Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. Recent metabolomics studies have revealed pathogenic mechanisms and provided new perspectives for diagnosis. This study aimed to analyze plasma metabolic alterations and construct a preliminary diagnostic model for HCM based on untargeted metabolomics and machine learning (ML) algorithms, in order to explore potential pathogenic pathways and improve diagnostic accuracy during screening. A total of 76 HCM patients and 35 normal participants were consecutively recruited from August, 2023 to December, 2023. Data were split into discovery and validation sets at a ratio of 7:3 and the feature combinations were selected using support vector machine (SVM) and random forest (RF). Stepwise multivariate linear regression analysis was performed to identify key metabolites associated with left ventricular wall thickness. Metabolic pathway analysis was performed using KEGG. Totally 1481 metabolites were identified with 640 differential metabolites and 240 significant differential metabolites. Multivariate statistical analysis showed that metabolism results could effectively differentiate the two cohorts (OPLS-DA positive ion mode R2Y = 0.744, Q2 = 0.456; negative ion mode R2Y = 0.611, Q2 = 0.441). SVM and RF screened the same combination of features including 7-keto-8-aminopelargonic acid (KAPA), γ-linolenoyl ethanolamid, nitrilotriacetic acid, D-quinovose and N-acetyl-l-aspartic acid (NAA), which could effectively and accurately differentiate HCM patients from normal participants (in discovery and validation sets, the SVM model AUROC was 0.996 and 0.985 with accuracies of 96.1% and 97.1%, respectively; the RF model AUROC was 1.000 with accuracies of 94.8% and 100.0%, respectively). In metabolic pathway analysis, central carbon metabolism in cancer and protein digestion and absorption were significantly upregulated in HCM patients, which were connected by alanine, aspartate and glutamate metabolism. Stepwise multivariate linear regression analysis revealed that NAA was correlated with left ventricular mass index and RV5+SV1 (P < 0.05), which may be the central target of the connecting pathway. Plasma metabolite diagnostic model including KAPA, γ-linolenoyl ethanolamid, nitrilotriacetic acid, D-quinovose and NAA can effectively and accurately screen HCM patients. Metabolomics combined with ML algorithm showed that alanine, aspartate and glutamate metabolism may be the pathogenic pathway leading to the occurrence of HCM with NAA as the central target.

For double-strand breaks (DSBs) formed by radiation, onset of 5' to 3' end resection is a deciding factor in repair pathway choice, favoring homologous recombination (HR) over non-homologous end-joining (NHEJ). Studying HR-proficient MCF7 breast cancer cells, we confirmed a role for PARP1 in promoting DSB repair and limiting resection stress and identify the hexosamine biosynthetic pathway (HBP)-dependent post-translational modification O-GlcNAcylation as an independent regulator. Using pharmacological and genetic perturbations of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), we showed that O-GlcNAcylation can limit end resection as measured by BrdU and RPA staining, recruitment of HR proteins BRCA1 and RAD51, and accumulation of cytosolic DNA in S/G2-phase cells. These effects were independent of PARP1 but required the histone methyltransferase EZH2. Loss of OGT or EZH2 phenocopied PARP inhibition, leading to hyperresection after irradiation. The OGA inhibitor PUGNAc suppressed hyperresection due to PARP1 knockout while PARP inhibitor veliparib exacerbated defects in OGT- or EZH2-deficient cells. In each case, increased resection correlated with cytosolic DNA accumulation, suggesting a link to inflammatory signaling. These findings implicate the Warburg effect, via the HBP and O-GlcNAcylation, in favoring NHEJ over HR and suggest that disrupting EZH2 may sensitize HR-proficient tumor cells to radiation via resection-dependent mechanisms. Our results highlight the potential of targeting cancer-associated metabolic reprogramming to overwhelm HR repair and drive resection stress. Combining PARP inhibition with blockade of O-GlcNAcylation or EZH2 may offer a strategy to radiosensitize proliferating, HR-proficient cancers while sparing non-cycling normal tissues.

Abstract: Mitochondrial dysfunction and the Warburg effect, characterized by aerobic glycolysis, are hallmarks of cancer metabolism, facilitating tumor progression and resistance to therapies. These metabolic shifts allow cancer cells to prioritize glycolysis over oxidative phosphorylation, contributing to rapid proliferation, immune evasion, and metastasis. This review explores the intricate regulation of the Warburg effect by enzymes, transcription factors, and non-coding RNAs. Key players, such as hexokinase, pyruvate kinase M2, and glucose transporters, are discussed as central drivers of glycolysis. This review highlights therapeutic strategies targeting these pathways, including small-molecule inhibitors, combination therapies, and traditional medicines. Advanced diagnostic tools, such as FDG-PET imaging and metabolic profiling, are evaluated for their potential to personalize cancer treatment. The role of synthetic lethality, immunotherapy, and novel drug combinations in addressing metabolic vulnerabilities is also examined. Furthermore, the review underscores the impact of metabolic reprogramming on the tumor microenvironment and its implications for immune modulation. Targeting the Warburg effect presents a promising avenue for overcoming drug resistance and enhancing cancer therapy. This review provides a comprehensive framework for integrating metabolic reprogramming into advanced therapeutic and diagnostic strategies, paving the way for personalized cancer treatment approaches.

Computational studies of target-specific radiopharmaceuticals for theranostics.

Cellular metabolism has emerged as a pivotal factor influencing the viability and functionality of cancer cells. To satisfy their substantial anabolic requirements, tumor cells adopt a distinct metabolic reprogramming divergent from that of non-transformed somatic cells. This review aims to examine metabolic reprogramming in head and neck squamous cell carcinoma (HNSCC), examining its role as a fundamental aspect of cancer progression and resistance to treatment. The article systematically summarizes the key mechanisms of metabolic reprogramming in HNSCC, including enhanced glycolysis, remodeling of amino acid metabolism, and dysregulation of lipid synthesis, and discusses how these metabolic pathways facilitate tumor proliferation and metastasis by influencing the microenvironment, antioxidant defenses, and resistance to ferroptosis. Additionally, the review examines the dynamic interactions between metabolic reprogramming and the tumor microenvironment, particularly focusing on HIF-1α-driven metabolic adaptation and immune evasion mechanisms under hypoxic conditions. Finally, the potential of metabolic-targeted therapies is discussed, highlighting future research directions and their applications in personalized treatment strategies.

ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway.

Tumor-activated nanocomplex reprograms cancer and macrophage metabolism in opposite directions to overcome immune suppression.

Early diagnosis of cancer is essential for improving patient outcomes. Metabolomics analysis has shown promise in detecting cancer and distinguishing its metastatic burdens in previous studies. We hypothesized that metabolomics data can differentiate between people with and without cancer at a population level, uncovering new biomarkers and deepening our understanding of cancer metabolism. A total of 1,386 metabolites were measured by two commonly used metabolomics platforms: Nightingale and Metabolon, in baseline plasma samples from participants in the population-based Rotterdam Study, with sample sizes of 2,538 and 5,057, respectively. Logistic regression and competing risk Cox proportional hazards models were employed to examine associations between these metabolites and both baseline prevalent and incident during follow-up of all and cause-specific cancers. Statistical significance was defined by a false discovery rate (FDR) < 0.05. There were 654 cancer cases at baseline, and 618 new cases also occurred during follow-up of nearly 10 years. In the cross-sectional study, 68, 7, and 10 metabolites were significantly associated with prevalent blood, colorectal, and all cancer, after multivariate adjustment. In the longitudinal study, 19, 11, 2, 3, and 1 metabolites were significantly associated with incident blood, colorectal, lung, prostate, and all cancer, respectively. Among these, 17 and 2 metabolites were associated with both prevalent and incident blood and colorectal cancer. This study indicates several circulating metabolites that are associated with different cancers. These metabolites may contribute to better understanding of the metabolic pathways of cancer and serve as biomarkers for early cancer diagnosis.

Bladder cancer persists as a formidable clinical challenge due to its high recurrence rate, intrinsic chemoresistance, and suboptimal immunotherapy response. Copper-based nanomaterials have emerged as promising therapeutic platforms leveraging distinctive copper redox biology and tumor vulnerabilities to copper-induced cell death mechanisms-particularly cuproptosis. This review systematically analyzes dysregulated copper metabolism in bladder cancer and its mechanistic roles in mediating oxidative stress, ferroptosis, and cuproptosis, while classifying four principal nanomaterial categories: metallic Cu structures, copper-based polymers, copper-based compounds, and copper composites-highlighting their synthesis strategies, physicochemical properties, and therapeutic applications. These platforms facilitate photothermal, photodynamic and chemo-/immunotherapeutic synergies through precise modulation of redox homeostasis and tumor immunity. Despite these advances, key clinical translation barriers including biosafety concerns, pharmacokinetic variability, targeting inefficiency, immune unpredictability, and regulatory hurdles are critically examined. Future directions propose physics-informed material design, biomarker-guided patient stratification, and integrated therapy-monitoring platforms, demonstrating copper-based nanomedicine's significant potential to redefine precision intravesical therapy through mechanistically tailored, translationally optimized strategies.

Mebendazole impairs the expression and function of enzymes in nucleotide metabolism pathways, leading to Selective Cytotoxicity, Cell Cycle Arrest, and Damage to Cell Morphology in Gastric Cancer.

Abstract Background: Tryptophan (Trp), an essential amino acid, is metabolized through the kynurenine, indole, and serotonin pathways. Imbalances in Trp metabolism have been implicated in cancer progression. However, clinical trials targeting indoleamine-2,3-dioxygenase (IDO), a key enzyme in Trp catabolism, have yielded unsatisfactory results, prompting the exploration of alternative therapeutic targets within the Trp metabolic network. Emerging evidence discovers that several Trp-derived metabolites can bind to and activate the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor that is essential in immune response and tumorigenesis. Although AhR is widely expressed in various breast cancer subtypes, its precise role in breast cancer development remains unclear, likely due to disease complexity and the diversity of AhR ligands. Thus, investigating Trp metabolism in relation to AhR activation may provide novel insights into the role of Trp-activated AhR pathway in breast cancer progression. Methods: Clinical data and serum samples were collected from patients with breast cancer (n = 13) and age-matched individuals with breast fibroadenoma (n = 9). Eighteen Trp metabolites were quantified using Ultra-High Performance Liquid Chromatography (UHPLC). Metabolite levels were normalized using Z-score transformation and visualized via heatmap. Hierarchial clustering was performed to assess sample grouping. AhR mRNA expression levels were compared between primary breast cancer tissues (n = 1111) and benign tissues (n = 113) by retrieving RNA-sequencing data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma cohort. Results: Differential levels of Trp metabolites were identified between breast cancer and fibroadenoma groups, with Trp, cinnavalininate, 5-hydroxyindole-3-acetic acid and picolinic acid showing the most significant differences. Heatmap visualization revealed distinct Trp metabolite profiles across all samples. Hierarchical clustering showed partial segregation between the breast cancer and fibroadenoma groups. Analysis of TCGA data demonstrated significantly reduced AhR mRNA expression in breast cancer tissues compared to benign tissues. Conclusion: Trp metabolism is disrupted in breast cancer. The partial clustering of breast cancer and fibroadenoma samples reflects both the biological heterogeneity of breast cancer and the overlapping metabolic features between the two groups. The observed alterations in Trp metabolism, along with reduced AhR expression in breast cancer compared to benign tissues, suggest that impaired Trp-activated AhR signaling may play a critical role in breast cancer pathogenesis. These findings support further investigation into the Trp-activated AhR pathway as a potential therapeutic target in breast cancer management. Citation Format: Y. Wu, K. Wang, Z. Li. From Metabolites to Mechanisms: Linking Tryptophan Metabolism and AhR Activation in Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-17.

This study aimed to investigate characteristic changes in the upper respiratory tract (URT) microbiome and metabolome in children with asthma and explore their associations with lung function. Children with asthma aged 6 years and above admitted to the Children's Hospital of Soochow University from December 2022 to December 2023 comprised the study group. Age-matched healthy children undergoing physical examinations in the Department of Child Health were recruited as controls. Throat swabs were collected for microbiome detection using 16S rDNA sequencing and metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). (1) Significant differences in alpha and beta diversity were observed among the control group (H), chronic persistent asthma group (CA), and acute exacerbation group (AA). In both CA and AA groups, FVC% predicted (FVC%/Pred) and FEV1% predicted (FEV1%/Pred) were negatively correlated with URT microbiota abundance. Actinobacillus abundance was positively correlated with FEV1%/Pred, FEV1/FVC, FEF25%/Pred, FEF50%/Pred, and FEF75%/Pred. (2) Metabolite differences between CA and AA groups were analyzed, and the top 5 differential metabolites were evaluated for their accuracy as asthma assessment biomarkers. L-carnitine showed an AUC > 0.9, with a sensitivity of 85.7% and specificity of 85%. Other differential metabolites, including monoisobutyl phthalate, 4-hexyl-2,5-dimethyloxazole, and dibutyl phthalate, correlated with several lung function indices. The most relevant differential metabolic pathways included arginine biosynthesis, alanine-aspartate-glutamate metabolism, central carbon metabolism in cancer, and D-amino acid metabolism. The URT microbiota in asthmatic children exhibits alterations in composition, structure, and diversity, with lower diversity in acute asthma compared to chronic persistent asthma. At the genus level, some microbiota (Actinobacillus, Fusobacterium) were correlated with FEV1%/Pred, FEV1/FVC, FEF25%/Pred, FEF50%/Pred, FEF75%/Pred. The differential metabolite L-carnitine may be a potential biomarker for asthma assessment.

Abstract Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Monocarboxylate transporter 4 (MCT4) is a key lactate efflux transporter involved in cancer metabolism. However, the mechanistic role of MCT4 in TNBC progression and its potential as a therapeutic target remain unclear. Methods: MCT4 expression was analyzed in TNBC patient tissues and correlated with clinical outcomes. MDA-MB-231 cells were subjected to hypoxia treatment and paclitaxel (PTX) exposure. MCT4 was knocked down using siRNA. Cell proliferation, invasion, migration, and PTX sensitivity were assessed. In vivo xenograft experiments were performed to evaluate tumor growth and drug response. RNA-sequencing and KEGG pathway analysis were conducted. Lactate secretion and glucose uptake were measured. Western blot analysis examined MAPK pathway proteins and histone modifications. CUT&amp;Tag sequencing analyzed histone H3K9 lactylation changes and associated gene transcription. Results: MCT4 was significantly overexpressed in TNBC tissues and high expression correlated with poor patient prognosis. Both hypoxia and PTX treatment upregulated MCT4 expression in MDA-MB-231 cells. MCT4 knockdown markedly inhibited cell proliferation, invasion, and migration while enhancing PTX sensitivity. In vivo xenograft studies confirmed that MCT4 knockdown significantly retarded tumor growth and increased PTX sensitivity. RNA-sequencing revealed that MCT4 knockdown dramatically downregulated MAPK signaling pathway. Metabolically, MCT4 knockdown reduced both lactate secretion and glucose uptake. Western blot analysis confirmed that MCT4 knockdown decreased MAPK pathway-related proteins. Under hypoxic conditions, RNA-sequencing showed MAPK pathway activation, which was accompanied by increased histone lactylation levels and H3K9 lactylation. MCT4 knockdown reversed these histone modifications. CUT&amp;Tag analysis revealed that hypoxia-induced H3K9 lactylation promoted transcription of MAPK pathway genes. Notably, MCT4 was not identified among the genes with increased H3K9 lactylation-mediated transcription, suggesting that MCT4 functions as an upstream regulator of histone lactylation rather than a downstream target, establishing a direct mechanistic link between lactate metabolism and gene regulation. Conclusions: This study demonstrates that MCT4 promotes TNBC progression through a novel lactate-histone lactylation-MAPK axis. MCT4 facilitates lactate production and efflux, which drives histone H3K9 lactylation and subsequent activation of MAPK signaling genes, ultimately enhancing cancer cell aggressiveness and chemoresistance. Our findings are validated both in vitro and in vivo, providing strong mechanistic evidence for MCT4 as a therapeutic target in TNBC. Clinical Relevance: MCT4 represents a promising biomarker for TNBC prognosis and a novel therapeutic target. Targeting MCT4-mediated lactate metabolism could enhance chemotherapy efficacy and improve clinical outcomes in TNBC patients. This metabolic-epigenetic crosstalk mechanism opens new avenues for combination therapy strategies. Citation Format: Y. Peng, Q. Luo, S. Liu. Mct4 drives triple-negative breast cancer progression via lactate-induced histone lactylation and mapk pathway activation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-10.

Abstract Breast cancer is the most commonly diagnosed type of cancer worldwide in women. Estrogen receptor alpha (ERα), a well-studied transcription factor, is the major oncogene in over 70% of breast cancer cases. The majority of earlier studies have primarily focused on ERα transcriptional activity that promotes tumor progression. We discovered that ERα is a non-canonical RNA-binding protein that associates with over 1,000 mRNAs, mainly through their 3’-untranslated regions (UTRs), in breast cancer cells. Interestingly, recent studies have shown that a broad spectrum of transcription factors (TFs), including ERα, directly bind RNA; yet, how this association directly orchestrates gene expression remains largely unexplored. This led us to ask an outstanding question about the functional role of oncogenic ERα on RNA metabolism in breast cancer. Since the 3’-UTR is a molecular hub where cis and trans-regulatory elements converge to determine mRNA fate, we hypothesized that oncogenic ERα regulates the stability of a set of mRNAs by binding to its 3’-UTR, which in turn affects the downstream gene expression program that promotes breast cancer progression. To address this question, we performed SLAM-seq, a genome-wide approach for characterizing mRNA stability in MCF7 WT cells and MCF7 cells harboring an ER⍺ RNA binding domain mutation (ER⍺ RBDM). We found that the stability of a subset of ERα mRNA targets is decreased upon loss of ERα RNA-binding activity. We then focused on a critical oncogenic mRNA, NSUN2, an enzyme that catalyzes the 5-methylcytosine (m5C) modification on mRNA, which is an ERα target. NSUN2 is a m5C writer protein, a well-studied RNA methyltransferase enzyme, and is significantly upregulated in breast cancer. Interestingly, survival analysis shows that high NSUN2 correlates with poor prognosis in ER-positive breast cancer patients, but not in ER-negative patients. We show that ER⍺ WT strongly binds to the 3’UTR of NSUN2 mRNA, whereas the ER⍺ RNA binding mutant (ER⍺ RBDM) doesn’t bind to NSUN2 3’UTR. Strikingly, we observed that the loss of ERα RNA binding destabilizes NSUN2 mRNA and protein levels. Furthermore, we found that global RNA m5C methylation is significantly downregulated in breast cancer cells expressing the ERα RBD. Notably, ERα RBDM cells are impaired in forming tumors in vivo, and this phenotype is rescued by overexpressing NSUN2. This suggests the existence of ERα-mediated epitranscriptomic marks via NSUN2 in breast cancer progression. Citation Format: N. Mohan, A. Dabrowska, V. Subramanyam, I. Liu, D. Kuzuoglu-Öztürk, D. Ruggero. Oncogenic er alpha as an rna-binding protein controls mrna stability and epitranscriptome of breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-26.

Abstract Glucocorticoids promote metabolic reprogramming associated with enhanced proliferation of rat mammary gland cancer cells Exposure to chronic stressors can have a significant role in both disrupting normal mammary gland development as well as potentially negatively impacting the breast cancer outcome. Glucocorticoids (GCs) are stress responsive steroid hormones that mediate cellular and physiological stress responses via activating the GC receptor (GR). While several studies have sought to understand how prolonged physiological GC exposure and GR stimulation negatively impact mammary gland health and breast cancer outcomes, much work remains to be done. We used the rat mammary gland (MG) adenocarcinoma LA7 cell line, a rat MG cancer cell line derived in vitro from an in vivo DMBA carcinogen-induced mammary tumor; to begin to uncover how chronic stress hormones might affect metabolism and energy production in MG epithelial cancer as well as elucidate the molecular mechanisms underlying these effects. LA7 cells were treated either with or without 140nM (high physiological level) of the rat GC corticosterone for 0-72 hours to mimic acute to chronic stress exposure. RNA-Seq results from the LA7 cells demonstrated that under conditions of corticosterone-induced GR stimulation there was a significant increase in expression of mitochondrial-encoded genes such as MT-ND1, MT-CO1, and MT-ATP6, suggesting an unexpected rise in mitochondrial biogenesis. In addition, several nuclear genes encoding proteins involved in mitochondrial metabolism including Isocitrate Dehydrogenase and Succinate Dehydrogenase were also upregulated. We then asked whether these metabolic gene expression changes accompanied expected cell phenotypic changes. MitoTracker Green and Red staining was used to measure mitochondrial number/mass and mitochondrial membrane potential (MMP), respectively. These experiments confirmed that both mitochondrial number/mass and MMP was significantly upregulated by chronic GR activation with GC exposure. In agreement with the MMP staining data, intracellular ATP abundance was shown to be significantly upregulated by chronic GR activation. Using a Seahorse XF Mito-Stress test we observed metabolic reprogramming showing that chronic GR activation promoted significant elevation in basal, ATP-linked, and spare capacity respiration/oxidative phosphorylation (OXPHOS). Because OXPHOS activity is integrally linked to the process of glucose metabolism, we sought to determine if chronic GR activation in the LA7 cells impacts glycolysis. To do this we performed a Seahorse XF Glycolysis Stress test, as well as measured glucose uptake and lactate secretion. The Seahorse XF Glycolysis Stress test revealed an increase in basal glycolysis and glycolytic capacity in the LA7 cells. In parallel, both glucose uptake and lactate production and secretion were also elevated. Lastly, a cellular proliferation assay showed increased cell division following chronic stress hormone exposure. Overall, these observations suggest that in addition to upregulating mitochondrial biogenesis, OXPHOS, and glycolytic activity, corticosterone can contribute to rat MG cancer cellular proliferation. These data also suggest that chronic stress exposure and the resulting GC exposure leads to increased overall cellular metabolism and energy production and promotes a shift to a highly energetic and more proliferative phenotype in a model of mammary cancer. Citation Format: J. Dowgielewicz, J. Caraveo, B. Faubert, M. McClintock, S. Conzen, M. Brady. Glucocorticoids promote metabolic reprogramming that underlies enhanced proliferation of breast cancer stem and progenitor cells under conditions of chronic stress [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-13-04.

Unveiling the epigenetic landscape of AMPK regulation in cancer metabolism.

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Besides tumor-intrinsic factors, CRC risk and progression are strongly influenced by metabolic dysfunction - including obesity, insulin resistance, and T2DM. These implications emphasize the need for therapeutic strategies that address both tumor biology and the metabolic context. Objectives: This review examines the emerging role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in colorectal cancer biology, synthesizing mechanistic, preclinical, and human evidence to evaluate their potential relevance beyond well-known glycemic control. Methods: We integrate experimental studies, animal models, and epidemiologic and clinical data to evaluate the effects of GLP-1RAs on colorectal cancer–related pathways, tumor growth and progression, and resulting clinical outcomes, with special attention given to metabolic and signaling mechanisms. Key Findings: Preclinical evidence suggests that GLP-1RAs may modulate pathways involved in cancer cell proliferation, survival, metabolism, angiogenesis, and invasion, including PI3K/Akt/mTOR, ERK, and hypoxia-associated signaling. In vivo models showcase inhibitory effects on tumor growth and metastatic potential, heightened in metabolically dysregulated settings. Human observational studies report heterogeneous but generally neutral to protective associations between GLP-1RA exposure and CRC risk, while randomized trials have primarily addressed cardiometabolic outcomes rather than being tumor-focused. Conclusions: Collectively, current evidence supports a biologically plausible role for GLP-1 receptor signaling in colorectal cancer growth and progression. Definitive clinical data are lacking, but evidence regarding GLP-1RAs justifies further investigation into their potential relevance.

Tumor immunity and metabolism are interconnected through the tumor microenvironment (TME), with RNA modifications playing pivotal epigenetic regulatory roles. N4- acetylcytidine (ac4C) is the first acetylated modification identified on eukaryotic RNAs, and N- acetyltransferase 10 (NAT10) is the key enzyme catalyzing this modification, depositing ac4C on transfer RNA(tRNA), ribosomal RNA(rRNA), messenger RNA(mRNA), and long non-coding RNA(lncRNA) via its specific localization and expression. However, its systematic functions in tumor immunity and metabolic reprogramming have not been comprehensively summarized for clinical translation. This review systematically synthesizes recent research on NAT10-mediated ac4C modification in oncology, covering data from cell experiments, animal models, and clinical sample analyses across multiple tumor types (e.g. breast cancer(BC), liver, cervical cancer(CC). It integrates findings on NAT10's dual enzymatic activities, subcellular localization, regulation of cell cycle and DNA damage repair, mechanisms in TME remodeling and metabolic reprogramming, as well as preclinical progress of NAT10 inhibitors. NAT10 possesses dual enzymatic activities of protein acetylation and RNA acetylation. Its subcellular localization is redistributed in tumor tissues, which is closely associated with tumorigenesis and progression. In TME remodeling, the NAT10-ac4C axis regulates inflammasome activation, suppresses T-cell function, promotes M2 macrophage polarization, andrecruits tumor- associated macrophages, thereby creating an immunosuppressive microenvironment.In metabolic reprogramming, this axis drives glycolysis by stabilizing hexokinase 2(HK2)/lactate dehydrogenase A (LDHA) mRNA, regulates amino acid metabolism through the Khib-ac4C cascade, and modulates fatty acid metabolism and ferroptosis resistance. Furthermore, high NAT10 expression is associated with chemotherapy and radiotherapy resistance in various tumors, and its inhibitor Remodelin has shown synergistic antitumor effects when combined with immune checkpoint inhibitors in preclinical studies. NAT10-mediated ac4C modification is a critical regulatory node integrating tumor immunity and metabolism, serving as a promising potential target for precision cancer therapy. Current research still faces challenges such as insufficient sensitivity and specificity of ac4C detection technologies, unclearcell-type-specific mechanisms of NAT10, limited delivery efficiency of inhibitors, and the existence of compensatory pathways. Future research should focus on optimizing ac4C detection technologies, clarifying cell-type-specific mechanisms, developing targeted delivery systems, and further exploring the clinical translational value of combining NAT10-targeted therapy with immune checkpoint blockade, so as to provide new strategies and technical support for cancer treatment.

Cancer rates are expected to increase, with Src kinase playing a crucial role in cancer metabolism. This study explored bioactive compounds in royal jelly (RJ) as novel anticancer agents targeting Src kinase using computational methods. QM-AM1 was used for structure preparation, while MD simulations assessed protein-ligand stability, and advanced analyses provided post-MD data. The results indicated that, among the bioactive compounds in RJ, formononetin was promising, with a binding energy of 8.243 kcal/mol and interactions with the active sites of two Src kinase pockets. DFT calculations for formononetin suggested good stability and low reactivity. MD simulations demonstrated that the Src kinase–Formononetin complex adopted a stable, favorable binding pose, and subsequent MM-PBSA analysis indicated a markedly stronger binding affinity than that of the reference inhibitor AP23451. PCA analysis revealed overlapping energy distributions and a positive correlation between RMSDca and DCCM plots, providing insights into the stability and conformation of the Src kinase-formononetin complex. This study proposes formononetin as a novel anticancer inhibitor candidate through comprehensive in silico computational analysis, while acknowledging that further validation through in vitro and in vivo studies is required.

Ovarian cancer is one of the most lethal gynecological cancers worldwide and has one of the highest recurrence rates. Recently developed Chimeric Antigen Receptor (CAR) -T cell therapy has shown potent clinical efficacy against hematological malignancies. However, solid tumors, including ovarian cancer, possess several mechanisms that hinder T cell activity, and metabolic alteration of cancer cells has been shown to contribute to resistance to immune cell attack against solid tumors. Here, we explore the metabolic response of ovarian cancer cells to CAR-T cell attack using label-free high-content hyperspectral stimulated Raman scattering (h2SRS) imaging. Utilizing visible h2SRS imaging with much improved spatial resolution, we find an altered cholesterol metabolism, featured by increased storage of cholesteryl ester in lipid droplets and free cholesterol, in ovarian cancer cells that survive the CAR-T treatment. Administration of Avasimibe, an inhibitor of cholesteryl esterification, further enhances CAR-T cytotoxicity. Our study shows the promise of implementing metabolic modulation to facilitate CAR-T cell treatment of solid tumors.