Analysis of control of glycolysis in ischemic hearts having heterogeneous zones of anoxia.
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Acidosis↗
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Results for “Glycolysis heterogeneity”
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Intracellular pH measurement in frog muscle by means of 31P-nuclear magnetic resonance.
The 31P-NMR technique was used for the monitoring of intracellular pH and studying its heterogeneity in the femoral biceps muscle of Rana catesbiana under anaerobic conditions. The value of intracellular pH of fresh muscle calculated from the chemical shift of intracellular inorganic phosphate (P1) was 7.3 on average and the line width of P1 was about 0.2 ppm. As the line width determined by the relaxation mechanism was 0.099 ppm, the P1 signal in fresh muscle was concluded to consist of overlapped narrow components, which indicated the heterogeneity of muscular pH (about 0.2 pH unit). Living muscle showed gradual acidification due to glycolysis and the decrease in heterogeneity. When glycolysis was suppressed by iodoacetic acid, slight alkalization due to the breakdown of creatine phosphate was observed. When the Lohmann reaction was suppressed by 2, 4-dinitro-1-fluorobenzene, rapid acidification accompanied by the appearance of a new acidic component was observed with the onset of ATP decrease. This new component was not detected in the muscle pretreated with glycerol to disrupt the transverse tubules. Therefore, it is likely that this new acidic component originates in the intracellular compartment, and not in the cellular difference.
Animals↗
Integrated single-cell and spatial transcriptomic analyses reveal malignant epithelial glycolytic heterogeneity and spatial niche remodeling during colorectal cancer progression.
Colorectal cancer (CRC) progression is shaped by metabolic reprogramming and complex interactions within the tumor microenvironment. However, the cellular heterogeneity, spatial organization, and clinical relevance of glycolytic activity in CRC remain incompletely understood. In this study, we integrated single-cell RNA sequencing, bulk transcriptomics, and spatial transcriptomics data to systematically characterize glycolytic heterogeneity in CRC. Glycolytic activity was quantified using five independent scoring methods, consistently showing that epithelial cells exhibited the highest glycolytic activity across the two single-cell cohorts. Stratification of CopyKAT-verified aneuploid malignant epithelial cells into high-glycolysis (HG) and low-glycolysis (LG) subgroups by glycolysis scores revealed that HG cells exhibited higher stemness scores and chromosomal copy number variations. Cell-cell communication analysis revealed that, compared with LG cells, HG cells exhibited increased interaction frequency and strength with immune and stromal populations, indicating enhanced malignant epithelial-microenvironment crosstalk. Spatial transcriptomics analyses further revealed that glycolytic activity varied across normal colorectal tissue, primary CRC, and colorectal liver metastases, accompanied by progressive remodeling of epithelial-associated spatial niches and MIF-mediated intercellular communication. Bulk transcriptomic analysis identified a glycolysis-related prognostic signature with robust predictive performance, which served as an independent prognostic factor for overall survival in CRC cohorts. Collectively, these findings indicate that glycolytic heterogeneity is a key feature of CRC malignant epithelial cells and is closely associated with tumor progression, microenvironmental remodeling, and clinical outcomes.
Humans↗
Single-cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.
Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell differentiation, but its impact on gene expression in each epithelial cell type remains unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of rabbit cecum-derived organoid monolayers grown under immerged or ALI conditions. We then compared these organoid cell type-specific gene expression profiles to a scRNA-seq atlas of the rabbit cecal epithelium in vivo. We selected the rabbit model notably because, unlike mice, it possesses BEST4+ epithelial cells, a newly discovered subset of mature absorptive cells. Our analysis revealed a high degree of transcriptomic similarity between in vivo and organoid-derived stem and transit-amplifying cells. ALI culture markedly enhanced the differentiation of the secretory lineage, especially goblet cells, whose transcriptome closely resembled that of in vivo goblet cells. Furthermore, ALI was the only condition allowing the detection of enteroendocrine cells. BEST4+ cells, however, were absent from organoids in immerged or ALI conditions despite their presence in vivo. In addition, ALI culture led to a consistent downregulation of hypoxia and glycolysis-associated genes across all cell types, which suggests a metabolic shift likely driven by increased oxygen availability in ALI conditions. Cell-cell communication analyses further indicated that ALI more closely mirrored in vivo patterns than immerged condition. Altogether, these results demonstrate that ALI culture allows for better recapitulation of the in vivo cellular heterogeneity and molecular signatures of the intestinal epithelium.NEW & NOTEWORTHY Using single-cell RNA sequencing, this study shows that air-liquid interface (ALI) culture enhances secretory lineage differentiation of intestinal organoid cell monolayers and improves transcriptomic similarity to the native epithelium. ALI reduced hypoxia-associated gene expression and better recapitulates in vivo-like cell-cell interactions, supporting its value for modeling intestinal epithelial heterogeneity in organoids.
Animals↗
Carbohydrate metabolism in rat kidney: heterogeneous distribution of glycolytic and gluconeogenic key enzymes.
The distribution pattern of the unidirectional enzymes of gluconeogenesis and glycolysis, fructose-1,6-bisphosphatase (EC 3.1.3.11) and phosphofructokinase (EC 2.7.1.11), within the nephron was studied by the microdissection and oil-well techniques according to LOWRY and PASSONNEAU [11]. Fructose-1,6-bisphosphatase activity was found to be highest in the proximal convolution, whereas phosphofructokinase revealed its highest activity in the thick ascending limb of Henle's loop. Starvation and NH4Cl acidosis led to an increase of fructose-1,6-bisphosphatase activity in the proximal convolution. These results indicate a clear separation of the glucose synthesizing and degrading pathways within the nephron, which is maintained in conditions that stimulate gluconeogenesis.
Acidosis, Renal Tubular↗
Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.
BACKGROUND: The tumor microenvironment (TME) of glioma harbors diverse cell types; however, cell metabolic heterogeneity remains to be explored. This study aims to characterize the metabolic features of different cell types in the TME by integrating multiple datasets, including genomics, bulk and single-cell transcriptomics, and metabolomics. METHODS: Unsupervised machine learning was used to construct an energy metabolic classifier based on the metabolic pathways identified from bulk RNA-seq of gliomas in the TCGA dataset. The classifier was externally validated using multiple datasets, including genomics, bulk RNA-seq, snRNA-seq, and the metabolomics data. Furthermore, metabolic heterogeneity associated with the classifier was further characterized at single-cell resolution. RESULTS: The energy metabolism-based classifier stratified patients into two prognostic clusters: patients in cluster 1 were characterized by high pathway activity of glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), whereas patients in cluster 2 exhibited higher activity in glutaminolysis. This metabolic classifier revealed both intratumoral and intertumoral metabolic heterogeneity, and the complexity was further validated by the metabolomics profiling and snRNA-seq data from the CPTAC dataset. Notably, OSMR, highly expressed in cluster 1, showed significant co-expression with key glycolytic enzyme genes. The OSM/OSMR/JAK1/STAT3 axis potently drives malignant progression of glioma cells, specially enhancing their invasive and migratory capabilities. Single-cell resolution analyses demonstrated that tumor metabolic heterogeneity is primarily driven by malignant cells rather than non-malignant components, while tumor microenvironment (TME) factors were also found to modulate malignant cell metabolism. Significantly, glycolytic activity in glioma cells increased during the phenotypic transition from PN (proneural) to MES (mesenchymal), with cluster 1 metabolic phenotypes predominating in the tumor core. Compared to cluster 2, cluster 1 patients exhibited higher mRNA expression of immunosuppressive checkpoint genes, which correlated with pronounced immunosuppression in the TME. Furthermore, various immune cells demonstrated distinct metabolic preferences at single-cell resolution. CONCLUSIONS: This study developed an energy metabolic-based classifier for gliomas with prognostic and therapeutic potential. Metabolic reprogramming was linked with the PN-to-MES transition of glioma cells and immunosuppression in the tumor microenvironment. Multi-omics data, especially snRNA-seq, offered insights into metabolism heterogeneity at single-cell resolution, enabling personalized treatment strategies.
Humans↗
Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation.
BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and heterogeneous disorder lacking validated biomarkers or targeted therapies. Clinical variability and elusive pathophysiology hinder progress toward effective diagnostics and treatment. Core symptoms include persistent fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and pain. We tested whether an individualized, “n-of-1” genomic and transcriptomic framework combined with comprehensive, participant-informed phenotyping could reveal molecular signatures unique to each patient. METHODS: Clinical-grade whole-genome sequencing was conducted in 31 affected individuals from 25 families, with RNA-seq performed on a subset (16 affected, 7 unaffected) using blood samples. Machine-learning assisted variant triage, transcript-aware damage prediction, and expert review identified pathogenic or likely pathogenic variants in 8 of 25 probands (32%) and 12 of 31 affected individuals (39%). RESULTS: Findings revealed marked genetic heterogeneity, including large-effect rare and more common variants. Implicated pathways included ATP generation, oxidative phosphorylation, fatty acid oxidation; regulation of glycolysis, amino acid and lipid turnover; ion and solute homeostasis; synaptic signaling, excitability, oxygen transport, and muscle integrity, resilience, and post-exertional recovery; previously implicated processes. Plausible modifiers influencing disease onset, severity, and relapsing–remitting patterns and possibly explaining intrafamilial variability and inconsistent findings across studies, were also identified. Despite gene-level diversity, downstream effects converged on impaired energy production, reduced stress resilience, and vulnerability to post-exertional metabolic failure; disruptions consistent with core ME/CFS symptoms of exertional intolerance, cognitive fog, and fatigue. CONCLUSIONS: Our findings support the hypothesis that at least a subset of ME/CFS cases represent distinct molecular disorders that converge on shared physiological pathways. Validation in larger, more diverse cohorts will be essential to test this hypothesis and establish generalizability, but increase size alone is unlikely to resolve causation in a disorder defined by rarity, heterogeneity, and molecular complexity. We suggest that progress will require experimental designs that integrate individual-level genomic data with deep, participant-informed deep phenotyping, capturing the combined effects of rare and common variants and environmental modifiers on disease expression and progression. We believe that an individualized precision medicine framework will uncover molecular drivers and modifiers of ME/CFS previously obscured by heterogeneity, enabling biologically informed stratification, improved trial design, biomarker discovery, and targeted interventions in this historically neglected condition.
Humans↗
Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.
Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and profound metabolic alterations that contribute to immune dysfunction and organ failure. This Review synthesizes proteomic evidence on sepsis-associated alterations in proteins involved in metabolic pathways across circulating biofluids, immune cells, and organs. Across plasma and urine, proteomic studies identify disturbances in lipoprotein-associated pathways, redox homeostasis, mitochondrial function, and substrate metabolism, indicating that protein signatures of metabolic dysregulation are systemic and detectable across biofluids. In immune cells, monocytes and neutrophils, proteomic analyses reveal a shift toward glycolysis with concurrent impairment of mitochondrial pathways alongside phenotype-dependent differences in lipid and redox-related programs. Organ-level studies further show that metabolic responses are heterogeneous, with distinct trajectories in the kidney, heart, liver, lung, skeletal muscle, and brain. These observations support the concept that sepsis involves compartment-specific remodeling of metabolism-associated protein networks rather than a single convergent metabolic state. Proteomics also highlights potential translational opportunities by identifying metabolism-associated proteins linked to disease severity, clinical phenotypes, and biologically distinct patient subgroups, although the current evidence remains largely exploratory and context-dependent. Overall, proteomics provides a complementary framework for understanding the molecular regulation of sepsis-associated metabolic dysfunction and may refine biological stratification and therapeutic targeting, particularly when integrated with longitudinal sampling and multiomic data.
Humans↗
Single-cell profiling reveals a novel CAF subpopulation linking stromal heterogeneity to immune suppression in breast cancer subtypes.
BACKGROUND: The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are key regulators of these processes, yet their subtype-specific contributions in BC remain insufficiently defined. METHODS: We integrated three single-cell RNA sequencing datasets from 29 BC patients to characterize stromal populations. Bulk RNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between CAF subsets and immune infiltration. Gene signatures were derived to identify subtype-specific CAF-immune interactions, prognostic markers, and potential predictors of chemotherapy response. RESULTS: Three conserved stromal populations (iCAFs, myCAFs, and pericytes) were identified, along with a previously unrecognized subset, the cluster 3 (CL3) CAF-like cells, referred as metabolic stressed CAF (msCAF). msCAF cells displayed transcriptional programs associated with antigen presentation, stress response, glycolysis, and extracellular matrix remodeling. Their abundance was inversely correlated with T-cell infiltration and function, in a subtype-specific manner: triple negative breast cancer (TNBC) was enriched for msCAFs in immune-infiltrated but functionally constrained microenvironments, whereas Luminal A tumors exhibited weaker immune infiltration with heterogeneous CAF-immune associations. msCAFs were characterized by a conserved gene signature (HLA-A, HLA-C, IL32, EMP3) and subtype-specific genes related to T-cell exhaustion. Several genes demonstrated prognostic relevance with distinct patterns in Luminal A (IER3, TIMP1, TBX3, SEC61G) and TNBC (ADM, C4orf3, LDHA) tumors, as well as shared biomarkers (FN1, LOXL2, P4HA1). Multiple msCAF genes also predicted chemotherapy response, suggesting utility as treatment stratification biomarkers. CONCLUSION: msCAFs represent a clinically relevant CAF subset that drives immune suppression, impacts subtype-specific prognosis, and influences therapy response in BC. These findings highlight msCAFs as promising targets for enhancing immunotherapy and personalizing treatment strategies.
Humans↗
Intracellular buffering.
In the quantification of buffering the distinct roles of bicarbonate and of other buffers must be taken into account. The determination of the total non-bicarbonate buffer value, betaa, in intact tissues is complicated by active pH regulation and by heterogeneity of cytoplasm with respect to betaa, while heterogeneity with respect to pH in vivo could cause errors in estimates made with homogenates. Available estimates of betaa are discussed, as are the individual contributions of proteins, dipeptides and phosphates. A high betaa is appropriate in cells which sometimes have high rates of glycolysis, or which buffer extracellular fluid, but non-protein buffer concentrations can be well below the limits imposed by osmolarity, perhaps because buffering can upset ionic gradients.
Acid-Base Equilibrium↗
Metabolism of human erythrocytes. Studies in health and disease.
Deficiency states have been well established in nine enzymes of anaerobic glycolysis and suggested, but inadequantely confirmed, in others. In additon, hemolytic anemia has been defined in glucose-6-phosphate dehydrogenase deficiency, in certain enzymes glutathione metabolism of importance to the function of the oxidative hexsemonophosphate shunt, and in certain enzymes of nucleotide metabolism. In heterogeneous dyserythropoietic states with ineffective erythropoiesis, enzyme ratios are grossly distorted and differ greatly from those of either normal or reticullocyte-rich blood. Red blood cell (RBC) enzyme deficiencies show noticeable genetic polymorphism, most apparently recessively transmitted anemias actually resulting from inheritance of two different mutant, allelic genes. In addition to causing hemolytic syndromes in selected instances, deficiencies of enzymes more important to other tissues than to the RBC itself are detectable by assay of hemolystates.
Anemia, Hemolytic↗
Histochemical properties of skeletal muscle fibers in streptozotocin-diabetic rats.
The response of rat gastrocnemius muscle fibers to chronic streptozotocindiabetes was studied. Transverse sections of this muscle from normal and diabetic rats were histochemically assayed for reduced diphosphopyridine nucleotide-diaphorase, myofibrillar adenosine triphosphatase, mitochondrial alpha-glycerophosphate dehydrogenase, beta-hydroxybutyrate dehydrogenase, and alkaline phosphatase activities. Cross-sectional areas of the fiber types were measured, and fiber capillarization and populations estimated. Chemically-induced diabetes appeared to have little effect on the metabolic or morphological properties of slow-twitch fibers. However, a general dedifferentiation occurred in the 2 fast-twitch fiber populations. There was a loss of oxidative potential in the fast-twitch-oxidative-glycolytic fibers, and a significant decrease in size in the fast-twitch-glycolytic fibers. No change in the proportions of slow- and fast-twitch fibers in the muscles of diabetic rats occurred. It is concluded that hypoinsulinism has differential effects on the 3 fiber types in heterogeneous rat skeletal muscle, and that slow-twitch fibers are least affected by the diabetic condition.
Adenosine Triphosphatases↗
ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.
Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.
Animals↗
Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
Ferroptosis↗
Alterations of endothelial cell bioenergetics in congenital diaphragmatic hernia.
BACKGROUND: Pulmonary vascular development in congenital diaphragmatic hernia (CDH) is characterized by impaired angiogenesis and pathologic remodeling that contribute to pulmonary hypertension/hypoplasia. Mitochondria regulate endothelial energy, redox balance, and angiogenic signaling, suggesting a role in CDH vascular disease. METHODS: Endothelial cells (ECs) were isolated from umbilical veins of healthy and CDH newborns. Mitochondrial bioenergetics and glycolytic acidification were assessed by extracellular flux. Oxidative stress, mitochondrial membrane potential, and mitochondrial mass were measured by flow cytometry, while mitochondrial DNA copy number (mtDNA-CN) and morphology were evaluated by qPCR and microscopy. RESULTS: CDH ECs exhibited increased maximal respiratory capacity with elevated proton leak and reduced ATP coupling efficiency. Basal glycolytic activity was elevated. These changes were accompanied by increased mitochondrial superoxide and cellular reactive oxygen species and by severity-associated loss of membrane potential. Despite reduced MitoTracker Green, mtDNA-CN was unchanged, and confocal imaging revealed a highly branched, peripherally distributed network. CONCLUSIONS: These data define a distinct endothelial mitochondrial phenotype marked by metabolic activation, bioenergetic inefficiency, and oxidative stress, with concurrent upregulation of glycolysis and oxidative phosphorylation rather than a glycolytic shift. Structural remodeling with preserved mitochondrial content further indicates qualitative changes. Collectively, these findings link mitochondrial dysfunction to vascular pathology in CDH. IMPACT: Defines a distinct mitochondrial state in CDH endothelium, characterized by metabolic activation with inefficient oxidative phosphorylation, redox imbalance, and structural reorganization in primary human cells. Demonstrates that mitochondrial alterations in CDH occur without changes in mitochondrial content, supporting a model of qualitative remodeling. Provides rare human, cell-based data in CDH, addressing a major gap in a field largely reliant on animal models and indirect measures. Links mitochondrial alterations to clinical severity, supporting relevance to disease burden and heterogeneity. Establishes a framework for mitochondrial involvement in CDH vascular disease, with potential implications for future biomarker development and therapeutic targeting.
Journal Article↗
Activity patterns of phosphofructokinase, glyceraldehydephosphate dehydrogenase, lactate dehydrogenase and malate dehydrogenase in microdissected fast and slow fibres from rabbit psoas and soleus muscle.
Methods for standardized determination of phosphofructokinase (PFK), glyceraldehydephosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) activities in nanogram samples of microdissected single fibres of rabbit psoas and soleus muscle are described. Fast and slow fibres in soleus muscle show lower absolute activities of these enzymes than the respective fibre types in psoas muscle. Slow fibres represent a more uniform population in the two muscles according to absolute and relative activities of the enzymes investigated. Slow fibres are characterized by high activities of MDH and relatively low activities of glycolytic enzymes. Fast fibres in the soleus muscle represent a population with high activities of MDH and glycolytic enzymes. Fast fibres in psoas muscle represent a heterogeneous population with high activities of glycolytic enzymes and extremely variable activity of MDH. More than 10-fold differences exist in the MDH activities of the extreme types of this fibre population. Differences in the activity levels of MDH in single fast type fibres but also in the activities of glycolytic enzymes between fast and slow fibres are greater than those reported between extreme white and red rabbit muscles.
Animals↗
Intracellular pH: measurement, control, and metabolic interrelationships.
Recent work in the field of cell pH has been characterized by many developments in techniques of measurement, by increasing knowledge of the mechanism of control of cell pH, and by progress in the establishment of relationships between cell pHi and certain areas of intermediary metabolism. Though the weight of evidence is much in favor of control cell pH by active transport of H+, the situation remains somewhat unsatisfactory due to lack of a completely adequate explanation of the work of Carter's group. The heterogeneity of cell pH raises problems in the intrepretation of hydrogen ion equilibria across cell membranes and serious difficulties in correlating changes with alterations in metabolism. To put this into perspective, however, the later difficulties are no greater than many experienced with cell constituents other than hydrogen ions.90 As in other fields, knowledge must advance by making the best of the currently available methods until such time as better techniques become available.
Acid-Base Equilibrium↗
HIF1A+CSF3R+ neutrophils-dominated hypoxic niche induced metabolic reprogramming for neoadjuvant therapy resistance in NSCLC.
BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth. METHODS: On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A+ CSF3R+ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A+ CSF3R+ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen. RESULTS: Centered on HIF1A+ CSF3R+ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment. CONCLUSION: Our study emphasized the role of HIF1A+ CSF3R+ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A+ CSF3R+ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A+ CSF3R+ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.
Humans↗