Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer deaths, with resistance to targeted therapies posing a major clinical challenge. Drug-tolerant persister (DTP) cells are key contributors to resistance, and targeting them offers new strategies to enhance existing treatments. MicroRNAs (miRNAs), particularly the tumour-suppressive miR-15/107 family, offer promise due to their ability to target multiple oncogenic pathways. This study evaluated a synthetic consensus miRNA mimic, conmiR-15/107, in NSCLC cell line models. Dose-response assays showed robust, dose-dependent growth inhibition in both EGFR-mutant (PC9) and KRAS-mutant (H358 and A549) lung adenocarcinoma cells, but not in the human bronchial epithelial cell line BEAS-2B. When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells. RT-qPCR confirmed downregulation of conmiR-15/107 targets, including MEK1, BCL2 and BRCA1, suggesting a multi-target mechanism of action. Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

To determine whether the MutT Homolog 1 (MTH1) inhibition could increase the sensitivity of Castration-Resistant Prostate Cancer (CRPC) cells to Radiotherapy (RT), as well as to determine the appropriate application time of the MTH1 inhibitor and RT to achieve optimal radiosensitizing effects. PC-3 and DU-145 cells were selected as the model cell lines for CRPC. After 24 h of incubation, the cells were treated with various doses of the MTH1 inhibitor TH287 for 72 h, during which they were subjected to Ionizing Radiation (IR) treatment at 12, 24, and 48 h after the initial drug treatment. Cell survival was evaluated through the Cell Counting Kit 8 (CCK-8) assay. Apoptotic induction and cell cycle progression were evaluated through Western Blotting (WB) and flow cytometry analyses. The CCK-8 assay revealed that the TH287 + IR combination therapy significantly inhibited PC3 and DU145 cell survival, with the most potent effects observed in the combined IR administration at 12 h (P < 0.05). Furthermore, Annexin-V/PI (Propidium Iodide) dual staining revealed that the TH287 + IR combination treatment induced apoptotic tumor cell death more effectively than either treatment alone (P < 0.05). Moreover, WB analysis revealed that the TH287 + IR combination therapy significantly altered caspase-3 expression, indicating DNA damage induction and modulation of various cell cycle-related proteins. Moreover, flow cytometry analysis revealed that the TH287 + IR treatment caused significant G2/S-phase arrest in prostate cancer cells (P < 0.05). Overall, TH287 exhibited potent radiosensitization effects for CRPC treatment, effectively killing tumor cells when administered alongside IR at 12 h after the initial drug treatment.

HIF-1α and YBX1 Mediated Up-Regulation of NonO/p54nrb in Prostate Cancer Cells.

In this study, we analyzed bioactive compounds from six edible wild mushrooms: Amanita caesarea, Amanita vaginata, Amanita rubescens, Clitocybe gibba, Laccaria laccata, and Ramaria apiculata. The fruiting bodies were used to extract the compounds using methanol. Qualitative screening revealed that anthraquinones are predominantly found in R. apiculata. The highest amounts of flavonoids and total phenols, were found in A. caesarea, (17.4 mg GAE/g and 205.0 mg GAE/g, respectively). When quantifying antioxidant activity using DPPH, no differences were observed, except in C. gibba. However, with ABTS, L. laccata showed the highest activity (402.6 ± 42.4 µM Trolox/mg). The biological activity of the fungal extracts was also evaluated. Toxicity assays on Artemia salina showed LD50 values ranging from 27.6 to 118.6 µg/mL, indicating variying levels of toxicity depending on the species. Moreover, the extracts showed cytotoxic on various cancer cell lines. Specifically, C. gibba exhibited activity against MCF-7, HCT-15, CaOV3, and HeLa cells; A. vaginata was effective against MCF-7 cells; and L. laccata showed activity against HCT-15 and PC3 cells. These findings indicate that the evaluated fungal extracts contain metabolites associated with antioxidant and in vitro cytotoxic activities. However, further chemical characterization and mechanistic studies are required before suggesting potential pharmacological applications.

RAS mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC). Direct targeting of RAS proteins remains difficult due to the lack of suitable drug-binding pockets on their surfaces. LB42708 is a potent and selective farnesyltransferase (FTase) inhibitor that disrupts RAS farnesylation and downstream signaling. This study evaluates the anti-tumor effects of LB42708 in KRAS- and HRAS-mutant NSCLC cells, as well as gefitinib-resistant PC9 (PC9GR) cells. LB42708 significantly inhibits the proliferation, migration, invasion, stemness, and clonal growth of RAS-mutant NSCLC cells, while inducing apoptosis and cell cycle arrest. The inhibitory effects are further validated in patient-derived organoids and xenograft models. Mechanistically, LB42708 suppresses FTase activity, reduces RAS protein levels through proteasome-dependent degradation, and induces caspase-3–mediated degradation of the shared α-subunit of FTase and geranylgeranyltransferase-1 (GGTase-1). Combination treatment with LB42708 and the AKT inhibitor AZD5363 (capivasertib) produces synergistic anti-tumor activity in RAS-mutant NSCLC. Moreover, LB42708 enhances the sensitivity of PC9GR cells to gefitinib. Collectively, these findings demonstrate that LB42708, alone or in combination with AZD5363 or gefitinib, represents as a promising therapeutic candidate for NSCLC harboring RAS mutations or resistant to tyrosine kinase inhibitors (TKIs). Mutations in a family of genes called RAS are among the most common causes of cancer, especially non-small cell lung cancer (NSCLC). These mutations make cancer cells grow and spread uncontrollably. Unfortunately, RAS proteins are very hard to target directly with drugs because they lack good binding sites. In this study, we tested a compound called LB42708, which blocks an enzyme known as farnesyltransferase (FTase). This enzyme helps RAS proteins attach to cell membranes, a step that is essential for their cancer-promoting activity. By inhibiting FTase, LB42708 prevents RAS from functioning properly. We found that LB42708 strongly reduced the growth, movement, and stem cell–like behavior of lung cancer cells carrying KRAS or HRAS mutations. It also caused these cancer cells to stop dividing and undergo cell death. The same effects were observed in patient-derived tumor organoids and mouse models of lung cancer. Further experiments showed that LB42708 not only blocks FTase activity but also promotes the breakdown of RAS proteins through the cell’s natural protein degradation system, while also triggering caspase-3–mediated degradation of the FTase α-subunit, a key component required for RAS activation. When used together with another drug, AZD5363 (capivasertib), which inhibits the AKT signaling pathway, LB42708 produced even stronger anti-cancer effects. It also restored sensitivity to gefitinib, a drug that many lung cancers become resistant to. Overall, our results suggest that LB42708, either alone or in combination with other targeted therapies, could be a promising new treatment option for lung cancers with RAS mutations or drug resistance.

MYC typically drives the growth of prostate cancer (PCa) cells, but its role in the PCa tumor immune microenvironment (TIME) remains unclear. In this study, we aimed to investigate the function and regulatory mechanisms of MYC in the TIME of PCa. Firstly, single-cell RNA sequencing (scRNA-seq) analysis demonstrated that the proportion of CD8+ T cells in PCa samples was significantly lower than that in paracancerous samples, whereas the proportion of M2 was opposite. Additionally, the expression levels of MYC and SIRPα were upregulated in PCa cells and macrophages, showing a gradual increase with cellular differentiation. Subsequently, MYC was shown to potentially induce M2 polarization and decrease the proportion of CD8+ T cells, an effect that may be mediated by the CD47-SIRPα interaction, as confirmed by western blotting, transwell, colony-formation, EdU, immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and flow cytometry assays. Furthermore, polarized M2 can further facilitate the proliferation and migration of PCa cells. Finally, multiplex immunofluorescence confirmed a high infiltration level of M2 macrophages in PCa tissues, whereas CD8+ T cell infiltration was conversely low. These findings may reveal a mechanism for immune evasion in PCa, highlighting the potential for developing MYC-targeted therapeutics to overcome resistance to immune checkpoint therapy in PCa.

Plant derived exosome-like nanoparticles (PELNs) are emerging as a powerful tool for treating cancers. Among them, PELNs derived from traditional Chinese medicines have shown great potential in treating various cancers. However, many Chinese medicines remain to be explored, and currently, there are no reports on the use of PELNs for treating prostate cancer. In this study, we extracted Huangqi derived exosome-like nanoparticles (HELNs) from fresh Huangqi (Astragalus membranaceus) and systematically explored the effects and mechanisms of HELNs in treating prostate cancer through an integrated approach of single-cell sequencing, 16S rDNA sequencing, and bulk-RNA sequencing. We found that HELNs demonstrated robust cytotoxic effects against prostate cancer both in vitro and in vivo. HELNs reverse the polarization of M2 macrophages, promote their M1-like polarization, and increase the abundance of anti-tumor probiotics in the gut to exert anti-tumor effects. In terms of direct effects, HELNs downregulate the expression level of GPX4 protein in prostate cancer cells, thereby inducing ferroptosis. Finally, we loaded siGPX4 into HELNs to construct a new nanoparticle siGPX4@HELNs. siGPX4@HELNs induce more pronounced ferroptosis in prostate cancer cells, achieving better therapeutic outcomes while maintaining safety.

Studies of natural products and their semisynthetic derivatives are a valuable source of therapeutic agents. The aim of this work was to obtain new 30-phosphoramidate derivatives of betulin and determine their biological potential. The synthetic approach utilized the Staudinger reaction (the introduction of a phosphoramidate group), the Steglich reaction (the introduction of an alkynyl group), and the Jones reaction (the introduction of a carboxyl group). The structures of the target compounds were determined using spectroscopic methods (1H NMR, 13C NMR, 31P NMR, and HRMS). The new derivatives were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, and HCT116 cancer cells and against normal MCF-10A cells using the MTT and SRB methods. Apoptosis studies were performed for the most active compounds (6B and 7A), potential molecular targets (AutoDock software) were identified, and lipophilicity parameters (RP-TLC method, SwissADME website) were determined. The greatest effect on apoptosis and caspase 3/7 activation was observed for the diester derivative 7A. Compound 7A showed a high lipophilicity parameter in the study group.

Background: Silver nanoparticles (AgNPs) trigger apoptosis in cancer cells, while albumin nanoparticles enable effective drug delivery. This study compares the antitumor and cytotoxic effects of albumin-coated AgNPs (AgNPs-Alb) versus AgNPs on human prostate cancer cell lines. Method: AgNPs-Alb were synthesized and tested against PC3 and LNCaP prostate cancer cell lines. Characterization via Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Ultraviolet-Visible (UV-Vis) spectroscopy confirmed their properties. IC50 values were determined using MTT assay, with apoptosis assessed by Annexin-V/PI staining. DNA cell cycle was analyzed by PI staining. Migration, proliferation, and nuclear morphology were evaluated through scratch-wound, colony-forming, and Hoechst staining assays. Gene expression of Snail, E-cadherin, VEGF-C, VEGF-A, Bcl2, Bax, and P53 was analyzed using real-time PCR. Results: The IC50 values for AgNPs and AgNPs-Alb were 48 μM and 32 μM in PC3 cells, and 110 μM and 95 μM in LNCaP cells, respectively. AgNPs-Alb significantly inhibited PC3 cell migration compared to AgNPs (p < 0.001) and Bicalutamide (p < 0.0001). In both cell lines, AgNPs-Alb significantly reduced colony formation compared to AgNPs and Bicalutamide (p < 0.05). Flow cytometry revealed a higher percentage of apoptotic cells in PC3 with AgNPs-Alb treatment compared to AgNPs and Bicalutamide. In LNCaP cells, AgNPs-Alb induced a significantly higher percentage of Sub-G1 cells. AgNPs-Alb treatment caused greater mRNA suppression of VEGF-A and a higher Bax/Bcl2 ratio in PC3 and LNCaP cells (p < 0.05). Additionally, a significant increase in P53 and E-cadherin, alongside a decrease in VEGF-C expression in LnCAP cells, was observed (p < 0.05). Conclusions: This study suggests that AgNPs-Alb have stronger anticancer and cytotoxic effects compared to AgNPs alone against PCa cell lines and higher effects were observed on PC3 cells compared to LnCAP cells.

PRAC1, which is specifically expressed in prostate, rectal, and distal colon tissues, plays a critical role in the maintenance and self-renewal of prostate epithelial stem cells. However, the role of PRAC1 in prostate cancer is unclear. In this study, we found that PRAC1 expression is upregulated in prostate cancer cells and that PRAC1 knockdown represses the proliferation of prostate cancer cells. Moreover, lysine-specific demethylase 1 (LSD1) promoted prostate cancer cell proliferation by upregulating PRAC1 expression. TAK-418, an LSD1 inhibitor, suppressed prostate cancer cell proliferation by downregulating PRAC1 expression. Our results highlight PRAC1 or LSD1 inhibition as promising avenues for prostate cancer treatment.

Due to their multifaceted biological effects, anthraquinones have attracted increasing interest as potential anticancer agents. In this study alizarin has been analyzed for its activity against cervical and prostate cancer cell models, which represent malignancies with a high global disease burden. The effects of alizarin were studied in HeLa and DU145 cell lines using both two- and three-dimensional culture systems. Morphological and ultrastructural analyses revealed changes characteristic of apoptosis, accompanied by increased caspase-3/7 activity, phosphorylation of the antiapoptotic protein Bcl-2, activation of ATM and H2A.X in response to DNA damage, inhibition of the PI3K/MAPK signaling pathway, and alterations in mitochondrial morphology associated with elevated reactive oxygen species generation. Alizarin also induced features consistent with mitotic catastrophe and modulated autophagy-related processes. A synergistic proapoptotic effect was observed when alizarin was combined with Venetoclax, a selective Bcl-2 inhibitor, resulting in enhanced cytotoxicity in both cervical and prostate cancer cell models. The antiproliferative effects of alizarin were further associated with inhibition of cell migration, reduction of the mitotic index, and alterations in cell cycle progression, including accumulation of cells in the G2/M phase. Comparable cytotoxic effects were also observed in three-dimensional spheroid cultures. Overall, these findings indicate that alizarin affects multiple cellular pathways involved in cancer cell survival and proliferation and may be of interest in the context of combination anticancer strategies, although further studies are required to clarify the underlying molecular mechanisms.

Single-cell proteomics (SCP) platforms are widely sought-after biomedical tools to complement existing omics technologies. Here, we present MiProChip, a microfluidic platform that integrates cell capture, lysis, protein digestion, tandem mass tag (TMT) labeling, on-chip pooling, and desalting a streamlined workflow for multiplexed SCP profiling. We optimized a chip-compatible TMT multiplexing protocol with a carrier-boosting strategy, enabling high-throughput operation and deep proteome coverage. MiProChip was designed to effectively reduce the mass spectrometry (MS) operation time, minimize adsorptive losses, enhance mixing, and stabilize flow for on-chip pooling, leading to a superior performance in recovery. Using PC9 and H1975 cells with a 100-cell carrier, a total of 3362 protein groups with 2775 ± 36 proteins were confidently identified across TMT-10-plex single-cell channels. Demonstration on murine colon adenocarcinoma cells identified 3199 proteins with 1669 ± 261 proteins per single cell to characterize galectin-8- and TGF-β-specific responses. Single-cell principal component analysis (PCA) showed separation of the control from treated groups, partial overlap between galectin-8 and TGF-β, and close clustering of TGF-β with the combination treatment, supporting a dominant TGF-β effect. Pathway enrichment analysis reveals their responsive pathway and distinguishes galectin-8- and TGF-β-specific responses, revealing downregulation of metastasis-related markers to support antimetastasis potential of galectin-8, which was not detected by bulk proteomic analysis. Collectively, MiProChip captured subtle proteomic heterogeneity and treatment-dependent single-cell responses, establishing a sensitive and robust platform for high-throughput SCP analysis.

Prostate cancer (PCa) remains a leading cause of cancer-related morbidity and mortality among men, necessitating the elucidation of molecular drivers behind its progression. In this study, we demonstrated that CSDE1 was upregulated in PCa tissues, and its expression was associated with poorer progression-free survival in patients with high Gleason scores. Functional analyses revealed that CSDE1 knockdown reduced PCa cell proliferation, migration, and invasion, while suppressing metabolic activity, as evidenced by reduced extracellular acidification rates (ECAR), oxygen consumption rates (OCR), and lactate production. At the mechanistic level, CSDE1 was found to be associated with RAC1 expression and RAC1-related signaling markers, accompanied by changes in MAPK pathway phosphorylation. Genetic modulation of RAC1 partially reversed the cellular and metabolic effects associated with altered CSDE1 expression, supporting a functional role for RAC1 in CSDE1-associated phenotypes. In addition, CSDE1 expression was accompanied by increased levels of the glycolytic regulators GLUT1 and LDHA, and pharmacological inhibition of MAPK signaling partially attenuated CSDE1-associated glycolytic changes. Invivo models validated the oncogenic role of the CSDE1-RAC1 axis in tumor growth. Together, these findings support CSDE1 as a key driver that enhances RAC1-mediated MAPK signaling and metabolic profiles in PCa, suggesting that CSDE1 may serve as a promising prognostic biomarker and therapeutic target.

Nanotechnology-Enhanced Costunolide Delivery: Biocompatible Nanoemulsions Demonstrate Potent Anticancer Activity Against Prostate Cancer Cells.

Over 1.4 million new cases of prostate cancer (PCa) and 375,304 deaths were recorded in 2020. Piper guineense Schum and Thonn is used to treat various diseases including cancer. Three triterpenoid saponins namely guineenosides (Guin) A, B & C were recently isolated from this plant. This study marks the initial documentation of the anticancer potential of these compounds. Anti-cell growth (MTT), proliferation (CCK-8), clonogenic assays were evaluated. Furthermore, the most potent compound (Guin-B) was investigated for its potential to induce apoptosis, inhibit cell migration/invasion as well as cell adhesion. Some key proteins in cell proliferation and migration were evaluated. Out of the 3 saponins isolated from P. guineense, Guin-B exhibited significant and concentration-dependent inhibition of PC3 (IC50 =10 µg/mL or ~ 4.82 × 10− 6 µM) and LNCaP (IC50 = 8 µg/mL or 3.86 × 10− 6 µM) cell growth and proliferation as well as a potent inhibition (p < 0.001) of PC3 cell clone formation. Guin-B induced a potent (near 50%) increment of apoptotic cell population in PC3 and LNCaP cells at both 5 and 10 µg/mL; which was accompanied by a significant increase in caspase-3 activity. Guin-B induced a potent inhibition of PC3 cell migration and invasion and an increase in adherence of PC3 cells to the extracellular collagen and fibronectin matrix. A decrease in the expression of pAKT, AKT, mTOR and VEGF proteins was noticed following the treatment with Guin-B. Guineenosides B triggers apoptosis via mitochondrial pathway and PI3K/Akt/mTOR inactivation and inhibits metastasis at a low concentration, thus encouraging future investigation of this saponin.

Therapeutic management of prostate cancer remains challenging. Prostatic artery chemoembolization (PACE), an advanced minimally invasive technique derived from prostatic artery embolization (PAE), has shown promising potential in controling tumor growth and alleviating symptoms such as hematuria and lower urinary tract obstruction in prostate cancer, and has garnered widespread attention in recent research. However, preclinical progress is hindered by the limitations of existing animal models, and the development of a simple and reliable animal model to better understand the endovascular interventional treatment of prostate cancer is necessary. To develop and characterize a novel xenograft model of human prostate cancer in the rabbit auricle as a practical platform for experimental research on endovascular embolization techniques. Fresh human PC3 cell suspension (0.1ml containing ~ 9 × 106 cells) was injected subcutaneously into each auricle of 15 immunosuppressed New Zealand white rabbits. Tumor growth was measured periodically, and volume doubling time (VDT) was calculated. Digital subtraction angiography was performed via the central auricular artery when tumors were greater than 150mm3. Subsequently, histopathological and immunohistochemical analyses were conducted. Repeated-measures ANOVA was used to assess the significance of differences in the VDT of auricle tumors within-rabbits and between rabbits. The model achieved a high tumor take-rate of 86% (26/30 auricles). Angiography revealed distinct tumor-feeding vessels and uniform ring-like staining. Histopathology confirmed invasive growth of poorly differentiated, atypical tumor cells with high mitotic activity and no obvious necrosis. Immunohistochemistry showed high Ki67 expression (82.43 ± 3.68)%, indicating active proliferation. During the exponential growth stage, the mean VDT was 6.4 ± 1.8days. Repeated-measures ANOVA revealed significant variations in VDT among the rabbit subjects (P < 0.05); moreover, the VDT did not significantly differ between the left and right ears of each rabbit (P > 0.05), thereby reinforcing the consistency of the model employed. The rabbit auricle PC3 xenograft model is a valuable preclinical platform. It effectively simulates human prostate cancer with high reproducibility and clear vasculature, providing a foundational tool for subsequent investigations into the efficacy of endovascular therapies, such as PAE and PACE.

Molecular glue degraders represent a powerful modality for targeting proteins that are refractory to traditional inhibition. However, rational design principles for molecular glue degraders remain poorly defined. Previously, we reported a chemistry-centric strategy to identify covalent degradative handles that, when appended to established ligands, convert non-degradative inhibitors into molecular glue degraders by engaging permissive E3 ligases. This effort identified a fumarate-based electrophilic handle that covalently modified the E3 ligase RNF126, enabling degradation of multiple protein targets when transplanted across diverse ligands. Despite its conceptual impact, the high intrinsic reactivity and cytotoxicity of the fumarate handle limited its translational utility. Here, we report the development of an optimized and metabolically stabilized RNF126-targeting covalent handle incorporating a trans-cyclobutane linker that exhibits reduced glutathione reactivity and diminished cytotoxicity while retaining robust degradative activity. When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

Effector kinases of the lipid second messenger diacylglycerol (DAG), including protein kinase C (PKC) and protein kinase D (PKD) isozymes, have been widely implicated in the development and progression of prostate cancer. By acting as central hubs of growth factor-mediated signaling, these kinases integrate oncogenic signals with the androgen receptor (AR) pathway, contributing to prostate tumor growth. Distinct members of the DAG-regulated kinases contribute to the acquisition of castration-resistant prostate cancer (CRPC) and bypass AR dependence, promoting the proliferative, migratory, and invasive competencies of androgen-independent prostate cancer cells. As predicted from their coupling to signaling cascades that impact gene expression, PKC/PKD isozymes control the activation of transcription factors such as NF-κB, E2F, and STAT3, and additionally regulate epithelial-to-mesenchymal transition (EMT) transcription factors in prostate cancer cells, providing an additional layer of control in invasive signaling. The aberrant expression/activation of DAG-regulated kinases during prostate cancer progression results in pronounced deregulation and rewiring of transcriptional networks associated with cell cycle control, invasiveness, and cancer cell interactions with the tumor microenvironment (TME). The multifaceted regulation of nuclear functions by these pleiotropic kinases underscores their convoluted roles in prostate cancer development and progression, offering new opportunities for therapeutic targeting.

The emergence of the neuroendocrine phenotype in castration resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive PC cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine PC (NEPC). Here, we investigated physical and molecular interactions between poorly differentiated PC cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated pre-existing human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and PC-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of CRPC-NE in transgenic PC mice. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in PC patients receiving androgen-deprivation therapy.

Ferrite nanoparticles (NPs) have emerged as promising candidates for cancer therapy. In this study, Mg-doped copper ferrite NPs, MgₓCu₁₋ₓFe2O4 (x = 0.0, 0.5, and 1.0), were synthesized via a citrate–nitrate combustion method and evaluated for their anticancer potential. Structural and morphological characteristics were analyzed using powder X-ray diffraction, field-emission scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Cytotoxicity against human cancer cell lines was assessed using MTT and flow cytometry assays, along with analyses of reactive oxygen species (ROS) generation and apoptosis. Among the compositions studied, Cu0.5Mg0.5Fe2O4 demonstrated the highest cytotoxic efficacy, with IC₅₀ values of 17.2 ± 0.15 µg/mL (PC-3) and 25.04 ± 0.28 µg/mL (Caco-2). Flow cytometric analysis revealed increased total apoptosis of 42.08% and 34.95% in PC-3 and Caco-2 cells, respectively. Gene expression analysis revealed downregulation of Bcl-2 and Cyclin D and upregulation of BAX, P53, and Caspase-3, indicating ROS-mediated mitochondria-dependent apoptosis. The enhanced anticancer activity of Cu0.5Mg0.5Fe2O4 is attributed to its optimized size, surface charge, and composition, which promote cellular uptake, ROS generation, DNA damage, and interactions with cellular components. These findings highlight the potential of mixed-metal ferrite nanoparticles as effective nanomaterial-based cancer therapeutics.