Alternol, a natural compound, exhibits potent anti-tumor activity by selectively inducing oxidative stress in prostate cancer cells; however, the molecular mechanisms that coordinate adaptive survival responses to this stress remain poorly defined. In this study, we demonstrate that Alternol treatment triggers a robust, ROS-dependent autophagic response and Nrf2 transactivation in both cell lines and xenograft models. We identify that Alternol specifically drives the rapid, large-scale aggregation of SQSTM1/p62 through direct protein oxidation at Cys105 and Cys113. Distinct from traditional kinase-driven models, this structural aggregation is a primary redox-sensing event that occurs independently of, and prior to, p62 phosphorylation at Ser349 and Ser403. These oxidized p62 aggregates function as a signaling platform that sequesters KEAP1 for autophagic degradation, thereby liberating Nrf2 for nuclear translocation and the induction of downstream antioxidant genes such as AOX1 . Genetic depletion of p62 or disruption of its aggregation capacity via C105/113A mutation blunts KEAP1 turnover and Nrf2 activation, significantly sensitizing cancer cells to Alternol-induced apoptosis. Collectively, our findings define a novel "oxidation-aggregation" axis of p62 as a pivotal survival mechanism, suggesting that targeting the physical aggregation of p62 could provide a promising strategy to overcome adaptive resilience and enhance the efficacy of pro-oxidant cancer therapies.

SQSTM1/p62 is a multifunctional scaffold protein that plays important roles in selective autophagy and cellular redox homeostasis. While phosphorylation-dependent regulation of p62 has been extensively studied, the functional significance of oxidative modification remains incompletely understood. Our previous studies showed that the natural small compound Alternol induces cancer cell-specific killing via a xanthine oxidase-mediated strong oxidative stress. In this study, we investigated p62-associated oxidative responses under Alternol-induced oxidative stress conditions in prostate cancer cells. Using biochemical assays and cell-based models, we found that Alternol treatment was associated with the accumulation of oxidized and high-molecular-weight p62 species, accompanied by altered KEAP1 association and increased Nrf2-associated signaling. Furthermore, Alternol-induced p62 oxidative modification was associated with autophagy-related responses and adaptive cellular survival under oxidative stress conditions. Disruption of the Cys105/113-dependent oxidative modification response attenuated Nrf2-associated transcriptional activity and increased cellular sensitivity to Alternol treatment. Collectively, our findings support an association between p62 oxidative modification and redox-responsive autophagy- and antioxidant-associated signaling pathways under Alternol-induced oxidative stress conditions, providing new insight into adaptive stress responses in prostate cancer cells.

Prostate club-like cells have emerged as a recurrent but conceptually unsettled epithelial population across normal prostate, benign remodeling, inflammatory lesions, and prostate cancer. Although the term derives from airway biology, current evidence suggests that, in the prostate, these cells are better viewed as context-dependent noncanonical epithelial states than as a definitive lineage. Single-cell, spatial transcriptomic, and integrative studies place club-like cells most consistently in the prostatic urethra and proximal ducts under near-homeostatic conditions, whereas related programs reappear in benign prostatic hyperplasia, proliferative inflammatory atrophy, and tumor-associated niches. Across these contexts, club-like states intersect with androgen perturbation, inflammatory remodeling, epithelial plasticity, and treatment adaptation. Molecularly, they are defined less by a single marker than by a partially overlapping secretory, stress-associated, and remodeling-related gene program, with variable relationships to urethral luminal, intermediate, and progenitor-like epithelial states. This review synthesizes current evidence on the definition, distribution, molecular identity, functional implications, and disease relevance of prostate club-like cells. We argue that their main significance lies in clarifying prostate epithelial heterogeneity and state transitions, while key priorities include harmonized nomenclature, longitudinal sampling, spatial validation, and functional perturbation.

IntroductionWe and others demonstrated that the natural compound Alternol induces apoptosis preferentially in human cancer cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in cellular glycolysis, important for energy homeostasis, especially in cancer cells. We recently discovered that Alternol interacts with GAPDH, along with 4 Krebs cycle enzymes. In this study, we characterized the mechanism for Alternol-GAPDH interaction and the functional significance.MethodsMultiple human prostate cancer cell lines and a benign prostate epithelial cell line were utilized in the experiments. Enzyme activity assay in vitro with purified protein was used to examine Alternol inhibition of GAPDH activity. Computer-based docking assessment was performed to analyze Alternol interaction with GAPDH protein. Seahorse instrument was used to conduct glycolytic testing.ResultsOur data revealed that Alternol interacts with GAPDH protein on two sites, one of which is the NAD+ binding site on the active domain of the enzyme, postulating an inhibitory effect. As expected, Alternol directly inhibited GAPDH dehydrogenase activity in an in vitro assay with purified enzyme with nanomole IC50 value at 5.794 nM. Consistently, Alternol significantly suppressed its enzymatic activity in cultured cancer cells but not in benign cells. These inhibitory effects were associated with reduced glycolytic capacity in cancer cells as assessed by extracellular acidification rate (ECAR) and metabolomic analysis.ConclusionThese results suggest that Alternol potently inhibits GAPDH activity and specifically disrupts glycolytic flux in cancer cells.

BACKGROUND:Reprogramming of metabolic pathways represents a central indicator in cancer pathogenesis, but the metabolic heterogeneity of bladder cancer (BLCA) at different stages is not well understood. This study aims to analyze metabolic reprogramming in BLCA across stages and its impact on patient survival. METHODS:Single-cell sequencing data were used to examine metabolic heterogeneity of epithelial cells and cell subpopulation differentiation in BLCA at various clinical stages. Spatial transcriptome data were analyzed for copy number variability and riboflavin metabolism in BLCA epithelial cells. Bulk RNA sequencing data from BLCA patients were used for riboflavin pathway expression analysis and prognostic biomarker identification. The effects of three biomarkers (ENPP1, ACP1, and RFK) on BLCA risk were validated using RT-qPCR, Mendelian randomization and co-localization analysis. RESULTS:Epithelial cells exhibited significant metabolic heterogeneity during bladder cancer progression. Compared to normal control stage, riboflavin metabolic activity progressively increased with disease stage, as validated by spatial transcriptomics and bulk RNA-seq. High expression of ENPP1, ACP1, and RFK (riboflavin pathway) strongly correlated with poor overall survival. RT-qPCR confirmed their high expression in tumours, increasing with stage. Mendelian randomisation/co-localisation indicated these genes localise to bladder epithelium, and their genetic variation associates negatively with BLCA risk. CONCLUSION:Increased riboflavin metabolism is likely to be an important marker of malignant progression in BLCA. The ENPP1, ACP1 and RFK genes in this pathway may serve as valuable prognostic biomarkers for BLCA, with potential implications for early diagnosis, monitoring disease progression, and guiding personalized treatment strategies.

Background:Pyroptosis is an inflammatory form of programmed cell death that may remodel the tumor immune microenvironment and influence clinical outcomes. However, the prognostic value of pyroptosis-related molecular patterns and their translational implications in bladder cancer remain incompletely defined. This study aimed to identify pyroptosis-related molecular subtypes, develop and externally validate a subtype-derived prognostic signature, and explore its associations with immune and therapeutic features in bladder cancer. Methods:The Cancer Genome Atlas-bladder cancer cohort (TCGA-BLCA) was used as the development cohort, GSE13507 and GSE31684 as external validation cohorts, and IMvigor210 as an exploratory immunotherapy-treated cohort. Pyroptosis-related molecular subtypes were identified by non-negative matrix factorization (NMF), and pathway activity and immune infiltration were assessed by gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA). A subtype-derived six-gene prognostic signature was developed using least absolute shrinkage and selection operator Cox (LASSO-Cox) regression, and performance was evaluated by Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curves, and calibration. Results:Two pyroptosis-related molecular subtypes (C1/C2) with distinct survival and immune characteristics were identified. A subtype-derived six-gene prognostic signature comprising ECM1, FER1L4, FKBP10, ANXA1, ARL4C, and CTSE stratified patients into high- and low-risk groups in the development and validation cohorts and remained significantly associated with overall survival (OS) after multivariable adjustment in the TCGA-BLCA cohort. Higher risk scores were associated with higher pathological grade and advanced T stage. Risk stratification was also associated with mutational profiles, immune checkpoint expression, and immunophenoscore (IPS) differences, while CellMiner analysis generated exploratory drug-sensitivity clues. Conclusions:We established pyroptosis-related molecular subtypes and developed a subtype-derived six-gene prognostic signature that was evaluated across multiple independent cohorts. The model is associated with immune microenvironment features and genomic context, and offers translational clues for immunotherapy and targeted strategies, warranting further prospective and experimental validation.

Objectives: This study provides a comprehensive analysis of the expression profiles and clinical significance of homeobox (HOX) genes in prostate cancer (PCa). Methods: We utilized large-scale datasets including TCGA-PRAD, DKFZ-RNAseq, and metastatic castration-resistant prostate cancer (mCRPC) cohorts. We screened 228 HOX-related genes for gene expression related to disease progression, diagnosis, and prognosis. Gene expression was compared in patient subgroups stratified by clinical parameters. Survival prognosis was analyzed using the Kaplan-Meier survival curve approach. The AUC value of the altered gene was determined using the Receiver Operating Characteristic (ROC) curve analysis. The effect of castration on HOX-related gene expression was analyzed using the LuCaP35 xenograft dataset. Results: We identified 42 up-regulated and 56 down-regulated genes with significant differential expression between benign and malignant tissues. Further investigation into 22 key genes revealed their profound impact on diagnosis and prognosis. HOXC6 and NKX2-3 emerged as highly effective diagnostic biomarkers, demonstrating area under the curve (AUC) values of 0.917 and 0.936, respectively. Prognostically, NKX6-1 expression showed the strongest predictive potential for 5-year disease-specific survival (AUC = 0.881), while HOXB7 also served as a critical survival indicator (AUC = 0.909). Conversely, the down-regulation of EVX2 was uniquely associated with all clinicopathological and survival parameters, suggesting a significant tumor-suppressive role. In early-onset PCa, HOXC5, HOXC6, and MEIS2 correlated strongly with tumor mutation burden and biochemical recurrence. In the context of advanced disease, NKX2-3 was associated with Androgen Receptor (AR) activation scores, whereas MEIS2 showed a strong negative correlation. Notably, this study identified HOXB8/HOXD13 genes, like LHX2, as novel and consistent markers, significantly increased in treatment-induced neuroendocrine prostate cancer (t-NEPC). Conclusion: These findings highlight a distinct subset of HOX genes that govern prostate cancer progression and provide a framework for developing novel diagnostic and prognostic tools tailored to disease stage and subtype.

Background Active surveillance (AS) is widely used to manage low-risk prostate cancer and reduce overtreatment; however, it introduces significant psychological challenges linked to living with untreated cancer. This review synthesizes evidence on the psychological burden faced by AS patients, including anxiety, depression, fear of cancer progression, decision making distress, and threats to masculinity and sexual identity. Patients often grapple with uncertainty about disease trajectory, perceiving AS as passive inaction, which exacerbates emotional strain. Contributing factors include inadequate social support, gaps in clinician communication, and socioeconomic disparities that affect access to care. Interventions such as psychoeducation, cognitive-behavioral therapy to reframe catastrophic thinking, mindfulness-based stress reduction, and peer support groups demonstrate efficacy in reducing distress and enhancing quality of life. Objective This review underscores the necessity of integrating mental health support into AS protocols through routine psychological screening and multidisciplinary care. Conclusion Future research should prioritize longitudinal studies on psychological trajectories and culturally tailored interventions to address diverse patient needs. By addressing these psychological dimensions, clinicians can optimize patient-centered care, improve adherence to surveillance, and ensure AS remains a sustainable, holistic strategy for managing prostate cancer.

Glycosylated RNAs (glycoRNAs) are a newly discovered class of biomolecules that challenge the long-standing paradigm that glycosylation occurs exclusively on proteins and lipids. Early studies indicate that glycoRNAs are broadly distributed across cell types and can be detected at the cell surface as well as in other cellular compartments. Emerging evidence suggests that glycoRNAs may participate in processes such as intercellular communication and immune regulation, but their context-dependent functions in physiology and disease, including cancer, are only beginning to be elucidated. Recent advances in detection techniques have enabled more comprehensive profiling of glycoRNAs and their associated cell-surface RNA-binding proteins, providing initial links between glycoRNA patterns, tumor aggressiveness, immune checkpoint regulation and extracellular vesicle–mediated signaling. However, many of these connections remain correlative or are inferred by analogy to protein and lipid glycosylation. In this review, we summarize current knowledge of glycoRNA biosynthesis, cell-surface display and detection methods, with a particular focus on emerging observations in cancer-related contexts. We also discuss the potential of glycoRNAs as biomarkers and therapeutic targets, while highlighting key unanswered questions regarding their biosynthetic pathways, structural diversity and mechanistic roles. Addressing these challenges with integrated omics and spatial approaches will be essential for defining glycoRNA biology and evaluating their feasibility as tools for precision oncology.

Drug resistance to the androgen receptor (AR) antagonist is a critical obstacle in the clinic for advanced prostate cancers. Especially, AR antagonist treatment-induced neuroendocrine progression represents a lethal and therapy-resistant subtype. Although transcriptional and epigenetic lineage plasticity have been extensively implicated in treatment-induced neuroendocrine progression, the contribution of metabolic adaptation remains incompletely understood. Here, we identified a previously unrecognized metabolic reprogramming mechanism induced by AR antagonists in castration-resistant prostate cancer (CRPC) models. AR antagonist treatment markedly enhanced glycolytic activity and induced glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Genetic depletion of GAPDH suppressed AR antagonist-induced glycolytic activation, altered transcriptomic and metabolic programs, reduced neuroendocrine-associated marker expression, and inhibited xenograft tumor growth. Mechanistically, GAPDH promoter pulldown coupled with mass spectrometry, siRNA screening, and chromatin immunoprecipitation assays identified myeloid zinc finger-1 (MZF1) as a key transcription factor for Enzalutamide-induced GAPDH gene expression. Pharmacological inhibition of GAPDH using koningic acid (KA) or penta-O-galloyl-β-D-glucopyranose (PGG) significantly suppressed tumor growth and attenuated neuroendocrine-associated molecular programs in CRPC cell-derived xenograft and patient-derived t-NEPC xenograft models. Collectively, our findings identify an AR antagonist-induced MZF1-GAPDH signaling axis that promotes glycolytic activation and neuroendocrine-associated metabolic adaptation during treatment resistance. These results support targeting GAPDH-dependent metabolic reprogramming as a potential therapeutic strategy for treatment-resistant prostate cancer.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease of the bladder for which no effective therapy is currently available. Understanding the pathogenesis of IC/BPS and identifying effective intervention targets are of great clinical importance for its effective treatment. Our work focuses on elucidating the key targets and underlying mechanisms of IC/BPS. We established an experimental autoimmune cystitis (EAC) mouse model and generated gene knockout mice to elucidate key mediators triggering chronic inflammatory damage in IC/BPS through using single-cell RNA sequencing, proteomic sequencing, and molecular biology experiments. Our study revealed that the infiltration and activation of macrophages, T cells, and mast cells exacerbated inflammatory bladder damage in both IC/BPS and EAC mice. Notably, cell-cell communication among bladder immune cells was significantly enhanced in EAC mice. Macrophages, as the main cell types altered in EAC mice, received and transmitted the most intensity signalling. Mechanistically, macrophages synthesized and secreted S100A9, which in turn facilitated macrophage polarization and promoted the production of pro-inflammatory cytokines. S100A9 emerged as an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Further analysis demonstrated that S100A9 activation enhanced the inflammatory response and exacerbated bladder tissue damage in IC/BPS patients and EAC mice via TLR4/NF-κB and TLR4/p38 signalling pathways. Importantly, inhibition of S100A9 with paquinimod, as well as genetic knockout of S100A9, significantly attenuated the pathological process. S100A9 is an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Targeting S100A9-initiated signalling pathways may offer a novel therapeutic strategy for IC/BPS.

IntroductionThe human gamma-glutamyltransferase (GGT) is a membrane-bound extracellular glycoprotein with an enzymatic activity that cleaves gamma-glutamyl peptide bonds in glutathione and other peptides and transfers the gamma-glutamyl moiety to acceptors. It has been shown aberrant expression of GGT proteins in human cancers while their expression profiles in prostate cancers are not reported.MethodsIn this study, we analyzed the expression profiles of all protein-coding GGT genes using the TCGA-PRAD RNA-seq dataset derived from primary prostate cancers. GGT family gene expression profiles were also analyzed using the SU2C/PCF RNAseq dataset derived from aggressive late-stage prostate cancer patients. Androgen modulation of GGT family gene expression was analyzed using multiple NCBI/GEO datasets.ResultsOur results showed that prostate tissues expressed four major isoforms of GGT family genes (GGT1/5/6/7), of which GGT1 expression was upregulated but GGT6/GGT7 expression was downregulated in cancer tissues compared to benign tissues. However, GGT5 expression was increased along with tumor stage progression and associated with worse progression-free survival. GGT6 expression exhibited a superb AUC value in prostate cancer diagnosis and was associated with favorable progression-free survival. GGT1 expression was highly increased but GGT6/GGT7 expression was largely reduced in ERG-fusion-positive cases. In CRPC tumors, GGT6 expression was suppressed in patients with anti-AR therapies, which was reversed when patients were taken off the treatment. This AR-dependent modulation was confirmed in LNCaP cells and LuCaP35 xenograft models. In addition, compared to CRPC-Adeno tumors, treatment-induced NEPC tumors showed a reduced GGT1 but an elevated GGT7 level, which was in line with higher levels of GGT7 in NEPC H660 cells.ConclusionOur data suggests that GGT6 is a new AR downstream target but GGT7 is a potential NEPC biomarker.

Oncocytomas are clinically benign tumors composed of cells with abundant granular eosinophilic cytoplasm due to a high mitochondrial content. While typically non-metastatic, rare cases of metastatic oncocytomas have been documented. This report describes a unique case involving transcriptome analysis to identify genes associated with the oncocytoma signature. A 57-year-old woman presented to the emergency department with COVID-19 pneumonia. Incidentally, a CT chest scan revealed a large mass in the left upper quadrant. Further imaging of the abdomen and pelvis identified a 14 cm left renal mass and multiple low-density hepatic lesions. A liver biopsy confirmed a PAX-8 and CD10 positive carcinoma, consistent with metastatic renal cell carcinoma. Following neoadjuvant therapy, the patient underwent a left radical nephrectomy, partial hepatectomy, and cholecystectomy. This case emphasizes the rarity of metastatic oncocytoma and the importance of genomic testing in elucidating its molecular underpinnings. By identifying specific genetic alterations linked to the oncocytoma signature, genomic analysis offers critical insights into potential mechanisms of metastasis. These findings could enhance diagnostic accuracy and guide the development of targeted therapeutic strategies in rare metastatic cases of oncocytoma.

The surfactant protein-C (SFTPC) gene encodes a hydrophobic pulmonary surfactant protein essential for lung function and homeostasis. While primarily associated with lung diseases, emerging evidence suggests its potential involvement in human cancers. In addition, SFTPC expression was also found in human skin cells, however, its expression profile in cutaneous melanoma is unknown. In this study, we analyzed expression profiles of SFTP family genes including SFTPA1/2 , SFTPB , SFTPC , and SFTPD in human skin melanoma tissues. Our analysis revealed that SFTPC expression was the predominant SFTP gene and was associated with disease progression, including tumor stage, Clark level, and Breslow depth. High levels of SFTPC expression in skin melanoma tissues were significantly associated with patient survival outcomes including overall and disease-specific survival. The associations were specifically dictated in aggressive tumors, suggesting a potential role of SFTPC expression in melanoma progression. Interestingly, SFTPC expression was negatively correlated with T-helper cell infiltration in skin melanoma tissues. Gene enrichment analysis also indicated that SFTPC expression was in parallel with elevated expressions of mitochondrial energy biosynthesis-related genes and reduced IgE/IgG-mediated immunity-related genes. In conclusion, SFTPC upregulation is associated with disease progression and patient survival outcomes, possibly through enhancing ATP overproduction and suppressing antitumor immunity.

Background:Cystatins, encoded by the CST gene family, are a superfamily of cysteine protease inhibitors involved in a wide array of biological functions, including immune modulation and antimicrobial defense. Cystatin proteins are implicated in tumor progression through multiple mechanisms. However, their roles in bladder cancer remain poorly understood. Objective:This study examined the expression profiles of the cystatin family genes and analyzed their correlation with clinicopathological parameters using the Cancer Genome Atlas Bladder Cancer RNA-seq dataset. Methods:The RNAseq dataset derived from the Cancer Genome Atlas project was utilized for the gene expression analysis on the XIANTAO online platform. The UALCAN online platform was used for the analysis of gene expression in molecular subgroups. The differences among various subgroups were statistically analyzed to define the significance. Results:Our results showed that CST3, CST6, CST7, CSA, and CSTB were predominantly expressed in bladder tissues. CST6, CSTA, and CSTB were upregulated, while CST3 and CST7 were downregulated in bladder cancer tissues. CST1 and CST2 were moderately expressed but significantly upregulated in malignant tissues. Specifically, malignant tissues could be effectively differentiated from benign tissues in terms of CST1 expression, with an area under the curve value of 0.904. Upregulation of CST2 was associated with multiple clinicopathological parameters, while downregulation of CST3 was correlated with unfavorable outcomes in overall survival, disease-specific survival, and progression-free survival. Further analysis revealed that CST7 expression bore an association with immune infiltration, suggesting that it plays a role in the modulation of immune cells. Conclusion:CST genes were distinctly expressed in bladder cancer with different clinical implications.

Sideroflexin (SFXN) family genes encode for a group of mitochondrial proteins involved in cellular processes such as iron homeostasis, amino acid metabolism, and energy production. Recent studies showed that they were aberrantly expressed in certain human cancers. However, there is a paucity of information about their expression in prostate cancer. In this study, we took a comprehensive approach to investigate their expression profiles in benign prostate tissue, prostate-derived cell lines, and prostate cancer tissues using multiple transcriptome datasets. Our results showed that SFXN1/3/4 genes were predominantly expressed in prostate tissue and cell lines. SFXN2/4 genes were significantly upregulated while the SFXN3 expression was significantly downregulated in malignant tissues compared to benign tissues. SFXN4 expression was identified as a diagnostic biomarker and prognostic factor for unfavorite survival outcomes. In advanced prostate cancers, SFXN2/4 expressions were positively correlated with the androgen receptor signaling activity but negatively correlated with the neuroendocrinal features. Further analysis discovered that SFXN5 expression was significantly elevated in neuroendocrinal prostate cancers. In conclusion, SFXN2/4 expressions are novel biomarkers in prostate cancer diagnosis and prognosis.

Abstract Background Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported. Methods Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results. Results Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor. Conclusions In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.