Search Results (9,428)

Background: Nutritional deterioration and systemic inflammation frequently accompany gastrointestinal cancers and may negatively affect treatment tolerance, quality of life, and clinical outcomes. This study aimed to evaluate nutritional status, dietary behaviors, inflammatory biomarkers, and multidimensional nutritional–inflammatory profiles in patients with gastrointestinal cancers within the context of tertiary prevention. Methods: A cross-sectional study was conducted among 150 patients with gastrointestinal cancers. Nutritional status was assessed using the Mini Nutritional Assessment (MNA), while dietary behaviors were evaluated using an original questionnaire. Biochemical markers, including albumin, hemoglobin, C-reactive protein (CRP), fibrinogen, and neutrophil-to-lymphocyte ratio (NLR), were evaluated in participants with available laboratory data. Exploratory hierarchical clustering analysis was performed to identify multidimensional nutritional–inflammatory profiles. Results: According to the MNA classification, 79.3% of participants were at risk of malnutrition and 2.0% were malnourished despite predominantly normal or excessive body weight. Nutritional risk was identified in 91.4% of patients with normal BMI and in 79.5% of overweight patients. Only 32.0% of patients reported receiving dietary counseling during treatment, while oral nutritional supplements and therapeutic diets were used by 40.7% and 41.3% of participants, respectively. Biochemical analyses revealed elevated inflammatory markers accompanied by reduced albumin concentration and anemia-related abnormalities. Exploratory clustering analysis suggested three distinct nutritional–inflammatory profiles (Stable/Supported, Hidden Malnutrition, and Inflammatory Deterioration), highlighting metabolic heterogeneity within the study population. Conclusions: Patients with gastrointestinal cancers frequently present nutritional risk accompanied by inflammatory activation despite preserved or excessive body weight. A multidimensional assessment integrating nutritional screening, dietary evaluation, inflammatory biomarkers, and exploratory profile-based clustering may improve understanding of nutritional heterogeneity in gastrointestinal cancer patients and may support future research on individualized nutritional assessment and supportive care. Full article

Elevated levels of vitamin B12 (B12 hypervitaminemia) greater than 1000 pg/mL can be toxic and may serve as a marker for conditions such as cancer, autoimmune inflammatory diseases, or renal or hepatic failure. B12 hypervitaminemia, a complex generated by the binding of monomeric vitamin B12 and existing immunoglobulins in serum, can be detected in most available immunoassays. The purpose of this work was twofold: firstly, to evaluate a technique such as polyethylene glycol (PEG) precipitation in samples, before vitamin B12 determination, to prove that not all cases of B12 hypervitaminemia are related to oncological pathologies or serious diseases, and secondly, to address the patient’s condition. Materials and methods: Serum samples were collected from the patient and pre-treated with PEG. Baseline vitamin B12 levels and vitamin B12 levels in the supernatant following PEG precipitation were detected by chemiluminescence. Results: Ten samples were analysed in two different laboratories, classified as public and private; in all cases, vitamin B12 levels were above 1000 pg/mL, with a mean of 2550 pg/mL (1738–3899 pg/mL). PEG precipitation resulted in an 84.25% reduction in vitamin B12 levels. Conclusions: In cases of B12 hypervitaminemia in which there is no correlation between patient clinical symptoms and detected vitamin B12 levels, the PEG immunoprecipitation test before vitamin B12 determination is a simple and low-cost laboratory technique that can be routinely used in clinical practice to determine actual vitamin B12 levels. The technique would spare patients unnecessary complementary tests and inappropriate treatments. Full article

Prostate-specific antigen (PSA) is a well-established marker for prostate cancer screening, but current ≥4 ng/mL cutoff suffers from low specificity. This study aims to demonstrate the use of a long short-term memory (LSTM) network for accurate prediction of prostate cancer risk and next sequential PSA value. Hong Kong-wide PSA test data over a 25-year period, including PSA values, time difference between PSA tests, and PSA velocity change, were retrieved for model training with variable PSA cutoffs and sequence length. A total of 1,158,915 PSA tests from 499,342 patients (including 18,629 patients with prostate cancer) were included. Models predicting the next PSA level performed well (accuracy 0.724–0.910, AUROC 0.751–0.892). For a ≥4 ng/mL cutoff, the best model was at sequence length of 4 (AUROC 0.864). Temporal prediction of PSA performance was lower (accuracy 0.739–0.811, AUROC 0.740–0.849). Prostate cancer prediction performed excellent (AUROC 0.888–0.973), the sensitivity (0.734), and specificity (0.962) were high even at the shortest sequence length and a ≥4 ng/mL cutoff (4). Utilizing PSA levels only without additional markers or clinical data, LSTM-based models accurately predicted the next PSA level with modest temporal predictions while significantly improving the specificity of prostate cancer risk prediction, demonstrating their clinical utility. Full article

Background/Objectives: Chronic ulcers are common among older and multimorbid hospitalized patients and may reflect systemic vulnerability beyond the local wound condition. Malignancy recorded among secondary diagnoses may identify patients with reduced physiological reserve and increased inpatient risk, but its prognostic significance in hospitalized chronic ulcer populations remains insufficiently characterized. This study aimed to evaluate whether malignancy coded among secondary diagnoses was associated with in-hospital mortality among adults hospitalized with chronic ulcers. Methods: This nationwide retrospective cohort study used anonymized Romanian public-hospital discharge data for adults aged ≥18 years hospitalized with chronic ulcers between 1 January 2017 and 31 December 2022. The index-episode cohort included 69,349 patients generating 116,264 hospitalizations. Exposure was defined as at least one ICD-10 C00–C97 malignant neoplasm code recorded among secondary diagnoses in the relevant analytical hospitalization. The primary outcome was in-hospital mortality. Crude and adjusted odds ratios were estimated using logistic regression models. Results: Overall, 1837 patients had C00–C97 codes recorded among secondary diagnoses, with 73 deaths. In-hospital mortality was 3.97% among exposed patients and 1.78% among unexposed patients, corresponding to a crude odds ratio of 2.28 (95% CI 1.79–2.90). After adjustment for age group, sex, admission type, chronic ulcer category, and hospitalization pattern, malignancy recorded among secondary diagnoses remained associated with mortality (adjusted OR 1.87, 95% CI 1.42–2.45; p < 0.001). Additional adjustment for the number of non-malignant secondary diagnoses yielded similar results (adjusted OR 1.88, 95% CI 1.42–2.47; p < 0.001). Conclusions: Malignancy coded among secondary diagnoses may serve as a pragmatic administrative marker of increased in-hospital mortality risk among patients hospitalized with chronic ulcers. However, residual confounding and the absence of cancer-stage information limit causal interpretation. Full article

Melanoma incidence is steadily on the rise but widespread prevention awareness and novel treatment approaches have substantially ameliorated the prognosis of the disease. Microphthalmia-associated transcription factor (MITF) is an essential transcription factor that plays a central role in the transcriptional circuitry of both normal melanocytes and malignant melanoma. Since over 30 years have elapsed since its discovery in mice, a large number of its target genes have been identified in pigment cells. Many upstream regulators of MITF have also been identified. Despite these substantial discoveries, MITF function, especially in melanomas, still remains elusive in several aspects. MITF is absolutely required for melanin formation because it transcribes virtually all genes required for the synthesis, storage, and transport of the pigment. Importantly, MITF is necessary for prevention of apoptosis in melanomas, at least at the early stages. However, in some metastases, MITF may be absent in most cells and its antiapoptotic function is evidently replaced by other proteins that not yet been fully identified. Furthermore, MITF is a specific nevus and melanoma marker, which is routinely used in immunohistochemistry, along with other markers, to distinguish pigmented and other skin lesions. In melanomas, high-MITF melanoma cell subpopulations are considered differentiated, i.e., pigmented and rapidly proliferating. In contrast, low-MITF cells proliferate slowly but are invasive with cancer stem cell-like properties. Although MITF activates mostly antiapoptotic and pro-proliferative genes, it also activates typical cell cycle inhibitors such as the p16 and p21 proteins. Here we discuss the issues of MITF multifunctionality in melanoma and associated research prospects. Full article

Cartilage oligomeric matrix protein (COMP) influences extracellular matrix remodeling. We investigated its clinical, prognostic, and immunomodulatory significance in colorectal cancer (CRC). COMP was quantified via ELISA in 107 paired CRC and normal tissues. Expression was correlated with clinicopathological features, mutational profiles, microsatellite instability (MSI), tumor-infiltrating lymphocytes (TILs), immune checkpoints, and multiplex cytokine networks. For transcriptomic validation, the FieldEffectCrc dataset was used for Gene Set Enrichment Analysis (GSEA), and The Cancer Genome Atlas (TCGA) CRC cohort for survival analysis. COMP was significantly upregulated in CRC tissues (p < 0.001) and correlated with advanced T, N, and overall pathological stages (all p < 0.05, tau = 0.18, 0.21, and 0.23, respectively). High COMP expression was linked to restricted immune infiltration (reduced stromal TILs, p < 0.05, tau = −0.23), elevated levels in microsatellite stable (MSS) compared to MSI tumors (p < 0.01), and correlated positively with immune exhaustion markers (T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), galectin-9 (GAL9), sialic acid-binding Ig-like lectin 9 (SIGLEC9)). Transcriptomic data linked high COMP to worse disease-specific and progression-free survival, and enrichment in pro-tumorigenic pathways (epithelial-to-mesenchymal transition, angiogenesis, IL-6 signaling). COMP upregulation defines an immunosuppressive microenvironment in CRC, particularly in MSS tumors. It represents an important prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance. Full article

Background: Mutations in the KRAS oncogene occur in approximately 40% of colorectal cancers, predominantly within exon 2. Non-exon 2 mutations are less common and remain poorly characterized in terms of their clinical and biological significance. Systemic inflammatory markers are well-established prognostic indicators in colorectal cancer, yet whether their prognostic value differs across KRAS mutation subtypes has yet to be defined. We aimed to characterize and compare the clinicopathological and inflammatory profiles of patients with exon 2 versus non-exon 2 KRAS-mutated colorectal cancer and evaluate their prognostic implications. Methods: This retrospective cohort study analyzed 272 patients with microsatellite stable metastatic colorectal cancer with KRAS mutations, comprising 236 exon 2 and 36 non-exon 2 cases. Clinical, molecular, and laboratory data, including baseline systemic inflammatory markers, were extracted from electronic medical records. Survival outcomes and the prognostic impact of these variables were evaluated with Kaplan-Meier curves and univariable and multivariable Cox proportional hazards regression analyses. Results: Non-exon 2 mutations were significantly more frequent in female patients (64% vs. 45%, p = 0.048) and in left-sided primary tumors (83% vs. 64%, p = 0.035). Median overall survival was 45.7 months for the non-exon 2 group compared to 32.4 months for the exon 2 cohort; KRAS mutation subtype was not significantly associated with overall survival on univariable or multivariable analysis (univariable HR 1.36, 95% CI 0.85–2.16, p = 0.2; multivariable HR 1.376, 95% CI 0.794–2.383, p = 0.255). Systemic inflammation demonstrated distinct prognostic value, with elevated white blood cells, absolute neutrophil count, platelets, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and low albumin levels demonstrating association with worse overall survival in the exon 2 cohort. Conversely, only an elevated neutrophil-to-lymphocyte ratio predicted worse survival in the non-exon 2 group. Conclusions: KRAS exon 2 and non-exon 2 mutated metastatic colorectal cancers exhibit distinct clinical and inflammatory characteristics. Systemic inflammation exerts a significantly greater prognostic impact in exon 2 disease. As the therapeutic landscape for KRAS-mutated CRC continues to evolve, these findings hold promise for informing KRAS mutation-specific approaches to patient stratification and treatment planning. Full article

Background: Immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) inhibitors such as atezolizumab, have significantly improved outcomes in cancer therapy. However, these agents may cause immune-related adverse effects, including nephrotoxicity associated with oxidative stress and cellular stress responses. This study aimed to investigate and comparatively evaluate the protective effects of adenosine triphosphate (ATP) and taxifolin against atezolizumab-induced renal tissue injury in rats. Methods: Animals were divided into four groups: healthy (HG), atezolizumab (ATZ), ATP + atezolizumab (ATAZ), and taxifolin + atezolizumab (TXAZ). ATP (4 mg/kg, i.p.) and taxifolin (50 mg/kg, oral) were administered for six days, while atezolizumab (10 mg/kg, i.p.) was given on days 1 and 4. On day 7, renal tissues were collected for biochemical, histopathological, and double immunofluorescence analyses. Results: Atezolizumab significantly increased malondialdehyde (MDA) levels and decreased total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) levels, indicating enhanced oxidative stress and impaired antioxidant defense. These changes were accompanied by tubular degeneration and increased expression of apoptotic markers. Both ATP and taxifolin significantly ameliorated these alterations; however, ATP demonstrated a more pronounced protective effect. Conclusions: In conclusion, ATP and taxifolin attenuated the biochemical, histopathological, and immunofluorescence alterations associated with atezolizumab administration. ATP exhibited a more pronounced protective effect than taxifolin under the conditions of this experimental model. Nevertheless, further experimental studies are required to elucidate the mechanisms underlying these effects. Full article

Characterized by its highly aggressive behavior and propensity for metastasis, osteosarcoma remains a formidable clinical challenge with restricted treatment modalities. Cancer stem-like cells (CSCs) are widely recognized as central orchestrators of oncogenic progression and therapeutic intractability; however, the precise epigenetic regulations governing these processes are yet to be fully elucidated. Here, we investigated the role of the long non-coding RNA DANCR in regulating osteosarcoma stemness. DANCR expression was significantly upregulated in human osteosarcoma tissues and positively correlated with the stemness markers CD133, SOX2, and CD90. Functional assays demonstrated that DANCR overexpression enhanced stem-like properties, including an enriched CD133+/CD44+ cellular fraction and enhanced spheroid-forming capacity, concurrently accelerating in vitro cellular proliferation, migration, and invasive potential. In a xenograft mouse model, DANCR upregulation promoted in vivo tumor growth and lung metastasis. Mechanistically, dual-luciferase reporter assays and RNA immunoprecipitation (RIP) revealed that DANCR acts as a competing endogenous RNA (ceRNA) by sponging miR-145-5p, thereby facilitating the de-repression of CD133 and contributing to Akt/mTOR signaling activation. In addition, DANCR/miR-145-5p modulation was associated with changes in autophagy-associated markers. Collectively, these findings identify the DANCR/miR-145-5p/CD133 axis as a regulator of osteosarcoma stemness and progression, providing new insights into tumor biology and highlighting a potential molecular target for therapeutic investigation. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) are regulatory transcripts that contribute to diverse cellular processes and are increasingly recognized for their involvement in human diseases including cancer. In this context, long intergenic non-protein-coding RNA 1770 (LINC01770), also known as RRFERV, has been involved in nasopharyngeal cancer progression. However, its role in breast cancer (BC) remains unexplored. Here, we propose that LINC01770 plays a pivotal role in the development of aggressiveness traits such as invasion, migration, stemness, and tumorigenesis in BC cells. Methods: The LINC01770 overexpression was performed in BC cells using lentiviral transduction. Stemness and epithelial–mesenchymal transition markers, CD133⁺/44⁺ populations, cell migration, cell invasion, tumorigenesis in vitro, and chemoresistance were subsequently assessed via quantitative reverse transcription polymerase chain reaction (RT-qPCR), flow cytometry, Boyden chambers, soft agar, and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays, respectively. LINC01770 expression in BC tissues and mechanistic analyses were performed in silico. Results: LINC01770 promotes cell migration and invasion accompanied by increased expression of EMT-associated genes. Moreover, elevated LINC01770 levels lead to an expansion of CD133⁺/CD44⁺ cell populations and upregulation of stemness-related genes as well as increase tumorigenic capacity in vitro. In contrast, no significant effects on drug resistance were observed. Finally, bioinformatic analyses suggest a putative LINC01770/miR-335-5p/OCT4 regulatory axis, consistent with the observed increase in OCT4 expression after LINC01770 overexpression. Conclusions: Our findings demonstrate that LINC01770 drives BC progression by promoting migration, invasion, and stemness features via the miR-335-5p/OCT4 axis. To our knowledge, this is the first study identifying LINC01770 as a potential therapeutic target in BC. Full article

Background/Objectives: Glioblastoma remains the most aggressive and lethal form of brain cancer, with no effective cure to date. The molecular mechanisms sustaining its development and relentless proliferation are still not fully understood. SETMAR, a protein lysine methyltransferase involved in various DNA repair and chromatin processes, has been reported as dysregulated in several cancers, including glioblastoma. Interestingly, S-SETMAR, a shorter isoform of SETMAR, has been suggested to antagonize the oncogenic properties of the full-length protein. Here, we explored the cellular and molecular consequences of S-SETMAR overexpression in glioblastoma cells. Methods: We compared native glioblastoma cells (8MGBA) with a recombinant 8MGBA line stably over-expressing αS-SETMAR, a stable form of S-SETMAR, using complementary cellular and molecular approaches. Results: Overexpression of αS-SETMAR markedly prolonged the cell cycle duration (from 27 to 37 h), leading to a significant decrease in cell proliferation. Unexpectedly, αS-SETMAR triggered genomic alterations characterized by an increased DNA content and extensive chromosomal instability, including aneuploidy, chromoanasynthesis-like rearrangements, and tripolar mitoses. Moreover, αS-SETMAR-expressing cells displayed heightened sensitivity to stress conditions mimicking chemotherapy and radiotherapy, resulting in increased apoptosis. Conclusions: Our findings identify αS-SETMAR as a dual modulator of glioblastoma cell fate—simultaneously slowing proliferation and promoting chromosomal instability while enhancing vulnerability to genotoxic stress. These results suggest that αS-SETMAR could serve as both a prognostic marker and a potential therapeutic tool in glioblastoma management. Full article

Background/Objectives: Non-muscle invasive bladder cancer (NMIBC) is characterized by high recurrence rates despite appropriate treatment and surveillance. Identifying inexpensive and readily available biomarkers capable of improving risk stratification remains an important clinical challenge. The platelet-to-lymphocyte ratio (PLR), a marker of systemic inflammation, has emerged as a potential prognostic indicator in several malignancies. This study aimed to evaluate the association between preoperative PLR, tumor recurrence, and recurrence-free survival (RFS) in NMIBC patients treated with intravesical Bacillus Calmette–Guérin (BCG) or thermochemotherapy. Methods: This retrospective study included 153 patients diagnosed with NMIBC between January 2020 and January 2024. All patients underwent transurethral resection of bladder tumor (TURBT) followed by intravesical BCG (n = 123) or thermochemotherapy (n = 30). Preoperative PLR was calculated from complete blood counts obtained before surgery. Receiver operating characteristic (ROC) analysis was used to determine the optimal PLR cut-off value. Recurrence-free survival was evaluated using Kaplan–Meier survival analysis and Cox proportional hazards regression models. Results: During a mean follow-up period of approximately 19 months, recurrence was observed in 35.8% of patients treated with BCG and 30% of those treated with thermochemotherapy. ROC analysis demonstrated good discriminatory ability for recurrence prediction (AUC = 0.831, 95% CI: 0.761–0.901, p < 0.001) and identified an optimal PLR threshold of 120. Patients with elevated PLR values demonstrated higher recurrence rates and shorter recurrence-free survival. Kaplan–Meier analysis revealed a clear separation of survival curves according to PLR status. In multivariable Cox regression analysis, PLR > 120 remained independently associated with recurrence-free survival in the BCG group (HR = 2.703, 95% CI: 1.118–6.534, p = 0.027), whereas only a borderline association was observed in the thermochemotherapy group (HR = 23.265, 95% CI: 0.952–568.336, p = 0.054). Conclusions: Elevated preoperative PLR was associated with recurrence and recurrence-free survival in patients with NMIBC. The prognostic value of PLR appeared to be more pronounced in patients receiving intravesical BCG therapy. Given its low cost, accessibility, and ease of calculation, PLR may serve as a useful adjunctive biomarker for clinical risk stratification when used alongside established clinicopathological prognostic factors. Further prospective multicenter studies are required to validate these findings. Full article

CD8⁺ T-cell exhaustion is a key mechanism of tumor immune evasion and a major limitation of current cancer immunotherapy. However, the molecular factors sustaining dysfunctional CD8⁺ T-cell states across cancers are not fully understood. Here, we identify GPR171 as a common feature of exhausted CD8⁺ T cells across multiple solid tumors based on integrated pan-cancer single-cell transcriptomic analyses. GPR171 is enriched in exhausted CD8⁺ T cells and is closely associated with immunosuppressive and exhaustion-related gene programs. It also shows a strong association with key immune regulatory genes such as CTLA4 and NR4A2. Functional analyses suggest that reduced GPR171 activity is associated with decreased expression of exhaustion-related genes and a shift toward cytotoxic and immune-activating programs. In parallel, a CREM-centered regulatory network emerges in exhausted CD8⁺ T cells and may act in concert with GPR171-associated programs to reinforce dysfunctional states. Overall, our results identify GPR171 as a candidate marker of CD8⁺ T-cell dysfunction across cancers and provide a systematic pan-cancer single-cell characterization of its association with immunosuppressive T-cell states, supporting its potential as a therapeutic target for restoring antitumor immunity. Full article

Introduction: Cutaneous T cell lymphoma (CTCL), most commonly known as mycosis fungoides (MF), is characterized by an increasingly immunosuppressive tumor microenvironment (TME) as the disease progresses. Cancer-associated fibroblasts (CAFs) are key stromal components that support a permissive niche, in part through the secretion of small extracellular vesicles (sEVs), predominantly exosomes, that mediate intercellular communication. We investigated the immunomodulatory role of exosome-enriched sEVs derived from MF fibroblasts (MF-Fs) compared to normal fibroblasts (N-Fs). Materials and Methods: Primary MF-Fs from early-stage MF biopsies and N-Fs from healthy skin were cultured in vitro. sEVs enriched with exosomes were isolated by ultracentrifugation and characterized by flow cytometry (CD81), electron microscopy, Nanosight analysis, and protein quantification, and their uptake by normal peripheral blood mononuclear cells (nPBMCs) was confirmed using PKH26-labeled sEVs. nPBMCs, monocytes, CD4⁺ and CD8⁺ T cells from healthy donors were exposed to MF-F or N-F sEVs. Cell viability was assessed using MTT and trypan blue exclusion assays. Mass cytometry (CyTOF) profiled immune subsets and regulatory proteins for preliminary observation. Monocyte polarization was evaluated by flow cytometry for M1 (CD80, CD86) and M2 (CD163, CD206) markers and PD-L1 expression; M1/M2-associated cytokines and sEV-microRNAs were quantified by qRT-PCR. Results: Both MF-F and N-F sEVs were internalized by nPBMCs and reduced their viability, with a more pronounced effect observed for MF-F sEVs. In nPBMCs, MF-F sEVs also increased the frequency of M2-like macrophages, decreased M1 polarization, and enhanced PD-L1 expression. In primary monocytes, MF-F- compared with N-F-derived sEVs upregulated M2-associated cytokines (IL-10, TGF-β), increased PD-L1 expression, and generated M2-like cells that suppressed CD4⁺ and CD8⁺ T cell viability. Conclusions: MF-F sEVs promote an immunosuppressive TME and represent potential therapeutic or biomarker targets in MF. Full article

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is the major form of resistance to androgen receptor signaling inhibitors (ARSI) in advanced prostate cancer, characterized by pronounced invasiveness and lineage plasticity. Through in-depth analysis of prostate cancer cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient-derived xenografts (PDX), and NEPC patient samples. Their expression positively correlates with neuroendocrine markers and inversely correlates with androgen receptor (AR) activity. Additionally, functional analyses indicated that AR has a direct transcriptional inhibitory effect on GRIK2 and GRIK5, and the absence of AR signaling leads to the upregulation of GRIK2 and GRIK5. Further RNA sequencing analysis revealed that GRIK5 silencing reprograms the cellular transcriptome, resulting in significant downregulation of AR signaling and fatty acid metabolism, while simultaneously activating immune and inflammatory responses in enzalutamide-resistant prostate cancer cells. In both cell line and NEPC PDX organoid models, loss of GRIK5 impaired proliferation and clonogenic growth. Notably, GRIK5 also contributes to enzalutamide resistance. Pharmacological evaluation revealed that Pan-GRIK antagonists exhibit anti-tumor activity, although the required relatively high concentrations suggest that more potent therapeutic strategies should be developed. Collectively, this study establishes that GRIK family members play critical roles in enzalutamide resistance and NEPC progression, highlighting GRIK signaling as a potential therapeutic target for overcoming lineage plasticity in prostate cancer. Full article