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The review article titled CD39 Transforming Cancer Therapy by Modulating Tumor Microenvironment published in June 2024 in Cancer Letters provides a comprehensive overview of CD39's multifaceted roles in cancer, particularly its influence on immunoregulation, angiogenesis, and metabolic reprogramming within the tumor microenvironment (TME). This commentary builds on that foundation by incorporating recent advancements in CD39 research, highlighting unresolved issues, and proposing future research directions. We delve into the therapeutic potential of targeting CD39, addressing clinical translation challenges, and exploring the integration of CD39-based strategies into precision oncology.

Mercury is a hazardous pollutant of global concern. While advances have been made in identifying the detrimental effects caused by Hg species in phytoplankton, knowledge gaps remain regarding the metabolomic perturbations induced by inorganic mercury (Hg(II)) and monomethylmercury (MeHg) in these organisms. Diatoms represent a major phytoplankton group essential in various global biogeochemical cycles. The current study combined targeted metabolomics, bioaccumulation, and physiological response assays to investigate metabolic perturbations in diatom Cyclotella meneghiniana exposed for 2 h to nanomolar concentrations of Hg(II) and MeHg. Our findings highlight that such exposures induce reprogramming of the metabolism of amino acids, nucleotides, fatty acids, carboxylic acids and antioxidants. These alterations were primarily mercury-species dependent. MeHg exposure induced more pronounced reprogramming of the metabolism of diatoms than Hg(II), which led to less pronounced effects on ROS generation, membrane permeability and chlorophyll concentrations. Hg(II) treatments presented distinct physiological responses, with more robust metabolic perturbations at higher exposures. The present study provides first-time insights into the main metabolic alterations in diatom C. meneghiniana during short-term exposure to Hg species, deepening our understanding of the molecular basis of these perturbations.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR)

[Display omitted] • LPS-activated MSCs promote the expression of NLRP3 and the production of IL-10. • NLRP3 upregulates Glut1 expression and promotes glycolysis in MSCs. • Overexpression of Glut1 enhanced the therapeutic effect of Nlrp3 KO MSCs against DSS-induced colitis. • NLRP3 activation promotes IL-10 production by upregulating glycolysis levels, heightening the protective effects of MSCs treatment on DSS-induced colitis. Numerous studies demonstrated that NLRP3 has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Mesenchymal stem cells (MSCs) regulated the NLRP3 inflammasome, which has emerged as a novel therapeutic approach for treating IBD. The exact role of NLRP3 in regulating MSCs' function is unclear. Our study aimed to explore how NLRP3 affects the therapeutic effects of MSCs in colitis. We extracted MSCs from the bone marrow of C57BL/6 mice and Nlrp3 KO mice, and identified them using differentiation assays and flow cytometry. In vitro , Both WT MSCs and Nlrp3 KO MSCs were stimulated with inflammatory factor Lipopolysaccharide (LPS), and only WT MSCs were stimulated with varying concentrations of the NLRP3 inhibitor MCC950, then, quantified IL-10 levels in the supernatant. RNA-seq was performed to examine gene expression patterns and Seahorse was used to assess oxidative phosphorylation (OXPHOS) and glycolysis levels. Western blot was used to evaluate protein expression. In vivo , we treated DSS-induced colitis with either WT or Nlrp3 KO MSCs, monitoring weight, measuring colon length, and further evaluation. We also treated DSS-induced colitis with pretreated MSCs (BAY876, oe-Glut1, or oe-NLRP3), following the same experimental procedures as described above. Our results demonstrate that Nlrp3 deletion did not affect MSC phenotypes, but rather promoted osteogenic differentiation. However, the absence of Nlrp3 reduced IL-10 production in MSCs in the presence of LPS, leading to impaired protection on DSS-induced colitis. Conversely, overexpression of NLRP3 promotes the production of IL-10, enhancing therapeutic effects. Further investigation revealed that Nlrp3 deficiency downregulated Glut1 expression and glycolysis activation in MSCs, resulting in decreased IL-10 production. Notably, overexpressing Glut1 in Nlrp3 KO MSCs restored their therapeutic effect that was previously dampened due to Nlrp3 deletion. Our findings demonstrate that NLRP3 heightens the therapeutic effects of MSC treatment on DSS-induced colitis. [ABSTRACT FROM AUTHOR]

Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a pivotal biological process in which cellular metabolic patterns change to meet the energy demands of increased cell growth and proliferation. In this review, we explore metabolic reprogramming and its impact on fibrotic diseases, providing a detailed overview of the key processes involved in the metabolic reprogramming of renal fibrosis, including fatty acid decomposition and synthesis, glycolysis, and amino acid catabolism. In addition, we report that Chinese medicine ameliorates renal inflammation, oxidative stress, and apoptosis in chronic kidney disease by regulating metabolic processes, thereby inhibiting renal fibrosis. Furthermore, we reveal that multiple targets and signaling pathways contribute to the metabolic regulatory effects of Chinese medicine. In summary, this review aims to elucidate the mechanisms by which Chinese medicine inhibits renal fibrosis through the remodeling of renal cell metabolic processes, with the goal of discovering new therapeutic drugs for treating renal fibrosis. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a prevalent gynecologic malignancy with the second-highest mortality rate among gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for ovarian cancer; however, a majority of patients with ovarian cancer experience relapse and develop platinum resistance following initial treatment. Despite extensive research on the mechanisms of platinum resistance at the nuclear level, the issue of platinum resistance in ovarian cancer remains largely unresolved. It is noteworthy that mitochondrial DNA (mtDNA) exhibits higher affinity for platinum compared to nuclear DNA (nDNA). Mutations in mtDNA can modulate tumor chemosensitivity through various mechanisms, including DNA damage responses, shifts in energy metabolism, maintenance of Reactive Oxygen Species (ROS) homeostasis, and alterations in mitochondrial dynamics. Concurrently, retrograde signals produced by mtDNA mutations and their subsequent cascades establish communication with the nucleus, leading to the reorganization of the nuclear transcriptome and governing the transcription of genes and signaling pathways associated with chemoresistance. Furthermore, mitochondrial translocation among cells emerges as a crucial factor influencing the effectiveness of chemotherapy in ovarian cancer. This review aims to explore the role and mechanism of mitochondria in platinum resistance, with a specific focus on mtDNA mutations and the resulting metabolic reprogramming, ROS regulation, changes in mitochondrial dynamics, mitochondria-nucleus communication, and mitochondrial transfer. Highlights: Directly targeting mitochondria is one of the main mechanisms by which platinum induces apoptosis in tumor cells. mtDNA mutations occur frequently in ovarian cancer and significantly contribute to platinum resistance. The metabolic heterogeneity induced by mtDNA mutations can directly drive platinum resistance in ovarian cancer cells. Targeting mitochondria could be a novel approach for platinum-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Trial Registration Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune‐mediated anti‐tumour responses.ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921 [ABSTRACT FROM AUTHOR]

Despite numerous screening tools for colorectal cancer (CRC), 25 % of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS‐mutant HCT116 and SW837 cells, and KRAS wild‐type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient‐derived primary cells and cultures of patient tumors to predict effective drugs for individualized care. [ABSTRACT FROM AUTHOR]

The infant gut microbiota undergoes significant changes during early life, which are essential for immune system maturation, nutrient absorption, and metabolic programming. Among the various microbial metabolites, shortchain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, produced through the fermentation of dietary fibers by gut bacteria, have emerged as critical modulators of host-microbiota interactions. SCFAs serve as energy sources for colonic cells and play pivotal roles in regulating immune responses, maintaining gut barrier integrity, and influencing systemic metabolic pathways. Recent research highlights the potential neuroprotective effects of SCFAs in pediatric populations. Disruptions in gut microbiota composition and SCFA production are increasingly associated with a range of pediatric health issues, including obesity, allergic disorders, inflammatory bowel disease (IBD), and neurodevelopmental disorders. This review synthesizes current knowledge on the role of microbiota-derived SCFAs in pediatric health, emphasizing their contributions from gut development to neuroprotection. It also underscores the need for further research to unravel the precise mechanisms by which SCFAs influence pediatric health and to develop targeted interventions that leverage SCFAs for therapeutic benefits. [ABSTRACT FROM AUTHOR]

Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor. Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors. Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs. Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming. [Display omitted] • JAK/STAT3 pathway modulates mtDNA G4s in hypoxic cancer cells • mtDNA G4s are stabilized by RelA translocated to mitochondria upon JAK/STAT3 activation • RelA-induced mtDNA G4 formation allows the cancer cells to metabolically adapt to hypoxia Tang et al. employ molecular probes to elucidate how cancer cells manipulate mtDNA G-quadruplexes (G4s) to enhance glycolysis under hypoxia. This involves activating the JAK/STAT3 pathway and transporting RelA to mitochondria, which increases mtDNA G4 formation, exacerbates mitochondrial dysfunction, and promotes glycolysis as a response to hypoxic stress. [ABSTRACT FROM AUTHOR]

Introduction: Acute myeloid leukemia(AML) is a diverse malignancy with a prognosis that varies, being especially unfavorable in older patients and those with high-risk characteristics. Metabolic reprogramming has become a significant factor in AML development, presenting new opportunities for prognostic assessment and therapeutic intervention. Methods: Metabolism-related differentially expressed genes (mDEGs) were identified by integrating KEGG metabolic gene lists with AML gene expression data from GSE63270. Using TCGA data, we performed consensus clustering and survival analysis to investigate the prognostic significance of mDEGs. A metabolic risk model was constructed using LASSO Cox reg ression and enhanced by a nomogram incorporated clinical characteristics. The model was validated through receiver operating characteristic (ROC) curves and survival statistics. Gene network analysis was conducted to identify critical prognostic factors. The tumor immune microenvironment was evaluated using CIBERSORT and ESTIMATE algorithms, followed by correlation analysis between immune checkpoint gene expression and risk scores. Drug sensitivity predictions and in vitro assays were performed to explore the effects of mDEGs on cell proliferation and chemoresistance. Results: An 11-gene metabolic prognostic model was established and validated. High-risk patients had worse overall survival in both training and validation cohorts (p < 0.05). The risk score was an independent prognostic factor. High-risk patients showed increased immune cell infiltration and potential response to checkpoint inhibitors but decreased drug sensitivity. The model correlated with sensitivity to drugs such as venetoclax. Carbonic anhydrase 13 (CA13) was identified as a key gene related to prognosis and doxorubicin resistance. Knocking down CA13 reduced proliferation and increased cell death with doxorubicin treatment. Conclusion: A novel metabolic gene signature was developed to stratify risk and predict prognosis in AML, serving as an independent prognostic factor. CA13 was identified as a potential therapeutic target. This study provides new insights into the prognostic and therapeutic implications of metabolic genes in AML. [ABSTRACT FROM AUTHOR]

Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a global health problem caused by uncontrolled cell growth and changes in how cells get and use energy. This review compares cancer's hidden metabolic changes to dark matter and dark energy in the universe, which are mysterious and often ignored. It looks at how cancer cells alter their energy use, such as through the Warburg effect and changes in fat and protein production, driven by genetic mutations. These changes help cancer grow and survive. The review suggests that targeting these metabolic pathways could be a new way to treat cancer. It calls for more research to better understand these changes and develop new therapies by focusing on the "dark energy" that fuels cancer cells. Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research. [ABSTRACT FROM AUTHOR]

Background: Diabetic macroangiopathy has been the main cause of death and disability in diabetic patients. The mechanisms underlying smooth muscle cell transformation and metabolic reprogramming other than abnormal glucose and lipid metabolism remain to be further explored. Method: Single-cell transcriptome, spatial transcriptome and spatial metabolome sequencing were performed on anterior tibial artery from 11 diabetic patients with amputation. Multi-omics integration, cell communication analysis, time series analysis, network analysis, enrichment analysis, and gene expression analysis were performed to elucidate the potential molecular features. Result: We constructed a spatial multiomics map of diabetic blood vessels based on multiomics integration, indicating single-cell and spatial landscape of transcriptome and spatial landscape of metabolome. At the same time, the characteristics of cell composition and biological function of calcified regions were obtained by integrating spatial omics and single cell omics. On this basis, our study provides favorable evidence for the cellular fate of smooth muscle cells, which can be transformed into pro-inflammatory chemotactic smooth muscle cells, macrophage-like smooth muscle cells/foam-like smooth muscle cells, and fibroblast/chondroblast smooth muscle cells in the anterior tibial artery of diabetic patients. The smooth muscle cell phenotypic transformation is driven by transcription factors net including KDM5B, DDIT3, etc. In addition, in order to focus on metabolic reprogramming apart from abnormal glucose and lipid metabolism, we constructed a metabolic network of diabetic vascular activation, and found that HNMT and CYP27A1 participate in diabetic vascular metabolic reprogramming by combining public data. Conclusion: This study constructs the spatial gene-metabolism map of the whole anterior tibial artery for the first time and reveals the characteristics of vascular calcification, the phenotypic transformation trend of SMCs, and the transcriptional driving network of SMCs phenotypic transformation of diabetic macrovascular disease. In the perspective of combining the transcriptome and metabolome, the study demonstrates the activated metabolic pathways in diabetic blood vessels and the key genes involved in diabetic metabolic reprogramming. [ABSTRACT FROM AUTHOR]

Background: Monoclonal nonspecific suppressor factor β (MNSFβ), a ubiquitously expressed member of the ubiquitin-like protein family, is associated with diverse cell regulatory functions. It has been implicated in glycolysis regulation and cell proliferation enhancement in the macrophage-like cell line Raw264.7. This study aims to show that HIF-1α regulates MNSFβ-mediated metabolic reprogramming. Methods and results: In Raw264.7 cells, MNSFβ siRNA increased the oxygen consumption rate and reactive oxygen species (ROS) production but decreased ATP levels. Cells with MNSFβ knockdown showed a markedly increased ATP reduction rate upon the addition of oligomycin, a mitochondrial ATP synthase inhibitor. In addition, MNSFβ siRNA decreased the expression levels of mRNA and protein of HIF-1α—a regulator of glucose metabolism. Evaluation of the effect of MNSFβ on glucose metabolism in murine peritoneal macrophages revealed no changes in lactate production, glucose consumption, or ROS production. Conclusion: MNSFβ affects both glycolysis and mitochondrial metabolism, suggesting HIF-1α involvement in the MNSFβ-regulated glucose metabolism in Raw264.7 cells. [ABSTRACT FROM AUTHOR]

Background and Aims Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. Methods TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT–qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. Results VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout Apoe KO mice (Apoe KO Trap1 SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. Conclusions This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of β-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide. [ABSTRACT FROM AUTHOR]

Drought has a significant, negative impact on crop production; and these effects are poised to increase with climate change. Plants acclimate to drought and water stress through diverse physiological responses, primarily mediated by the hormone abscisic acid (ABA). Because plants lose the majority of their water through stomatal pores on aerial surfaces of plants, stomatal closure is one of the rapid responses mediated by ABA to reduce transpirational water loss. The dynamic changes in the transcriptome of stomatal guard cells in response to ABA have been investigated in the model plant Arabidopsis thaliana. However, guard cell transcriptomes have not been analyzed in agronomically valuable crops such as a major oilseed crop, rapeseed. In this study, we investigated the dynamics of ABA-regulated transcriptomes in stomatal guard cells of Brassica napus and conducted comparison analysis with the transcriptomes of A. thaliana. We discovered changes in gene expression indicating alterations in a host of physiological processes, including stomatal movement, metabolic reprogramming, and light responses. Our results suggest the existence of both immediate and delayed responses to ABA in Brassica guard cells. Furthermore, the transcription factors and regulatory networks mediating these responses are compared to those identified in Arabidopsis. Our results imply the continuing evolution of ABA responses in Brassica since its divergence from a common ancestor, involving both protein-coding and non-coding nucleotide sequences. Together, our results will provide a basis for developing strategies for molecular manipulation of drought tolerance in crop plants. [ABSTRACT FROM AUTHOR]

Maternal nutrition significantly influences fetal development and postnatal outcomes. This study investigates the impact of maternal overfeeding during mid to late pregnancy on gene expression in the round and sirloin muscles of Hanwoo neonatal calves. Eight cows were assigned to either a control group receiving standard nutrition (100%) or a treated group receiving overnutrition (150%). After birth, tissue samples from the round and sirloin muscles of neonatal calves were collected and subjected to RNA sequencing to assess differentially expressed genes (DEGs). RNA sequencing identified 43 DEGs in round muscle and 15 in sirloin muscle, involving genes related to myogenesis, adipogenesis, and energy regulation. Key genes, including PPARGC1A, THBS1, CD44, JUND, CNN1, ENAH, and RUNX1, were predominantly downregulated. Gene ontology (GO) enrichment analyses revealed terms associated with muscle development, such as "biological regulation," "cellular process," and "response to stimulus." Protein-protein interaction networks highlighted complex interactions among DEGs. Random Forest analysis identified ARC, SLC1A5, and GNPTAB as influential genes for distinguishing between control and treated groups. Overall, maternal overnutrition during mid-to-late pregnancy results in the downregulation of genes involved in muscle development and energy metabolism in neonatal Hanwoo calves. These findings provide insights into the molecular effects of maternal nutrition on muscle development. [ABSTRACT FROM AUTHOR]

The p53 mutation is the most common genetic mutation associated with human neoplasia. TP53 missense mutations, which frequently arise early in breast cancer, are present in over thirty percent of breast tumors. In breast cancer, p53 mutations are linked to a more aggressive course of the disease and worse overall survival rates. TP53 mutations are mostly seen in triple-negative breast cancer, a very diverse kind of the disease. The majority of TP53 mutations originate in the replacement of individual amino acids within the p53 protein's core domain, giving rise to a variety of variations referred to as "mutant p53s." In addition to gaining carcinogenic qualities through gain-of-function pathways, these mutants lose the typical tumor-suppressive features of p53 to variable degrees. The gain-of-function impact of stabilized mutant p53 causes tumor-specific dependency and resistance to therapy. P53 is a prospective target for cancer therapy because of its tumor-suppressive qualities and the numerous alterations that it experiences in tumors. Phenotypic abnormalities in breast cancer, notably poorly differentiated basal-like tumors are frequently linked to high-grade tumors. By comparing data from cell and animal models with clinical outcomes in breast cancer, this study investigates the molecular mechanisms that convert gene alterations into the pathogenic consequences of mutant p53's tumorigenic activity. The study delves into current and novel treatment approaches aimed at targeting p53 mutations, taking into account the similarities and differences in p53 regulatory mechanisms between mutant and wild-type forms, as well. [ABSTRACT FROM AUTHOR]

Background: Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear. Methods: This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity. Results: This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice. Conclusions: The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression. [ABSTRACT FROM AUTHOR]

The human skeleton is a multifunctional organ made up of multiple cell types working in concert to maintain bone and mineral homeostasis and to perform critical mechanical and endocrine functions. From the beginning steps of chondrogenesis that prefigures most of the skeleton, to the rapid bone accrual during skeletal growth, followed by bone remodeling of the mature skeleton, cell differentiation is integral to skeletal health. While growth factors and nuclear proteins that influence skeletal cell differentiation have been extensively studied, the role of cellular metabolism is just beginning to be uncovered. Besides energy production, metabolic pathways have been shown to exert epigenetic regulation via key metabolites to influence cell fate in both cancerous and normal tissues. In this review, we will assess the role of growth factors and transcription factors in reprogramming cellular metabolism to meet the energetic and biosynthetic needs of chondrocytes, osteoblasts, or osteoclasts. We will also summarize the emerging evidence linking metabolic changes to epigenetic modifications during skeletal cell differentiation. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a malignant disease worldwide. Angiopoietin-like protein 4 (ANGPTL4) plays a role in pathophysiological processes, including metabolic reprogramming, angiogenesis, proliferation, and metastasis. Current evidence shows conflicting findings regarding the role of ANGPTL4 in the progression of GC. ANGPTL4 in GC was confirmed through bioinformatic analysis and immunofluorescence staining. The impact of ANGPTL4 was subsequently validated in GC cell lines using various assays, including 5-ethynyl-2-deoxyuridine (EdU), 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow Cytometry (FCM), wound healing, transwell, tube formation, chorioallantoic membrane model, and nude mouse model assays. RNA-seq analysis, polymerase chain reaction (PCR), western blotting (WB), immunofluorescence (IF) and coimmunoprecipitation (co-IP) were conducted to determine the potential downstream mechanism of ANGPTL4. In SNU5 and MKN7 cells, ANGPTL4 was found to augment proliferation, migration, invasion, evasion of apoptosis, and angiogenesis. Conversely, in the AGS cell line, ANGPTL4 was observed to suppress these processes. Notably, the overexpression of ANGPTL4 in AGS cells led to the upregulation of LGALS7, which has emerged as a pivotal factor contributing to the manifestation of an anticancer phenotype induced by ANGPTL4. LGALS7, which is involved in the regulation of the hedgehog pathway and subsequent promotion of GC progression through various processes, such as proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis, was found to contribute to the contradictory effects of ANGPTL4. [ABSTRACT FROM AUTHOR]

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management. Mitochondrial diseases caused by ETC deficiencies affect cells differently. Here, the authors show that ETC inhibition activates a non-canonical TCA cycle to maintain NADPH levels, which explains the differential sensitivity observed between astrocytes and neurons. [ABSTRACT FROM AUTHOR]

The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function. T cell activation is a process that requires extra nutrients, which could be difficult to source from the tumor microenvironment in competition with tumor cells. Here authors increase the metabolic fitness of CAR-T cells by stable overexpression of the glucose transporter GLUT1, which allows them to increase their glucose intake and enhances their antitumour function. [ABSTRACT FROM AUTHOR]

Macrophages are most important immune cell population in the heart. Cardiac macrophages have broad-spectrum and heterogeneity, with two extreme polarization phenotypes: M1 pro-inflammatory macrophages (CCR2-ly6Chi) and M2 anti-inflammatory macrophages (CCR2-ly6Clo). Cardiac macrophages can reshape their polarization states or phenotypes to adapt to their surrounding microenvironment by altering metabolic reprogramming. The phenotypes and polarization states of cardiac macrophages can be defined by specific signature markers on the cell surface, including tumor necrosis factor a, interleukin (IL)-1b, inducible nitric oxide synthase (iNOS), C-C chemokine receptor type (CCR)2, IL-4 and arginase (Arg)1, among them, CCR2+/- is one of most important markers which is used to distinguish between resident and non-resident cardiac macrophage as well as macrophage polarization states. Dedicated balance between M1 and M2 cardiac macrophages are crucial for maintaining heart development and cardiac functional and electric homeostasis, and imbalance between macrophage phenotypes may result in heart ventricular remodeling and various heart diseases. The therapy aiming at specific target on macrophage phenotype is a promising strategy for treatment of heart diseases. In this article, we comprehensively review cardiac macrophage phenotype, metabolic reprogramming, and their role in maintaining heart health and mediating ventricular remodeling and potential therapeutic strategy in heart diseases. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV) is a double‐stranded DNA herpesvirus and establishes life‐long infection in 95% of the world's populations. Main body: EBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV‐mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV‐associated diseases. Conclusion: Growing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels. [ABSTRACT FROM AUTHOR]

Periprosthetic joint infection (PJI) is one of the most challenging complications following total knee arthroplasty. Despite its importance, there is a paucity of reports in the literature regarding its pathogenesis. Recently, cellular metabolic reprogramming has been shown to play an important role in the progression and outcome of infectious diseases. Therefore, the aim of this study was to evaluate the metabolites composition of the synovial fluid from patients with PJI or aseptic failure of total knee arthroplasties. The synovial fluids from 21 patients scheduled for revision total knee arthroplasty (11 with the diagnosis of PJI and 10 with aseptic failures) were analyzed using 1D 1H NMR spectroscopy. Univariate and multivariate statistical analyzes were used to identify metabolites that were differentially abundant between those groups. A total of 28 metabolites were identified and five of them found to be differentially abundant between infected and non‐infected synovial fluids. Lactate, acetate and 3‐hydroxybutyrate were found to be in a higher concentration, and glucose and creatine were found reduced in the synovial fluid from PJI patients. Synovial fluid from patients with PJI exhibit a distinct metabolic profile, possibly reflecting metabolic adaptation that occurs in the infected periprosthetic microenvironment. Further research and studies are warranted to gain a broader insight into the metabolic pathways engaged by both pathogen and immune cells in the context of a PJI. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblast (CAF) composition within the same organ varies across different cancer subtypes. Distinct CAF subtypes exhibit unique features due to interactions with immune cells and the tumor microenvironment. However, data on CAF subtypes in individuals with vestibular schwannoma (VS) are lacking. Therefore, we aimed to distinguish CAF subtypes at the single-cell level, investigate how stem-like CAF characteristics influence the tumor immune microenvironment, and identify CAF subtype-specific metabolic reprogramming pathways that contribute to tumor development. Data were analyzed from three patients with VS, encompassing 33,081 single cells, one bulk transcriptome cohort, and The Cancer Genome Atlas Pan-Cancer database (RNA sequencing and clinical data). Our findings revealed that antigen-presenting CAFs are linked to substantially heightened immune activity, supported by metabolic reprogramming, which differs from tumorigenesis. High expression of the stem-like CAF gene signature correlated with poor prognosis in low-grade gliomas within the pan-cancer database. This is the first study to classify CAF subtypes in VS patients and identify a therapeutic vulnerability biomarker by developing a stem-like CAF gene signature. Personalized treatments tailored to individual patients show promise in advancing precision medicine. [ABSTRACT FROM AUTHOR]

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors. [ABSTRACT FROM AUTHOR]

Around 13% of women will likely develop breast cancer during their lifetime. Advances in cancer metabolism research have identified a range of metabolic reprogramming events, such as altered glucose and amino acid uptake, increased reliance on glycolysis, and interactions with the tumor microenvironment (TME), all of which present new opportunities for targeted therapies. However, studying these metabolic networks is challenging in traditional 2D cell cultures, which often fail to replicate the three-dimensional architecture and dynamic interactions of real tumors. To address this, organoid models have emerged as powerful tools. Tumor organoids are 3D cultures, often derived from patient tissue, that more accurately mimic the structural and functional properties of actual tumor tissues in vivo, offering a more realistic model for investigating cancer metabolism. This review explores the unique metabolic adaptations of breast cancer and discusses how organoid models can provide deeper insights into these processes. We evaluate the most advanced tools for studying cancer metabolism in three-dimensional culture models, including optical metabolic imaging (OMI), matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and recent advances in conventional techniques applied to 3D cultures. Finally, we explore the progress made in identifying and targeting potential therapeutic targets in breast cancer metabolism. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs. [ABSTRACT FROM AUTHOR]

Linoleic acid (LA), the primary ω-6 polyunsaturated fatty acid (PUFA) found in the epidermis, plays a crucial role in preserving the integrity of the skin's water permeability barrier. Additionally, vegetable oils rich in LA have been shown to notably mitigate ultraviolet (UV) radiation-induced effects, including the production of reactive oxygen species (ROS), cellular damage, and skin photoaging. These beneficial effects are primarily ascribed to the LA in these oils. Nonetheless, the precise mechanisms through which LA confers protection against damage induced by exposure to UVB radiation remain unclear. This study aimed to examine whether LA can restore redox and metabolic equilibria and to assess its influence on the inflammatory response triggered by UVB radiation in keratinocytes. Flow cytometry analysis unveiled the capacity of LA to diminish UVB-induced ROS levels in HaCaT cells. GC/MS-based metabolomics highlighted significant metabolic changes, especially in carbohydrate, amino acid, and glutathione (GSH) metabolism, with LA restoring depleted GSH levels post-UVB exposure. LA also upregulated PI3K/Akt-dependent GCLC and GSS expression while downregulating COX-2 expression. These results suggest that LA induces metabolic reprogramming, protecting against UVB-induced oxidative damage by enhancing GSH biosynthesis via PI3K/Akt signaling. Moreover, it suppresses UVB-induced COX-2 expression in HaCaT cells, making LA treatment a promising strategy against UVB-induced oxidative and inflammatory damage. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the leading causes of cancer-related mortality. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) differ in aggressiveness, proliferation speed, metastasis propensity, and prognosis. Since tumor cells notably change lipid metabolism, especially phospholipids and fatty acids (FA), this study aimed to identify FA alterations in lung cancer tissues. We detected significant changes in lipid metabolism in both lung cancer types compared to healthy tissues (especially higher levels of pro-inflammatory arachidonic acid), and we pointed out differences in FA profiles in tissue between SCLC and NSCLC. Our findings can be useful for further research concerning molecular lung cancer therapies. Background: Lung cancer is one of the leading causes of cancer-related mortality. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) differ in aggressiveness, proliferation speed, metastasis propensity, and prognosis. Since tumor cells notably change lipid metabolism, especially phospholipids and fatty acids (FA), this study aimed to identify FA alterations in lung cancer tissues. Methods: Our study included patients with newly diagnosed, histologically confirmed SCLC (n = 27) and NSCLC (n = 37). Samples were collected from both malignant and healthy tissues from each patient, providing they were within subject design. Results: In both NSCLC and SCLC tumor tissues, FA contents were shifted toward pro-inflammatory profiles, with increased levels of some individual n-6 polyunsaturated FA (PUFA), particularly arachidonic acid, and elevated activity of Δ6 desaturase. Compared to healthy counterparts, lower levels of alpha-linolenic acid (18:3n-3) and total saturated FA (SFA) were found in NSCLC, while decreased levels of linoleic acid (18:2n-6) and all individual n-3 FA were found in SCLC tissue in comparison to the healthy tissue control. When mutually compared, SCLC tissue had higher levels of total SFA, especially stearic acid, while higher levels of linoleic acid, total PUFA, and n-3 and n-6 PUFA were detected in NSCLC. Estimated activities of Δ6 desaturase and elongase were higher in SCLC than in NSCLC. Conclusions: Our findings indicate a notable impairment of lipid metabolism in two types of lung cancer tissues. These type-specific alterations may be associated with differences in their progression and also point out different therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid cancer (PTC) with the BRAFV600E mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAFV600E mutation is associated with altered glucose metabolism in PTC. Methods: This study examined the effect of BRAFV600E and dynamin-related protein 1 (DRP1) on various cellular processes in PTC cells, including cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation, and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAFV600E and DRP1 was investigated through Western blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and the inhibitory effects of dabrafenib and 2-deoxy-d-glucose (2-DG) in vitro and in vivo. Results: We found that the BRAFV600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating hexokinase 2 expression and thereby increasing aerobic glycolysis. Second, it inhibits apoptosis by promoting mitochondrial fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and dabrafenib markedly impedes the progression of BRAFV600E-positive PTC. Conclusion: The BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAFV600E-positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and dabrafenib has the potential to improve the outcome of PTC patients with BRAFV600E. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EVs) facilitate cell–cell interactions in the tumour microenvironment. However, standard and efficient methods to isolate tumour tissue‐derived EVs are lacking, and their biological functions remain elusive. Methods: To determine the optimal method for isolating tissue‐derived EVs, we compared the characterization and concentration of EVs obtained by three previously reported methods using transmission electron microscopy, nanoparticle tracking analysis, and nanoflow analysis (Nanoflow). Additionally, the differential content of small RNAs, especially tsRNAs, between hepatocellular carcinoma (HCC) and adjacent normal liver tissues (ANLTs)‐derived EVs was identified using Arraystar small RNA microarray. The targets of miRNAs and tsRNAs were predicted, and downstream functional analysis was conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, non‐negative matrix factorization and survival prediction analysis. Results: A differential centrifugation‐based protocol without cell cultivation (NC protocol) yielded higher EV particles and higher levels of CD9+ and CD63+ EVs compared with other isolation protocols. Interestingly, the NC protocol was also effective for isolating frozen tissue‐derived EVs that were indistinguishable from fresh tissue. HCC tissues showed significantly higher EV numbers compared with ANLTs. Furthermore, we identified different types of small RNAs in HCC tissue‐derived EVs, forming a unique multidimensional intercellular communication landscape that can differentiate between HCC and ANLTs. ROC analysis further showed that the combination of the top 10 upregulated small RNAs achieved better diagnostic performance (AUC =.950 [.895–1.000]). Importantly, most tsRNAs in HCC tissue‐derived EVs were downregulated and mitochondria‐derived, mainly involving in lipid‐related metabolic reprogramming. Conclusion: The NC protocol was optimal for isolating EVs from HCC, especially from frozen tissues. Our study emphasized the different roles of small‐RNA in regulating the HCC ecosystem, providing insights into HCC progression and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aim Method Outcome There is increasing evidence that maternal factors such as nutritional status (both under and over‐nutrition) and diabetes, alongside prenatal exposure to endocrine disrupting chemicals (EDCs), are associated with early pubertal onset in offspring. Such children are also at increased risk of the metabolic syndrome during adolescence and young adulthood.This literature review focuses on the role of the prenatal environment in programming pubertal onset, and the impact of prenatal metabolic stressors on the declining average age of puberty.A review of all relevant literature was conducted in PubMed by the authors.The mechanism for this appears to be mediated through metabolic signals, such as leptin and insulin, on the kisspeptin‐neuronal nitric oxide‐gonadotropin releasing hormone (KiNG) axis. Exposed children have an elevated risk of childhood obesity and display a phenotype of hyperinsunlinaemia and hyperleptinaemia. These metabolic changes permit an earlier attainment of the nutritional “threshold” for puberty. Unfortunately, this cycle may be amplified across subsequent generations, however early intervention may help “rescue” progression of this programming. [ABSTRACT FROM AUTHOR]

Liquid–liquid phase separation (LLPS) has emerged as a pivotal biological phenomenon involved in various cellular processes, including the formation of membrane‐less organelles and the regulation of biomolecular condensates through precise spatiotemporal coordination of signaling pathways in cells. Dysregulation of LLPSs results in aberrant biomolecular condensates, which are widely implicated in tumorigenesis and cancer progression. Here, we comprehensively summarize the multifaceted roles of LLPS in tumor biology from the perspective of cancer hallmarks, including genomic stability, metabolic reprogramming progression, ferroptosis, and metastasis, to unveil the intricate mechanisms by which LLPS occurs in tumorigenesis. We discuss current discoveries related to therapeutic involvement and potential clinical applications of LLPS in cancer treatment, highlighting the potential of targeting LLPS‐driven processes as novel therapeutic strategies. Additionally, we discuss the challenges associated with new approaches for cancer treatment based on LLPS. This in‐depth discussion of the impact of LLPS on fundamental aspects of tumor biology provides new insights into overcoming cancer. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA. [Display omitted] • Nucleolin is a lactylation target that mediates iCCA pathogenesis. • Nucleolin is lactylated predominantly at lysine 477 by P300 in glycolytic iCCA cells. • Lactylated nucleolin upregulates MADD by preventing RNA mis-splicing. • Lactylated nucleolin/MADD/pERK predicts poor prognosis of patients with iCCA. [ABSTRACT FROM AUTHOR]

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T reg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T reg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nT reg cells, but not iT reg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nT reg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nT reg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nT reg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nT reg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nT reg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nT reg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion. • Acidity enhances T reg cell suppressive functions independent of lactate in vitro and in vivo. • T reg cell oxidative metabolic capacity increases as a result of exposure to acidity. • Treatment with acidity results in T reg cell transcriptional and metabolic changes in one-carbon folate metabolism. • Exposure to acidity ex vivo for 48 hours facilitates increased T reg suppressive functions against T eff cells in the TME and promotes tumor growth in the MC38 colon cancer model. • Treatment of T reg cells with acidity and formate restores suppressive capacity induced by acidity and decreases tumor burden in the MC38 colon cancer model. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways. The creatine pathway significantly upregulated in the metabolic reprogramming of AML mice, driven by both biosynthesis and the creatine transporter Slc6a8. The elevated creatine supports metastatic leukemia cell survival by enhancing OXPHOS and glycolysis. The Slc6a8 inhibitor ompenaclid could effectively inhibit AML cell proliferation and infiltration both in vitro and in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC)-based therapies have emerged as promising methods for regenerative medicine; however, how to precisely enhance their tissue repair effects is still a major question in the field. Circulating extracellular vesicles (EVs) from diseased states carry diverse pathological information and affect the functions of recipient cells. Based on this unique property, we report that disease-derived circulating EV (disease-EV) preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease models. Briefly, plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured MSCs. Disease-EV preconditioning improved the performance (including proliferation, migration, and growth factor production) of MSCs through metabolic reprogramming (such as via enhanced oxidative phosphorylation and lipid metabolism) without inducing an adverse immune response. Consequently, compared with normal MSCs, disease-EV-preconditioned MSCs exhibited superior tissue repair effects (including anti-inflammatory and antiapoptotic effects) in diverse types of tissue injury (such as acute lung or kidney injury). Disease-derived EVs may serve as a type of "off-the-shelf" product due to multiple advantages, such as flexibility, stability, long-term storage, and ease of shipment and use. This study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies. Disease-derived circulating extracellular vesicles preconditioning enables the transferring of various disease-specific information to mesenchymal stem cells (MSCs) and thus precisely enhances their therapeutic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell–intrinsic and –extrinsic factors during tumor progression is critical for developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N6‐methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase‐like 3 (METTL3)‐mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures‐induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin–endoperoxide synthase 2 expression through an m6A–YTHDF2‐dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic‐specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis‐related diseases. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study's findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival. [ABSTRACT FROM AUTHOR]