bims-meproc 2026-06-07 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–06–07
nineteen papers selected by
Grigor Varuzhanyan, UCLA

Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
Histone methyltransferase KMT2D promotes castration-resistant prostate cancer progression by reactivating AR through FOXA1.
APOL3 Orchestrates Metastasis and Enzalutamide Resistance via STAT3-DAB2IP Signaling in Prostate Cancer.
Cholesterol-Mediated Metabolic-mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer.
DMBX1 facilitates tumor progression via triggering epithelial-mesenchymal transition and cancer cell stemness mediated by DMBX1/PAX2/SOX5 axis in prostate cancer cells.
CCT2 Promotes Prostate Cancer Progression Through EIF3F-Dependent Stabilization of FASN.
c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.
USP2 is an androgen-repressed survival factor that stabilises oncoproteins to facilitate therapy resistance in prostate cancer.
The miR-5681b/Beclin-1 axis regulates tumor autophagy to affect the proliferation and apoptosis of prostate cancer cells.
Ubiquitination-anchored signature defines neuroendocrine prostate cancer: hub genes and single-cell ecosystem insights from integrated bioinformatics analysis of public transcriptomic datasets.
Integrating network toxicology, machine learning, and single-cell sequencing to reveal the FASN-mediated role of phenolic endocrine disruptors in water in promoting prostate cancer.
The innate immune mediator group IIA secreted phospholipase A2 modulates lipid droplet formation in prostate cancer cells.
Molecular Design and Preclinical Evaluation of GenSci143, a Novel B7-H3- and PSMA-Directed Bispecific Antibody-Drug Conjugate, for the Treatment of Prostate Cancer.
Therapeutic pressure drives the evolution of a protective ecotype characterized by AR-loss-induced senescence in prostate cancer.
Targeting regulatory T cells in the prostate cancer microenvironment: From mechanisms to therapeutics (Review).
Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer.
Inflammation-driven transcriptional reprogramming in prostate cancer: Convergence of NFκB, JAK/STAT3, and epigenetic remodeling in castration-resistant disease.
Ferroptosis and prostate cancer: A translational path from molecular mechanisms to precision therapy.
Specifically targeted engineered exosomes loaded with circAKR1A1 enhance tumorigenesis and metastasis in prostate cancer by activating the PI3K/Akt signalling pathway.

Free Radic Biol Med. 2026 May 30. pii: S0891-5849(26)00827-0. [Epub ahead of print]253 463-477

Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.

Kai Li, Chenggong Luo, Heng Zhang, Ting Yue, Tengda Wang, Yong Ban, Zhaoxuan Li, Xuan Liu, Lingyue An, Guangheng Luo, Zehua Ma.

  Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) is critical for development of androgen receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates reactive oxygen species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.

Keywords:  Androgen receptor signaling inhibitors; Castration-resistant prostate cancer; Metabolic remodeling; Mitochondria; Oxidative phosphorylation; PGC-1α

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.323
Oncogene. 2026 May 30.

Histone methyltransferase KMT2D promotes castration-resistant prostate cancer progression by reactivating AR through FOXA1.

Mayao Luo, Chenwei Wu, Manli Zhou, Rui Liu, Yifan Zhang, Yadong Li, Yuanpeng Liao, Xin Huang, Chuance Du, Shidong Lv, Qiang Wei.

Prostate cancer (PCa) progression, particularly to castration-resistant prostate cancer (CRPC), is driven by androgen receptor (AR) reactivation and epigenetic alterations. Here, we identify lysine methyltransferase 2D (KMT2D) as a critical epigenetic oncogene in PCa. KMT2D expression is elevated in PCa and correlates with poor prognosis. Mechanistically, KMT2D facilitates AR signaling by recruiting the pioneer factor FOXA1 to AR-specific enhancers, promoting chromatin accessibility and activating AR target genes. FOXA1 mutations impair this regulation, demonstrating their functional interplay. Furthermore, KMT2D-FOXA1-AR axis modulates ketone body metabolism via transcriptional control of HMGCS2, supporting tumor growth. Pharmacological inhibition of UTX, a COMPASS complex demethylase essential for KMT2D function, disrupts H3K4me1 deposition and suppresses AR signaling and tumor proliferation. Altogether, we characterize KMT2D as a key driver of AR-dependent PCa progression and propose UTX inhibition as a promising therapeutic strategy.

DOI: https://doi.org/10.1038/s41388-026-03828-3
Curr Gene Ther. 2026 May 25.

APOL3 Orchestrates Metastasis and Enzalutamide Resistance via STAT3-DAB2IP Signaling in Prostate Cancer.

Quanxin Wang, Songlin Zuo, Lin Chen, Fangning Wan, Zhe Hong, Wenhao Xu, Wenting Hou, Dingwei Ye.

   BACKGROUND: In advanced Prostate Cancer (PCa), metastatic spread and the inevitable emergence of enzalutamide resistance represent major clinical hurdles. Although apolipoprotein L3 (APOL3) is linked to oncogenesis, its precise mechanistic role in PCa progression and antiandrogen resistance, particularly its regulation of the STAT3-DAB2IP axis, remains largely unexplored.
METHODS: Publicly available clinical datasets were analyzed to evaluate APOL3 expression and its prognostic value. The functional consequences of modulating APOL3 and DAB2IP levels were assessed using in vitro and in vivo PCa models, including an established enzalutamide-resistant cell line (C4-2R). Mechanistic insights into cellular proliferation, motility, angiogenesis, and drug response were derived from RNA sequencing, reciprocal co-immunoprecipitation (Co-IP), and dual-targeting phenotypic assays.
RESULTS: APOL3 is significantly upregulated in PCa, strongly correlating with elevated Gleason scores, advanced stage, TP53 mutational status, and poor prognosis. Functionally, APOL3 promotes PCa proliferation, metastasis, and angiogenesis. Mechanistically, APOL3 sustains STAT3 phosphorylation and suppresses the tumor suppressor DAB2IP. Notably, Co-IP assays revealed a direct, bidirectional physical interaction between APOL3 and DAB2IP. Furthermore, we discovered that elevated APOL3 drives enzalutamide resistance not by enhancing classical Androgen Receptor (AR) activity, but by directly binding the Glucocorticoid Receptor (GR). This APOL3-GR complex activates a bypass signaling pathway entirely independent of the AR. While restoring DAB2IP resensitized cells to enzalutamide, it triggered a compensatory upregulation of APOL3. Consequently, concurrent APOL3 knockdown and DAB2IP overexpression yielded a powerful synergistic effect, profoundly dismantling malignant phenotypes, suppressing pro-metastatic markers (p-STAT3, VEGF, SNAIL, MMP2), and restoring enzalutamide sensitivity.
DISCUSSION: These findings establish APOL3 as a central driver of prostate cancer metastasis and enzalutamide resistance. APOL3 drives these aggressive phenotypes by directly binding and suppressing DAB2IP to sustain oncogenic STAT3 signaling, and by activating an AR-independent bypass pathway through its physical interaction with the Glucocorticoid Receptor (GR). The enrichment of APOL3 in TP53-mutated and resistant tumors underscores its critical role in tumor plasticity. Consequently, synergistically co-targeting APOL3 alongside DAB2IP restoration represents a highly promising therapeutic strategy to overcome adaptive antiandrogen resistance and halt metastatic progression.
CONCLUSION: APOL3 is a central driver of PCa aggressiveness and enzalutamide resistance, functioning via the direct modulation of the DAB2IP/STAT3 axis and the activation of the GR bypass pathway. Cotargeting APOL3 alongside DAB2IP restoration represents a highly promising, synergistic therapeutic strategy to circumvent adaptive resistance and halt metastatic progression in advanced castration-resistant prostate cancer.

Keywords:  APOL3; Prostate cancer (PCa); STAT3-DAB2IP axis; castration-resistant prostate cancer (CRPC).; enzalutamide resistance; metastasis

DOI:  https://doi.org/10.2174/0115665232490462260522095123
Adv Sci (Weinh). 2026 Jun 04. e75977

Cholesterol-Mediated Metabolic-mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer.

Shaojie Liu, Chao Xu, Jun Jiang, Limin He, Yike Zhou, Zhengxuan Li, Yu Li, Keying Zhang, Fa Yang, Tong Lu, Hongtao Song, Hai Zhu, Zhihao Hu, Xiaolong Zhao, Kai Gan, Hongji Li, Bo Yang, Rui Zhang, Weihong Wen, Donghui Han, Weijun Qin.

  Biophysical microenvironment fuels therapeutic resistance, yet the contribution of matrix stiffness to castration-resistant prostate cancer (CRPC) remains poorly understood. In this study, we established a metabolic-mechanotransductive crosstalk wherein cholesterol-driven stromal reprogramming amplifies CRPC progression. Mechanistically, full androgen deprivation (FAD) induces cholesterol metabolic rewiring in prostate cancer (PCa) cells that orchestrates the CH25H-dependent phenotype transformation of cancer-associated fibroblast (CAF) into myofibroblastic CAF (myCAF). In turn, the resulting matrix stiffness induces unfolded protein response (UPR) and potentiates IRE1α kinase activity for Xbp1 splicing, while concurrently activating the integrin αVβ3/FAK/STAT3 axis to transcriptionally replenish Xbp1 substrate in PCa cells. This mechanosensitive adaptation thereby confers PCa with resistance to apoptosis induced by FAD. Consequently, pharmacological disruption of this metabolic-mechanotransductive axis by targeting cholesterol metabolism or blockade of IRE1α-XBP1s signaling significantly suppress tumor growth, representing a promising therapeutic strategy for CRPC progression.

Keywords:  CRPC; cancer associated fibroblast; cholesterol; matrix stiffness; mechanotransduction

DOI:  https://doi.org/10.1002/advs.75977
Exp Cell Res. 2026 Jun 01. pii: S0014-4827(26)00211-9. [Epub ahead of print] 115094

DMBX1 facilitates tumor progression via triggering epithelial-mesenchymal transition and cancer cell stemness mediated by DMBX1/PAX2/SOX5 axis in prostate cancer cells.

Zhaochen Li, Kailai Chen, Zhenming Pan, Li Zhong, Yakun Luo, Changyi Quan.

  Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with metastatic and castration-resistant disease posing significant therapeutic challenges largely driven by epithelial-mesenchymal transition (EMT) and cancer stemness (CSC). This study identifies the transcription factor DMBX1 as a potential upstream regulator of these aggressive phenotypes in vitro and in subcutaneous xenograft models. DMBX1 is significantly upregulated in PCa tissues and cell lines, and its high expression correlates with advanced disease stage and poor patient prognosis. Functional assays demonstrated that DMBX1 knockdown suppressed PCa cell proliferation, migration, invasion, and tumor growth in vivo, while its overexpression promoted these malignant behaviors. Mechanistically, RNA sequencing and subsequent analyses revealed that DMBX1 transcriptionally activates PAX2 by directly binding to its promoter. DMBX1 and PAX2 proteins physically interact and form a complex that co-occupies the promoter of the core pluripotency factor SOX5, synergistically driving its expression. This novel DMBX1/PAX2/SOX5 axis facilitates PCa progression by concurrently activating the PI3K/AKT, MAPK, and JAK/STAT3 signaling pathways, thereby altering the expression of EMT- and CSC-related markers. Collectively, our findings establish the DMBX1/PAX2/SOX5 transcriptional axis as a potential regulator associated with the control of EMT- and CSC-related markers in prostate cancer, revealing a crucial signaling hub and a promising therapeutic target for advanced PCa.

Keywords:  CSC; DMBX1; EMT; PAX2; SOX5; prostate cancer

DOI:  https://doi.org/10.1016/j.yexcr.2026.115094
Adv Sci (Weinh). 2026 Jun 03. e75915

CCT2 Promotes Prostate Cancer Progression Through EIF3F-Dependent Stabilization of FASN.

Shun Xu, Yifan Zhang, Haolin Li, Shengyu Zhao, Xiaoran Dai, Qili Xu, Mintian Fei, Chun Li, Zhihui Zou, Baojun Wang, Li Zhang, Hui Wang, Ligang Zhang, Chaozhao Liang.

  Prostate cancer (PCa) is increasingly recognized to be driven by dysregulated lipid metabolism. Although fatty acid synthase (FASN) is highly expressed in PCa, the mechanisms governing FASN protein stability and its functional integration into oncogenic lipid metabolism remain poorly defined. In this study, we identified chaperonin-containing TCP1 subunit 2 (CCT2) as a key oncogenic regulator that promotes lipid synthesis and enhances malignant phenotypes both in vitro and in vivo. Mechanistically, CCT2 transcription is upregulated by the transcription factor Forkhead Box A1 (FOXA1); the CCT2 protein interacts with eukaryotic translation initiation factor 3 subunit F (EIF3F) and FASN to facilitate the assembly of a CCT2/EIF3F/FASN ternary complex. This complex enhances the EIF3F-mediated deubiquitination of FASN, increasing FASN stability and lipid synthesis, and accelerating tumor progression. Either orlistat-mediated FASN inhibition or Y043-8015-induced disruption of the CCT2-EIF3F interaction effectively suppressed CCT2-driven tumor progression in vivo. Importantly, combined treatment produced synergistic antitumor effects, significantly reducing tumor growth and metastatic burden across multiple in vivo models, including isograft and patient-derived xenograft models. This study reveals that CCT2 promotes lipid metabolic reprogramming and tumor progression in prostate cancer by cooperating with EIF3F to stabilize FASN, highlighting the CCT2-EIF3F-FASN axis as a potential target for metabolic intervention.

Keywords:  CCT2; EIF3F; FASN; lipid metabolism reprogramming; prostate cancer

DOI:  https://doi.org/10.1002/advs.75915
Cell Death Dis. 2026 May 31.

c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.

Liyan Ao, Zhiqiang Chen, Jingliang Zhang, Qi Wang, Jin Luo, Zhuoran Li, Qilong Jiao, Bobin Ning, Shiyuan Peng, Wenhao Hu, Yuqi Jia, Weimin Ci, Baojun Wang, Zhouhuan Dong, Xu Zhang, Shaoxi Niu.

Prostate cancer is a highly heterogeneous malignancy, with distinct subtypes displaying unique molecular and metabolic profiles. This study identifies a compensatory shift in α-ketoglutarate (α-KG) metabolism in prostate cancer, where the tumor relies on IDH1 to incorporate citrate into the TCA cycle. IDH1 inhibition, leads to lower α-KG levels. Since α-KG is required for HIF-1α hydroxylation, IDH1 inhibition stabilizes HIF-1α, which subsequently upregulates c-Fos. C-Fos enhances GLUD1 transcription, promoting the conversion of glutamate to α-KG as a compensatory mechanism. Additionally, c-Fos upregulates downstream effectors, including FOXC1 and SOX2, driving neuroendocrine differentiation in prostate cancer. Targeting α-KG-metabolizing enzymes, such as IDH1 or GLUD1, presents promising therapeutic strategies for prostate cancer subtypes by inhibiting tumor proliferation and inducing oxidative stress, thus sensitizing tumors to ferroptosis. Overall, these findings uncover a metabolic adaptation in response to IDH1 inhibition and highlight the pivotal role of c-Fos in mediating this compensatory pathway, offering new insights into potential metabolic targets for prostate cancer treatment and ferroptosis-based therapies.

DOI: https://doi.org/10.1038/s41419-026-08918-4
Cell Death Dis. 2026 Jun 02.

USP2 is an androgen-repressed survival factor that stabilises oncoproteins to facilitate therapy resistance in prostate cancer.

Danielle Meiwen Fang, Raj K Shrestha, Beatriz German, Razia Rahman, Scott L Townley, Jianling Xie, Adrienne R Hanson, Richard Iggo, Zeyad D Nassar, Madison Helm, Shashikanth Marri, Alex D Colella, Giles Best, Margaret M Centenera, Wayne D Tilley, Tim K Chataway, Leigh Ellis, Lisa M Butler, Luke A Selth.

In prostate cancer, the development of resistance to androgen receptor (AR)-targeted therapies (ATTs) and chemotherapies is associated with the emergence of new phenotypic states with altered molecular features. Here, we identify ubiquitin-specific peptidase 2 (USP2) as a mediator of this phenomenon. USP2 is induced in response to ATTs and more highly expressed in aggressive, castration-resistant prostate tumours that have lost dependence on AR as an oncogenic driver. Overexpression of USP2 in prostate cancer cells elicited elevated rates of glycolysis, neuroendocrine features and resistance to docetaxel, an important chemotherapeutic agent for advanced prostate cancer. USP2 stabilised key oncoproteins, including Aurora kinase A, cyclin D1 and fatty acid synthase. An unbiased proteomic approach identified potential new USP2 substrates and a USP2-regulated proteome that is associated with metastatic disease. Genetic or pharmacological targeting of USP2 caused cell death in human and mouse models of aggressive prostate cancer and the USP2 inhibitor ML364 exhibited potent anti-tumour effects against an orthotopic xenograft model of AR-null disease. Collectively, this study identifies USP2 as a critical regulator of proteins involved in prostate cancer progression and therapy resistance, positioning it as a viable therapeutic target.

DOI: https://doi.org/10.1038/s41419-026-08923-7
Neoplasma. 2026 May 29. pii: 250619N272. [Epub ahead of print]

The miR-5681b/Beclin-1 axis regulates tumor autophagy to affect the proliferation and apoptosis of prostate cancer cells.

Yanmei Zhang, Jiaojiao Li, Quan Li, Yuan Cao.

Prostate cancer (PCa) is a leading cause of cancer-related mortality among men. This study aims to investigate the regulatory effect of microRNA (miR)-5681b, a potential upstream miR of Beclin-1, on PCa cell proliferation and apoptosis. Two PCa cell lines (PC3 and LnCaP cells) with relatively low miR-5681b expression were treated with miR-5681b mimic, pcDNA3.1-Beclin-1, or an autophagy activator Rapamycin. A xenograft tumor model was established in nude mice, and the tumor-bearing mice were treated with agomir miR-5681b. The levels of miR-5681b, Beclin-1 mRNA, and apoptosis- and autophagy-associated proteins were evaluated using western blot and RT-qPCR. The binding between Beclin-1 and miR-5681b was testified by dual-luciferase reporter gene assay. Cell biological behaviors, as well as Ki-67-positive cells and apoptosis in mouse tumor tissues, were examined. The results showed that miR-5681b was downregulated in PCa cells and targeted Beclin-1. miR-5681b overexpression in PCa cells significantly suppressed cell proliferation and B-cell lymphoma 2 (Bcl-2) levels while augmenting cell apoptosis and the levels of Bcl-2-associated X (Bax) and cleaved caspase-3. Importantly, miR-5681b inhibited PCa cell proliferation and autophagy but promoted PCa cell apoptosis, whereas Beclin-1 upregulation reversed these effects. Activating autophagy also reversed miR-5681b-regulated proliferation and apoptosis of PCa cells. In vivo, miR-5681b overexpression inhibited PCa tumor growth by modulating the Beclin-1-mediated autophagy pathway. Collectively, these findings suggested that miR-5681b was lowly expressed in PCa cells, and miR-5681b overexpression inhibited autophagy by targeting Beclin-1, thereby suppressing the growth of PCa.

DOI: https://doi.org/10.4149/neo_2026_250619N272
Aging Male. 2026 Dec 31. 29(1): 2680719

Ubiquitination-anchored signature defines neuroendocrine prostate cancer: hub genes and single-cell ecosystem insights from integrated bioinformatics analysis of public transcriptomic datasets.

Zhenkun Zhao, Lei Qiu, Ziang Li, Jialong Wu, Qianyang Ni, Sijie Li, Hongyin Wang, Chengdong Shi, Xiushi Lin, Yixiao Liu, Jian Lu.

   BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory state that often emerges under androgen-receptor pathway inhibition. We hypothesized that dysregulated ubiquitination underpins NEPC lineage plasticity and that integrating bulk and single-cell transcriptomes would define a ubiquitination-centered signature and tumor microenvironment (TME) circuits of diagnostic and therapeutic relevance.
METHODS: Public bulk transcriptomic datasets were combined to compare NEPC with prostate adenocarcinoma, including a GEO discovery cohort of 49 tissue samples from GSE32967 and GSE104786, and intersected with a curated ubiquitination-related gene universe to derive ubiquitination-related differentially expressed genes (URDEGs). Co-expression networks, functional enrichment, and protein-protein interaction (PPI) network topology analyses were used to identify and prioritize candidate hub genes. An independent scRNA-seq cohort was integrated for biological contextualization to map cellular lineages, hub gene localization, and intercellular communication.
RESULTS: We identified 317 URDEGs that clearly segregated NEPC from conventional prostate cancer and clustered into NEPC-associated modules enriched for cell-cycle and mitotic programs. Network integration yielded an 11-gene hub panel, including AURKA, CCNA2, EZH2, FGFR1, and TTK. In the single-cell dataset, 25,325 cells were retained after quality control, and UMAP resolved 17 clusters annotated into 8 major lineages. Single-cell mapping further revealed lineage-biased hub gene expression and highlighted a prominent stromal-vascular as well as immune MIF-CD74/CXCR4 signaling axis.
CONCLUSIONS: This integrative analysis identifies a ubiquitination‑anchored transcriptomic signature and associated hub‑gene network that are consistently associated with NEPC in public bulk datasets and supported by cell‑type-resolved patterns in an independent scRNA‑seq cohort; these findings nominate candidate biomarkers and therapeutic hypotheses that warrant external validation in prospectively collected, clinically annotated cohorts with protein‑level assessment.

Keywords:  Neuroendocrine prostate cancer; single-cell RNA sequencing; tumor microenvironment; ubiquitination; weighted gene co-expression network analysis (WGCNA)

DOI:  https://doi.org/10.1080/13685538.2026.2680719
PLoS One. 2026 ;21(6): e0350638

Integrating network toxicology, machine learning, and single-cell sequencing to reveal the FASN-mediated role of phenolic endocrine disruptors in water in promoting prostate cancer.

Xinyao Zhu, Qilong Wu, Yuqi Li, Zhiyu Liu, Yang Zeng, Zhiqiang Zeng, Yubo Zhou, Lunhong Zou, Xiaochun Wu, Dan Zhao, Qingfu Deng, Tao Zhou.

BACKGROUND: Phenolic endocrine-disrupting chemicals (EDCs) like nonylphenol (NP) and octylphenol (OP) are widespread water pollutants. Their estrogen-like properties are suspected contributors to prostate cancer, but their precise molecular mechanisms remain unclear.
METHODS: We employed a multidimensional framework to investigate this link. Potential NP/OP targets were predicted using SwissTargetPrediction, SEA, and CTD databases and cross-referenced with prostate cancer-associated genes from GeneCards and OMIM. Differential expression analysis of the GSE46602 dataset (36 tumor vs. 14 benign samples) identified candidate genes, which were refined to core genes using Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) algorithms. Their diagnostic power was evaluated via an Artificial Neural Network (ANN) model and validated in The Cancer Genome Atlas (TCGA) cohort. Single-cell RNA sequencing data from six prostate cancer samples (GSE137829) were analyzed to reveal cell-type-specific expression patterns. Molecular docking and molecular dynamics (MD) simulations assessed binding stability between pollutants and target proteins.
RESULTS: We identified 143 overlapping genes between NP/OP targets and prostate cancer-associated genes, significantly enriched in lipid metabolism and prostate cancer pathways (adjusted P < 0.05). Dual-algorithm screening identified four core genes (ENPP2, FASN, PTGS2, and CHRM1). Among them, Fatty Acid Synthase (FASN) exhibited the best diagnostic performance in the TCGA validation cohort (AUC = 0.800), outperforming PTGS2 (0.783), ENPP2 (0.621), and CHRM1 (0.605), and was significantly overexpressed in prostate cancer tissues (|log2FC| > 1, adjusted P < 0.05). Single-cell analysis across seven annotated cell types revealed specific FASN overexpression in epithelial cells, with expression progressively upregulated along pseudotime disease trajectories. Gene Set Variation Analysis (GSVA) demonstrated significant activation of oncogenic pathways - including PI3K-AKT-mTOR, androgen response, and early estrogen response - in FASN-high epithelial cells. Molecular docking confirmed favorable binding of NP and OP to FASN (binding affinities of -6.0 and -6.1 kcal/mol, respectively), and MD simulations showed that both complexes reached stable equilibrium with RMSD fluctuations below 0.3 nm. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations further yielded binding free energies of -19.70 kcal/mol (NP-FASN) and -17.24 kcal/mol (OP-FASN).
CONCLUSION: This study computationally identifies FASN as a potential molecular hub that may link phenolic EDC exposure to prostate cancer. Our bioinformatic analyses suggest a hypothetical mechanism involving pollutant-driven disruption of lipid metabolic reprogramming via FASN, potentially activating a pro-oncogenic network, which warrants future experimental validation.

DOI: https://doi.org/10.1371/journal.pone.0350638
Front Cell Dev Biol. 2026 ;14 1774027

The innate immune mediator group IIA secreted phospholipase A2 modulates lipid droplet formation in prostate cancer cells.

Monavvar Andarva, Maria George Elias, Mila Sajinovic, Timothy J Mann, Jasmine M Zhou, Albert S Mellick, Tara Laurine Roberts, Paul de Souza, Kieran F Scott.

   Introduction: We and others have shown that elevated human Group IIA secreted phospholipase A2 (hGIIA) has both catalysis-dependent and -independent functions that are associated with both acute and chronic inflammatory disorders including cancer. Our novel inhibitors that selectively block hGIIA's catalysis-independent function slow tumor growth in animal models via interaction with vimentin. The mechanism of this interaction and its consequences for cancer aggressiveness remains unexplored.
Methods: We have used established patient-derived androgen-independent prostate cancer (PCa) cell lines, DU145, PC-3 and vimentin-knockout DU145 (DU145vim-) cells treated with hGIIA protein in the presence and absence of our cyclic peptide inhibitor Kesonotide (also known as c2). As lipid metabolism is known to be regulated by vimentin, we examined whether this aspect of vimentin biology was influenced by interaction with hGIIA, focusing on lipid droplet (LD) formation, LD-associated perilipin proteins (PLIN2 and PLIN3) and lipid biosynthetic enzymes (DGAT and FASN). To do this we used the combination of single cell quantitative immunofluorescence and Western blot analysis.
Results: We found that addition of exogenous hGIIA increased LD metabolism as evidenced by LD immunofluorescence signal and this increase is dependent on vimentin in PCa. The response is dependent on hGIIA levels with high concentrations of hGIIA associated with PLIN2 loss, PLIN3 suppression, and DGAT1 induction without FASN upregulation. Kesonotide alone was largely inert. However, at high concentration of hGIIA, Kesonotide attenuated lipid metabolism by neutralizing perilipin remodelling and attenuating DGAT1 induction in knockout cells.
Discussion: Taken together, these findings identify a context-dependent hGIIA LD-remodelling program that is shaped by vimentin, implicating for the first time the hGIIA-vimentin axis in inflammatory cue-driven lipid metabolic rewiring in aggressive PCa.

Keywords:  BODIPY; DGAT; FASN; PLIN2; PLIN3; immunofluorescence; kesonotide; vimentin

DOI:  https://doi.org/10.3389/fcell.2026.1774027
Mol Cancer Ther. 2026 May 29.

Molecular Design and Preclinical Evaluation of GenSci143, a Novel B7-H3- and PSMA-Directed Bispecific Antibody-Drug Conjugate, for the Treatment of Prostate Cancer.

Yao Xu, Fu Li, Zhiyu Cui, Hongmei Xie, Liang Xu, Yihui Lin, Tete Li, Nan Li, Dechen Cao, Weiming He, Wenqiang Zhai, Xiaozhen Wang, Shu Zhang, Haizhou Zhang, Fanglong Yang, Siqin Wang, Lei Jin, John L Xu.

Antibody-drug conjugate (ADC) has rapidly transformed the treatment landscape for solid tumors; however, due to heterogeneity in target antigen expression, suboptimal efficacy and emergence of acquired resistance present significant challenges to the development of curative ADCs for cancers. Here, we report the preclinical evaluation of GenSci143, a novel B7-H3 × PSMA-directed bispecific ADC (BsADC), designed to overcome tumor antigen heterogeneity-associated drug resistance for the treatment of metastatic castration-resistant prostate cancer (mCRPC). GenSci143 comprises a highly active topoisomerase 1 inhibitor payload conjugated to a dual-targeting antibody via a plasma-stable linker to minimize off-target toxicity. Gene profiling analysis reveals high co-expression of B7-H3 and PSMA in prostate cancer (PCa), laying the biological basis of dual targeting strategy. In vitro, GenSci143 exhibited strong binding, efficient internalization, and potent cytotoxicity against PCa cells expressing either or both target antigens, as well as a robust bystander killing effect, outperformed single-target benchmark ADCs that are currently in clinical development. In multiple cancer cell line-derived and patient-derived xenograft (CDX/PDX) models of PCa, GenSci143 induced profound tumor regression and demonstrated superior antitumor activity vs. competitor ADCs. Furthermore, GenSci143 displayed excellent plasma stability and favorable pharmacokinetic properties in non-human primates. The compelling preclinical efficacy across cancer models with varying levels of target antigen expression and its exceptional plasma stability support the translational relevance of GenSci143. These results indicate that GenSci143 is a promising therapeutic candidate for castration resistant PCa and potentially other malignancies, warranting its further clinical development.

DOI: https://doi.org/10.1158/1535-7163.MCT-26-0395
Theranostics. 2026 ;16(12): 6803-6826

Therapeutic pressure drives the evolution of a protective ecotype characterized by AR-loss-induced senescence in prostate cancer.

Limin He, Jun Jiang, Shaojie Liu, Hongtao Song, Tong Lu, Zhihao Hu, Yu Li, Hai Zhu, Yike Zhou, Zhengxuan Li, Fa Yang, Keying Zhang, Rui Zhang, Tao Wu, Kai Gan, Bin Zhao, Jingliang Zhang, Dailing Si, Rui Zhang, Changhong Shi, Weihong Wen, Donghui Han, Chao Xu, Weijun Qin.

   Rationale: Prostate cancer treatment relies heavily on androgen deprivation therapy, yet the progression to a lethal treatment-resistant state presents a nearly universal clinical challenge. While tumor-intrinsic changes are well documented, the manner in which the broader tumor microenvironment dynamically reorganizes into distinct macroscopic ecological states under therapeutic pressure remains elusive. This underscores that dismantling specific therapy-induced TME niches may represent a promising strategy for CRPC treatment.
Methods: We constructed a comprehensive single-cell atlas comprising 399,276 cells from 133 clinical samples to systematically investigate sample-level microenvironmental heterogeneity. Integrative bioinformatics and a meta-analysis of 1,259 patients were utilized to validate the clinical relevance. The upstream regulatory role of the androgen receptor on the NF-κB2/p52 pathway in cancer-associated fibroblasts was elucidated and validated using CRISPR-Cas9, ChIP-qPCR, and dual-luciferase reporter assays. Functional studies and therapeutic strategies targeting this axis were conducted using gain- and loss-of-function assays, and evaluated through in vitro organoid co-cultures and in vivo transgenic and xenograft mouse models.
Results: We demonstrated that hormonal therapy drives a convergent systemic evolution toward a specific treatment-refractory ecological state termed Ecotype 4. Rather than isolated cellular events, this highly malignant ecosystem is characterized by a TGF-β-driven rigid vascular-stromal barrier enforcing immune exclusion and the prominent accumulation of an androgen receptor-negative senescent fibroblast population. Mechanistically, we identified that the loss of the androgen receptor releases a physiological brake on the non-canonical NF-κB pathway, forcing these fibroblasts into a pro-tumorigenic senescence phenotype. Importantly, pharmacologically blocking this NF-κB2/p52 pathway with the inhibitor SN52 reverses the supportive nature of this niche and restores sensitivity to standard antiandrogens in vivo.
Conclusions: This study demonstrates that castration resistance is driven by the dynamic, systemic evolution of the microenvironment into a highly structured protective ecotype. Targeting the therapy-associated stromal p52 senescence switch effectively dismantles this ecological sanctuary and offers a new valued therapeutic strategy for advanced CRPC.

Keywords:  TME ecotype; cancer-associated fibroblasts; castration-resistant prostate cancer; non-canonical NF-κB signaling; senescence

DOI:  https://doi.org/10.7150/thno.134940
Mol Med Rep. 2026 Aug;pii: 218. [Epub ahead of print]34(2):

Targeting regulatory T cells in the prostate cancer microenvironment: From mechanisms to therapeutics (Review).

Hua Luo.

  Prostate cancer (PCa) is a heterogeneous cancer. Regulatory T cells (Tregs) within the tumor microenvironment play a pivotal role in promoting immune evasion and disease progression. This review systematically outlines the development, functional characteristics and regulatory networks of Tregs in this environment. Synthesis of recent spatial transcriptomic and single‑cell RNA‑sequencing data revealed that the functional heterogeneity and spatial distribution of Tregs within the tumor stroma, rather than their absolute abundance alone, are critical determinants of immune evasion. For instance, a high stromal density of Tregs is associated with a >2‑fold increased risk of biochemical recurrence, and an activated, highly suppressive Treg subset predominates in high‑Gleason score tumors. The impact of current and emerging therapeutic strategies, including monoclonal antibody‑based and combination immunotherapies, on Treg function, was critically evaluated. The present analysis indicates that while anti‑cytotoxic T‑lymphocyte‑associated protein (CTLA)‑4 monotherapy has failed to show a survival benefit in Phase III trials for metastatic castration‑resistant PCa, fragment crystallizable‑enhanced anti‑CTLA‑4 antibodies achieve up to 50% intratumoral Treg depletion in preclinical models. The rationale for targeting specific Treg subsets was highlighted, such as C‑C motif chemokine receptor 4+ and glycoprotein‑A repetitions predominant+ and integrating Treg‑directed approaches with androgen deprivation therapy (ADT) or radiotherapy to mitigate treatment‑induced Treg expansion (e.g., ADT can increase intratumoral Tregs by 30‑40%). Existing challenges and prospects for the clinical translation of Treg‑targeting approaches were also discussed, emphasizing the need for patient stratification guided by Treg‑related biomarkers.

Keywords:  immune evasion; immunotherapy; prostate cancer; regulatory T cells; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.3892/mmr.2026.13928
Neoplasia. 2026 May 30. pii: S1476-5586(26)00051-5. [Epub ahead of print]78 101321

Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer.

Lisha G Brown, Ilsa M Coleman, Tony L H Chu, Erolcan Sayar, Radhika A Patel, Brian Hanratty, Mohamed Adil, Dapei Li, Yongtao Li, Holly M Nguyen, Conner J Sessions, Erin L Sweeney, Joshi J Alumkal, Rui M Gil da Costa, Yuzhuo Wang, Daniel W Lin, Lawrence D True, Ruth Dumpit, Eva Corey, John K Lee, Peter S Nelson, Li Xin, Michael C Haffner, Colm Morrissey.

  Treatment-induced neuroendocrine prostate cancer (NEPC) represents an aggressive form of castration-resistant prostate cancer (CRPC) associated with lineage plasticity and therapeutic resistance. In this study, we investigated the role of the Hippo signaling axis in the transdifferentiation from androgen receptor-positive prostate cancer (ARPC) to NEPC. RNA sequencing analyses of CRPC metastases revealed coordinated alterations in Hippo pathway components, with decreased expression of YAP1, LATS2, and TEAD2 and increased expression of LATS1, TEAD1, and the RNA splicing regulator RBFOX2 in NEPC. These transcriptional alterations were consistently observed across multiple model systems and patient samples. Epigenetic analyses demonstrated that reduced expression of YAP1, TEAD2, and LATS2 was associated with increased DNA methylation, whereas elevated TEAD1 expression correlated with DNA hypomethylation in NEPC. NEPC selectively retained TEAD1 expression, including a spliced isoform not detected in ARPC. Proteomic interactome analyses revealed that TEAD1 associated with RNA splicing factors and DNA repair proteins. Functional studies showed that TEAD1 knockdown led to the reversion of gene programs associated with epithelial differentiation. These findings indicate that the conversion of ARPC to NEPC involves coordinated loss of AR, YAP1, and REST activity alongside sustained TEAD1 expression and altered RNA processing. Our data identify TEAD1 as a transcriptional regulator associated with the NEPC state and suggest a role for TEAD1-linked transcriptional and post-transcriptional mechanisms in prostate cancer lineage plasticity.

Keywords:  Neuroendocrine; Prostate; RBFOX2; TEAD1; YAP

DOI:  https://doi.org/10.1016/j.neo.2026.101321
Cancer Lett. 2026 Jun 01. pii: S0304-3835(26)00410-6. [Epub ahead of print]655 218647

Inflammation-driven transcriptional reprogramming in prostate cancer: Convergence of NFκB, JAK/STAT3, and epigenetic remodeling in castration-resistant disease.

Madhu Krishna, Pankaj Garg, David Horne, Ravi Salgia, Sharad S Singhal.

  Chronic inflammation has emerged as a central driver for the initiation, progression, and therapeutic resistance of prostate cancer (CaP). While androgen receptor (AR) signaling serves as the primary axis for prostate tumorigenesis, mounting evidence suggests that continuous activation of inflammatory signaling pathways, especially nuclear factor kappa B (NFκB) and interleukin-6 (IL6)/Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways, profoundly reshape the transcriptional and epigenetic landscape of advanced disease. These signaling pathways largely converge with AR signaling to form a common axis and promote tumor survival, proliferation, angiogenesis, immune evasion, epithelial to mesenchymal transition (EMT), and metastasis. Furthermore, prolonged exposure to cytokines such as IL6 and tumor necrosis factor-α (TNFα) leads to constitutive activation of STAT3 and NFκB signaling pathways. This persistent inflammatory signaling increases AR transcriptional activity even under androgen-deprived conditions, thereby facilitating the development of castration-resistant prostate cancer (CRPC). Apart from transcriptional crosstalk, inflammatory signaling pathways interact with epigenetic remodeling mechanisms, including histone modifications, DNA methylation, and dysregulation of chromatin modifiers such as EZH2, LSD1, and BRD4. These epigenetic variations stabilize aberrant gene expression programs and promote therapeutic resistance in metastatic CRPC. The present review discusses the crosstalk between inflammatory signaling, AR reprogramming, and epigenetic remodeling, and illustrates emerging therapeutic strategies targeting NFκB and JAK/STAT3 signaling pathways. This review highlights the importance of the integrated inflammatory-AR-epigenetic axis in CRPC progression and emphasizes its potential for improved biomarker stratification and the development of effective combinatorial therapeutic strategies to overcome resistance and improve clinical outcomes in advanced CaP.

Keywords:  Androgen receptor (AR); Castration-resistant prostate cancer (CRPC); Epigenetic remodeling; Interleukin-6 (IL6); Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3); Nuclear factor kappa B (NFκB); Prostate cancer (CaP)

DOI:  https://doi.org/10.1016/j.canlet.2026.218647
Genes Dis. 2026 Sep;13(5): 101967

Ferroptosis and prostate cancer: A translational path from molecular mechanisms to precision therapy.

Yixiang Huang, Yuanxin Ma, Jiachen He, Tanjing Song.

  Castration-resistant prostate cancer represents a critical clinical challenge due to its propensity for resistance to conventional therapies and limited treatment efficacy. Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation. It holds therapeutic potential and can be induced by glutathione peroxidase 4 (GPX4) inhibition, glutathione depletion, or iron overload using compounds such as RSL3 and Erastin. These approaches show promise in overcoming drug resistance and enabling synergistic effects with anti-androgen therapy, chemotherapy, and immunotherapy. This review systematically summarizes the core regulatory networks of ferroptosis in prostate cancer (such as the PI3K-AKT-mTOR, Hippo/YAP, PGE2, and their downstream pathways), summarizes combination treatment strategies and clinical trial progress, proposes a three-pronged translational framework of "ferroptosis regulatory network-biomarkers-precision therapy", and discusses the challenges it faces in terms of drug resistance, targeting accuracy, and clinical translation. These insights aim to accelerate biomarker discovery, optimization of multimodal combination regimens, and the translation of ferroptosis from fundamental research into transformative therapeutic interventions.

Keywords:  Combination therapy; Ferroptosis; Ferroptosis-inducing compounds; Lipid peroxidation; Prostate cancer

DOI:  https://doi.org/10.1016/j.gendis.2025.101967
Oncogene. 2026 May 30.

Specifically targeted engineered exosomes loaded with circAKR1A1 enhance tumorigenesis and metastasis in prostate cancer by activating the PI3K/Akt signalling pathway.

Shenglong Li, Yue Kang, Yujing Guan, Jiahang Li, Runze Jiang, Shouyi Zhang, Enduo Qiu, Tianfu Wang, Rui Liu, Shanlin Wang, Cong Ning, Xing Niu, Yuming Wang, Yu Zeng.

Determining effective treatment strategies for prostate cancer patients with bone metastasis remains a difficult issue. Targeted engineered exosomes have the potential to deliver anticancer drugs to tumor sites in a highly efficient and precise manner while minimizing treatment-related side effects. Here, we assessed the function and value of targeted engineered exosomes loaded with circAKR1A1 (OE-circAKR1A1-exosomes) in bone metastatic prostate cancer cells. The function and underlying mechanism of OE-circAKR1A1-exosomes were investigated via in vivo and in vitro experiments. We observed a positive correlation between circAKR1A1 expression and prostate cancer metastasis and progression. Both in vivo and in vitro experiments confirmed that OE-circAKR1A1-exosomes specifically targeted prostate cancer cells in the bone microenvironment. This targeting mechanism activated the PI3K/Akt signalling pathway, thereby facilitating tumor invasion and metastasis. Collectively, our findings suggest that circAKR1A1 is a driver and treatment target for metastatic prostate cancer. Targeted delivery of therapeutic circRNAs via engineered exosomes represents a highly promising clinical therapeutic approach. The schematic diagram of this study E3 aptamer-modified engineered exosomes loaded with circAKR1A1 specifically target bone metastases in PCa, thereby activating the PI3K/Akt signalling pathway to facilitate tumor invasion and metastasis.

DOI: https://doi.org/10.1038/s41388-026-03833-6