Global lactylation is downregulated despite lactate accumulation: lactylome data and functional insights during ISKNV infection.

Metal-phenolic nanoparticles with ROS/pH dual-responsiveness for liver fibrosis therapy via synergistic microenvironment remodeling and metabolic reprogramming.

Effects of artificial diet on glycolytic pathway and immune response in mandarin fish (Siniperca chuatsi).

Small-cell lung cancer (SCLC) is characterized by rapid growth and a pronounced neuroendocrine phenotype, accompanied by marked metabolic plasticity. Although metabolic reprogramming is a hallmark of SCLC, the molecular mechanisms coordinating glycolytic and lipid metabolic pathways remain poorly defined. Untargeted metabolomic profiling and RNA sequencing were performed on 46 surgically resected SCLC tissues, 39 paired non-tumorous lung tissues, and corresponding serum samples to identify dysregulated metabolic pathways and key regulatory genes. NCAPG expression and function were evaluated using quantitative real-time PCR, Western blotting, Seahorse extracellular flux analysis, and xenograft mouse models. Cell proliferation, apoptosis, ATP production, and reactive oxygen species (ROS) levels were quantified using standard biochemical and flow cytometric assays. Metabolomic analysis identified 438 significantly altered metabolites in SCLC, including 215 shared between tumor tissues and serum samples, indicating systemic metabolic reprogramming. Pathway enrichment analysis revealed marked activation of glycolysis, glycerophospholipid metabolism, and oxidative phosphorylation. Transcriptomic profiling identified NCAPG as one of the most upregulated genes in SCLC (fold change = 4.7, FDR < 0.001), with elevated expression associated with advanced pathological stage and poor overall survival (HR = 1.47, P = 0.002). Functional depletion of NCAPG in H69 and H446 cells reduced cell viability by 45-60% and increased apoptosis approximately twofold. Seahorse analysis demonstrated a ~ 40% reduction in extracellular acidification rate accompanied by increased oxygen consumption, indicating a metabolic shift from glycolysis toward oxidative phosphorylation. In vivo, NCAPG knockdown suppressed xenograft tumor growth by 58% and significantly downregulated key glycolytic and glycerophospholipid enzymes, including HK2, LDHA, and CHPT1. NCAPG promotes metabolic reprogramming in SCLC by sustaining coupled glycolytic and glycerophospholipid flux, thereby supporting tumor energy production and biosynthetic demands. Targeting this NCAPG-mediated metabolic axis may represent a promising therapeutic strategy for small-cell lung cancer.

Synergistic disruption of brain metabolism and inflammatory signaling in adult zebrafish by co-exposure to alternariol monomethyl ether and titanium dioxide nanoparticles at physiologically relevant levels.

Immunometabolism has emerged as a central regulator of immune responses, linking cellular metabolism to inflammatory signaling and tissue homeostasis. Among tricarboxylic acid (TCA) cycle-derived metabolites, itaconate has gained recognition as an important metabolic feedback regulator promoting inflammatory resolution. Mesenchymal stromal/stem cells (MSCs) are multipotent cells widely recognized for their immunomodulatory and regenerative properties, primarily mediated through paracrine signaling and metabolic adaptation. Increasing evidence indicates that MSC immunoregulatory function is closely associated with metabolic reprogramming involving glycolysis, mitochondrial activity, lipid metabolism, and amino acid pathways. Within this context, itaconate has emerged as a potential metabolic interface linking innate immune activation to MSC function. This narrative review summarizes current evidence supporting both direct and indirect interactions between itaconate signaling and MSC biology. Itaconate and its derivatives influence MSC viability, apoptosis resistance, differentiation potential, and redox balance, while indirectly modulating macrophage polarization and inflammatory microenvironment remodeling through extracellular vesicles and paracrine communication. Despite these advances, critical questions remain regarding endogenous itaconate production by MSCs and its effects on MSC secretome composition and immunoregulatory activity. A deeper understanding of the itaconate-MSC axis may enable metabolic preconditioning strategies aimed at enhancing MSC-based therapies for inflammatory and immune-mediated diseases.

HMGA1 Lactylation-Mediated Regulation of the SP1/VEGFA Axis in Pathological Angiogenesis Under Diabetic Retinopathy.

As a promising challenging anti-cancer strategy, cuproptosis is limited by the metabolic adaptations of solid tumors. That is, tumor hypoxia inhibits mitochondrial respiration, while compensatory hyperactive glycolysis contributes to metabolic escape. For overcoming this dual resistance, a Metabolic NanoLock strategy was proposed in this study, that is a photothermal-chemical dual-mode oxygen-generating nanosystem (PCFI) to achieve lethal metabolic reprogramming. Upon activation in the tumor microenvironment, the released Cu+ catalyse H2O2 to generate O2 through Fenton-like reaction. Concurrently, the thermal effect induced by ICG under 808 nm laser irradiation promotes O2 release from oxygen-loaded perfluorocarbon, ensuring sustained oxygen supply. This dual action restores mitochondrial electron transport chain activity while enhancing tricarboxylic acid cycle engagement, compelling tumor cells to rely on respiratory metabolism. Meanwhile, the ROS storm induced by copper and ICG suppresses pyruvate kinase activity, blocking the glycolytic pathway and eliminating the Warburg effect compensation mechanism. Tumor cells were forced into a non-adaptive metabolic state that cannot sustain glycolysis or mitochondrial compensation, effectively trapped in a designed metabolic cage, thereby amplifying cuproptosis sensitivity. In addition to directly inducing metabolic collapse, this locked metabolic state also promotes immunogenic cell death, driving downstream antitumor immune activation. This study establishes metabolic locking as a universal strategy to overcome cuproptosis metabolic resistance, providing a conceptually unique framework for leveraging tumor metabolic vulnerability to achieve durable anticancer efficacy. STATEMENT OF SIGNIFICANCE: Solid tumors often develop metabolic resistance by shifting their energy pathways under hypoxic conditions, favoring glycolysis over mitochondrial respiration. This metabolic adaptation significantly diminishes the efficacy of cuproptosis, a recently identified copper-dependent cell death pathway. In this work, we constructed a multifunctional nanoplatform (PCFI) utilizing a "Metabolic NanoLock" strategy to overcome this therapeutic barrier. The system promotes mitochondrial respiration through in situ oxygen generation and simultaneously inhibits glycolytic escape via ROS-mediated enzyme suppression. By effectively locking tumor cells into a respiration-dependent state, the platform markedly sensitizes tumors to cuproptosis under both normoxic and hypoxic conditions. This study provides a rational metabolic-regulation design for biomaterials and offers a promising strategy for enhancing copper-mediated cancer therapy.

BACKGROUNDRight ventricular failure (RVF) is a major determinant of mortality in pulmonary arterial hypertension (PAH), and hepatic dysfunction predicts adverse outcomes. However, the cell-specific effects of PAH/RVF on the human liver remain poorly defined.METHODSWe performed single-nucleus RNA-seq (snRNA-seq) of autopsy-derived liver tissue from 5 patients with PAH and 4 healthy individuals (non-PAH) treated as controls and compared these findings with publicly available snRNA-seq datasets from nonalcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). Transcriptomic analyses were integrated with histologic assessment, mitochondrion-enriched proteomics, and correlations with clinical markers of PAH/RVF severity.RESULTSPAH livers showed cell-specific metabolic, inflammatory, and fibrotic remodeling distinct from NASH and FALD. PAH hepatocytes exhibited a hypoxia-adapted, Warburg-like metabolic phenotype with reduced fatty acid metabolism, gluconeogenesis, cytochrome P450 activity, and ketone metabolism. PAH endothelial cells demonstrated increased glycolytic pathway activity and altered adhesion/barrier signaling. PAH hepatic stellate cells (HSCs) displayed HIF-1 and PI3K/Akt pathway activation, increased IL-6 expression, and histologic evidence of perivascular fibrotic remodeling. PAH macrophages showed complement activation with reduced JAK/STAT signaling. HSC HIF-1 activity correlated with clinical markers of PAH/RVF severity.CONCLUSIONPAH induces a distinct metabolic and inflammatory hepatopathy characterized by hepatocyte metabolic reprogramming, HSC activation, macrophage complement signaling, and suppressed ketone metabolism. These findings support PAH-associated hepatopathy as a disease-specific end-organ phenotype linked to RVF severity.FUNDINGNIH grants F31 HL170585, R01 HL158795, and R01 HL162927.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and was ranked among the top seven leading causes of cancer-related deaths in South Africa in 2020. Highlighting the urgent need for ongoing research to identify reliable biomarkers to improve clinical outcomes. This study compared the plasma proteomes of patients with PDAC, those with benign biliary pathologies (BBP), and healthy controls (HC). We used Mag-Net, a magnetic-bead-based method that enriches membrane-bound vesicles. Comparative analyses identified distinct and overlapping dysregulated proteins between PDAC, BBP, and HC. PDAC showed enrichment for epithelial-mesenchymal transition, complement activation, hypoxia, glycolysis, and extracellular matrix remodeling pathways, consistent with aggressive tumor biology. Proteins including SPP1, THBS2, PTX3, FBLN2, SDC1, CTSS, and VCAN were significantly increased in PDAC, with LRG1 showing the strongest association with disease severity. Proteins, namely GPNMB, H4C1, SAA1, and CCDC47, demonstrated progressive upregulation across disease comparisons, suggesting potential relevance to disease progression. These findings demonstrate that plasma proteomics provides discriminatory molecular insights and supports the development of population-relevant biomarker panels. While several candidate proteins show promise for inclusion in multianalyte panels, further validation in larger cohorts is necessary to establish their diagnostic and translational utility for early detection, risk stratification, and improved differential diagnosis of PDAC.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes and obesity, have recently attracted attention for potential anti-tumor effects, although their mechanisms remain unclear. Given their role in metabolic regulation, we hypothesized that GLP-1RAs may target cancer-specific metabolic vulnerabilities. Hepatocellular carcinoma (HCC) is characterized by metabolic reprogramming and enhanced glycolysis, which contribute to therapeutic resistance. Here, we investigated the anti-tumor effects of a GLP-1RA in HCC, focusing on its ability to modulate glycolytic pathways and enhance sensitivity to Lenvatinib. Lenvatinib-resistant HCC cells exhibited suppressed AMPKα1 and increased HIF-1α and PFKFB3 expression, promoting glycolytic adaptation. GLP-1RA treatment restored AMPKα1 activity while suppressing HIF-1α/PFKFB3 signaling, thereby reducing glycolytic activity and enhancing apoptosis. Combination treatment with GLP-1RA and Lenvatinib significantly inhibited tumor cell growth in resistant models. These findings suggest that the AMPKα1/HIF-1α/PFKFB3 axis represents a metabolic vulnerability in Lenvatinib-resistant HCC and support GLP-1RA-based combination strategies.

Introduction Cyperotundone (CYT), a vital component of Cyperus rotundus L., is known to suppress tumor growth effectively. This investigation was performed to reveal the antibreast cancer(BC) effect of CYT and its mechanism. Methods CCK-8 assay, colony formation, cell cycle/apoptosis assays, and subcutaneous tumor model were used to investigate the anticancer effects of CYT. RNA sequencing was used to predict the targets of CYT, which were then verified by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking. The pan-cancer analysis on PLK1 was excavated by the comprehensive use of datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx). Western blotting, immunohistochemical staining (IHC), and RT-qPCR were used to determine protein and gene levels. Pyruvate and lactate production assays were used to represent the glycolysis level. Results In vitro, CYT inhibited the proliferation of BC cells, as well as causing apoptosis and blocking the cell cycle. In vivo, CYT decreased tumor regression without obvious toxicity. PLK1 was identified as a key target of CYT. High PLK1 expression was associated with early diagnostic value and poor survival of BC. Of note, PLK1 is positively correlated with glycolysis. CYT can inhibit the key proteins of glycolysis and production of metabolites through the PTEN/AKT pathway in BC cells. In the rescue experiments, CYT significantly inhibited the overexpression of PLK1-induced elevation of glycolysis levels. Discussion This is the first study to reveal the correlation between PLK1 and glycolysis and the regulation of glycolysis by PLK1 in TNBC cells. Although PLK1 was identified as a target of CYT, the research on how CYT exerts its anti-BC effect through PLK1 is still insufficient. Other molecular pathways involved in CYT action, how disruption of glycolytic pathways contributes to its anticancer effects, and its potential compensatory mechanisms in cancer cells are needed to explore. Conclusion CYT is a potent PLK1 inhibitor that has an anticancer effect in BC cells by decreasing glycolytic function.

Clostridioides difficile is a spore-forming bacterium that commonly causes pseudomembranous colitis in patients exposed to antibiotics, with infections leading to 30,000 deaths annually in the United States. We conducted further in vitro and in vivo analyses to determine how proline reductase modulates C. difficile colonization, growth, and metabolism, and showed that this pathway is critical to Clostridium sardiniense's ability to cross-feed with the pathogen to cause toxic megacolon. We demonstrated that sporulation and toxin production are delayed when C. difficile's proline reductase pathway is interrupted through the deletion of the prdB gene. Survival was enhanced in mice co-colonized with C. sardiniense and the C. difficile ΔprdB mutant, as C. difficile relies on glycolytic pathways over Stickland fermentations. The present findings support the central role of proline reductase metabolism in early pathogen growth, metabolism, and toxin, and as a potential therapeutic target against C. difficile infection.

Single-nucleus RNA sequencing reveals molecular determinants of functional and physiological differences between extraocular and quadriceps muscles in Macaca fascicularis.

Aberrant metabolism is a hallmark of tumours. Cancer cells develop metabolic patterns distinct from those of normal cells, characterized by the conversion of glucose into lactate under both aerobic and hypoxic conditions. The intermediates and end products generated in this process modulate the function and survival of immune cells within the tumour microenvironment (TME). In this review, we summarize recent advances in the interplay between glycolysis and the immune microenvironment, potential therapeutic targets within the glycolytic pathway, and the clinical translation of glycolysis-related molecules. Through in-depth research into the glycolytic process, it has been found that the aberrant glycolytic metabolism of tumor cells not only supports their own proliferation but also reshapes the tumor microenvironment. This, in turn, forces immune cells to alter their metabolic profiles, ultimately resulting in an imbalanced anti-tumor immune response. To date, multiple small-molecule inhibitors targeting key molecules and nodes in the glycolytic pathway have been developed, some of which demonstrate promising anti-tumor efficacy in preclinical models. The review emphasizes the significance of glycolysis in shaping the immune response within the TME and underscores the therapeutic potential of targeting glycolytic pathways, with several inhibitors showing promise for future clinical translation.

The metabolic reprogramming known as the Warburg effect, in which cancer cells preferentially convert glucose to lactate even in the presence of oxygen, is a defining hallmark of malignant transformation. Rather than reflecting defective mitochondria or a simple adaptation to hypoxia, aerobic glycolysis now emerges as a central hub that integrates glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, and lactate metabolism to sustain the bioenergetic, biosynthetic, and redox demands of cancer cells. Enhanced glycolytic flux supports rapid ATP generation, nucleotide and lipid biosynthesis, NADPH production, and acetyl-CoA-dependent epigenetic regulation, thereby promoting DNA repair, antioxidant defense, chromatin remodeling, and proliferation. Beyond these metabolic outputs, many glycolytic enzymes, such as hexokinase 2, phosphoglycerate mutase 1, pyruvate kinase M2, phosphoglucose isomerase/autocrine motility factor, and aldolase A, exert non-enzymatic "moonlighting" functions that regulate apoptosis, checkpoint signaling, transcriptional programs, cytoskeletal remodeling, and epithelial-mesenchymal transition. Through this combination of enzymatic and non-enzymatic activities, the Warburg effect reinforces multiple dimensions of therapeutic resistance, including ATP-dependent drug efflux, resistance to DNA-damaging therapies, immune evasion, and invasive, EMT-associated phenotypes. In this review, we summarize current evidence linking aerobic glycolysis, lactate metabolism, and the pentose phosphate pathway to resistance against chemotherapy, radiotherapy, targeted therapy, and immunotherapy, with a particular focus on the non-metabolic functions of glycolytic enzymes. We further discuss how targeting glucose uptake, glycolysis, lactate transport, or pentose phosphate pathway flux, alone or in combination with conventional therapies and immune checkpoint blockade, may provide metabolism-informed strategies to overcome drug resistance in cancer.

Persistent CD4+ T cell hyporesponsiveness during recovery from prolonged symptomatic SARS-CoV-2 infection.

Carnosol targets KAT2B/H3K18la axis to regulate histone lactylation and inhibit proliferation of lung cancer cells.

KRAS mutations are prevalent in lung cancer, but KRASG12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione (GSH) metabolism and increased glycolysis. Glutathione S-transferase zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism; however, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRASG12C inhibitors in non–small cell lung cancer (NSCLC) cells. Untargeted metabolomics now revealed significant alterations in GSH and glycolytic pathways, marked by lowered lactate levels and increased oxidized GSH following GSTZ1 ablation. Moreover, pharmacologic inhibition of GSH synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRASG12C inhibition. Our data reveal GSTZ1-associated metabolic and signaling alterations that contribute to drug resistance and identify GSTZ1 as a potential complementary target to sensitize KRAS-mutant NSCLC to KRAS-directed treatments.Significance:Targeting GSTZ1 sensitized KRASG12C-mutant NSCLC cells to KRASG12C inhibitors by disrupting glycolysis, GSH metabolism, and protein phosphorylation. GSTZ1 emerges as a mediator of drug resistance and a therapeutic target, supporting rational combination strategies that exploit metabolic vulnerabilities to enhance KRAS-targeted therapy efficacy and improve outcomes.

7,8-Dihydroxyflavone enhances recombinant proteins expression in CHO cells by modulating SIRT1 signalling to improve mitochondrial respiratory capacity and redox homeostasis.