Exposure to metal(loid)s and glucose metabolism may influence the progression of gastric precancerous lesions (GPLs) or gastric cancer (GC), but their combined effects remain unclear. Our study aimed to elucidate the combined impact of metal (including metalloid and trace element) exposure and disturbances in glucose metabolism on the progression of GPLs and GC. From a prospective observational cohort of 1829 individuals, their metal(loid) levels and blood metabolism were analysed via inductively coupled plasma‒mass spectrometry and targeted metabolomics gas chromatography‒mass spectrometry, respectively. From healthy normal controls (NC) or GPLs to GC, we observed that the aluminum and arsenic levels decreased, whereas the vanadium, titanium and rubidium levels increased, but the iron, copper, zinc and barium levels initially decreased but then increased; these changes were not obvious from the NC to GPL group. With respect to glucose homeostasis, most metabolites decreased, except for phosphoenolpyruvate (PEP), which increased. Multiple logistic regression analysis revealed that titanium and phosphoenolpyruvate might be risk factors for GPLs, that barium is a protective factor for GC, and that D-glucaric acid might be a protective factor for GPLs and GC. Selenium, vanadium, titanium, succinate, maleate, isocitrate, PEP, and the tricarboxylic acid cycle (TCA) had good predictive potential for GPL and GC. Additionally, metal(loid)s such as arsenic, titanium, barium, aluminum, and vanadium were significantly correlated with multiple glucose metabolites involved in the TCA cycle in the GPL and GC groups. Our findings imply that metal(loid) exposure disrupts glucose metabolism, jointly influencing GPL and GC progression.

The relationship between metabolism and cancer is a major focus of current research, with an increasing number of studies highlighting the significant role of various metabolites in tumor cells, such as lactate, acetic acid, lysine, serine, tryptophan, palmitic acid, succinate, etc. These metabolites are involved in numerous biological processes within tumor cells, including transcription, translation, post-translational modification (PTM) of proteins, cell cycle regulation, and metabolism, thereby modulating tumor proliferation, migration, and drug resistance. Metabolite-mediated PTMs of proteins undoubtedly play a vital role in tumor cells, affecting both histones and non-histone proteins, covering modifications such as lactylation, crotonylation, acetylation, palmitoylation, and succinylation. Therefore, this review aims to elaborate on the abnormal levels of some major metabolites, related metabolic pathways, and the latest protein acyl PTMs they mediate in tumor cells, providing new insights for diagnosis and therapy in the field of oncology.

A bibliometric approach was employed to systematically analyze the trends and potential future developments in lactic acid-related cancer research over the past 10 years.

We conducted a bibliometric analysis of literature on lactic acid in cancer research from 2015 to 2024, using data collected from the Web of Science database. A bibliometric analysis was conducted to identify general research directions and trends in current publications, as well as to determine the most prolific and influential authors, institutions, countries, and keywords in lactate and cancer research. The data were collected and analyzed using VOSviewer (Leiden University, Leiden, Netherlands), Microsoft Excel (Microsoft, Redmond, Washington, USA), CiteSpace, and Biblioshiny, with a focus on analysis and visualization.

A total of 5,999 publications were analyzed, focusing on various aspects of the relevant literature, including year of publication, country, institution, author, journal, category, keywords, and research frontiers. The analysis of these publications reveals a general upward trend in publication volume from 2015 to 2024, with China and University of California System emerging as the most prolific country and institution, respectively. SCIENTIFIC REPORTS is the most frequently published journal, while Oncotarget is the most cited journal in the field. Zhang Y. was the most prolific author, publishing 100 documents over 10 years, with the highest citation count and an H-index of 28.Keyword analysis revealed five key themes in lactate-cancer research (2013-2023): Metabolic-epigenetic crosstalk, Tumor immunosuppressive microenvironment, Innovative therapies/drug delivery, Lactate-mediated signaling, Metabolic-targeted treatment strategies. Current research emphasizes the application of lactic acid metabolism in metabolic intervention, immune microenvironment regulation, combination of new therapeutic techniques and applications in specific cancer types.

Research on lactic acid in cancer is growing rapidly, with China at the forefront of this field. Research into lactic acid's role in immune cell regulation, metabolism, and signaling pathways, combined with multi-modal imaging, big data analytics, and innovative drug delivery, is set to become a key trend in future studies, which promises new directions for identifying therapeutic targets, biomarkers, and developing advanced treatments.

Hypoxia induces immunosuppressive phenotypes in tumor cells even in the presence of cytosolic DNA accumulation. The mechanisms by which tumor cells suppress hypoxia-induced cGAS-STING activation for immune evasion remain largely unclear. Here, we demonstrate that hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis. This phosphorylation triggers the interaction between PCK1 and cGAS. The PCK1 associated with cGAS competitively consumes GTP, a substrate shared by both PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, leading to promoted tumor growth in mice. The blockade of PCK1 function, in combination with anti-PD-1 antibody treatment, exhibits an additive therapeutic effect on tumor growth. Additionally, PCK1 S151 phosphorylation is inversely correlated with cGAS-STING activation in human breast cancer specimens and patient survival. These findings reveal a novel regulation of cGAS-STING pathway and uncover the metabolic control of immune response in tumor cells.

In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.

Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.

Cell cycle progression is timely interconnected with oscillations in cellular metabolism. Here, we first describe how these metabolic oscillations allow cycling cells to meet the bioenergetic needs specifically for each phase of the cell cycle. In parallel, we highlight how the cytosolic level of citrate is dynamically regulated during these different phases, being low in G1 phase, increasing in S phase, peaking in G2/M, and decreasing in mitosis. Of note, in cancer cells, a dysregulation of such citrate oscillation can support cell cycle progression by promoting a deregulated Warburg effect (aerobic glycolysis), activating oncogenic signaling pathways (such as PI3K/AKT), and promoting acetyl-CoA production via alternative routes, such as overconsumption of acetate. Then, we review how administration of sodium citrate (at high doses) arrests the cell cycle in G0/G1 or G2/M, inhibits glycolysis and PI3K/AKT, induces apoptosis, and significantly reduces tumor growth in various in vivo models. Last, we reason on the possibility to implement citrate administration to reinforce the effectiveness of cell cycle inhibitors to better cure cancer.

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.

Glucose metabolic enzymes and their metabolites not only provide energy and building blocks for synthesizing macromolecules but also possess non-canonical or moonlighting functions in response to extracellular and intracellular signalling. These moonlighting functions modulate various cellular activities, including gene expression, cell cycle progression, DNA repair, autophagy, senescence and apoptosis, cell proliferation, remodelling of the tumour microenvironment and immune responses. These functions integrate glucose metabolism with other essential cellular activities, driving cancer progression. Targeting these moonlighting functions could open new therapeutic avenues and lead to cancer-specific treatments.

Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1 expression. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labeling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labeled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 knockdown cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation in the context of palmitic acid supplementation, suggesting that the effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.

Rapid ascent to high altitudes by unacclimatized individuals significantly increases the risk of brain damage, given the brain's heightened sensitivity to hypoxic conditions. Investigating hypoxia-tolerant animals can provide insights into adaptive mechanisms and guide prevention and treatment of hypoxic-ischemic brain injury. In this study, we exposed Brandt's voles to simulated altitudes (100 m, 3000 m, 5000 m, and 7000 m) for 24 h and performed quantitative proteomic and phosphoproteomic analyses of brain tissue. A total of 3990 proteins and 9125 phosphorylation sites (phospho-sites) were quantified. Differentially expressed (DE) analysis revealed that while protein abundance changes were relatively modest, phosphorylation levels exhibited substantial alterations, suggesting that Brandt's voles rapidly regulate protein structure and function through phosphorylation to maintain cellular homeostasis under acute hypoxia. Clustering analysis showed that most co-expressed proteins exhibited non-monotonic responses with increasing altitude, which were enriched in pathways related to cytokine secretion regulation and glutathione metabolism, contributing to reduced inflammation and oxidative stress. In contrast, most co-expressed phospho-sites showed monotonic changes, with phospho-proteins enriched in glycolysis and vascular smooth muscle contraction regulation. Kinase activity prediction identified nine hypoxia-responsive kinases, four of which belonging to the CAMK family. Immunoblot validated that the changes in CAMK2A activity were consistent with predictions, suggesting that CAMK may play a crucial role in hypoxic response. In conclusion, this work discovered that Brandt's voles may cope with hypoxia through three key strategies: (1) vascular regulation to enhance cerebral blood flow, (2) glycolytic activation to increase energy production, and (3) activation of neuroprotective mechanisms.

Pancreatic cancer (PC) is a highly invasive tumor characterized by delayed diagnosis, rapid progress, and resistance to chemotherapy. Mitochondria, as the "power chamber" of cells, not only play a central role in energy metabolism but also participate in the production of reactive oxygen species (ROS), calcium signaling, regulation, and differentiation of the cell cycle. The abnormal activity of mitochondria is closely related to the development of PC. In this paper, we discussed the key role of mitochondria in PC, including mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics, metabolic regulation, ROS generation, and mitochondrial-dependent apoptosis. We elaborated on the importance of these mitochondrial mechanisms in the development of PC and emphasized the potential of targeted mitochondrial therapy strategies for these mechanisms in the treatment of PC. In addition, this article also reviews the latest developments in innovative drug carriers such as cell-penetrating peptides, nucleic acid aptamers, and nanomaterials, which can achieve precise localization of mitochondria and drug delivery. Therefore, this article comprehensively analyzed the important role of mitochondria in the treatment of PC and clarified the effectiveness and necessity of targeting mitochondria in the treatment of PC.

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related mortality, with poor prognosis and limited therapeutic options, underscoring the urgent need for a deeper understanding of OC biology. In this study, we identified a marked reduction in dual-specificity phosphatase 4 (DUSP4) expression in OC tissues compared to benign ovarian masses, with even further decreases observed in metastatic lesions. Moreover, DUSP4 expression varied among OC subtypes, with the lowest levels observed in serous ovarian cancer, and was associated with P53 and KI67 protein levels, altered TP53 mutation rates, advanced tumor stages, and poorer prognosis. Functional experiments demonstrated that DUSP4 overexpression suppressed OC cell proliferation, migration, and invasion in vitro. Phosphoproteomic profiling via LC-MS/MS analysis identified the MAPK pathway and cellular metabolism as key downstream targets of DUSP4. Notably, DUSP4 overexpression reduced phosphorylation of PGK1 at Ser203, a critical regulator of anaerobic glycolysis, and decreased its mitochondrial localization, leading to reduced lactate production and increased ROS levels. Mechanistically, DUSP4 dephosphorylated p-ERK, disrupting its interaction with PGK1 and subsequently reducing PGK1 S203 phosphorylation. In vivo, DUSP4 overexpression significantly inhibited tumor growth in mouse models, accompanied by decreased p-ERK and PGK1 S203 levels. These findings highlight a regulatory axis involving DUSP4, p-ERK, and PGK1, through which DUSP4 modulates glycolysis and tumor progression. This study establishes DUSP4 as a prognostic biomarker and a potential therapeutic target for OC, offering new insights into its role in tumor metabolism and growth.

Bovine herpesvirus 1 (BoHV-1) productive infection stimulates β-catenin-dependent transcription to facilitate virus replication. Phosphoglycerate kinase 1 (PGK1), which catalyses the initial step of ATP production during glycolysis, also has a mitochondrial form that is implicated in tissue injury across various diseases. However, the relationship between BoHV-1 replication and the PGK1 signalling pathway is not yet fully understood. In this study, we discovered that PGK1 signalling significantly influences BoHV-1 replication, with the virus infection leading to a marked increase in the accumulation of PGK1 proteins in mitochondria. Overexpression of β-catenin reduces PGK1 steady-state protein levels while overexpressing PGK1 boosts β-catenin protein expression-a phenomenon that reverses upon virus infection. Importantly, consistent with PGK1's vital role in virus replication, PGK1 stimulates β-catenin-dependent transcriptional activity, partly by promoting the nuclear accumulation of transcriptionally active β-catenin and phospho-β-catenin (S552) in virus-infected cells. In summary, our findings suggest for the first time that PGK1 signalling may be involved in BoHV-1 replication and contribute to virus pathogenicity.

Glioblastoma (GBM) patients frequently develop resistance to temozolomide (TMZ), the standard chemotherapy. While targeting cancer metabolism shows promise, the relationship between metabolic perturbation and drug resistance remains poorly understood.

We performed high-throughput CRISPR interference screens in GBM cells to identify genes modulating TMZ sensitivity. Findings were validated using multiple GBM cell lines, patient-derived glioma stem cells, and clinical data. Molecular mechanisms were investigated through transcriptome analysis, metabolic profiling, and functional assays.

We identified phosphoglycerate kinase 1 (PGK1) as a key determinant of TMZ sensitivity. Paradoxically, while PGK1 inhibition suppressed tumor growth, it enhanced TMZ resistance by inducing metabolic stress. This activated AMPK and HIF-1α pathways, leading to enhanced DNA damage repair through 53BP1. PGK1 expression levels correlated with TMZ sensitivity across multiple GBM models and patient samples.

Our study reveals an unexpected link between metabolic stress and chemoresistance, demonstrating how metabolic adaptation can promote therapeutic resistance. These findings caution against single-agent metabolic targeting and suggest PGK1 as a potential biomarker for TMZ response in GBM.

Phosphoglycerate kinase 1 (PGK1), a pivotal enzyme in the glycolysis pathway, contributes to tumor progression through diverse biological activities like cell metabolism, angiogenesis, proliferation, and epithelial-mesenchymal transformation (EMT). Although PGK1 has been intensively researched in specific cancer types, its overarching significance in pan-cancer contexts remains underexplored. This study leveraged various public database resources, including the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Tumor Immune Estimation Resource (TIMER2.0), and cBioPortal, to analyze the gene expression, gene alteration characteristics, prognostic value, subcellular localization, biological function, immune characteristics, and drug sensitivity of PGK1 in 33 different cancer types. R software was used to visualize these data. Furthermore, the effects of PGK1 on the proliferation, apoptosis, migration, and invasion of esophageal squamous cell carcinoma (ESCC) cells were also examined in vitro using 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, CCK-8 assay, Annexin V-FITC/PI assay, migration assay, and invasion assay. The findings suggested that PGK1 is upregulated in various cancer types and closely associated with poor prognosis. In terms of functional enrichment analysis, PGK1 primarily plays a role in glycolysis, hypoxia, EMT, and immune-related pathways. Furthermore, PGK1 is highly expressed in immune and malignant cells in the tumor microenvironment. Notably, PGK1 expression varied significantly among immune cells with distinct activation states. The results of experiments in vitro showed that PGK1 was significantly upregulated in ESCC cells, and its knockdown led to significant inhibition of proliferation, migration, and invasion while increasing cell apoptosis; conversely, overexpression promoted proliferation, migration, and invasion while reducing apoptosis. PGK1 can serve as a prognostic biomarker and therapy target for various cancers, and it may be a promising focal point of immunological studies.

Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member of type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification of various substrate proteins. This study investigates the role of PRMT3 in PD-L1-associated tumor immunosuppression in hepatocellular carcinoma (HCC). Hepatocyte-specific knockout of Prmt3 significantly suppressed HCC progression in DEN-CCL4-treated mice. Knockout of Prmt3 in HCC cells markedly increased CD8+ T cell infiltration, and reduced lactate production in tumors. PRMT3 interacted with pyruvate dehydrogenase kinase 1 (PDHK1), asymmetric dimethylation of PDHK1 at arginine 363 and 368 residues and increased its kinase activity. The R363/368 K mutant or inhibition of PDHK1 by JX06 blocked the effect of PRMT3 on lactate production. JX06 treatment also attenuated the tumor-promoting role of PRMT3 in HCC in vitro and in vivo. Furthermore, RNA-seq analysis revealed that knockout of PRMT3 downregulates the tumor-associated immune checkpoint, PD-L1, in tumor tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that PRMT3 promotes lactate-induced PD-L1 expression by enhancing the direct binding of histone H3 lysine 18 lactylation (H3K18la) to the PD-L1 promoter. Tissue microarray analysis showed a positive correlation between PRMT3 and PD-L1 expression in HCC patients. Anti-PD-L1 treatment reversed PRMT3-induced tumor growth and restored CD8+ T cell infiltration. Our research links PRMT3-mediated metabolic reprogramming and immune evasion, revealing that the PRMT3-PDHK1-lactate-PD-L1 axis may be a potential target for improving the efficacy of immunotherapy in HCC.

Improving the "cold" tumor immune microenvironment (TIME) of small-cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune-cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1.

The cytotoxic effects of ACT001 on SCLC cell lines NCI-H1688 and NCI-H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull-down assays, LC-MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti-tumor activity of ACT001.

ACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions.

ACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.

This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.

Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent histone H3 lysine 4 trimethylation (H3K4me3) modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1's protein kinase activity, but not its HK activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression.

Ketone bodies generated in hepatocytes in the adult liver are used for nonhepatic tissues as an energy source. However, ketolysis is reactivated in hepatocellular carcinoma (HCC) cells with largely unelucidated mechanisms. Here, we demonstrate that 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting enzyme in ketolysis, interacts with SUCLA2 upon IGF1 stimulation in HCC cells. This interaction results from ERK2-mediated SUCLA2 S124 phosphorylation and subsequent PIN1-mediated cis-trans isomerization of SUCLA2. OXCT1-associated SUCLA2 generates succinyl-CoA, which not only serves as a substrate for OXCT1 but also directly succinylates OXCT1 at K421 and activates OXCT1. SUCLA2-regulated OXCT1 activation substantially enhances ketolysis, HCC cell proliferation, and tumor growth in mice. Notably, treatment with acetohydroxamic acid, an OXCT1 inhibitor used clinically for urinary infection, inhibits liver tumor growth in mice and significantly enhances lenvatinib therapy. Our findings highlight the role of SUCLA2-coupled regulation of OXCT1 succinylation in ketolysis and unveil an unprecedented strategy for treating HCC by interrupting ketolysis.

Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.

KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis of fatty acids and nucleotides. However, the beyond mechanisms of KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related metabolic alterations in cancer cells and explore the prevalence and significance of KRAS mutation in shaping the tumor microenvironment and influencing epigenetic modification via various molecular activities. Given that cancer cells rely on these metabolic changes to sustain cell growth and survival, targeting these processes may represent a promising therapeutic strategy for KRAS-driven cancers.

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Mitochondria are pivotal in cellular energy metabolism and have garnered significant attention for their roles in cancer progression and therapy resistance. Despite this, the functional diversity of mitochondria across various cancer types remains inadequately characterized. This study seeks to fill this knowledge gap by introducing and validating MitoScore-a novel metric designed to quantitatively assess mitochondrial function across a wide array of cancers. Our investigation evaluates the capacity of MitoScore not only to distinguish between tumor and adjacent normal tissues but also to serve as a predictive marker for clinical outcomes. We analyzed gene expression data from 24 cancer types and corresponding normal tissues using the TCGA database. MitoScore was calculated by summing the normalized expression levels of six mitochondrial genes known to be consistently altered across multiple cancers. Differential gene expression was assessed using DESeq2, with a focus on identifying significant changes in mitochondrial function. MitoScore's associations with tumor proliferation, hypoxia, aneuploidy, and clinical outcomes were evaluated using Spearman's correlation, linear regression, and Kaplan-Meier survival analyses. MitoScore was significantly higher in tumor tissues compared to normal tissues across most cancer types (p < 0.001). It positively correlated with tumor proliferation rates (r = 0.46), hypoxia scores (r = 0.61), and aneuploidy (r = 0.44), indicating its potential as a marker of aggressive tumor behavior. High MitoScore was also associated with poorer prognosis in several cancer types, suggesting its utility as a predictive biomarker for clinical outcomes. This study introduces MitoScore, a metric for mitochondrial activity often elevated in tumors and linked to poor prognosis. It correlates positively with hypoxia and negatively with stromal and immune infiltration, highlighting mitochondria's role in the tumor microenvironment. MitoScore's association with genomic instability, such as aneuploidy, suggests mitochondrial dysfunction contributes to cancer progression. Despite challenges in mitochondrial-targeted therapies, MitoScore may identify tumors responsive to such treatments, warranting further research for clinical application.

Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.

Fine particulate matter (PM2.5) exposure has been associated with increased incidence and mortality of lung cancer. However, the molecular mechanisms underlying PM2.5 carcinogenicity remain incompletely understood. Here, we identified that PM2.5 suppressed the expression of tRNA methyltransferase FTSJ1 and Am modification level of tRNA in vitro and in vivo. FTSJ1 downregulation enhanced glycolytic metabolism of non-small cell lung cancer (NSCLC) cells, as indicated by increased levels of lactate, pyruvate, and extracellular acidification rate (ECAR). Whereas treatment with glycolytic inhibitor 2-DG reversed this effect. In contrast, upregulation of FTSJ1 significantly suppressed glycolysis of NSCLC cells. Mechanistically, the silencing of FTSJ1 increased NSCLC cell proliferation and glycolysis through enhancing the expression and translation of PGK1. In human NSCLC tumor samples, FTSJ1 expression was negatively correlated with PGK1 expression level and the SUVmax value of PET/CT scan. In summary, our work reveals a previously unrecognized function of PM2.5-downregulated FTSJ1 on PGK1-mediated glycolysis in NSCLC, suggesting that targeted upregulation of FTSJ1 may represent a potential therapeutic strategy for NSCLC.

Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered 'untargetable'. Although specific KRASG12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.

Diabetic cardiomyopathy (DbCM) is one of the most common vascular complications of diabetes, and can cause heart failure and threaten the life of patients. The pathogenesis is complex, and key genes have not fully identified. In this study, bioinformatics analysis was used to predict DbCM-related gene targets. Published datasets from the NCBI Gene Expression Omnibus with accession numbers GSE62203 and GSE197850 were selected for analysis. Differentially expressed genes (DEGs) were identified by the online tool GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID online database. Protein-protein interaction network construction and hub gene identification were performed using STRING and Cytoscape. We used 30 mM and 1 μM hydrocortisone-stimulated AC16 cells as an in vitro model of diabetic cardiomyopathy. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression levels of hub genes. A total of 73 common DEGs were identified in both datasets, including 47 upregulated and 26 downregulated genes. GO and KEGG pathway enrichment analyses revealed that the DEGs were significantly enriched in metabolism, hypoxia response, apoptosis, cell proliferation regulation, and cytoplasmic and HIF signalling pathways. The top 10 hub genes were LDHA, PGK1, SLC2A1, ENO1, PFKFB3, EGLN1, MYC, PDK1, EGLN3 and BNIP3. In our in vitro study, we found that PGK1, SLC2A1, PFKFB3, EGLN1, MYC, EGLN3 and BNIP3 were upregulated, ENO1 was downregulated, and LDHA was unchanged. Except for PGK1 and ENO1, these hub genes have been previously reported to be involved in DbCM. In summary, we identified DEGs and hub genes and first reported PGK1 and ENO1 in DbCM, which may serve as potential candidate genes for DbCM targeted therapy.

The prolonged post-fermentation stage of Doubanjiang imparts unique flavors but may reduce microbial vitality and increase contamination, affecting quality. This study investigated the effect of Zygosaccharomyces rouxii inoculation during post-fermentation. Results showed a 46.7% increase in amino nitrogen and a significant rise in volatile compounds like phenethyl alcohol, 3-methyl-1-butanol, and ethyl octanoate. The relative abundances of Staphylococcus and Pantoea increased among bacteria, while Pichia, Wickerhamiella, and Zygosaccharomyces increased among fungi. Redundancy analysis showed a positive correlation between these genera and the main volatiles. Microbial ecological network analysis showed that inoculating Z. rouxii increased nodes and edges, resulting in tighter inter-module connections and enhanced robustness. Key genera included Zygosaccharomyces, Staphylococcus, Kazachstania, and Weissella. Metaproteomic results demonstrated that upregulated proteins were predominantly enriched in pathways related to flavor formation, while downregulated proteins were associated with ribosome and DNA synthesis-related pathways. PICRUSt2 analysis results showed higher expression of enzymes related to volatiles in innoculated samples. Inoculating Z. rouxii during the post-fermentation could boost core microorganisms, curb foodborne pathogens, stabilize the microbial community, and enhance Doubanjiang quality.

Myocardial infarction remains a disease with high morbidity and death rate among cardiovascular diseases. Macrophages are abundant immune cells in the heart. Under different stimulatory factors, macrophages can differentiate into different phenotypes and play a dual pro-inflammatory and anti-inflammatory role. Therefore, a potential strategy for the treatment of myocardial infarction is to regulate the energy metabolism of macrophages and thereby regulate the polarization of macrophages. Tan IIA is an effective liposolubility component extracted from the root of Salvia miltiorrhiza and plays an important role in the treatment of cardiovascular diseases. On this basis, this study proposed whether Tan IIA could affect phenotype changes by regulating energy metabolism of macrophages, and thus exert its potential in the treatment of MI.

Establishing a myocardial infarction model, Tan IIA was given for 3 days and 7 days for intervention. Cardiac function was detected by echocardiography, and cardiac pathological sections of each group were stained with HE and Masson to observe the inflammatory cell infiltration and fibrosis area after administration. The expression and secretion of inflammatory factors in heart tissue and serum of each group, as well as the proportion of macrophages at the myocardial infarction site, were detected using RT-PCR, ELISA, and immunofluorescence. The mitochondrial function of macrophages was evaluated using JC-1, calcium ion concentration detection, reactive oxygen species detection, and mitochondrial electron microscopic analysis. Mechanically, single-cell transcriptome data mining, cell transcriptome sequencing, and molecular docking technology were used to anchor the target of Tan IIA and enrich the pathways to explore the mechanism of Tan IIA regulating macrophage energy metabolism and phenotype. The target of Tan IIA was further determined by gene knockdown and overexpression assay.

The intervention of Tan IIA can improve the cardiac function, inflammatory cell infiltration and fibrosis after MI, reduce the expression of inflammatory factors in the heart, enhance the secretion of anti-inflammatory factors, increase the proportion of M2-type macrophages, reduce the proportion of M1-type macrophages, and promote tissue repair, suggesting that Tan IIA has pharmacological effects in the treatment of MI. In terms of mechanism, RNA-seq results suggest that the phenotype of macrophages is strongly correlated with energy metabolism, and Tan IIA can regulate the PGK1-PDHK1 signaling pathway, change the energy metabolism mode of macrophages, and then affect its phenotype.

Tan IIA regulates the energy metabolism of macrophages and changes its phenotype through the PGK1-PDHK1 signaling pathway, thus playing a role in improving MI.