁻ subpopulations were purified via MACS/FACS. Angiogenic function and secretory profiles were assessed through tube formation assays, ELISA, and antibody arrays. THY1 knockdown and CXCR2 inhibition were used for mechanistic studies. Clinical relevance was evaluated via qPCR and multiplex immunohistochemistry on tissue microarrays.
RESULTS: High CAF abundance correlated with aggressive clinicopathological features and poor prognosis in PCa. The 8-gene signature effectively predicted biochemical recurrence (BCR). scRNA-seq revealed THY1⁺ CAFs as a proangiogenic subpopulation. THY1⁺ CAFs enhanced angiogenesis via increased secretion of CXCL6 and VEGFA. CXCL6 promoted endothelial tube formation through CXCR2 activation, while THY1 knockdown downregulated VEGFA and impaired angiogenesis. High THY1⁺ CAF infiltration was associated with significantly worse recurrence-free survival.
CONCLUSION: THY1⁺ CAFs represent a proangiogenic subset that drives PCa progression via the CXCL6/CXCR2 axis and THY1-mediated VEGFA expression. These findings highlight stromal THY1 and the CXCL6/CXCR2 pathway as potential therapeutic targets.

Keywords:  Angiogenesis; CXCL6; Cancer-associated fibroblasts (CAFS); Heterogeneity; Prognostic signature; Prostate cancer; Single-cell RNA sequencing; Thy1 (CD90); Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2026.102664
Prostate Cancer. 2026 ;2026 7871208

Inhibition of Growth and Induction of Apoptosis of Human Prostate Cancer Cells by Enzymatic Blockage of Kallikreins.

Fabienne Lehner, Souzan Salemi, Christopher Millan, Christoph Kündig, Daniel Eberli.

   Background: Most therapy options for castration-resistant prostate cancer (CRPCa) target the androgen axis. Human kallikrein-related peptidase (KLK) 2, a serine protease, is a downstream target gene of the androgen receptor (AR) involved in cancer progression, but also known to have an AR-independent function. Tissue KLKs, especially KLK2, are promising targets for therapy in advanced PCa because of their high PCa specificity and their correlation to the rising cancer grade and stage. By inhibition with the recombinant protease inhibitor MDPK67b targeting KLK2 and other trypsin-like KLKs including KLK4 and KLK14, we investigated the antitumor response and the influence on AR downstream target genes with MDPK67b in PCa cell lines in vitro.
Methods: Human PCa cells were cultured in a charcoal-stripped media and treated with MDPK67b (0.75 mg/mL). Cell viability was measured by CellTiter-Glo luminescent assay, cell death by flow cytometry. Gene analysis of AR, PSA, and PSMA was performed by qPCR. Correlating protein levels were evaluated by immunoblotting and confirmed by immunocytochemical staining.
Results: Treatment with 0.75 mg/mL MDPK67b led to a reduction of cell proliferation of 40% by day 5 in androgen-sensitive LNCaP cells. Immunostaining confirmed the decrease in cell proliferation by antibody labeling of Ki-67. Treatment induced apoptosis, which was visible by flow cytometry of annexin V in LNCaP cells. Further, MDPK67b induced a reduction in AR and PSA gene and protein expression but upregulated PSMA, a target for PCa imaging and therapy.
Conclusion: Treatment with MDPK67b demonstrates a significant antitumor effect by relevant reduction in cell proliferation and upregulation of apoptosis in LNCaP cells. Blockage of secreted KLKs can downregulate the AR and thereby influence its downstream target genes like PSA and PSMA. Upregulation of PSMA can lead to a theranostic, that is, therapeutic and diagnostic, advantage in clinics in a CR setting. Therefore, inhibition of KLKs represents a promising and AR-independent approach to treat advanced and CRPCa.
Trial Registration: ClinicalTrials.gov ID: NCT04644770.

Keywords:  androgen receptor; apoptosis; kallikrein 2; prostate-specific membrane antigen; theranostics

DOI:  https://doi.org/10.1155/proc/7871208
Nan Fang Yi Ke Da Xue Xue Bao. 2026 Jan 20. pii: 1673-4254(2026)01-0183-08. [Epub ahead of print]46(1): 183-190

[Overexpression of lncRNA SNHG12 promotes docetaxel resistance of prostate cancer cells by activating PI3K/AKT signaling via interacting with ELAVL1].

Cheng Zhao, Wen Li, Baoshou Zheng, Guangming Wang, Zhisong Xiao, Yunpeng Li.

   OBJECTIVES: To investigate the regulatory role of lncRNA SNHG12 in docetaxel (DTX) resistance of prostate cancer (PCa) cells.
METHODS: Tumor-bearing male BALB/c nude mouse models were stablished by dorsal subcutaneous injection of PC-3 cells or DTX-resistant PC-3 (PC-3R) cells, either with or without transfection with sh-SNHG12 prior to the injection (n=5). The expressions of the key genes and proteins in the tumor tissues were detected using RT-qPCR, Western blotting, immunofluorescence staining or immunohistochemistry. The proliferation and migration of the treated cells were evaluated with CCK-8, clone formation and Transwell migration assays. RIP-qPCR technique was used to determine the binding between the RNAs and proteins.
RESULTS: SNHG12 expression was significantly up-regulated in PC-3R cells. SNHG12 knockdown effectively inhibited proliferation and migration of PC-3R cells in vitro and suppressed tumor growth in nude mice. While 10 nmol/L DTX treatment alone did not significantly affect proliferation or migration of PC-3R cells, its combination with SNHG12 knockdown strongly inhibited cell proliferation and migration both in vitro and in the tumor-bearing mice. The expression of ELAVL1 was obviously up-regulated in PC-3R cells, and increased activation level of PI3K/AKT signaling pathway was detected in both PC-3R cells and the xenografts. The effect of SNHG12 knockdown was significantly weakened by treatment with the PI3K activator 740 Y-P. SNHG12 was found to bind to ELAVL1 in PC-3R cells, and mechanistic studies showed that their binding activated the PI3K/AKT signaling pathway to result in DTX resistance in PCa.
CONCLUSIONS: SNHG12 knockdown inhibits DTX resistance of PCa cells by reducing SNHG12 binding to ELAVL1 to inhibit the activation the PI3K/AKT signaling pathway.

Keywords:  ELAVL1; PI3K / AKT signaling pathway; docetaxel; drug resistance; lncRNA SNHG12; prostate cancer

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2026.01.20
Cancer Med. 2026 Jan;15(1): e71519

Theranostic Nanoparticles in Prostate Cancer: Disrupting Hypoxia-Induced Glycolysis by Targeting Hypoxia-Inducible Factor-1 Alpha and Downstream Metabolites.

Daniel Ejim Uti, Wilson Achu Omang, Esther Ugo Alum, Inalegwu Bawa, Okechukwu Paul-Chima Ugwu, Ayodeji Oluwafemi Idowu, Item Justin Atangwho, Godwin Eneji Egbung.

   BACKGROUND: Prostate cancer (PCa) is a major cause of cancer-associated death in men. A crucial factor in its development and treatment resistance is tumor hypoxia, which drives metabolic reprogramming (especially reconfiguration towards glycolysis), mediated to a great extent by hypoxia-inducible factor-"HIF-1 alpha" (HIF-1a).
AIMS: The present review summarizes (i) the mechanisms underlying hypoxia-induced glycolysis that enhances the aggressiveness of and treatment failure in PCa and (ii) recent developments in the field of theranostic nanoparticles (TNPs) with dual actions of inhibiting HIF-1a and downstream metabolic targets, while facilitating the imaging and treatment of the tumor.
MATERIALS AND METHODS: We summarize available evidence for the hypoxia-glycolysis signaling in PCa and assess nanotechnology achievable theranostic approaches (i.e., liposomal-, polymer- and metallic nanoplatforms) to promote drug delivery, real-time tumor picture and modulation of hypoxic tumor microenvironments.
RESULTS: Hypoxia-inducible factor-1 alpha (HIF-1a) driven hypoxia is a common phenotypic feature that underlies the increased glycolysis and aggressive tumor phenotype. TNPs have been developed with the aim of (a) enhancing the drug bioavailability, (b) enabling the selectivity of tumor and imaging, and (c) reducing the hypoxia-linked metabolic pathways. The use of PCa as a model for TNP development is especially timely as hypoxia crosses the intersection of androgen receptor (AR) signaling heavens (hormone therapy resistance) leading to progression to castration-resistant PCa (CRPC) and as the Prostate-Specific Membrane Antigen (PSMA) is greatly overexpressed and is a validated target for custom imaging and treatment.
DISCUSSION: Compared with other hypoxia mediated solid tumors, hypoxia AR axis and PSMA overexpression have unique biological leverage for precision theranostics in PCa. Nevertheless, translation is limited by the issues of biocompatibility, complexities resulting from systematic regulations and constraints of scale-up manufacturing.
CONCLUSION: TNPs are a promising platform to integrate diagnosis and treatment of PCa as they incorporate features of targeted delivery, on-line monitoring and interference with HIF-1a regulated glycolysis. Future advances will require interdisciplinary optimization, development of better tumor-targeting approaches, and artificial intelligence guided nanoparticle design to facilitate clinical scale up and regulation of technically and clinically acceptable theranostics of nanomedicines for PCa.

Keywords:  HIF‐1α; glycolysis; hypoxia; metabolic reprogramming; prostate cancer; theranostic nanoparticles; tumor microenvironment

DOI:  https://doi.org/10.1002/cam4.71519
Sci Adv. 2026 Jan 16. 12(3): eady5324

Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.

Diwei Zhao, Zijun Mo, Tianyou Zhang, Xinyang Cai, Zhenyu Yang, Dong Chen, Junliang Zhao, Yuanwei Li, Fangjian Zhou, Zhen Li, Yonghong Li, Jun Wang.

Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1+ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.

DOI: https://doi.org/10.1126/sciadv.ady5324
Cancer Res. 2026 Jan 13.

MECOM Function is Critical for AR-Driven Treatment-Resistant Prostate Cancer.

Surendra Gulla, Tej Sharma, Ephraim Gardner, Chennan Li, Tanaya A Purohit, Chao Xue, Sean Colligan, Shreya Shyam Sundar, Bing Yang, Shana Y Trostel, Brian Capaldo, Jonathan E Bard, Tobilola Ogunbowale, Abbas Jawadwala, Min Ma, Jun Qu, Fatima Karzai, Roberto Pili, David F Jarrard, Adam G Sowalsky, David J VanderWeele, Remi Adelaiye-Ogala.

Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on reprogrammed/non-canonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). Here, we identified EVI1, an oncogenic nuclear transcription factor encoded by MECOM, as an AR-recruited co-activator of non-canonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SEs), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic transcription factors, along with increased pro-apoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1720
Transl Androl Urol. 2025 Dec 31. 14(12): 3806-3816

ZDHHC14 enhances P16 stability via palmitoylation to inhibit prostate cancer progression.

Jian Zhao, Gang Ni, Zhichao Wu, Chunhong Zhang.

   Background: The progression of prostate cancer is closely associated with dysregulation of tumor suppressor genes. P16 (CDKN2A), a key cell cycle regulator, is frequently downregulated in malignant phenotypes, yet the role of its post-translational modifications, particularly palmitoylation, remains unclear. This study aimed to investigate the regulatory mechanism of palmitoylation on P16 stability and explore the functional role of ZDHHC14 in this process, as well as its impact on the malignant behaviors of prostate cancer cells.
Methods: CDKN2A was overexpressed in prostate cancer cells (PC-3 and DU-145) via plasmid transfection. The inhibitory effects of P16 on proliferation, migration, and invasion were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, colony formation assay, and Transwell assays. The palmitoylation modification site (Cys 72) and its regulatory role in P16 stability were analyzed through palmitoylation inhibitor [2-bromopalmitate (2-BP)] and agonist [hexadecyl acetyl phosphate (HAM)] treatments, site-directed mutagenesis (C72S), ubiquitination assays, and molecular docking. Bioinformatics screening, small interfering RNA (siRNA) knockdown, and co-immunoprecipitation (Co-IP) were employed to validate the interaction between ZDHHC14 and P16 and their functional relationship.
Results: Overexpression of CDKN2A significantly inhibited the proliferation, migration, and invasion of prostate cancer cells. Palmitoylation at the Cys 72 site enhanced P16 stability by suppressing its ubiquitination-dependent degradation. ZDHHC14 was identified as the palmitoyltransferase responsible for modifying P16, and its expression positively correlated with patient survival. Knockdown of ZDHHC14 markedly reduced P16 protein levels, and their direct interaction was confirmed to mediate the palmitoylation process.
Conclusions: This study reveals for the first time that ZDHHC14 enhances P16 stability and suppresses its ubiquitination-mediated degradation via palmitoylation at the Cys 72 residue, thereby exerting antitumor effects. These findings provide a theoretical foundation for developing therapeutic strategies targeting the ZDHHC14/P16 axis in prostate cancer.

Keywords:  P16; Prostate cancer; ZDHHC14; palmitoylation

DOI:  https://doi.org/10.21037/tau-2025-552
Cancer Res. 2026 Jan 14.

A Double-Negative Prostate Cancer Subtype is Vulnerable to SWI/SNF-Targeting Degrader Molecules.

Phillip Thienger, Irene Paassen, Xiaosai Yao, Philip D Rubin, Marika Lehner, Nicholas Lillis, Andrej Benjak, Sagar R Shah, Alden King-Yung Leung, Simone de Brot, Alina Naveed, Bence Daniel, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Andrea Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Yu Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K Y Ng, David A Quigley, Robert L Yauch, Mark A Rubin.

Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the pro-proliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2928
Clin Nutr ESPEN. 2026 Jan 09. pii: S2405-4577(26)00009-4. [Epub ahead of print] 102914

The Role of Nutrition in Prostate Cancer Risk, Progression, and Mortality: A Comprehensive Review.

Ariela A Souroujon, Vinaik Sundaresan, Aleksandra Golos, Michael Leapman, Olga A Gomez-Santamaría, Marianne Casilla-Lennon.

   BACKGROUND: Prostate cancer (PCa) is one of the most prevalent malignancies among men worldwide, yet evidence-based nutritional recommendations for its prevention and progression remain limited. Growing research indicates that diet may play a significant role in modulating PCa risk, tumor behavior, and mortality.
OBJECTIVE: This narrative review synthesizes current evidence on major dietary components, including carbohydrates, protein sources, fats, vegetables, vitamins, and minerals. It evaluates their associations with PCa incidence, progression, and disease-specific mortality.
METHODS: This narrative review synthesized evidence from PubMed/MEDLINE, Embase, and Web of Science (up to 2025), including randomized trials, observational studies, and meta-analyses, to evaluate associations between dietary factors and prostate cancer incidence, progression, and mortality.
FINDINGS: High intake of simple sugars and refined carbohydrates is associated with elevated PCa risk, whereas complex carbohydrates are associated with a more favorable metabolic profile. Evidence consistently supports increased fish consumption and suggests potential benefit from soy products. In contrast, high intake of red/processed meats and full-fat dairy may increase the risk of aggressive disease. Total and saturated fat intake is associated with poorer outcomes, although evidence on omega-3 fatty acids is mixed. Cruciferous vegetables show a strong protective factor, supported by epidemiologic data, whereas evidence for allium vegetables is emerging. Findings for micronutrients were highly heterogeneous: lycopene and physiologic vitamin E levels may confer benefit, whereas high-dose vitamin A derivatives, supplemental folic acid, selenium, and excessive dairy-derived calcium may increase PCa risk.
CONCLUSION: Although evidence is often inconsistent, several dietary patterns appear promising for PCa prevention and decreasing mortality. Emphasizing complex carbohydrates, fish, soy, plant-based fats, and cruciferous vegetables-while limiting simple sugars, red/processed meats, whole milk, saturated fats, and unnecessary supplementation-may support improved outcomes. High-quality randomized trials remain urgently needed to clarify causality and refine clinical nutrition guidance for PCa.

Keywords:  Dietary patterns; Micronutrients; Nutrition; Prevention; Prostate cancer

DOI:  https://doi.org/10.1016/j.clnesp.2026.102914
Saudi Pharm J. 2026 Jan 12. 34(1): 2

Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions.

Saad Alobid.

  Prostate cancer (PCa) is among the most common malignancies and remains a leading cause of cancer-related mortality in men worldwide. One of the main drivers is the dysregulation of the downstream signalling machinery. The PI3K, AKT, and mTOR signalling pathways play a pivotal role in cellular sustenance, growth, metabolism, and proliferation. In prostate cancer this pathway is generally altered due to the mutation or deletion of the PTEN (phosphatase and tensin homolog) gene and unnecessary activities of some components of PI3K, AKT, or mTOR. Extracellular communication of the androgen receptor (AR) with a wide array of oncogenic signatures is a primary evasion mechanism of cancer therapy and metastasis. This review focuses on the structure and function of the PI3K/AKT/mTOR pathway to better understand its role in prostate tumor biology. Furthermore, current therapeutic strategies that combinatorically target individual components of this pathway, such as allosteric and ATP-competitive AKT inhibitors, isoform-selective PI3K inhibitors, first- and second-generation mTOR inhibitors, are under consideration. The study particularly focuses on the combined use of immunotherapy (checkpoint inhibitors), chemotherapy (docetaxel), and androgen deprivation therapy (ADT), which are designed to break through the resistance-generating mechanisms and increase clinical efficacy. Overall, the findings support the need to conduct comprehensive preclinical and clinical studies on these alternative treatment regimens, and the eventual goal is to develop new treatment options for prostate cancer. The evidence of the pathway-specific therapy approach for the treatment of prostate cancer in recent clinical trials still failed to give a conclusive result. The current discussion also investigates the emerging areas of focus and perfection of combination regimens. The combination of all these developments makes it clear that the PI3K/AKT/mTOR signalling pathway is a key strategic point for developing therapeutics.

Keywords:  AKT and Targeted therapy; AR; PI3K; PSA; Prostate cancer (PCa); mTOR

DOI:  https://doi.org/10.1007/s44446-025-00056-w
Int J Biol Sci. 2026 ;22(2): 641-662

Targeting the HSP60/p53 Axis with Extracellular Vesicle-Delivered siRNA Reprograms Glycolysis in Prostate Cancer.

Meng-Yao Xu, Sheng Ma, Si-Yang Ma, Chen-Qian Liu, Jian-Xuan Sun, Ye An, Jin-Zhou Xu, Si-Han Zhang, Na Zeng, Xing-Yu Zhong, Xiao-Hua Zhu, Shao-Gang Wang, Qi-Dong Xia.

  Prostate cancer (PCa), a most prevalent urologic malignancy in men, remains a therapeutic challenge due to limited targeted strategies. This study investigates heat shock protein 60 (HSP60) (HSPD1-encoded), employing multi-dimensional approaches to decipher its oncogenic role and develop siRNA-loaded extracellular vesicles (siRNA@EVs) for PCa targeted therapy. Bioinformatics screening identified HSPD1 overexpression in PCa, which was validated via qPCR/Western blot in clinical tissues and cell lines. Metabolomic-transcriptomic integration and molecular biology experiments revealed HSP60-mediated glycolytic reprogramming. EVs were harvested from UV-irradiated PCa cells via high-speed centrifugation. siRNA@EVs were constructed via electroporation and evaluated in vitro (glycolysis phenotyping: glucose consumption, lactate/pyruvate production, hexokinase activity, and ATP production) and in vivo using xenograft models. Data were analyzed using R 4.3.1 and GraphPad Prism 9.0 (two-tailed t-test, P < 0.05). Multiple bioinformatics analyses (DepMap/TCGA/HPA) confirmed that HSP60 is specifically overexpressed and associated with advanced PCa progression and poor prognosis. HSPD1 knockdown and pharmacological HSP60 inhibition suppressed proliferation, metastasis, and subcutaneous tumor growth, while overexpression exacerbated oncogenicity. Multi-omics integration revealed HSP60 enhances glycolysis via p53 suppression, driving metabolic reprogramming. siRNA@EVs achieved significant HSPD1 silencing, effectively inhibiting the proliferation and metastasis of PCa cells, and blocking xenografts tumor growth in nude mice with safety. siRNA@EVs targeting HSPD1 demonstrate precision therapeutic potential with robust efficacy and safety, offering a novel approach for targeted therapy in PCa.

Keywords:  HSP60; extracellular vesicles; glycolysis; p53; prostate cancer

DOI:  https://doi.org/10.7150/ijbs.120760
Br J Cancer. 2026 Jan 10.

Pre-diagnostic circulating untargeted metabolomics and risk of overall and clinically significant prostate cancer: a systematic review and meta-analysis.

Harriett Fuller, Orietta P Agasaro, Jim M Guevara, Burcu F Darst.

BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associations between circulating metabolites with overall and clinically significant PCa risk has not been quantitively aggregated.
METHODS: We performed a systematic review and meta-analysis of untargeted pre-diagnostic circulating metabolomic studies across four clinically distinct outcomes: overall, low- to intermediate-risk, high- to very high-risk, and lethal PCa, each compared to controls.
RESULTS: Twelve studies were identified in the systematic review, and up to 408 metabolites were meta-analysed across the four PCa outcomes. Three, eleven, and nineteen metabolites were significantly associated with risk of overall, high- to very high-risk, and lethal PCa, respectively. Metabolites associated with high- to very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. In follow-up analyses, 13 of the significant metabolites were found to be modifiable by drugs and/or diet.
CONCLUSIONS: These findings suggest a strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.

DOI: https://doi.org/10.1038/s41416-025-03312-x
Mol Cancer Res. 2026 Jan 16.

Landscape of allele-specific expression in prostate cancer reveals recurrent, stage-specific events in AR signaling and resistance pathways.

Margaret Tsui, Kevin Hu, Hanbing Song, Sarah C Hsu, Yih-An Chen, Lorraine Nuniz, Julia H Pham, Chih-Hao Chang, Keliana S F Hui, David A Quigley, Jingjing Li, Franklin W Huang.

The effects of cis-regulatory alterations in prostate cancer (PCa) are insufficiently characterized, presenting an opportunity to discover driver genes and therapeutic targets. To comprehensively study these effects, we identify genes undergoing allele-specific expression (ASE) in localized PCa and metastatic castration-resistant PCa (mCRPC) samples. By defining recurrent ASE events across prostate tissue and tumor-enriched ASE, we develop CASEDI, a computational framework for prioritizing cancer drivers by integrating ASE and clinical data. CASEDI reveals genes showing recurrent ASE and altered expression in PCa, including AR-regulated and oncogenic ACSM1. mCRPC samples show enrichment of ASE in DNA repair, resistance pathways, and oncogenes and increased frequency of monoallelic expression (MAE) compared to localized tumors. We define an mCRPC gene signature based on MAE status that identifies a subgroup of localized patients with worse prognosis. Using ASE analysis, we expand the landscape of cis-regulatory events in PCa to inform the identification of additional therapeutic targets. Implications: This study develops a framework for identifying cancer drivers using prostate cancer allele-specific expression (ASE) data, generates a comprehensive dataset of ASE in prostate cancer and highlights candidate targets in tumorigenesis and metastasis.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0754
APMIS. 2026 Jan;134(1): e70141

Comparative miRNA Expression Profiling Reveals Candidates Involved in Prostate Cancer Radioresistance.

Sercan Ergun, Sezgin Güneş, Neslihan Hekim, Senanur Aslan, Dilbeste Demir Yeşilyurt, Elzem Nisa Alkan, Sümeyye Kayaoğlu, Alparslan Serarslan, Telat Aksu, Hasan Gülbiçim, Nilgün Özbek Okumuş.

  Prostate cancer is the most common malignancy among men worldwide, and treatment response depends on tumor radiosensitivity. Micrornas (mirnas) are key regulators of cell proliferation, apoptosis, and dna damage response, and have been implicated in therapy resistance. However, their roles in prostate cancer radioresponse remain incompletely understood. This study investigated the expression patterns of ten selected mirnas associated with radiation resistance in other cancers in prostate cancer models. Radiation-resistant pc-3, radiation-sensitive lncap, and normal prostate epithelial (hprec) cells were exposed to 0, 2, 4, 6, and 8 gy of ionizing radiation. Mirna expression levels were analyzed by quantitative pcr using snord48 as an internal control and calculated with the 2 - δδct method. In pc-3 cells, mir-20a-5p, mir-128-3p, and mir-135b-5p showed significant dose-dependent upregulation, whereas mir-23b-3p and mir-381-3p were downregulated. Mir-128-3p correlated positively with radiation dose, while mir-23b-3p and mir-381-3p showed negative correlations. Lncap cells exhibited moderate, non-dose-dependent mirna changes. Distinct mirna signatures differentiate radiation-resistant and radiation-sensitive prostate cancer cells. Mir-20a-5p, mir-128-3p, and mir-135b-5p may contribute to radioresistance, whereas mir-23b-3p and mir-381-3p may act as radiosensitizers.

Keywords:  microrna; prostate cancer; radiation therapy; radioresistance

DOI:  https://doi.org/10.1111/apm.70141
Int J Urol. 2026 Jan;33(1): e70352

Editorial Comment on (Abiraterone Acetate Triggers ER Stress-Mediated Androgen Receptor Suppression via PERK/ATF4/CHOP Signaling in Prostate Cancer).

Fatih Kar.

DOI: https://doi.org/10.1111/iju.70352
Acta Biochim Biophys Sin (Shanghai). 2026 Jan 13.

Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer.

Zhouda Cai, Jianming Lu, Shanshan Mo, Jipu Liu, Chuanfan Zhong, Yongding Wu, Fen Zou, Jianheng Ye, Zhaodong Han, Yuxiang Liang, Le Zhang, Fengping Liu, Weide Zhong.

  Lethal prostate cancer is marked by tumor heterogeneity and resistance to androgen receptor signaling inhibitors (ARSIs). In this study we identify glycolysis as a driver of disease progression and therapy resistance. Using single-sample gene set enrichment analysis (ssGSEA) on the SU2C cohort, we demonstrate that elevated glycolysis activity is associated with poor progression-free and overall survival. The glycolysis-based prognostic score (GLY score) is derived from the HALLMARK_GLYCOLYSIS gene set which includes CLN6, SDHC, B4GALT2, RPE, NANP, and KIF20A, via LASSO-Cox regression. The GLY score effectively stratifies risk in the SU2C and WDCT cohorts, with higher scores predicting worse outcomes and increased SYNE1 mutation frequency. Pan-cancer analysis across TCGA datasets confirm its prognostic value. In vitro, enzalutamide-resistant prostate cancer cell lines exhibit heightened glycolysis, and 2-DG inhibition reverses this effect, restoring drug sensitivity. CLN6 knockdown reduces glycolytic activity and cell proliferation. The GLY score offers robust prognostic value, and CLN6 represents a promising therapeutic target for precision medicine in lethal prostate cancer.

Keywords:  AR signaling inhibitor; CLN6; enzalutamide; glycolysis; lethal prostate cancer

DOI:  https://doi.org/10.3724/abbs.2025257
J Clin Invest. 2026 Jan 16. pii: e190928. [Epub ahead of print]136(2):

Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models.

Xiang Li, Rui Sun, Hao Li, Jacob J Orme, Xu Zhang, Yu Hou, Sean S Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang.

  Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically "cold" cancers such as prostate cancer.

Keywords:  Immunology; Innate immunity; Oncology; Prostate cancer; Therapeutics

DOI:  https://doi.org/10.1172/JCI190928
Int J Cancer. 2026 Jan 13.

Screening anticancer peptides performance in organotypic prostate tumor-stroma 3D models.

Bárbara Matos, Maria V Monteiro, Matilde R Lagarto, John Howl, Carmen Jerónimo, Vítor M Gaspar, João F Mano, Margarida Fardilha.

  Prostate cancer (PCa) poses a significant concern in the realm of cancer, representing a continuous challenge for the scientific community to discover effective therapeutic approaches. Among emerging strategies, anticancer peptides have garnered attention for their potential to disrupt protein-protein interactions. Targeting protein phosphatase 1 (PP1) complexes through PP1-disrupting peptides holds promise for selectively impeding critical pathways in the development and progression of cancer. In this context, CAVPENET peptide was designed to specifically target and disrupt the complex formed between PP1 and caveolin-1, a contributor to the progression of PCa. Previous research has revealed that CAVPENET inhibits the growth of PCa cell 2D monolayers, primarily by modulating PP1 activity. In this study, we developed an increasing physiomimetic human 3D PCa/prostate cancer-associated fibroblast heterotypic spheroid model to evaluate the tumor-suppressive activity of CAVPENET peptide in a more relevant preclinical context. Our findings reveal the formation of morphologically well-defined tumor microtissues that increase their size and cellular density over time, characteristics of in vivo tumors. Upon incubation with CAVPENET, PCa spheroids exhibited decreased growth and viability. In contrast, CAVPENET treatment (20 μM) did not influence CAFs monotypic spheroids growth. In conclusion, our results underscore the relevance of employing 3D PCa-stroma heterotypic models for evaluating anticancer therapeutics and emphasize the therapeutic potential of CAVPENET peptide for PCa.

Keywords:  3D spheroids; cancer treatment; heterotypic spheroids; peptide; prostate cancer

DOI:  https://doi.org/10.1002/ijc.70333
Discov Oncol. 2026 Jan 16.

DIAPH3 is a multifaceted prognostic biomarker that links immunotherapy response to tumor microenvironment in prostate cancer.

Yuxuan Chen, Ping Wang, Shuping Yang, Gang Jia, Lei Jia, Rui Zhu.



Keywords:  DIAPH3; Immunotherapy; Prognosis; Prostate cancer; Radiotherapy

DOI:  https://doi.org/10.1007/s12672-026-04413-6
Cell Signal. 2026 Jan 12. pii: S0898-6568(26)00017-3. [Epub ahead of print] 112368

Cooperative interaction between YAP1 and EphA3 receptor tyrosine kinase regulates cellular plasticity and treatment response in prostate cancer.

Marwah M Al-Mathkour, Abdulrahman M Dwead, Kezhan Kazaw, Bekir Cinar.

  The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.

Keywords:  Cancer progression; Cancer stem cells; Cell signaling; Cellular plasticity; EMT; EPAH3 receptor tyrosine kinase; Prostate cancer; RHOA; ROCK1/2; TEAD1; Treatment resistantce; YAP1

DOI:  https://doi.org/10.1016/j.cellsig.2026.112368
Pharmacol Res. 2026 Jan 09. pii: S1043-6618(26)00002-2. [Epub ahead of print] 108087

FASN targeting by G28UCM impairs mitochondrial fatty acid synthesis and reveals a FASN-SDHB Synthetic Interaction.

Nastasia Wilfinger-Lutz, Kristina M Kuehrer, Maria J Bueno, Michaela Schwaiger-Haber, Wang Wen Ann, Katrin Krejci, Ronald Mekis, Nicolle Gobbo Oliveira Erünlü, Anne Miller, Alexandra Junza, Siegfried Reipert, Michael Bergmann, Oscar Yanes, Arvand Haschemi, Gunda Koellensperger, Miguel Quintela-Fandino, Karin Nowikovsky.

  Metabolic reprogramming in cancer relies on lipid synthesis and mitochondrial function, yet how these processes, other than citrate flux and β-oxidation, intersect remains unclear. While inhibitors of lipogenic pathways have been developed as potential therapeutic agents in cancer therapy, their impact on oxidative metabolism is underexplored. Here, we identify the fatty acid synthase (FASN) inhibitor G28UCM as a compound that additionally destabilizes mitochondrial fatty acid synthase (mtFAS) and succinate dehydrogenase subunit B (SDHB), thereby targeting cytosolic and mitochondrial metabolism. Unexpectedly, the decreased abundance of SDHB was linked to disruption of mtFAS, most notably downregulation of Lipoyl Synthase (LIAS). G28UCM induced profound metabolic stress, including pseudohypoxia, oxidative stress, endoplasmic reticulum stress, and ferroptosis. In contrast, genetic depletion of FASN failed to reproduce these effects. In addition to investigating the mechanism of action of G28UCM, our study revealed a genetic interaction between FASN and SDHB, establishing that their dual but not single loss of function is sufficient to impair tumor growth. The synthetic interaction was conserved across prostate cancer, neuroendocrine tumors, and renal carcinoma cell models, including patient-derived cells, and combined inhibition of FASN and SDH markedly suppressed tumor progression in a breast cancer mouse model. Our findings point to new therapeutic opportunities for FASN inhibition beyond tumor initiation, with particular relevance to cancers associated with malignant SDHB mutations.

Keywords:  Cancer; FASN; G28UCM; LIAS; SDHB; mtFAS

DOI:  https://doi.org/10.1016/j.phrs.2026.108087
Mol Oncol. 2026 Jan 14.

PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer.

Nicolas Gordon, Peter T Gallagher, Orly I Richter, Neermala Poudel Neupane, Amy C Mandigo, Jennifer J McCann, Emanuela Dylgjeri, Irina Vasilevskaya, Christopher McNair, Channing J Paller, Wm Kevin Kelly, Karen E Knudsen, Matthew J Schiewer, Ayesha A Shafi.

  Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. While organ-confined disease has a reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the entire CRPC population. The use of ascorbate, more commonly known as ascorbic acid or Vitamin C, has demonstrated antitumor activity in a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anticancer effects. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitors, by inhibiting DNA damage repair, would augment the toxicity of ascorbate, leading to improved antitumor effects. Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic effects with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and noncastrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control. These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo. These findings implicate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.

Keywords:  PARP; ascorbate; drug combinations; novel therapeutics; prostate cancer

DOI:  https://doi.org/10.1002/1878-0261.70183
Comput Biol Chem. 2026 Jan 08. pii: S1476-9271(26)00004-6. [Epub ahead of print]122 108879

Cross-omics interpretable neural network for discovery of molecular markers in prostate cancer.

Xin Chen, Sheng Yi, Anwaier Yuemaierabola, Yuhan Liu, Liang He, Jing Ma, Wenjia Guo, Gang Sun.

  Determining molecular markers that mediate clinically aggressive phenotypes in prostate cancer is a significant challenge. While traditional linear models offer some interpretability, they often lack the precision needed for complex multi-omics data. Conversely, conventional deep learning methods provide robust predictions but typically remain opaque, hindering the identification of impactful molecular markers and biological mechanisms. To address this, we propose the Cross-omics Interpretable Neural Network (CINN), a biomimetic framework designed to predict prostate cancer states and identify key molecular markers by integrating diverse omics data. CINN innovatively leverages prior biological knowledge from either pathway or protein-protein interaction (PPI) networks, combined with a novel trainable mask layer. This mask dynamically optimizes the strength of pre-defined biological connections, thereby enhancing both knowledge representation and model interpretability. The framework effectively integrates multi-omics data, including gene expression, somatic mutations, and copy number variations, to provide a holistic view of the disease. Extensive experiments on a prostate cancer dataset demonstrate that CINN achieves substantial and statistically significant performance enhancements over a strong baseline (P-NET). Specifically, our best-performing variant, CINN-pw with a trainable mask, improved F1 scores by 13.1% to 0.843, Accuracy by 8.3% to 0.894, and AUC by 2.3% to 0.949. These gains were consistently statistically significant (p<0.0001 for most key metrics), underscoring the robustness of our approach. Crucially, CINN's inherent interpretability facilitated the identification of pivotal molecular candidates, including TBP and TAF2, which are implicated in prostate cancer progression. These findings are supported by existing literature and provide valuable insights into the underlying mechanisms of prostate cancer, offering potential avenues for targeted therapeutic interventions and precision medicine.

Keywords:  Causal network; Cross-omics; Interpretability; Prostate cancer

DOI:  https://doi.org/10.1016/j.compbiolchem.2026.108879
Eur Urol Open Sci. 2026 Jan;83 173-184

Downregulation of ANPEP Is Associated with Aggressive Prostate Cancer and Poor Disease-specific Outcomes.

Ryan M Putney, Purvish Trivedi, Shivanshu Awasthi, Amparo Serna, Jasreman Dhillon, Christopher J Sweeney, R Jeffrey Karnes, Matthew R Cooperberg, Alejandro Berlin, Paul L Nguyen, Daniel E Spratt, Elai Davicioni, James Proudfoot, Monica Ryu, Esther Katende, Jong Y Park, Timothy R Rebbeck, Asmaa El-Kenawi, Kosj Yamoah.

   Background and objective: Aminopeptidase N (ANPEP) is linked to malignancy in certain tumor types, but its role in aggressive prostate cancer (PCa) is less well defined. Our aim was to characterize ANPEP expression in various PCa stages to determine whether it is a robust prognostic biomarker of aggressive disease.
Methods: We established baseline ANPEP expression in benign prostate tissue using multiple large databases. Next, we determined the association between ANPEP expression and various clinicopathologic features and molecular subtypes using ∼170 000 tumor samples from the GRID registry. We calculated median expression values, and reported standardized mean differences. We used receiver operating characteristic and Cox regression analyses to evaluate the diagnostic and prognostic significance of ANPEP for several endpoints, and performed preranked gene set enrichment analysis (GSEA) to identify biological pathways over-represented by race or ANPEP category according to hallmark gene sets.
Key findings and limitations: ANPEP expression was higher in normal prostate tissues than in prostate tumors. Advanced clinical stage, higher National Comprehensive Cancer Network risk category, and worse Gleason grade group were all associated with lower median ANPEP expression. Genomic markers of aggressive PCa, such as high Decipher scores, low androgen receptor (AR) activity, ERG overexpression, and loss of PTEN expression, were correlated with lower ANPEP expression. Among patients with locally advanced or metastatic PCa, higher ANPEP expression was significantly associated with more favorable PCa-specific outcomes, including biochemical recurrence, distant metastasis, castration-resistant PCa, and overall survival. GSEA revealed AR upregulation for the ANPEP-high group and men with genomic-derived African race. Conversely, the G2-M DNA damage checkpoint and MYC target genes were enriched in the ANPEP-low and genomic-derived European race groups.
Conclusions and clinical implications: Our findings show that ANPEP downregulation is linked to a more aggressive PCa phenotype. Higher ANPEP levels were associated with more favorable outcomes, thereby, establishing ANPEP expression as a prognostic factor for treatment response.
Patient summary: We looked at levels of a protein called aminopeptidase N (ANPEP) in prostate tumors using information from large databases. We found that ANPEP is linked to markers that indicate more aggressive disease and that higher ANPEP levels are associated with more favorable treatment outcomes.

Keywords:  African American men; Aminopeptidase N; Biochemical recurrence; Decipher genomic classifier score; Distant metastasis; Gene set enrichment analysis; Prostate cancer

DOI:  https://doi.org/10.1016/j.euros.2025.12.011
Aging Male. 2026 Dec 31. 29(1): 2615561

Genetic relationships between the gut microbiota and prostate cancer: Mendelian randomization combined with bioinformatics analysis.

Wenjie Li, Chen Li, Xing Li, Zhan Gao.

   BACKGROUND: Prostate cancer (PCa) is a leading cause of male cancer-related death globally. While the gut microbiota is linked to PCa, its genetic association remains unclear.
METHODS: We screened genetic instruments related to the gut microbiota and paired them with PCa genome-wide association study data to conduct Mendelian randomization (MR) analysis. Positive MR findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus (GEO) dataset to perform differential expression analysis, aiming to identify differentially expressed associated genes (DEAGs). We determined the importance scores of these DEAGs through four machine learning models and constructed a nomogram based on these findings, and then validated it in another group of the GEO dataset.
RESULTS: MR analysis found 16 gut bacteria causally linked to PCa (7 risk, 9 protective), with 144 related genes. PLCL1, VSNL1, ROR2, NRXN3, and TEAD1 were identified as feature genes for constructing a nomogram that provides a quantitative prediction of the risk of PCa onset.
CONCLUSIONS: This study indicates that there are causal links between the gut microbiota and PCa. Feature genes may affect the occurrence of PCa by inhibiting the epithelial-mesenchymal transition, proliferation, migration, and invasion of cells.

Keywords:  Mendelian randomization; Prostate cancer; bioinformatics; gut microbiota; machine learning

DOI:  https://doi.org/10.1080/13685538.2026.2615561
Cell Mol Biol Lett. 2026 Jan 14. 31(1): 5

Methylation-induced silencing of AZGP1 enhances prostate cancer metastasis by stimulating tumoral glycolysis.

Lu Li, Jinguang Luo, Linyue Zhao, Lu Tian, Jianfeng Wang, Yifei Cheng, Xiao Li.



Keywords:   AZGP1 ; Glycolysis; Metastasis; Prostate cancer

DOI:  https://doi.org/10.1186/s11658-025-00818-3