Inhibition Of Glycolysis Research Articles

Metformin inhibits the histone methyltransferase CARM1 and attenuates H3 histone methylation during gluconeogenesis.

Hyperglycemia is a hallmark of metabolic disorders, yet the precise mechanisms linking epigenetic regulation to glucose metabolism remain underexplored. Coactivator-associated arginine methyltransferase 1 (CARM1), a type I histone methyltransferase, promotes transcriptional activation through the methylation of histone H3 at arginine residues H3R17 and H3R26. Here, we identify a novel mechanism by which metformin, a widely prescribed antidiabetic drug, inhibits CARM1 activity. Using biochemical and biophysical assays, we show that metformin binds to the substrate-binding site of CARM1, reducing histone H3 methylation levels in CARM1-overexpressing hepatic cells and liver tissues from metformin-fed mice. This epigenetic modulation suppresses the expression of gluconeogenic enzymes (G6Pase, FBPase, and PCK1), thereby reversing CARM1-induced glycolytic suppression and regulating gluconeogenesis. Importantly, metformin does not alter CARM1 protein levels and its recruitment to gluconeogenic gene promoters but diminishes H3R17me2a marks at these loci. Our findings reveal a previously unrecognized epigenetic mechanism of metformin action, offering new therapeutic insights for hyperglycemia management.

Inflammation induced PFKFB3-mediated glycolysis promoting myometrium contraction through the PI3K-Akt-mTOR pathway in preterm birth mice.

Inflammation is a significant risk factor for preterm birth. Inflammation enhances glycolytic processes in various cell types and contributes to the development of myometrial contractions. However, the potential of inflammation to activate glycolysis in pregnant murine uterine smooth muscle cells (mUSMCs) and its role in promoting inflammatory preterm birth remain unexplored. In this study, lipopolysaccharide was employed to establish both cell and animal inflammation models. We found that inflammation of mUSMCs during late pregnancy could initiate glycolysis and promoted cell contraction. Subsequently, the inhibition of glycolysis using the glycolysis inhibitor 2-deoxyglucose can reverse inflammation-induced cell contraction. The expression of 6-phosphofructokinase 2 kinase (PFKFB3) was significantly upregulated in mUSMCs following lipopolysaccharide stimulation. Additionally, lactate accumulation and enhanced contraction were observed. Inhibition of PFKFB3 reversed the lactate accumulation and enhanced contraction induced by inflammation. We also found that inflammation activated the phosphatidylinositol 3-kinase (PI3K) - protein kinase B (Akt) - mammalian target of rapamycin (mTOR) pathway, leading to the upregulation of PFKFB3 expression. The PI3K-Akt pathway inhibitor LY294002 and the mTOR pathway inhibitor Rapamycin effectively inhibited the upregulation of PFKFB3 protein expression, lactate production, and the enhancement of cell contraction induced by lipopolysaccharide. This study indicates that inflammation regulates PFKFB3 through the PI3K-Akt-mTOR pathway, which enhances the glycolytic process in pregnant mUSMCs, ultimately leading to myometrial contraction.

Glycolysis in asthma: Its role and potential as a diagnostic or therapeutic target.

Asthma is a heterogeneous disease characterized by chronic airway inflammation and hyperresponsiveness. A number of immune cells are involved in asthma pathogenesis, such as eosinophils, mast cells, T lymphocytes and neutrophils, as well as airway epithelial cells. Glycolysis plays a crucial role in glucose metabolism, and serves as a bridge between metabolic and inflammatory dysfunction. Research has found that abnormal glycolytic metabolism in various immune cells may contribute to the pathogenesis of asthma by inducing dysregulation in congenital and adaptive immune responses. Therefore, the inhibition of glycolysis can be a viable approach to prevent airway inflammation in asthma. The present study reviews the relationship between glycolysis and inflammatory cells in different asthma subtypes, and its potential therapeutic significance.

The role of the circ_DOCK1-miR-1297-HOXA9 regulatory network in the development of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a public health concern. The current study aimed to explore the role of circRNA Dedicator of Cytokinesis 1 (circ_DOCK1) and associated action mode in OSCC. The expression of circ_DOCK1 and microRNA-1297 (miR-1297) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). EdU assay, colony formation assay, transwell assay and glycolysis stress test were applied for functional analyses. The expression level of Homeobox A9 (HOXA9) was detected by western blot. The interaction between miR-1297 and circ_DOCK1 or HOXA9 was verified by dual-luciferase reporter assay. Xenograft model was established to determine the role of circ_DOCK1 in vivo. Circ_DOCK1 was highly expressed in OSCC tumor tissues and cell lines. Circ_DOCK1 knockdown suppressed colony formation, migration, invasion and glycolysis of OSCC cells. MiR-1297 was targeted by circ_DOCK1, and its inhibition reversed the anticancer effects of circ_DOCK1 knockdown. HOXA9 was a target of miR-1297, and its overexpression recovered miR-1297 reintroduction-evoked inhibition of colony formation, migration, invasion and glycolysis in OSCC cells. Furthermore, circ_DOCK1 knockdown repressed tumor growth in vivo. Circ_DOCK1 exerted its carcinogenic role in OSCC partially via the circ_DOCK1-miR-1297-HOXA9 regulatory network, which will broaden our insights to understand the pathogenesis of OSCC and provide promising biomarkers for the diagnosis and treatment of OSCC.

Chronic heat stress is capable of reducing the growth performance, causing damage to the liver structure, and altering the liver glucose metabolism and lipid metabolism in largemouth bass (Micropterus salmoides L.).

High temperatures cause abnormal energy metabolism and inhibit the growth of fish in aquaculture. However, the mechanism of energy metabolism under chronic heat stress is still unknown. In this study, largemouth bass (Micropterus salmoides, LMB) was treated with 25℃, 29℃, and 33℃ for 8weeks. Then, the growth performance, liver tissue damage, serum lipid indicator, hepatic glycogen, and triglyceride levels were analyzed. The growth data showed that the 33℃ group had a lower weight gain rate (WGR), specific growth rate (SGR), feeding rate (FR), and higher feed conversion rate (FCR) in comparison with those in the 25℃ and 29℃ groups. However, there were no significant differences between the 25℃ and 29℃ groups. The most severe damage to liver tissue was observed in the 33℃ group, characterized by cellular vacuolation and marginalization of cell nuclei. The levels of triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in the serum were decreased with the rising temperatures. However, the hepatic triglyceride levels were increased, with a decrease in hepatic glycogen levels. Compared with the 25℃ group, the expressions of gluconeogenesis pathway-related genes (phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pase)) and glucose transport pathway-related gene (glucose transporter 2 (Gltu2)) were down-regulated in the 33℃ group. In contrast, the expression of the glycolysis pathway-related gene (pyruvate kinase (Pk)) was up-regulated. In addition, the expressions of fatty acid β oxidation pathway-related genes (peroxisome proliferator-activated receptor-Alpha (Pparα) and carnitine palmityl transferase 1 (Cpt1)), adipogenesis pathway-related genes (peroxisome proliferator-activated receptor-Gamma (Pparγ), fatty acid synthase (Fas), acetyl-CoA carboxylase (Acc)), and lipolysis pathway-related genes (adipose triglyceride lipase (Agtl) and hormone-sensitive lipase (Hsl)) were down-regulated under chronic heat stress. In conclusion, our results indicated that enhancement of the glycolysis pathway and inhibition of the gluconeogenesis pathway and lipid metabolism contribute to coping with chronic heat stress for LMB. Our study provides useful information for alleviating the heat stress response of LMB through nutritional regulation in the future.

Local glycolysis-modulating hydrogel microspheres for a combined anti-tumor and anti-metastasis strategy through metabolic trapping strategy.

Anti-glycolysis is well-recognized for inhibition of tumor proliferation. However, tumor metabolic heterogeneity confers great challenges in the therapeutic efficacy of glycolysis inhibitors. Here, a metabolic trapping strategy was employed to avoid metabolism heterogeneity in tumors. Unlike usual glycolysis inhibition, the glycolysis level was first promoted. Then excessive metabolite of lactate was transformed into H2O2 and hydroxyl radical by lactate oxidase (LOX) and MIL-101 (Fe) nanoparticles (MF). Finally, the ATP production was inhibited, and the tumor was suppressed by the generation of toxic reactive oxygen species (ROS). We realized this strategy via methacrylated gelatin (GelMA) hydrogel microspheres, co-loaded with metformin (MET) and LOX@MF. The results showed that MET was completely released within 2h, followed by most LOX@MF released within 72h. LOX@MF and MET synergistically suppressed tumor proliferation and angiogenesis both in vitro and in vivo. Compared with control, the primary tumor volume was reduced by 75.7%, and the average number of lung metastasis nodules decreased from 15.5 to 1.0. Regarding the metabolism, higher glycolytic enzymes expressions were observed initially, followed by lower lactate and vascular endothelial growth factor (VEGF), and finally elevated ROS levels. Overall, our study provides new insights to improve metabolism heterogeneity-limited metabolic cancer therapy.

Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization

Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.

Metal Ion and Antibiotic Co-loaded Nanoparticles for Combating Methicillin-Rresistant Staphylococcus aureus-Induced Osteomyelitis.

Methicillin-resistant Staphylococcus aureus (MRSA) causes osteomyelitis (OM), which seriously threatens public health due to its antimicrobial resistance. To increase the sensitivity of antibiotics and eradicate intracellular bacteria, a Zn2+ and vancomycin (Van) codelivered nanotherapeutic (named Man-Zn2+/Van NPs) was fabricated and characterized via mannose (Man) modification. Man-Zn2+/Van NPs exhibit significant inhibitory activity against extra- and intracellular MRSA and obviously decrease the minimum inhibitory concentration of Van. Man-Zn2+/Van NPs can be easily internalized by MRSA-infected macrophages and significantly accumulated in infected bone via Man-mediated targeting. In vivo experiments in a mouse OM model verified that Man-Zn2+/Van NPs significantly reduce the extra- and intracellular MRSA burden, improve gait patterns, increase bone mass, and decrease inflammatory cytokine expression. The antibacterial mechanism of Man-Zn2+/Van NPs includes destruction of the MRSA membrane, degeneration of intracellular proteins and DNA, inhibition of MRSA glycolysis, and intervention in the energy metabolism of bacteria. Overall, this metal-antibiotic nanotherapeutics strategy provides new insight for combating extra- and intracellular infections caused by MRSA-induced OM.

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME. Analysis of 18F-FDG uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of Endosulfine alpha (ENSA-K63la), a crucial step that triggers STAT3-CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. Therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Hyper-energy metabolism of oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells

The concept of dual-state hyper-energy metabolism characterized by elevated glycolysis and OxPhos has gained considerable attention during tumor growth and metastasis in different malignancies. However, it is largely unknown how such metabolic phenotypes influence the radiation response in aggressive cancers. Therefore, the present study aimed to investigate the impact of hyper-energy metabolism (increased glycolysis and OxPhos) on the radiation response of a human glioma cell line. Modulation of the mitochondrial electron transport chain was carried out using a 2,4-dinitrophenol (DNP). Metabolic characterization was carried out by assessing glucose uptake, lactate production, mitochondrial mass, membrane potential, and ATP production. The radiation response was examined by cell growth, clonogenic survival, and cell death assays. Macromolecular oxidation was assessed by DNA damage, lipid peroxidation, and protein carbonylation assay. Hypermetabolic OPM-BMG cells exhibited a significant increase in glycolysis and OxPhos following irradiation as compared to the parental BMG-1 cells. Enhanced radioresistance of OPM-BMG cells was evidenced by the increase in α/β ratio (9.58) and D1 dose (4.18 Gy) as compared to 4.36 and 2.19 Gy in BMG-1 cells respectively. Moreover, OPM-BMG cells were found to exhibit increased resistance against radiation-induced cell death, and macromolecular oxidation as compared to BMG-1 cells. Inhibition of glycolysis and mitochondrial complex-II significantly enhanced the radiosensitivity of OPM-BMG cells compared to BMG-1 cells. Our results demonstrate that the hyper-energy metabolism of increased glycolysis and OxPhos confer radioresistance. Consequently targeting glycolysis and OxPhos in combination with radiation may overcome therapeutic resistance in aggressive cancers like glioma.

β-Catenin Regulates Glycolytic and Mitochondrial Function in T-Cell Acute Lymphoblastic Leukemia

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by a poor prognosis. β-catenin is implicated in the progression of T-ALL, yet the precise mechanisms of β-catenin involvement in the pathogenesis of T-ALL, particularly concerning metabolic processes, remain inadequately elucidated. Methods: A β-catenin knockout cell line was generated in the human leukemic cell line Jurkat using the CRISPR-Cas9 technique. Subsequently, assays were performed to evaluate cell proliferation, apoptosis, and metabolic activity. Comparative transcriptomic analysis was conducted between control cells and β-catenin knockout cells. Finally, a mouse xenograft model was employed to assess whether β-catenin knockout attenuates tumor growth and infiltration in vivo. Results: The deletion of β-catenin significantly inhibited proliferation and induced apoptosis. Additionally, the silencing of β-catenin led to the inhibition of glycolysis and a reduction in both mitochondrial mass and membrane potential. These results indicate that β-catenin may play a crucial role in regulating cell proliferation and apoptosis through the modulation of glycolytic activity and mitochondrial function in T-ALL. Conclusions: In summary, our findings uncover a novel mechanism by which β-catenin influences glycolysis and mitochondrial function in the progression of T-ALL, thereby identifying a potential therapeutic target for patients with relapsed T-ALL.

Epstein-Barr virus Infection Exacerbates Ulcerative Colitis by Driving Macrophage Pyroptosis via the Upregulation of Glycolysis

Abstract Background Epstein-Barr virus (EBV) infection is associated with clinical symptoms, treatment response, need for surgical intervention, and an enhanced likelihood of lymphoma among patients with ulcerative colitis (UC). However, existing studies have primarily concentrated on the epidemiological and clinical associations between EBV and UC, leaving the mechanisms by which EBV exacerbates colitis poorly understood. Methods Clinical specimens of UC patients with EBV infection and a mouse model of dextran sulfate sodium (DSS)-induced colitis with concurrent murine γ-herpesvirus 68 (MHV-68) infection were utilized to investigate the relationship between EBV infection and macrophage pyroptosis. In vivo, adoptive transfer of MHV-68-induced macrophages and macrophage depletion were performed to elucidate the underlying mechanisms. In vitro, myeloid leukemia mononuclear cells of human (THP-1) and macrophages derived from mouse bone marrow (BMDMs) were stimulated with EBV and MHV-68, respectively, to assess macrophage pyroptosis and glycolysis. Results EBV-induced activation of macrophage pyroptosis was positively correlated with clinical disease activity in UC patients. Furthermore, MHV-68 infection activated pyroptosis by upregulating Gasdermin D, NLRP3, interleukin-1β, and interleukin-18 in colonic tissues and peritoneal macrophages of mice with colitis. In vitro, EBV and MHV-68 also mediated activation of pyroptosis in human THP-1 cells and mouse BMDMs, respectively. Additionally, the adoptive transfer of MHV-68-induced BMDMs aggravated murine colitis, whereas macrophage depletion attenuated MHV-68-induced intestinal injury. Mechanistically, MHV-68 promoted macrophage pyroptosis by upregulating glycolysis, while the glycolysis inhibitor, 2-Deoxy-d-glucose, blocked this process in vitro. Conclusion EBV infection exacerbates UC by driving macrophage pyroptosis through upregulation of glycolysis, indicating a potential therapeutic approach to mitigate EBV-induced intestinal inflammation.

Organoid modeling identifies USP3-AS1 as a novel promoter in colorectal cancer liver metastasis through increasing glucose-driven histone lactylation.

Dysregulation of long non-coding RNAs (lncRNAs) is common in colorectal cancer liver metastasis (CRLM). Emerging evidence links lncRNAs to multiple stages of metastasis from initial migration to colonization of distant organs. In this study we investigated the role of lncRNAs in metabolic reprogramming during CRLM using patient-derived organoid (PDO) models. We established five pairs of PDOs from primary tumors and matched liver metastatic lesions, followed by microarray analysis. We found that USP3-AS1 was significantly upregulated in CRLM-derived PDOs compared to primary tumors. High level of USP3-AS1 was positively associated with postoperative liver metastasis and negatively correlated with the prognosis of colorectal cancer (CRC) patients. Overexpression of USP3-AS1 significantly enhanced both sphere formation efficiency and liver metastasis in PDOs. Gene set enrichment analysis revealed that USP3-AS1 upregulation significantly enriched glycolysis and MYC signaling pathways. Metabolomics analysis confirmed that USP3-AS1 promoted glycolysis in PDOs, whereas glycolysis inhibition partially attenuated the effects of USP3-AS1 overexpression on PDO growth and liver metastasis. We revealed that USP3-AS1 stabilized MYC via post-translational deubiquitination, thereby promoting glycolysis. We demonstrated that USP3-AS1 increased the stability of USP3 mRNA, resulting in higher USP3 protein expression. The elevated USP3 protein then interacted with MYC and promoted its stability by deubiquitination. The USP3-AS1-MYC-glycolysis regulatory axis modulated liver metastasis by promoting H3K18 lactylation and CDC27 expression in CRC. In conclusion, USP3-AS1 is a novel promoter of CRLM by inducing histone lactylation.

Metabolic activities are selective modulators for individual segmentation clock processes

Numerous cellular and molecular processes during embryonic development prompt the fundamental question of how their tempos are coordinated and whether a common global modulator exists. While the segmentation clock tempo scales with the kinetics of gene expression and degradation processes of the core clock gene Hes7 across mammals, the coordination of these processes remains unclear. This study examines whether metabolic activities serve as a global modulator for the segmentation clock, finding them to be selective instead. Several metabolic inhibitions extend the clock period but affect key processes differently: glycolysis inhibition slows Hes7 protein degradation and production delay without altering intron delay, while electron transport chain inhibition extends intron delay without influencing the other processes. Combinations of distinct metabolic inhibitions exhibit synergistic effects. We propose that the scaled kinetics of segmentation clock processes across species may result from combined selective modulators shaped by evolutionary constraints, rather than a single global modulator.

HVEM as a Tumor-Intrinsic Regulator in Non-Small Cell Lung Cancer: Suppression of Metastasis via Glycolysis Inhibition and Modulation of Macrophage Polarization.

Herpes virus entry mediator (HVEM) is a novel costimulatory molecule which mediates stimulatory or inhibitory signals in immune responses which makes it an attractive target in cancer therapeutics. However, the role of tumor cell intrinsic HVEM on tumor biology remains largely unknown. In this study, We demonstrated that CK+HVEM+ tumor correlates with better survival using Multiplex immuno histochemistry (mIHC) in Human Lung Adenocarcinoma Tissue microarray. Next, we showed that HVEM knockdown promoted NSCLC cell invasion and metastasis in vitro whereas exhibited no effect on proliferation. Conversely, HVEM overexpression results in the opposite phenotype. Meanwhile, the conclusion were further confirmed in vivo experiment that overexpression of HVEM reduced the invasion and metastasis of NSCLC whereas no effect on tumor mass. Besides, vivo experiment showed that M1 TAMs in the HVEM overxrpression group was increased and the proportion of M2 macrophages was decreased compared to the vector group. Mechanistically, The C-terminal 228-283 amino acid segment of HVEM protein interacts with the N-terminal 1-383 amino acid segment of MPRIP protein, inhibiting its downstream glycolysis signaling pathway and suppressing NSCLC cells progression. In addition, macrophage coculture assay suggested that HVEM overexpression inhibited M2 macrophage polarization through GM-CSF/GM-CSFRα axis. In summary, our study has demonstrated that tumor cell intrinsic HVEM is a potential tumour metastasis suppressor, which may serve as a potential target for immunotherapy.

Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.

Bibliometric analysis of glycolysis and prostate cancer research from 2004 to 2024

BackgroundProstate cancer (PCa) ranks as the second most common disease among men and the fourth most prevalent cancer worldwide. Enhanced glycolysis and excessive lactate secretion are recognized as critical factors driving the progression of various cancers. This study systematically investigated the research trends associated with glycolysis in PCa through bibliometric analysis.MethodIn this study, we conducted a systematic search of the Web of Science and PubMed databases for literature pertaining to the glycolysis of PCa that was published between January 1, 2004, and June 30, 2024. To achieve this objective, we employed CiteSpace software to generate visualizations that illustrate countries/regions, institutions, journals, and keywords. Additionally, we extracted pertinent quantitative data. Furthermore, we utilized VOSviewer software to create a collaboration network map among various journals.ResultsBetween 2004 and 2024, a total of 408 research articles on glycolysis in PCa were published, indicating a consistent upward trend in the annual publication rate. In this field, the United States not only leads in the volume of research papers but also has the highest degree of centrality. The journal "Cancer Research" is recognized as the most influential in the field, whereas "Prostate and Cancer" serves as a significant platform for disseminating research related to glycolysis in PCa. Keyword analysis has identified four primary research directions that have dominated this field over the past two decades. The role of glycolysis and its associated enzymes in PCa underpins this research. Glycolysis has also demonstrated significant clinical value in the diagnosis and prognosis of PCa. Moreover, drugs targeting glycolytic inhibitors and natural products have exhibited therapeutic potential against this disease. By modulating glycolytic mechanisms, there is potential to increase resistance in PCa. Currently, leading research in this area encompasses the application of nanotechnology to PCa glycolysis, the roles of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) in this metabolic pathway, and the interactions between glycolysis and other biological processes in PCa.ConclusionThis study employs bibliometric analysis to provide a comprehensive overview of research on glycolysis in PCa over the past two decades. It highlights the current state of knowledge in this field, identifies key research hotspots, and explores emerging frontiers, particularly nanotechnology, lncRNA, and miRNA, which are driving innovative research directions.

Copper-Based Bio-Coordination Nanoparticle for Enhanced Pyroptosis-Cuproptosis Cancer Immunotherapy through Redox Modulation and Glycolysis Inhibition.

Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability to induce oxidative stress and cuproptosis in cancer cells. However, their antitumor effectiveness is constrained by the dynamic redox balance and the metabolic shift between oxidative phosphorylation and glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) is designed for combined pyroptosis-cuproptosis cancer immunotherapy by amplifying reactive oxygen species (ROS) production and regulating cellular metabolism. The intracellular redox imbalance is achieved through the synergistic effects of α-KG-induced mitochondrial metabolic reprogramming, photothermally enhanced superoxide dismutase-like activity of polydopamine, and glutathione depletion by copper ions. The multifaceted redox modulation results in a substantial increase in intracellular ROS levels, triggering oxidative stress and subsequent pyroptosis in cancer cells. Furthermore, α-KG shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby enhancing cuproptosis induced by copper ions. The combination of ROS dyshomeostasis and glycolysis inhibition results in a potent enhancement of pyroptosis-cuproptosis-mediated cancer therapy. In a murine model of colorectal cancer, CKPP exhibited a remarkable anticancer effect, achieving a tumor inhibition rate of 96.3% and complete tumor eradication in two out of five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates significant potential for treating cancer through combined pyroptosis-cuproptosis cancer immunotherapy.

MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst.

Mitochondrial Ca2+ uniporter (MCU) provides a Ca2+ influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca2+ rise stimulates ATP production and cell growth. MCU is highly expressed in various cancer cells including breast cancer cells, thereby increasing the capacity of mitochondrial Ca2+ uptake, ATP production, and cancer cell proliferation. The objective of this study was to examine MCU inhibition as an anti-cancer mechanism. The effects of MCU-i4, a newly developed MCU inhibitor, on cell viability, apoptosis, cytosolic Ca2+, mitochondrial Ca2+ and potential, glycolytic rate, generation of ATP, and reactive oxygen species, were examined in breast cancer BT474 cells. MCU-i4 caused apoptotic cell death, and it decreased and increased, respectively, mitochondrial and cytosolic Ca2+ concentration. Inhibition of MCU by MCU-i4 revealed that cytosolic Ca2+ elevation resulted from endoplasmic reticulum (ER) Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RYR). Unexpectedly, MCU-i4 enhanced glycolysis and ATP production; it also triggered a large production of reactive oxygen species (ROS) and mitochondrial membrane potential collapse. Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS. It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis. Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.

Electroacupuncture Pretreatment Reduces Ischemic Brain Injury by Inhibiting the Lactate Production and Its Derived Protein Lactylation Formation.

Given that electroacupuncture (EA) pretreatment inhibits lactate production and lactate-derived lysine lactation (Kla) aggravates ischemic brain injury, we aimed to investigate whether the formation of Kla protein is involved in EA pretreatment to alleviate ischemic brain injury. EA was performed on the Baihui acupoint (GV20) of male C57BL/6J mice before receiving the permanent middle cerebral artery occlusion (pMCAO) surgery. Western blot and immunofluorescent staining were used to observe neuronal survival, astrocyte activation, and protein Kla levels, and the lactate levels in ischemic brains were assayed with a commercial kit. TTCstaining and neurological function scores are performed to evaluate the brain damage in mice. We found that the increased lactate content and protein Kla levels were significantly decreased in ischemic brain tissue of mice after receiving EA pretreatment, and accompanied by the reduction of astrocyte activation and neuronal injury and death. Meantime, we found that EA pretreatment was effective in reversing the worsening of ischemic brain injury caused by lactate supplementation. However, EA pretreatment did not further reduce the lactate content and protein Kla levels and ameliorate brain injury in ischemic stroke mice after inhibition of glycolysis. Our study reveals that EA pretreatment reduced ischemic brain damage by inhibiting lactate production and its derived protein Kla formation in mice with ischemic stroke.