Breast cancer (BC) is the primary cause of cancer-related deaths in women. Currently, the discovery of biomarkers primarily relies on single platform, which might overlook other potential biomarkers and lead to inaccurate diagnoses. This study aims to: (1) expand the detection range of biomarkers through multiple analytical techniques, thereby improving the accuracy of BC diagnosis, and (2) analyze the metabolic pathways of the biomarkers to explore the metabolic mechanisms underlying BC. Urine samples from BC patients and healthy controls were analyzed using two techniques: Ultra-high performance liquid chromatography combined with Quadrupole-Exactive-Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap-MS), and headspace solid-phase microextraction combined with gas chromatography-high resolution mass spectrometry (HS-SPME/GC-HRMS). Data from each platform was analyzed independently using both univariate and multivariate statistical approaches to identify candidate biomarkers. Subsequently, a mid-level data fusion approach was applied to integrate the candidate biomarkers identified by each platform. The fused data were used to construct orthogonal partial least squares discriminant analysis (OPLS-DA) models and random forest (RF) models, which were then compared against models based on individual platform. The fused RF and OPLS-DA models demonstrated enhanced diagnostic accuracy compared to the individual model. Integrating GC-HRMS and UPLC-Q-Exactive Orbitrap-MS achieved the best performance, with an AUC value of 0.967, sensitivity of 86.37 %, and specificity of 89.19 %. Metabolic pathway analysis revealed that 10 metabolic pathways exert an impact on BC. Four pathways-pyruvate metabolism, sulfur metabolism, taurine and hypotaurine metabolism, and tyrosine metabolism-were found to be associated with BC in both metabolomics and volatolomics studies, indicating that these pathways play pivotal roles in BC. This study confirmed the potential of merging multi-platforms to enhance the accuracy of BC diagnosis, offering new avenues for understanding the metabolic mechanisms of BC.

The detection and imaging of cysteine (Cys) are vital for clinical applications, given its critical role as a biomarker in various diseases. In this study, a cationic fluorescent probe (probe T) was synthesized, featuring benzothiazole as a fluorescent group and acrylate as a Cys recognition site. Compared to other biothiols, probe T specifically detects Cys while targeting mitochondria and nuclei. In addition, probe T has low cytotoxicity and successfully imaged mitochondria and nuclei in MCF-7 cells. The fluorescence intensity ratio (F560 nm/F500 nm) of probe T was linearly correlated with the Cys concentration under 360 nm excitation, and the limit of detection was 60.4 nM. When quantifying Cys in complex biological samples, background interferences often lead to biased quantitative results. To mitigate this, chemometric method based on spectral shape deformation (SSD) theory was used to correct the spectral shape and intensity changes caused by background signals. By combining the SSD model with the ratiometric fluorescence sensing method, it was able to accurately quantify Cys in cell lysate, and the quantitative results were consistent with the kit. Therefore, this method not only provides a new diagnostic tool for the study of Cys-related diseases, but also provides an effective solution for background interference correction.

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodrugs were designed. In this review, we underscore the synergistic relationship among the various organelles and advocate for a holistic view of organelle-targeting design. Through the integration of biology and material science, recent advancements in organelle targeting, escaping, and collaborating are consolidated to offer fresh perspectives for the development of antitumor nanomedicines.

Radioresistance in tumors, driven by the insufficiency and rapid depletion of reactive oxygen species (ROS), limits the efficacy of radiotherapy (RT). This study introduces an Ir@Au nanozyme that enhances tumor radiosensitivity by disrupting energy homeostasis and inducing ferroptosis in tumor cells. The Ir@Au nanozyme mimics glucose oxidase to block the tumor's energy supply, continuously produces hydrogen peroxide (H2O2), and lowers the pH to optimize Fenton reactions. Acting as a peroxidase (POD), it generates additional ROS for chemodynamic therapy (CDT), depletes glutathione (GSH), and perturbs the tumor's antioxidant defenses. Upon exposure to ionizing radiation, the nanozyme absorbs photons and emits electrons, interacting with water to amplify ROS production. This ROS accumulation, combined with radiation, enhances DNA damage and lipid peroxidation, reversing radioresistance and promoting ferroptosis. Additionally, Ir@Au serves as a contrast agent for computed tomography, enabling precise RT through the delineation of tumor boundaries. In summary, the Ir@Au nanozyme effectively disrupts tumor energy homeostasis, initiating ROS-based cascades that inhibit tumor growth. It thus offers a promising strategy for overcoming radioresistance during cancer therapy.

Pampus argenteus, a species distributed throughout the Indo-West Pacific, plays a significant role in the yield of aquaculture species. However, cultured P. argenteus has always been characterised by unbalanced growth synchronisation among individuals, slow growth rate, and lack of excellent germplasm resources. Therefore, we conducted mass selection for fast-growing strain P. argenteus for several consecutive years. Various genetic improvement programs have modified its genome sequence through selective pressure, leaving nucleotide signals that can be detected at the genomic level. In the present study, we combined bulked segregant analysis and transcriptome sequencing to identify candidate single nucleotide polymorphisms (SNPs) and key genes for growth-related traits in P. argenteus. A total of 7,280,936 SNPs and 2,212,379 insertions/deletions were identified in the extreme phenotypes of the fast-growing and slow-growing groups. Based on the examination of SNP frequency differences and sliding-window analysis, 42 SNPs were identified as candidate markers. Moreover, 14 of the 42 SNPs linked to growth-related traits were confirmed to be credible SNPs, and eight growth-related genes were screened, namely myb-binding protein 1 A, insulin A/B chains, α-1B adrenoceptor, engulfment and cell motility protein 3, myosin light chain kinase family member 4, insulin receptor located, unconventional myosin-9b, and matrilin-1. An optimal three-factor model (SNP4&SNP12&SNP14) was constructed using the generalized multifactor dimensionality reduction method, and its accuracy was verified as 67.72 %. These results may benefit genetic studies and accelerate genetic improvement of fast-growing strains of P. argenteus.

The brain naturally synthesizes hydrogen sulfide (H2S) via enzymes such as cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), cysteine aminotransferase (CAT), and cystathionine-γ-lyase (CSE). From a physiological point of view, H2S serves as a neuromodulator with antioxidant and neuroprotective properties. Recent research suggests that H2S is crucial in regulating learning and memory, as its downregulation is commonly observed in cognitive impairment diseases. Preclinical studies suggest that external supplementation, through donors like sodium hydrosulfide (NaHS), can improve cognitive impairment in various cognitive disorder models. Moreover, numerous molecular mechanisms have been proposed to explain the effects of these H2S donors. This review aims to detail the roles of H2S in various models of cognitive impairment and in human subjects, highlighting its potential mechanisms and providing experimental support for its use as a novel therapeutic approach in treating cognitive disorders. Overall, H2S plays a significant role in the treatment of cognitive impairment diseases, but further large-scale studies are still required to support the results of current research.

Cellular metabolism is a dynamic and essential process, with alterations in metabolic pathways serving as hallmark features of cancer. In this study, we developed a chip-based solid-phase extraction mass spectrometry (Chip-SPE-MS) platform for high-sensitivity, high-throughput analysis of cellular metabolites and real-time tracking of metabolic fluxes. The system achieved detection limits ranging from 0.10 to 9.43 μmol/mL for various amino acids and organic acids, with excellent linearity (r ≥ 0.992). By incorporating isotope tracing, the platform enabled derivatization-free, real-time monitoring of 13C-labeled metabolites, such as lactic acid. Our analysis revealed significant metabolic differences between normal (L02) and cancerous (HepG2, HCT116) cells, including enhanced glycolytic activity and elevated lactate production in cancer cells. Furthermore, treatment with 1,25-dihydroxyvitamin D3 was shown to suppress glucose uptake and modulate metabolic activity in HCT116 cells, highlighting the regulatory effects of vitamin D3 on cancer metabolism. This study not only provides novel insights into the metabolic reprogramming associated with cancer but also demonstrates the potential of the Chip-SPE-MS platform as a powerful tool for real-time monitoring of dynamic metabolic processes. The findings have broad implications for cancer therapy and the study of metabolic diseases.

Lipid metabolism has been increasingly recognized to play an influencing role in tumor initiation, progression, metastasis, and therapeutic drug resistance. Targeting lipid metabolic reprogramming represents a promising therapeutic strategy. Despite their structural complexity and poor targeting efficacy, lipid-metabolizing drugs, either used alone or in combination with chemotherapeutic agents, have been employed in clinical practice. The advent of nanotechnology offers new approaches to enhancing therapeutic effects, includingthe targeted delivery and integration of lipid metabolic reprogramming with chemotherapy, photodynamic therapy (PDT), and immunotherapy. The integrated nanoformulation, nanomedicine, could significantly advance the field of lipid metabolism therapy. In this review, we will briefly introduce the concept of cancer lipid metabolism reprogramming, then elaborate the latest advances in engineered nanomedicine for targeting lipid metabolism during cancer treatment, and finally provide our insights into future perspectives of nanomedicine for interference with lipid metabolism in the tumor microenvironment.

Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.

Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer 13C6-glucose, the Nalm6/DOX cells showed an increase in the abundance of 13C-alanine and a decrease in the levels of 13C-lactate, indicating impaired utilization of 13C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.

A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.

The serine hydrolase LYPLAL1 is a poorly characterised enzyme with emerging roles in hepatic metabolism. A multitude of association studies have shown links between variants of this gene locus and metabolic conditions such as obesity and insulin resistance. However, the enzyme's function is still largely unknown. Recent biochemical studies have revealed that it may play a role in hepatic glucose metabolism and that its activity is allosterically regulated. Herein, we use a selective activity-based probe to delineate LYPLAL1's involvement in hepatic metabolism. We show that the enzyme's activity is modulated during metabolic stress, specifically pointing to a putative role in negatively regulating gluconeogenesis and upregulating glycolysis. We also determine that knock-out of the enzyme does not affect liver lipid profiles and bring forth evidence for insulin-mediated control of LYPLAL1 in HepG2 cells. Furthermore, LYPLAL1 activity appears to be largely post-translationally regulated as gene expression levels remain largely constant under insulin and glucagon treatments. Taken together these data point to an enzymatic role in regulating glucose metabolism that may be part of a feedback mechanism of signal transduction.

Adenosine 5'-triphosphate (ATP) plays a pivotal role as an essential intermediate in energy metabolism, influencing nearly all biological metabolic processes. Cancer cells predominantly rely on glycolysis for ATP production, differing significantly from normal cells. Real-time in situ monitoring and rapid response to intracellular ATP levels offers more valuable insights into cancer cell physiology. Herein, we report a novel ratiometric luminescent probe, Ru-Rho, comprised of a ruthenium(II)-based complex and rhodamine 6G (Rho 6G) with excellent water solubility and photostability. Notably, Ru-Rho selectively responds to ATP at acidic conditions, matching the need of monitoring ATP under the acidic intracellular environment of cancer cells. Moreover, the fast ratiometric detection and imaging of ATP under single wavelength excitation improve the detection accuracy. Ru-Rho has been effectively utilized not only for ratio imaging ATP in cells and zebrafish, but also for assessing the efficacy of glycolysis-inhibiting anticancer drugs in intracellular levels, which accelerates the screening process for anticancer drugs and supports the development of new therapeutic agents. The design strategy based on transition metal ruthenium(II) complexes opens a new pathway for constructing ATP luminescent probes, allowing for better adaptation to complex detection requirements.

The present study aimed to investigate the role of 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 4 (PFKFB4) in endometrial cancer cells and to explore its potential molecular mechanisms. PFKFB4 expression in endometrial cancer tissues was detected by immunohistochemistry. Cell Counting Kit‑8, Transwell assays and flow cytometry were used to detect cell proliferation, invasion and apoptosis in endometrial cancer cells after PFKFB4 knockdown. An enzyme‑linked immunosorbent assay was used to detect the glucose and lactic acid contents. Western blotting was performed to detect the levels of glycolysis‑related enzymes, steroid receptor coactivator‑3 (SRC‑3), and phosphorylated SRC‑3. In vivo experiments were performed to investigate the tumorigenic potential of PFKFB4. PFKFB4 expression was upregulated in endometrial cancer tissues compared with that in normal controls, and its upregulation was positively correlated with the depth of myometrial invasion, lymph node metastasis, surgical pathological stage and vascular invasion. PFKFB4 knockdown significantly inhibited proliferation and invasion, increased apoptosis, and decreased oxygen consumption and lactic acid production in endometrial cancer cells. PFKFB4 knockdown decreased SRC‑3 phosphorylation. After simultaneous PFKFB4 knockdown and SRC‑3 overexpression in cancer cells, oxygen consumption, lactic acid production, and glycolysis‑related protein expression were increased compared with those in control cells. PFKFB4 knockdown inhibited tumor proliferation, apoptosis and the expression of Ki‑67. PFKFB4 may regulate glycolysis in endometrial cancer cells by targeting SRC‑3, thus promoting endometrial cancer progression.

The kidney is frequently exposed to high levels of drugs and their metabolites, which can injure the kidney and the proximal tubule (PT) in particular. In order to detect nephrotoxicity early during drug development, relevant in vitro models are essential. Here, we introduce a robust and versatile cell culture insert-based iPSC-derived PT model, which can be maintained in a microphysiological system for at least ten days. We demonstrate the model's ability to predict drug-induced PT injury using polymyxin B, cyclosporin A, and cisplatin, and observe that perfusion distinctly impacts our model's response to xenobiotics. We observe that the upregulation of metallothioneins that is described in vivo after treatment with these drugs is reliably detected in dynamic, but not static in vitro PT models. Finally, we use our model to alleviate polymyxin-induced nephrotoxicity by supplementing the antioxidant curcumin. Together, these findings illustrate that our perfused iPSC-derived PT model is versatile and well-suited for in vitro studies investigating nephrotoxicity and its prevention. Reliable and user-friendly in vitro models like this enable the early detection of nephrotoxic potential, thereby minimizing adverse effects and reducing drug attrition.

Acute myeloid leukemia, myelodysplasia‑related (AML‑MR), a challenging and aggressive subtype of AML, is characterized by unique genetic abnormalities and molecular features, which contribute to its poor prognosis compared with other AML subtypes. The present review summarizes the current understanding of AML‑MR pathogenesis, highlighting notable advancements in genetic and cytogenetic insights. Critical mutations, such as those in the tumor antigen p53 and additional sex combs like 1 genes, and their role in disease progression and resistance to treatment, are explored. The review further investigates how clonal evolution and cellular microenvironment alterations drive AML‑MR transformation and impact patient outcomes. Despite the poor outlook typically associated with AML‑MR, developments in treatment approaches offer hope. The present review considers the efficacy of novel therapeutic agents, including CPX‑351, hypomethylating agents and targeted molecular therapies. Additionally, innovations in immunotherapy and allogeneic hematopoietic stem cell transplantation are discussed as promising avenues to improve patient survival rates. The challenges of treating AML‑MR, particularly in elderly and pretreated patients, underline the necessity for individualized treatment strategies that consider both the biological complexity of the disease and the overall health profile of the patient. The present review focuses on the mechanisms of AML‑MR transformation, highlighting factors that may offer a crucial theoretical foundation and pave the way for future applications in precision medicine. Future research directions include exploring novel targeted therapies and combination regimens to mitigate the transformation risks and enhance the quality of life of patients with AML‑MR.

The initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA-sequencing (RNA-seq), we discovered that Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β-oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade-off involving the reduction of a high-yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial-mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

Hypoxia, a prevalent characteristic of solid tumors, substantially impairs the efficacy of cancer treatments. However, there are no feasible clinical approaches for treating hypoxic tumors. Here, we develop metal-phenolic networks (CuGI) utilizing the natural glycolysis inhibitor (epigallocatechin gallate) and the essential metal element in the human body (copper ions), specifically targeting and annihilating hypoxic cancer cells. CuGI redirects the metabolic pathway of hypoxic cancer cells from anaerobic glycolysis to oxidative phosphorylation, thereby enhancing reactive oxygen species production and promoting oligomerization of lipoylated proteins in the tricarboxylic acid cycle. Through targeted induction of oxidative and proteotoxic stresses, CuGI induces apoptosis and cuproptosis specifically in cancer cells under hypoxic conditions while sparing normal cells. Moreover, cancer cell membrane-coated CuGI (CuGI@CM) exhibits enhanced tumor penetration effect and demonstrates commendable biocompatibility, effectively suppressing colorectal tumor growth. Importantly, CuGI@CM, when combined with vascular disruptors or radiotherapy which aggravate tumor hypoxia, synergistically potentiates therapeutic efficacy. Thus, CuGI represents a specific and potent nanotherapeutic capable of selectively eliminating hypoxic tumors, offering promise in combination therapies to address tumor hypoxia.

Heterogeneous nuclear ribonucleoprotein M (hnRNPM), a splicing regulatory factor with a majority of studies focused on its RNA-binding properties and effects on splicing outcome, is implicated in the progression of various kinds of human cancers, but its mechanisms remain largely enigmatic. Applying the global SUMOylated proteomic screening in colorectal cancer cells, herein we find that hnRNPM is SUMOylated at lysine 17 and Sentrin-specific protease 1 (SENP1) is essential for its de-SUMOylation. Although hnRNPM SUMOylation does not affect its known pre-mRNA splicing-related effects, more intriguingly, it remarkably influences lactate production. Mechanistically, SUMOylated hnRNPM interacts with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to affect its localization and inhibit its phosphorylation, thus suppressing glycolysis. Accordingly, SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice. Also, a negative correlation between hnRNPM SUMOylation and SENP1 expression or phosphorylated PFKFB3 levels can be found in CRC patient samples. These findings not only enhance our understanding of the multifaceted roles of hnRNPM in cancer biology but also open new avenues for the development of targeted therapies aimed at modulating hnRNPM SUMOylation.

Diabetes is a major risk factor for Alzheimer's disease (AD), yet the effect of specific carbohydrate sources in the diet on AD pathology remains unclear. The primary neuroimmune cell, microglia, undergo a metabolic shift during neuroinflammation associated with AD pathology. We utilized existing gene expression data and identified changes in sugar transporters (increased Slc2a1 (glucose) and decreased Slc2a5 (fructose) expression). To examine gene expression with respect to primary sugar source, N9 cells, a mouse microglia cell line, were cultured in glucose or fructose supplemented media and stimulated with lipopolysaccharide (LPS). RNA-sequencing analyses indicated significant changes between control and sugar supplemented media and several differentially expressed genes between glucose and fructose media. Concurrently, 5XFAD mice received equicaloric diets with specific carbohydrate sources: dextrose or fructose. Regardless of diet, sex, or genotype, all mice developed high blood sugar levels; confocal microscopy analyses indicated similar amyloid plaque burden and microglial response relative to the control diet, but there was a change in the microglial response between dextrose and fructose fed mice. Overall, these data indicate microglia preferentially express sugar transporters and sugar source may influence microglial reactivity in response to plaque pathology.

N7-methylguanosine (m7G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m7G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m7G tRNA modifications in promoting GC progression. Upregulation of m7G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression in vitro and in vivo. Mechanistically, METTL1 knockdown reduces the expression of m7G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m7G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.

Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.

The extensive application of plasticizers has led to significant environmental issues. This study focused on the ecotoxic effects on earthworms of the traditional plasticizer di(2-ethylhexyl) phthalate (DEHP) and non-phthalate plasticizers di(ethylhexyl) terephthalate (DEHT) and acetyltributyl citrate (ATBC). At an environmentally relevant concentration (50 mg/kg), significant accumulation of ROS was observed in earthworms, with a trend of DEHP > DEHT > ATBC, inducing oxidative stress and lipid peroxidation. DEHP, DEHT, and ATBC impaired the energy metabolism in earthworms, as evidenced by a sharp reduction in ATP content ranging from 43.2 % to 75.8 %, which was attributed to the disruption of glycolysis and the TCA cycle. Concurrently, the numbers of cocoons and juvenile earthworms decreased by 23.3 %-76.7 % and 24.2 %-75.8 %, respectively, indicating a significant decline in reproductive capacity. Using qPCR, AlphaFold2, and molecular docking techniques, this study is the first to report that because of their similar molecular structures, the alternatives to DEHP exhibit estrogen-like effects in earthworms, which may be a key mechanism of reproductive toxicity. These results provide valuable references and profound insights for the development of novel plasticizer alternatives and the assessment of their impact on soil ecosystems.

Excessive lipid accumulation can lead to obesity, metabolic-associated fatty liver disease, and type 2 diabetes. However, there are currently few drugs that could effectively and safely inhibit the accumulation of intracellular lipids. In this study, we observed that baicalin significantly altered cellular respiration by reducing mitochondrial oxygen consumption while enhancing glycolytic flux, accompanied by increased phosphorylation of AMPK and ACC, suggesting an adaptation to altered energy availability. Baicalin effectively reduced lipid droplet formation and intracellular triglyceride levels in adipocytes, as marked by downregulating genes and proteins associated with lipid storage, including Cd36, Fabp4, and FASN. Transcriptomic analysis identified 2150 differentially expressed genes in baicalin-treated adipocytes, with significant enrichment in metabolic pathways such as glycolysis, gluconeogenesis, and lipid metabolism. Further analysis revealed that baicalin upregulated glycolytic and fatty acid β-oxidation (FAO) pathways while downregulating pyruvate dehydrogenase, inducing a shift toward glycolysis and FAO for energy production. Molecular docking analysis revealed that Adenosine A1 receptor (ADORA1) was the target of baicalin, which inhibited the maturation of sterol regulatory element binding protein 1 (SREBP1) and finally alleviated lipid deposition. These results demonstrate that baicalin induces metabolic reprogramming of adipocytes by inhibiting glucose aerobic metabolism while enhancing anaerobic glycolysis and FAO. Meanwhile, baicalin targets ADORA1, which subsequently influences the processing of SREBP1 and downregulates lipid biosynthesis, positioning baicalin as a potential therapeutic agent against obesity and related metabolic disorders.

Metabolic dysregulation is a critical feature of various cancers, including brain tumors. Studying metabolic changes in tumor cells and tissues significantly improves our understanding of tumor development, progression, and treatment response. In this study, we utilize hyperspectral stimulated Raman scattering (SRS) imaging combined with biochemical spectral modeling to identify unique histological and molecular signatures linked to metabolic diversity across different glioma grades, without the need for labeling. By employing rapid label-free SRS histopathology and multivariate curve resolution analysis, we uncover changes in lipid profiles and varying levels of neuron demyelination from low-grade (LG) to high-grade (HG) gliomas. Quantitative analysis of key metabolites using non-negative least-squares regression spectral modeling reveals a significant increase in cellular proteins, DNA, and cholesterol levels, alongside a reduced redox ratio (flavin adenine dinucleotide (FAD)/NADH) in the glioblastoma (GBM, grade IV) tissue compared to pilocytic astrocytoma (PA, grade I) and healthy brain tissues, indicating a shift toward a pro-malignant metabolic state. A neural network diagnostic classifier, trained on 4547 SRS spectra (healthy: 1263; LG: 815; HG: 2469) from 45 patients with PA and GBM, achieves 99.6% accuracy in detecting and grading brain tumors. This study highlights the potential of hyperspectral SRS imaging for rapid, label-free, and spatially resolved analysis of metabolic heterogeneity in human gliomas, paving the way for metabolome-targeted therapeutic strategies in precision brain tumor treatment.

Recent advancements in single-cell (sc) resolution analyses, particularly in sc transcriptomics and sc proteomics, have revolutionized our ability to probe and understand cellular heterogeneity. The study of metabolism through small molecules, metabolomics, provides an additional level of information otherwise unattainable by transcriptomics or proteomics by shedding light on the metabolic pathways that translate gene expression into functional outcomes. Metabolic heterogeneity, critical in health and disease, impacts developmental outcomes, disease progression, and treatment responses. However, dedicated approaches probing the sc metabolome have not reached the maturity of other sc omics technologies. Over the past decade, innovations in sc metabolomics have addressed some of the practical limitations, including cell isolation, signal sensitivity, and throughput. To fully exploit their potential in biological research, however, remaining challenges must be thoroughly addressed. Additionally, integrating sc metabolomics with orthogonal sc techniques will be required to validate relevant results and gain systems-level understanding. This perspective offers a broad-stroke overview of recent mass spectrometry (MS)-based sc metabolomics advancements, focusing on ongoing challenges from a biologist's viewpoint, aimed at addressing pertinent and innovative biological questions. Additionally, we emphasize the use of orthogonal approaches and showcase biological systems that these sophisticated methodologies are apt to explore.

The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment.

L-Lactate has emerged as a crucial metabolic intermediate, moving beyond its traditional view as a mere waste product. The recent discovery of L-lactate-driven protein lactylation as a post-translational modification has unveiled a pathway that highlights the role of lactate in cellular signalling. In this Perspective, we explore the enzymatic and metabolic mechanisms underlying protein lactylation and its impacts on both histone and non-histone proteins in the contexts of physiology and diseases. We discuss growing evidence suggesting that this modification regulates a wide range of cellular functions and is involved in various physiological and pathological processes, such as cell-fate determination, development, cardiovascular diseases, cancer and autoimmune disorders. We propose that protein lactylation acts as a pivotal mechanism, integrating metabolic and signalling pathways to enable cellular adaptation, and highlight its potential as a therapeutic target in various diseases.

Phototherapy has emerged as a promising modality in cancer treatment, garnering considerable attention for its minimal side effects, exceptional spatial selectivity, and optimal preservation of normal tissue function. This innovative approach primarily encompasses three distinct paradigms: Photodynamic Therapy (PDT), Photothermal Therapy (PTT), and Photoimmunotherapy (PIT). Each of these modalities exerts its antitumor effects through unique mechanisms-specifically, the generation of reactive oxygen species (ROS), heat, and immune responses, respectively. However, significant challenges impede the advancement and clinical application of phototherapy. These include inadequate ROS production rates, subpar photothermal conversion efficiency, difficulties in tumor targeting, and unfavorable physicochemical properties inherent to traditional phototherapeutic agents (PTs). Additionally, the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions. To address these limitations, ongoing research is fervently exploring innovative solutions. The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches' effectiveness. Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1α pathway may alleviate tumor hypoxia. Moreover, utilizing self-luminescent materials, near-infrared excitation sources, non-photoactivated sensitizers, and wireless light delivery systems can improve light penetration. Furthermore, integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT. This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges-ultimately illuminating pathways for future research aimed at amplifying this intervention's therapeutic efficacy.

Oxidative stress, metabolism, and epigenetics are deeply interconnected processes that collectively influence cellular function, health status, and contribute to disease progression. This review highlights the critical role of metabolic intermediates in epigenetic regulation, focusing on lactate, glutathione (GSH), and S-adenosylmethionine (SAM). Beyond its traditional role in energy metabolism, lactate modulates epigenetic mechanisms, influencing gene expression and cellular adaptation. Meanwhile, GSH and SAM serve as key regulators of DNA methylation and histone post-translational modifications, maintaining epigenetic homeostasis. These processes are tightly controlled by redox balance and oxidative stress, underscoring the intricate interplay between metabolism and epigenetic regulation. GSH depletion disrupts methylation homeostasis, while oxidative post-translational modifications (oxPTMs) on histones-including S-glutathionylation, carbonylation, and nitrosylation-alter chromatin architecture and transcriptional regulation. dditionally, we focus on histone lactylation, particularly its role in regulating innate and adaptive immune responses. We also explore how GSH and oxidative stress influence lactate levels, potentially inducing histone lactylation or S-glutathionylation through S,D-lactoylglutathione (LGSH), thereby impacting epigenetic regulation. By integrating insights into metabolic-epigenetic crosstalk, this review underscores the role of oxidative stress and central metabolic pathways in regulating epigenetic mechanisms, a concept known as "redox epigenetics." Understanding these intricate interactions offers new perspectives for therapeutic strategies aimed at restoring redox homeostasis and metabolic integrity to counteract disturbances in the epigenetic landscape.

Immunotherapy in the treatment of cancer, with immune inhibitors helps in many cancer types. Many patients still encounter resistance to these treatments, though. This resistance is mediated by metabolic changes in the tumour microenvironment and cancer cells. The development of novel treatments to overcome resistance and boost immunotherapy's effectiveness depends on these metabolic changes.

This review concentrates on the molecular mechanisms through which metabolic transformation contributes to cancer immunotherapy resistance. Additionally, research therapeutic approaches that target metabolic pathways to enhance immunotherapy for resistance.

We used databases available on PubMed, Scopus, and Web of Science to perform a thorough review of peer-reviewed literature. focusing on the tumor microenvironment, immunotherapy resistance mechanisms, and cancer metabolism. The study of metabolic pathways covers oxidative phosphorylation, glycolysis, lipid metabolism, and amino acid metabolism.

An immunosuppressive tumour microenvironment is produced by metabolic changes in cancer cells, such as dysregulated lipid metabolism, enhanced glutaminolysis, and increased glycolysis (Warburg effect). Myeloid-derived suppressor cells and regulatory T cells are promoted, immune responses are suppressed, and T cell activity is impaired when lactate and other metabolites build up. changes in the metabolism of amino acids in the pathways for arginine and tryptophan, which are nutrients crucial for immune function. By enhancing their function in the tumour microenvironment, these metabolic alterations aid in resistance to immune checkpoint inhibitors.

Metabolic change plays a key role in cancer immunotherapy resistance. Gaining knowledge of metabolic processes can help develop efficient treatments that improve immunotherapy's effectiveness. In order to determine the best targets for therapeutic intervention, future studies should concentrate on patient-specific metabolic profiling.

This review delves into the pivotal role and intricate mechanisms of aerobic glycolysis in nasopharyngeal carcinoma (NPC). NPC, a malignancy originating from the nasopharyngeal epithelium, displays distinct geographical and clinical features. The article emphasizes the significance of aerobic glycolysis, a pivotal metabolic alteration in cancer cells, in NPC progression. Key enzymes such as hexokinase 2, lactate dehydrogenase A, phosphofructokinase 1, and pyruvate kinase M2 are discussed for their regulatory functions in NPC glycolysis through signaling pathways like PI3K/Akt and mTOR. Further, the article explores how oncogenic signaling pathways and transcription factors like c-Myc and HIF-1α modulate aerobic glycolysis, thereby affecting NPC's proliferation, invasion, metastasis, angiogenesis, and immune evasion. By elucidating these mechanisms, the review aims to advance research and clinical practice in NPC, informing the development of targeted therapeutic strategies that enhance treatment precision and reduce side effects. Overall, this review offers a broad understanding of the multifaceted role of aerobic glycolysis in NPC and its potential impact on therapeutic outcomes.

Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.

Developing a catalytic nanoenzyme activated by the tumor microenvironment (TME) shows excellent potential for in situ cancer treatment. However, the rational design of a cascade procedure to achieve high therapeutic efficiency remains challenging. In this study, the colorectal TME-responsive multifunctional cascade nanoenzyme Cu2-xO@MnO2@glucose oxidase (GOx)@hyaluronic acid (HA) was developed to target in situ cancer starvation/chemodynamic therapy (CDT)/photothermal therapy (PTT). First, the MnO2 nanolayer specifically decomposes within the acidic TME to generate Mn2+ and oxygen (O2), thereby alleviating the hypoxic TME. Subsequently, Cu2-xO can be vulcanized into Cu2-xS by overexpressing sulfuretted hydrogen (H2S) gas in the colorectal tumor for a second near-infrared (NIR-II) light-triggered deep tissue PTT. Cu2-xS nanoparticles can react with hydrogen peroxide (H2O2) to generate hydroxyl radical (OH) for the CDT. In addition, GOx catalyzes the conversion of glucose into H2O2 for starvation therapy and enhances the CDT efficiency by self-supplying H2O2. Interestingly, the generated reactive oxygen species (ROS) induce immunogenic cell death (ICD), which further activates adaptive cancer immunity for anti-tumor immunotherapy. Finally, therapeutic efficiency was greatly improved after coating with tumor-targeted HA. Collectively, these TME-responsive cascade nanoenzymes can realize PTT, CDT starvation therapy, and immunotherapy, paving the way for the design of TME-responsive cascade nanoenzymes for synergistically enhanced tumor-specific therapy.

Radiofrequency ablation (RFA), a thermoablative treatment for small hepatocellular carcinoma (HCC), has limited therapeutic benefit for advanced HCC patients with large, multiple, and/or irregular tumors owing to incomplete RFA (iRFA) of the tumor mass. It is first identified that iRFA-treated tumors exhibited increased pyruvate kinase M2 (PKM2) expression, exacerbated tumor immunosuppression featured with increased tumor infiltration of suppressive immune cells and increased proliferation, and programmed cell death ligand 1 expression of cancer cell and ultimately a poor prognosis. Herein, a multifunctional nanomedicine is fabricated by encapsulating nanoassemblies of anti-PD-L1 and spermidine-grafted oxidized dextran with shikonin-containing lipid bilayers to reverse iRFA-induced treatment failure. Shikonin, a PKM2 inhibitor, is used to suppress glycolysis in cancer cells, while anti-PD-L1 and spermidine are introduced to collectively reprogram the proliferation and functions of infiltrated CD8+ T lymphocytes. Combined with iRFA, which promoted the exposure of tumor antigens, the intravenous injection of liposomal SPS-NPs effectively stimulated dendritic cell maturation and reversed tumor immunosuppression, thus eliciting potent antitumor immunity to synergistically suppress the growth of residual tumor masses and lung metastasis. The as-prepared liposomal nanomedicine is promising for potentiating the therapeutic benefits of RFA toward advanced HCC patients through reprogramming iRFA-induced tumor immunosuppression.

Gliomas are intricate tumors with numerous metabolic and genetic abnormalities contributing to their aggressive phenotypes and poor prognoses. The study aims at identifying the key molecular metabolic as well as gene expressional variations that could be used to differentiate between different grades of glioma to obtain deeper insights the about metabolic status of glioma that may serve as good candidates of diagnosis in future. In the present study, the metabolomic profiling along with clinical and expressional analyses of glioma biopsies (n = 52; patients comprising both of benign and malignant lesions) was analyzed. The biopsies were subjected to gene/protein expressional analysis using RT-PCR and western blotting and also were subjected to metabolite analyses. The results of the gene/protein expressional analysis exhibited elevated levels of carnitine palmitoyltransferase, monoglyceride lipase, human phosphofructokinase, and isocitrate dehydrogenase in higher grades of glioma when compared to those of control. Our study suggested that the metabolites and gene/protein expressional levels were found to be discriminative among the grades of glioma. The study is deemed as a provider of deeper insights that are essential for differential therapeutic approaches that specifically target the dysregulated metabolome to the benefit of patients.

Metabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

The three-phase structure of solid-state fermentation (SSF) directly affects substrate degradation and fermentation efficiency. However, the mechanism of three-phase regulation on lignocellulose utilization and microbial metabolism is still unclear. Based on comparative transcriptome analysis, a lignocellulose degrading enzyme, manganese peroxidase (GlMnP), which was significantly affected by water stress meanwhile related to triphase utilization, was screened to reveal the mechanism using Ganoderma lucidum as the reference strain. The results showed that GlMnP directly participates in lignocellulose degradation by positively regulating the activity of carboxymethylcellulase (CMCase), filter paper (FPAse), and laccase (LACase) enzymes, and indirectly participates in lignocellulose degradation by negatively regulating the redox levels in microorganisms. In addition, GlMnP can also control microbial glycolysis rate to enhance lignocellulose utilization. The results indicated that GlMnP participates in the liquid-solid-gas triphase regulation on lignocellulose degradation by G. lucidum in SSF.