Diabetic liver injury (DLI) is a significant complication of diabetes mellitus, leading to severe liver dysfunction and non-alcoholic fatty liver disease (NAFLD). Understanding the metabolic alterations and reprogramming in DLI is critical for identifying therapeutic targets. Despite the prevalence of DLI, its underlying metabolic mechanisms remain poorly understood, and effective treatments are lacking. In this study, we employed a multimodal mass spectrometry imaging approach, combining air-flow-assisted desorption electrospray ionization (AFADESI-MSI) with matrix-assisted laser desorption ionization (MALDI-MSI) to achieve a comprehensive spatial analysis of metabolic changes in DLI model rats, focusing on the potential therapeutic effects of ferulic acid, a compound known for its antioxidant and anti-inflammatory properties. This approach allowed for the wide-coverage and high-resolution visualization of over 200 metabolites in the liver tissues of DLI model rats. The study involved comparing metabolic profiles between control, DLI, and ferulic acid-treated groups, with ferulic acid administered at a dosage of 50 mg/kg daily for 20 weeks. The analysis revealed significant metabolic reprogramming in DLI, characterized by alterations in glucose, lipid, bile acid, and nucleotide metabolism. Specifically, we identified over 100 metabolites with heterogeneous distributions across liver sections, highlighting region-specific metabolic impairments. Ferulic acid treatment notably reversed many of these metabolic disturbances, particularly in glucose and lipid metabolism, suggesting its potential to restore metabolic homeostasis in DLI. This study provides critical insights into the metabolic underpinnings of DLI and demonstrates the therapeutic potential of ferulic acid in modulating these pathways. The findings underscore the utility of AFADESI- and MALDI-MSI in studying liver diseases and suggest that the metabolites identified could serve as novel biomarkers for DLI diagnosis and treatment.

Fracture healing in patients with type 2 diabetes mellitus (T2D) is markedly impaired, characterized by a prolonged inflammation phase and defective osteoblast differentiation at the fracture site. In this study, we identified aberrant cellular glycolysis at T2D fracture sites, with bone marrow mesenchymal stem cells (BMSCs) exhibiting suppressed glycolysis and macrophages displaying enhanced glycolysis, mediated by the dysregulation of hypoxia-inducible factor-1α (HIF-1α). To rectify these metabolic imbalances, we developed a multifunctional nanocomposite PN@MHV hydrogel. Myricitrin, a flavonoid glycoside, forms the MHV hydrogel by cross-linking with HA-PBA and PVA via hydrogen bonds, and upregulates glycolysis through HIF-1α, thus promoting osteoblast differentiation under high glucose environment. To further regulate the inflammatory microenvironment, we incorporated nanoparticles loaded with PX-478, a HIF-1α specific inhibitor, into the hydrogel, with folic acid covalently modified to target proinflammatory M1 macrophages. This PN@MHV hydrogel bidirectionally regulated glycolysis via HIF-1α, enhancing osteoblast differentiation while attenuating macrophage-mediated inflammation. Comprehensive in vitro and in vivo experiments in a T2D fracture mouse model confirmed the hydrogel's ability to improve the inflammatory microenvironment and accelerate bone healing. Our findings underscore the therapeutic potential of targeting cellular glycolysis as a promising approach for enhancing fracture healing in diabetic patients.

Cuproptosis-a novel cell death mechanism-is an innovative strategy for tumor therapy. However, the insufficient efficacy of cuproptosis, primarily owing to the low sensitivity of tumor cells to Cu ions, remains a major challenge. In this study, we design TiCuMOF@PEG@l-Arg@TPP (TCPAT) nanoparticles to facilitate self-sensitized cuproptosis for anti-tumor therapy through the dual upregulation of p53. TiMOF serves as a microwave sensitizer by generating reactive oxygen species (ROS). Notably, the uniformly distributed Cu ions within the MOF serve as co-catalysts to provide reactive sites that enhance ROS generation. Additionally, the ROS generated are utilized to oxidize l-arginine, thus resulting in the release of nitric oxide (NO), which has a long half-life and diffusion distance, thereby enabling it to penetrate deep into the tumor regions that are typically inaccessible to ROS. Furthermore, TCPAT not only induces cuproptosis but also leverages the efficiently generated ROS and cascade-released NO for the dual upregulation of p53. This upregulation subsequently inhibits glycolysis, increases cellular sensitivity to Cu ions, and facilitates self-sensitized cuproptosis. Consequently, the self-sensitized cuproptosis strategy, dependent on the efficient generation of ROS, presents a promising avenue for tumor therapy based on cuproptosis mechanisms.

Diets high in red and processed meat and low in plant-based foods are associated with an increased risk of colorectal cancer. We investigated whether berry supplementation can impact gut metabolism to counteract the presumably cancer promoting luminal environment sustained by high red and processed meat consumption. Altogether 43 healthy adults were randomized either into Meat group (150 g/d red and processed pork meat) or Meat & Berries group (150 g/d red and processed meat and 200 g/d of mixed berries). Fecal samples and 3-d food records were collected at baseline and at the end of the four-week intervention. Intakes of vitamin C, vitamin E, manganese, insoluble fiber, and the polyphenols available in the database were significantly higher in the Meat & Berries than Meat group. While between-group comparisons found no significant differences in the gut microbiota, the within-group analyses showed that the relative abundances of beneficial Roseburia and Faecalibacterium were decreased and an unclassified group of Peptostreptococcaceae increased significantly in the Meat group. In comparison to the Meat group, berry consumption resulted in higher fecal concentrations of p-coumaric and protocatechuic acids and lower viability of fecal water (FW) -treated CV1-P fibroblastoma and human colon adenocarcinoma HCA-7 and Caco-2 cells (P<.05 with 30% FW). Berry consumption provided protective nutrients and mitigated potentially unfavourable gut microbiota changes seen in the Meat group, increased fecal polyphenol metabolites, and reduced viability of FW-treated colon adenocarcinoma cells, collectively suggesting that berries may protect against colorectal cancer development.

Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

Chronic arsenic exposure enhances the probability of lung cancer with the underlying mechanisms remain unknown. Glutamine-driven synthetic metabolism, including nucleotide synthesis, amino acid production, TCA cycle replenishment, glutathione synthesis, and lipid biosynthesis, is crucial for both cancer initiation and progression. This study demonstrated that chronic exposure to 0.1 μM arsenite for as long as 36 weeks induced malignant transformation in human bronchial epithelial cells (BEAS-2B). Metabolomics were used to systematically disclose metabolic characteristics in arsenic-transformed malignant (As-TM) cells. Significantly changed metabolites were enriched in alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, glutathione metabolism, butanoate metabolism, TCA cycle, and arginine and proline metabolism. It is worth noting that glutamate located at the intersection of the enriched metabolism pathways. Glutamine deprivation attenuated the oncogenic phenotypes, including capacity of wound healing and proliferation, in As-TM cells. And the expression levels of mRNA and proteins associated with glutamine metabolism-related transporters and enzymes, including SLC7A11, GCLM, and GCLC, were significantly increased, with SLC7A11 exhibiting the most substantial increase. Moreover, arsenite transformation progressively elevated SLC7A11 mRNA and protein levels over time. The SLC7A11 inhibitor sulfasalazine remarkably attenuated arsenite-induced oncogenic phenotypes. Collectively, our data suggest that chronic arsenite exposure enhances glutamine metabolism through upregulation of SLC7A11, thereby promoting cell proliferation and malignant transformation. These results provide new insights for preventive and therapeutic strategies for lung cancer linked to arsenic exposure.

Acute myeloid leukemia (AML) comprises a diverse group of blood cancers with varying genetic, phenotypic, and clinical traits, making development of targeted therapy challenging. Metabolic reprogramming in AML has been described as relevant for chemotherapy effectiveness. 3-Bromopyruvate (3-BP) is an anticancer agent that undermines energy metabolism of cancer cells. However, the effect of 3-BP in hematologic malignancies, such as AML, needs further investigation. Thus, we aimed to explore 3-BP as a chemo-sensitizing agent in AML. Different approaches of combining 3-BP with classical chemotherapy (daunorubicin and cytarabin) were tested in diverse AML cell lines. Cell sensitivity to the different drug combinations was analyzed by Trypan blue staining. The effect of pre-treatment with a non-toxic concentration of 3-BP was assessed on the AML cell metabolic profile (Western blot and immunofluorescence), mitochondrial activity (cytometry flow), and antioxidant capacity (colorimetric detection kit). KG-1 and MOLM13 cells showed increased sensitivity to chemotherapy (decreased EC50 values) after exposure to a non-toxic concentration (5 μM) of 3-BP. In both cell lines, 5 μM 3-BP decreased glucose consumption without changing extracellular lactate levels. 5 μM 3-BP treatment increased reactive oxygen species levels and decreased cell antioxidant capacity by depleting reduced glutathione levels in both KG-1 and MOLM13 cells. Our results demonstrate that non-toxic concentrations of 3-BP enhance the effect of classical chemotherapy in AML cells through a pro-oxidant mechanism. These data unveiled a new approach for AML treatment, using 3-BP or other pro-oxidant agents as co-adjuvants of chemotherapy, subsiding chemotherapy-induced side effects.

Fatty acid oxidation (FAO) denotes the mitochondrial aerobic process responsible for breaking down fatty acids (FAs) into acetyl-CoA units. This process holds a central position in the cancer metabolic landscape, with certain tumor cells relying primarily on FAO for energy production. Over the past decade, mounting evidence has underscored the critical role of FAO in various cellular processes such as cell growth, epigenetic modifications, tissue-immune homeostasis, cell signal transduction, and more. FAO is tightly regulated by multiple evolutionarily conserved mechanisms, and any dysregulation can predispose to cancer development. In this view, we summarize recent findings to provide an updated understanding of the multifaceted roles of FAO in tumor development, metastasis, and the response to cancer therapy. Additionally, we explore the regulatory mechanisms of FAO, laying the groundwork for potential therapeutic interventions targeting FAO in cancers within the metabolic landscape.

Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify the mechanism underlying their relationship. To investigate whether systemic inflammation against high-fat diet (HFD)-related dysbiosis promotes the Warburg effect in tumors at the squamocolumnar junction (SCJ), we applied K19-Wnt1/C2mE (Gan) mice, fed either HFD or control diet ± acidic bile salts (ABS) with/without clodronate liposomes (CLs), and in vitro studies using MKN7 cells with/without THP1-derived macrophages. Then, we assessed the involvement of oxidative stress (OS) in the Warburg effect by comparing nuclear factor-erythroid 2-related factor 2 (Nrf2) knockout Gan mice with Gan mice. Tumors with macrophage infiltration in the HFD + ABS group were larger than in the control group. Gene Set Enrichment Analysis revealed enhancement of the OS signaling in tumor of the HFD + ABS group. The HFD + ABS group mice demonstrated induction of OS, Nqo1, tumor necrosis factor alpha (TNFα), and the Warburg effect in tumors and mucosal barrier dysfunction of dysbiotic gut. All of them were abolished with diminishing macrophage infiltration by additional CL treatment. Stimulation with TNFα, but not ABS nor lipopolysaccharide, on MKN7 cells activated the Warburg effect. In MKN7 cells cocultured with the macrophages whose TNFα expression was induced by the lipopolysaccharide pretreatment, the Warburg effect was enhanced in TNFα concentration-dependent manners. In Nrf2 knockout Gan mice, tumors shrank with reducing OS, TNFα, and Warburg effect, along with decreasing macrophage infiltration. Accordingly, MetS may develop GCA through the Nrf2-related Warburg effect under the TNFα stimulation from the macrophages activated by both local ABS exposure and systemic lipopolysaccharide exposure from leaky gut with HFD-related dysbiosis.NEW & NOTEWORTHY In K19-Wnt1/C2mE (Gan) mice, a high-fat diet accompanied by orally taking acidic bile salts (ABS) promoted inflammation-associated carcinogenesis at the squamocolumnar junction (SCJ), maybe due to transudates from dysbiotic gut into systemic circulation. Systemic lipopolysaccharide exposure and local ABS exposure at the SCJ activate macrophages to induce the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) and TNFα, which might promote Warburg effect in cancer cells. These phenomena were abolished in the Nrf2-knockout Gan mice.

Aberrant lipid metabolism is increasingly recognized as a hallmark of cancer, contributing to tumor growth, metastatic dissemination, and resistance to therapy. Cancer cells reprogram key metabolic pathways-including de novo lipogenesis, lipid uptake, and phospholipid remodeling-to sustain malignant progression and adapt to microenvironmental demands. This review summarizes current insights into the role of lipid metabolic reprogramming in oncogenesis and highlights recent advances in lipidomics that have revealed cancer type- and stage-specific lipid signatures with diagnostic and prognostic relevance. We emphasize the dual potential of lipid metabolic pathways-particularly those involving phospholipids-as sources of clinically relevant biomarkers and therapeutic targets. Enzymes and transporters involved in these pathways have emerged as promising candidates for both diagnostic applications and pharmacological intervention. We also examine persistent challenges hindering the clinical translation of lipid-based approaches, including analytical variability, insufficient biological validation, and the lack of standardized integration into clinical workflows. Furthermore, the review explores strategies to overcome these barriers, highlighting the importance of incorporating lipidomics into multi-omics frameworks, supported by advanced computational tools and AI-driven analytics, to decipher the complexity of tumor-associated metabolic networks. We discuss how such integrative approaches can facilitate the identification of actionable metabolic targets, improve the specificity and robustness of lipid-based biomarkers, and enhance patient stratification in the context of precision oncology.

The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.

In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2 %, 24.0 %, and 5.7 %, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6 %), conversion from serine (45.1 %), and other sources (9.4 %). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7 %) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3 %) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100 %), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.

By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.

Colorectal cancer (CRC) exhibits significant diversity and heterogeneity, posing a requirement for novel therapeutic targets. Polysulfides are associated with CRC progression and immune evasion, but the underlying mechanisms are not fully understood. Sulfide: quinone oxidoreductase (SQR), a mitochondrial flavoprotein, catalyzes hydrogen sulfide (H2S) oxidation and polysulfides production. Herein, we explored its role in CRC pathogenesis and its potential as a therapeutic target. Our findings revealed that SQR knockout disrupted polysulfides homeostasis, diminished mitochondrial function, impaired cell proliferation, and triggered early apoptosis in HCT116 CRC cells. Moreover, the SQR knockout led to markedly reduced tumor sizes in mice models of colon xenografts. Although the transcription of glycolytic genes remained largely unchanged, metabolomic analysis demonstrated a reprogramming of glycolysis at the fructose-1,6-bisphosphate degradation step, catalyzed by aldolase A (ALDOA). Both Western blot analysis and enzymatic assays confirmed the decrease in ALDOA levels and activity. In conclusion, the study establishes the critical role of SQR in mitochondrial function and metabolic regulation in CRC, with its knockout leading to metabolic reprogramming and diminished tumor growth in HCT116 tumor xenografts. These insights lay a foundation for the development of SQR-targeted therapies for CRC.

The intracellular pH (pHi) is critical for understanding various pathologies, including brain tumors. While conventional pHi measurement through 31P-MRS suffers from low spatial resolution and long scan times, 1H-based APT-CEST imaging offers higher resolution with shorter scan times. This study aims to directly predict 31P-pHi maps from CEST data by using a fully connected neuronal network. Fifteen tumor patients were scanned on a 3-T Siemens PRISMA scanner and received 1H-based CEST and T1 measurement, as well as 31P-MRS. A neural network was trained voxel-wise on CEST and T1 data to predict 31P-pHi values, using data from 11 patients for training and 4 for testing. The predicted pHi maps were additionally down-sampled to the original the 31P-pHi resolution, to be able to calculate the RMSE and analyze the correlation, while higher resolved predictions were compared with conventional CEST metrics. The results demonstrated a general correspondence between the predicted deepCEST pHi maps and the measured 31P-pHi in test patients. However, slight discrepancies were also observed, with a RMSE of 0.04 pH units in tumor regions. High-resolution predictions revealed tumor heterogeneity and features not visible in conventional CEST data, suggesting the model captures unique pH information and is not simply a T1 segmentation. The deepCEST pHi neural network enables the APT-CEST hidden pH-sensitivity and offers pHi maps with higher spatial resolution in shorter scan time compared with 31P-MRS. Although this approach is constrained by the limitations of the acquired data, it can be extended with additional CEST features for future studies, thereby offering a promising approach for 3D pH imaging in a clinical environment.

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.

4'-Iodobiphenyl nonaethylene glycol ether (9bw) is a novel small molecule, composed of a biphenyl unit and 9 ethylene glycol (EG) units. Recently, we found that 9bw induces apoptosis in cancer cells by inhibiting mitochondrial respiratory complex I (CI) and accordingly reducing cellular ATP level. In addition, 9bw shows little effect on normal cells, suggesting that 9bw is a potential antitumor agent with few adverse effects. However, the exact molecular mechanisms by which 9bw acts on CI are still elusive. To clarify the molecular structure critical for 9bw's function, we tested the function of 9bw analogues on human oral squamous cell carcinoma lines HSC4 and Ca9-22. The analogues were 4-hydroxy-4'-iodobiphenyl (HIOP), I-BP-EG3, I-BP-EG6, and I-BP-EG12 containing 0, 3, 6, and 12 EG units, respectively. Our results demonstrated that I-BP-EG6 and I-BP-EG12 inhibited CI to a similar extent as 9bw, whereas I-BP3 and HIOP showed no effect on CI activity. These observations indicate that the number of EG units is crucial for the activity of 9bw and its analogues. As high-performance liquid chromatography (HPLC) analysis demonstrated that both HIOP and I-BP-EG3 could be incorporated into mitochondria abundantly, the number of EG units probably affects CI inhibitory function of 9bw and its analogues rather than their efficacy to enter cell and mitochondria.

Mitochondria are traditionally viewed as the powerhouses of eukaryotic cells, i.e., the main providers of the metabolic energy required to maintain their viability and function. However, the role of these ubiquitous intracellular organelles far extends energy generation, encompassing a large suite of functions, which they can adjust to changing physiological conditions. These functions rely on a sophisticated membrane system and complex molecular machineries, most of which imported from the cytosol through intricate transport systems. In turn, mitochondrial plasticity is rooted on mitochondrial biogenesis, mitophagy, fusion, fission, and movement. Dealing with all these aspects and terminology can be daunting for newcomers to the field of mitochondria, even for those with a background in biological sciences. The aim of the present educational article, which is part of a special issue entitled "Mitochondria in aging, cancer and cell death", is to present these organelles in a simple and concise way. Complex molecular mechanisms are deliberately omitted, as their inclusion would defeat the stated purpose of the article. Also, considering the wide scope of the article, coverage of each topic is necessarily limited, with the reader directed to excellent reviews, in which the different topics are discussed in greater depth than is possible here. In addition, the multiple cell type-specific genotypic and phenotypic differences between mitochondria are largely ignored, focusing instead on the characteristics shared by most of them, with an emphasis on mitochondria from higher eukaryotes. Also ignored are highly degenerate mitochondrion-related organelles, found in various anaerobic microbial eukaryotes lacking canonical mitochondria.

One of the crucial enzymes for cancer cell growth is lactate dehydrogenase (LDH, E.C. 1.1.1.27), an oxidoreductase that catalyzes the conversion between pyruvate and lactate. It has been found that in cancer cells metabolism, the LDH isoenzyme profile changes, with forms rich in the muscle-type subunit beginning to dominate over those in which the heart-type predominates. This suggests that by examining changes in the enzymatic activity of isoforms with a specific subunit content, it may be possible to quickly distinguish a physiological sample from a pathological one.

This article focuses on the development of an analytical strategy that enables the estimation of the ratio of LDH fraction activities as a basis for a simple and quick screening test. Spectrophotometric detection of LDH activity is based on the ferrozine photometric reaction with ferrous ions generated during the biocatalytic reduction of ferric ions by NADH. The developed Multicommutated Flow Analysis (MCFA) system, coupled with an optoelectronic flow-through detector, enables the use of a kinetic method based on the inhibition of LDH subunits to monitor the enzyme reaction kinetics. The distinctly different responses of the muscle-type and heart-type subunits to the selected inhibitors revealed a linear relationship between the obtained analytical signal and the percentage content of each subunit. The calibration curves for selected inhibitors are linear within the tested range of standards with coefficients of determination equal to 0.99 each.

The developed MCFA system was utilized in the analysis of human serum samples obtained from both healthy patients and patients with cancer. The analysis demonstrates that the proposed approach can differentiate oncological serum samples from reference ones based on the LDH fractions activity ratio, even when their total LDH activity level is low.

Microphysiological systems, such as multicellular spheroids, hold great promise for drug screening experiments. Spheroids may be dosed statically, where the drug is introduced to the growing chamber at one time point, or dynamically, where the drug is introduced via a fluidic component. Dynamic dosing can generate pharmacokinetic curves that more closely represent those seen in vivo than static dosing. In this work, we demonstrate the dynamic dosing of colorectal cancer spheroids in a 3D printed fluidic device with liposomal doxorubicin. Spheroids are valuable models to evaluate dynamic dosing, as they recapitulate the nutrient, oxygen, and pH gradients of solid tumors. Spheroids feature distinct cellular populations with a necrotic core, quiescent middle layer, and proliferative outer layer. Drug and liposome penetration are tracked with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and fluorescence imaging, showing that liposomal doxorubicin is stable to fluidic dosing and penetrates spheroids after 48 h. To provide a comprehensive pharmacodynamic profile of the distinct cellular regions within spheroids, we employ spatially stable isotopic labeling by amino acids in cell culture (spatial SILAC) proteomics to isotopically label the core and outer layers. Proteomic analysis reveals 714 upregulated proteins in the core upon treatment and 30 in the outer layers, as well as 103 downregulated proteins in the core and 1276 in the outer layers. Spatial SILAC uncovers the differential regulation of proteins associated with glycolysis, the TCA cycle, and lipid synthesis upon drug treatment between the spheroid core and outer layers. Using MALDI MSI and spatial SILAC proteomics, we interrogate the effects of dynamic dosing with liposomal doxorubicin on spheroid regions that would be overlooked by bulk analysis.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

Notch signaling is a widely preserved communication pathway that supports essential cellular functions by allowing adjacent cells to interact. The Notch signaling pathway consists of Notch ligands (DSL proteins), Notch receptors, DNA-binding proteins, and downstream target genes. Hepatocellular carcinoma (HCC) represents the predominant cause of cancer-related deaths globally and poses a significant threat to human health. For highly malignant HCC, current treatment options, including chemotherapy, radiotherapy, immunotherapy, targeted therapies, and surgical procedures, often have poor prognoses. Therefore, there is a need to explore additional therapeutic strategies. Many studies have found that abnormal activation of the Notch signaling pathway contributes to tumor initiation and progression by promoting HCC proliferation, metastasis, stem cell-like properties, and drug resistance. In this research, we reveal the composition and activation mechanisms of the Notch signaling pathway, as well as the molecular mechanism underlying its aberrant activation in HCC. Furthermore, we summarize recent advances in targeting Notch signaling for the treatment of HCC. This review aims to highlight the promising potential of investigating the Notch pathway as a therapeutic target in HCC.

The circadian clock is a crucial regulator of mammalian physiology, controlling daily oscillations in key biological processes, such as cell proliferation, apoptosis, and DNA damage repair. Disruption of circadian rhythms has been identified as a significant risk factor for cancer development and progression, yet the specific molecular mechanisms linking circadian dysfunction to cancer remain poorly understood. Recent studies have increasingly focused on the role of diet in modulating circadian rhythms, highlighting the potential for dietary interventions in cancer management. However, how dietary factors like glucose restriction interact with circadian rhythms to influence cancer cell behavior remains an open question. Here, we investigate the mechanisms underlying glucose restriction-induced apoptosis in non-small cell lung cancer (NSCLC) cells, with a focus on the role of circadian clock genes. Analysis of the GEPIA database revealed that the circadian gene Bmal1 is highly expressed in normal tissues and associated with better prognosis in lung adenocarcinoma patients. In NSCLC cells, Bmal1 expression correlated with proapoptotic gene activity. In a tumor xenograft model using severe combined immunodeficiency (SCID) mice, a glucose-restricted (ketogenic) diet significantly delayed tumor growth and increased the expression of Bmal1 and proapoptotic genes. These findings suggest that glucose restriction promotes apoptosis in NSCLC cells through a Bmal1-mediated pathway, providing novel insights into the intersection between circadian regulation and cancer biology. Targeting core circadian clock genes like Bmal1 may represent a promising therapeutic strategy for managing lung cancer, broadening our understanding of how circadian rhythms can be harnessed for cancer prevention and treatment.

Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) synergizes with OXPHOS inhibitor IACS-010759 in liver cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGF-β signaling, which is crucial for OXPHOS-inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter solute carrier family 1 member 5 (SLC1A5) transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGF-β signaling on transcription of SLC1A5, leading to intrinsic resistance of liver cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy.

Gliomas are the most common primary malignant brain tumors, characterized by aggressive invasion, limited therapeutic options, and poor prognosis. Despite advances in surgery, radiotherapy, and chemotherapy, the median survival of glioma patients remains disappointingly low. Therefore, identifying glioma-associated therapeutic targets and biomarkers is of significant clinical importance. Circular RNAs (circRNAs) are a class of naturally occurring long non-coding RNAs (lncRNAs), notable for their stability and evolutionary conservation. Increasing evidence indicates that circRNA expression is dysregulated in gliomas compared to adjacent non-tumor tissues and contributes to the regulation of glioma-related biological processes. Furthermore, numerous circRNAs function as oncogenes or tumor suppressors, mediating glioma initiation, progression, and resistance to temozolomide (TMZ). Mechanistically, circRNAs regulate glioma biology through diverse pathways, including acting as miRNA sponges, binding RNA-binding proteins (RBPs), modulating transcription, and even encoding functional peptides. These features highlight the potential of circRNAs as diagnostic and prognostic biomarkers, as well as therapeutic targets for glioma. This review summarizes the dysregulation and functions of circRNAs in glioma and explores key mechanisms through which they mediate tumor progression, including DNA damage repair, programmed cell death (PCD), angiogenesis, and metabolic reprogramming. Our aim is to provide a comprehensive perspective on the multifaceted roles of circRNAs in glioma and to highlight their potential for translational application in targeted therapy.

Single-cell metabolomics reveals cell heterogeneity and elucidates intracellular molecular mechanisms. However, general concentration measurement of metabolites can only provide a static delineation of metabolomics, lacking the metabolic activity information of biological pathways. Herein, we develop a universal system for dynamic metabolomics by stable isotope tracing at the single-cell level. This system comprises a high-throughput single-cell data acquisition platform and an untargeted isotope tracing data processing platform, providing an integrated workflow for dynamic metabolomics of single cells. This system enables the global activity profiling and flow analysis of interlaced metabolic networks at the single-cell level and reveals heterogeneous metabolic activities among single cells. The significance of activity profiling is underscored by a 2-deoxyglucose inhibition model, demonstrating delicate metabolic alteration within single cells which cannot reflected by concentration analysis. Significantly, the system combined with a neural network model enables the metabolomic profiling of direct co-cultured tumor cells and macrophages. This reveals intricate cell-cell interaction mechanisms within the tumor microenvironment and firstly identifies versatile polarization subtypes of tumor-associated macrophages based on their metabolic signatures, which is in line with the renewed diversity atlas of macrophages from single-cell RNA-sequencing. The developed system facilitates a comprehensive understanding single-cell metabolomics from both static and dynamic perspectives.

A new perspective on cancer metabolism suggests that it varies by context and is diverse. Cancer metabolism reprogramming can create a heterogeneous microenvironment that affects immune cell infiltration and function, complicating the selection of treatment methods. However, the specifics of this relationship remain unclear in breast cancer. This research aims to explore how glycolysis and fatty acid metabolism (GF) influence the immune microenvironment and their predictive capabilities for immunotherapy responses and overall survival.

We at first time identified 602 GF-related genes. Utilizing multiple datasets from various centers and employing 10 different machine learning algorithms, we developed a GF-related signature called GFSscore, driven by artificial intelligence.

The GFSscore served as an independent prognostic indicator and demonstrated greater robustness than other models. Its validity was validated through multiple databases. Our study found that breast cancer patients with a high GFSscore, indicative of a greater tendency towards glycolytic activity, experienced poorer prognosis due to immunosuppression from distinct immune evasion mechanisms. Conversely, those with a low GFSscore, more inclined towards fatty acid metabolism, had better outcomes. Additionally, the GFSscore has the potential to forecast how well a patient might respond to immunotherapy and their susceptibility to chemotherapy medications. Moreover, we found that the overexpressed ACSL5 gene inhibits the proliferation of BRCA through experiments.

The GFSscore may offer patients personalized therapy by identifying new therapeutic targets for tumors. By understanding the relationship between cancer metabolism and the immune microenvironment, we can better tailor treatments to individual patients.

Mitochondrial dysfunction is closely associated with cancer development. Colorectal cancer (CRC) cells often exhibit altered energy metabolism, characterized by increased glycolysis and reduced oxidative phosphorylation. Enhancing mitochondrial biogenesis and function may represent a promising therapeutic approach. High-dose vitamin C has demonstrated anti-tumor properties and the ability to reverse the Warburg effect, but its role in regulating mitochondrial biogenesis and function remains unclear.

We evaluated the altered mitochondrial functional status of HCT116 colorectal cancer cells compared to FHC colorectal epithelial cells, assessed the effects of high-dose vitamin C on mitochondrial biogenesis and function in HCT116 cells, and explored the underlying regulatory mechanisms.

HCT116 cells exhibited mitochondrial dysfunction compared to FHC cells, including decreased expression of electron transport chain complexes III and IV, reduced TFAM levels, and lower mtDNA content. Vitamin C treatment significantly enhanced mitochondrial biogenesis and function, as reflected by increased AMPK phosphorylation, upregulation of PGC-1α, SOD2, NRF2, TFAM, MT-CYB, and MTCO1, elevated mtDNA content, restored membrane potential, enhanced oxidative phosphorylation, and reduced glycolytic activity. Furthermore, vitamin C markedly suppressed HCT116 cell viability and clonogenic capacity, while these effects were substantially diminished by cotreatment with Compound C.

This study demonstrates that high-dose vitamin C ameliorates mitochondrial dysfunction and promotes mitochondrial biogenesis and function in colorectal cancer cells through activation of the AMPK-PGC-1α signaling pathway, thereby suppressing tumor cell proliferation. These findings suggest that vitamin C may serve as a promising therapeutic agent for targeting mitochondrial metabolism in colorectal cancer.

Uracil incorporation into DNA, as a result of nucleotide pool imbalances or cytosine deamination (e.g., through APOBEC3A/3B), can result in replication stress and is the most common source of mutations in cancer and aging. Despite the critical role of uracil in genome instability, cancer development, and cancer therapy, only now is there emerging data on its impact on fundamental processes such as DNA replication and genome stability. Removal of uracil from DNA by base excision repair (BER) can generate a DNA single-strand break (SSB), which can trigger homologous recombination (HR) repair or replication fork collapse and cell death. Unprocessed uracil can also induce replication stress directly and independently of BER by slowing down replication forks, leading to single-stranded DNA (ssDNA) gaps. In this perspective, we review how genomic uracil induces replication stress, the therapeutic implications of targeting uracil-induced vulnerabilities, and potential strategies to exploit these mechanisms in cancer treatment.

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations in human cancers and overgrowth syndromes. The ubiquitous expression of the activating Pik3caH1047R mutation results in reduced survival, organomegaly, hypoglycaemia and hypoinsulinemia in mice. Here we demonstrate that in vivo expression of Pik3caH1047R attenuates the rise in blood glucose in response to oral glucose administration, stimulates glucose uptake in peripheral tissues, inhibits hepatic gluconeogenesis and pancreatic insulin secretion, and increases adipose lipolysis and white adipose tissue browning. Together, our data reveal that the systemic activation of the PI3K pathway in mice disrupts glucose homeostasis through the regulation of hepatic gluconeogenesis, and leads to increased lipolysis of adipose tissue.

Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in the pathogenesis of these malignancies globally. This review delves into the contributions of various known viruses-specifically Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV)-in the development of haematological malignancies. These viruses are shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, and remodeling of the immune microenvironment. By directly disrupting fundamental cellular functions and altering metabolic and epigenetic pathways, these viruses foster an immune milieu that supports both viral persistence and tumor growth. A thorough understanding of these viral oncogenic processes is crucial not only for etiological discovery but also for developing targeted interventions. This review emphasizes the need for continued research into the specific ways these viruses manipulate the host cell's metabolic and epigenetic environments, aiming to provide insights that could guide future advancements in treatment modalities.

Metabolic reprogramming is a distinctive characteristic of colorectal cancer (CRC) which provides energy and nutrients for rapid proliferation. Although numerous studies have explored the rewired metabolism of CRC, the metabolic alterations occurring in CRC when the cell cycle is arrested by treatment with 5-fluorouracil (5-FU), an anticancer drug that arrests the S phase, remain unclear.

A systematic profiling analysis was conducted as ethoxycarbonyl/methoxime/tert-butyldimethylsilyl derivatives using gas chromatography-tandem mass spectrometry in HT29 cells and media following 5-FU treatment in a concentration- and time-dependent manner.

In HT29 cells of 24 h after 5-FU treatment (3-100 μM) and 48 h after 5-FU treatment (1-10 μM), six amino acids, including valine, leucine, isoleucine, serine, glycine, and alanine and two organic acids, including pyruvic acid and lactic acid, were significantly increased compared to the DMSO-treated group. However, 48 h after 5-FU treatment (30-100 μM) in HT29 cells, the levels of these metabolites decreased along with an approximately 50% reduction in viability, an increase in the level of reactive oxygen species, induction of cycle arrest in the G1 phase, and the induction of apoptosis. On the other hand, the levels of fatty acids showed a continuous increase in HT29 cells 48 h after 5-FU treatment (1-100 μM). In the media, the decreased availabilities in the cellular uptake of nutrient metabolites, including valine, leucine, isoleucine, serine, and glutamine, were observed at 48 h after 5-FU treatment in a dose-dependent manner.

It is assumed that there is a possible shift in energy dependence from the tricarboxylic acid cycle to fatty acid metabolism. Thus, metabolic profiling analysis revealed altered energy metabolism in CRC cells following 5-FU treatment.

We investigate the association between serum lactate dehydrogenase and prognosis in patients with urothelial carcinoma who were treated with avelumab maintenance therapy in combination with other biomarkers.

We identified 54 patients with advanced or metastatic urothelial carcinoma that received avelumab maintenance therapy between June 2021 and February 2024 at our institutions. We retrospectively analyzed progression-free survival and overall survival from the initiation of avelumab maintenance therapy. Best overall response was evaluated based on the RECIST guidelines v1.1. To investigate factors potentially associated with response to avelumab maintenance therapy and overall survival, we conducted an assessment of markers that have been previously reported as prognostic factors, including urothelial carcinoma and other cancers.

The median overall survival by best overall response of first-line chemotherapy was not reached for complete response, partial response, or 15-month stable disease (p = 0.27). As for avelumab maintenance therapy, median overall survival by best overall response was not reached for complete response, partial response, and not evaluable; it was 18 months for stable disease and 13 months for progressive disease, with significant differences (p = 0.04). In multivariable analysis, lactate dehydrogenase level below the upper limit of normal prior to first-line chemotherapy was a significant independent factor in predicting disease control rate (p < 0.01) and overall survival (p = 0.04) in avelumab maintenance therapy.

Normal serum lactate dehydrogenase level prior to first-line chemotherapy was a significant predictor of favorable response or prognosis for avelumab maintenance therapy in our cohort.

Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the "benchmark" for cancer models to recapitulate. It is particularly difficult to model patients' tumor microenvironment (TME) with its complex cell-cell/cell-matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based 'omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.

Carbohydrates are key components of many microbial cell walls and play a versatile role in immune recognition. In this study, we analyzed the carbohydrate cell wall composition of Cutibacterium acnes strains associated with healthy skin (denoted as CH) and acne-prone skin (denoted as CA) to understand their influence on host immune responses in acne. We identified glucose, mannose, and galactose as the primary monosaccharides, with minor amounts of fucose, N-acetylgalactosamine, and N-acetylglucosamine. Linkage analysis revealed structural variations between CH and CA strains: CH strains showed a balanced and diverse polysaccharide structure, whereas CA strains displayed a more rigid structure with 1→4 and branched 1→6 linkages, potentially contributing to inflammatory properties. Immunostimulatory assays revealed that C acnes carbohydrates induced IL-6 and IL-17 but not IL-1β, highlighting the role of carbohydrate structures in influencing cytokine responses. Treatment with sodium meta-periodate impaired this immunostimulatory activity, indicating that carbohydrate integrity is crucial for immune activation. In addition, analysis of single-cell RNA-sequencing data from acne lesions revealed elevated glycolytic activity in acne lesions in comparison with that in nonlesional skin, suggesting a Warburg-like effect that promotes inflammation. Our findings highlight the role of C acnes polysaccharides in immune modulation and inflammation, suggesting their potential as therapeutic targets for acne treatment.

Cancer cells reprogram their energy metabolism pathways, but the mechanisms that enable them to meet their energy demands remain poorly understood. This study investigates the anticancer effects of ethyl p-methoxycinnamate (EMC) in Ehrlich ascites tumor cells (EATCs) and reveals that de novo fatty acid synthesis, rather than glycolysis, plays a pivotal role in sustaining energy homeostasis in cancer cells. EMC significantly reduced ATP levels despite enhancing glycolytic activity. It suppressed the expression of key enzymes involved in de novo fatty acid synthesis, including Acly, Acc1, and Fasn, resulting in decreased intracellular triglyceride (TG) levels. The addition of exogenous palmitic acid reversed EMC-induced ATP depletion and mitigated its anti-proliferative effects. Mechanistically, the ATP reduction caused by EMC was associated with inhibition of the c-Myc/SREBP1 pathway and arrest of the G1/S cell cycle transition. These findings demonstrate that EMC inhibits EATC proliferation by reducing ATP levels via suppression of de novo fatty acid synthesis. This study highlights the critical role of de novo fatty acid synthesis, rather than glycolysis, in maintaining energy homeostasis in cancer cells and provides novel insights into targeting cancer metabolism.

The tumour microenvironment (TME) exerts a profound influence on cancer progression and treatment outcomes. Recent investigations have elucidated the crucial role of intratumoural microbiota and their metabolites in shaping the TME and modulating anti-tumour immunity. This review critically assesses the influence of intratumoural microbial metabolites on the TME and cancer immunotherapy. We systematically analyse how microbial-derived glucose, amino acid, and lipid metabolites modulate immune cell function, cytokine secretion, and tumour growth. The roles of specific metabolites, including lactate, short-chain fatty acids, bile acids, and tryptophan derivatives, are comprehensively examined in regulating immune responses and tumour progression. Furthermore, we investigate the potential of these metabolites to augment the efficacy of cancer immunotherapies, with particular emphasis on immune checkpoint inhibitors. By delineating the mechanisms through which microbial metabolites influence the TME, this review provides insights into novel microbiome-based therapeutic strategies, thereby highlighting a promising frontier in personalised cancer medicine.

Significance: The mitochondria play a key role in maintaining oxygen homeostasis under normal oxygen tension (normoxia) and during oxygen deprivation (hypoxia). This is a critical balancing act between the oxygen content of the blood, the tissue oxygen sensing mechanisms, and the mitochondria, which ultimately consume most oxygen for energy production. Recent Advances: We describe the well-defined role of the mitochondria in oxygen metabolism with a special focus on the impact on blood physiology and pathophysiology. Critical Issues: Fundamental questions remain regarding the impact of mitochondrial responses to changes in overall blood oxygen content under normoxic and hypoxic states and in the case of impaired oxygen sensing in various cardiovascular and pulmonary complications including blood disorders involving hemolysis and hemoglobin toxicity, ischemia reperfusion, and even in COVID-19 disease. Future Directions: Understanding the nature of the crosstalk among normal homeostatic pathways, oxygen carrying by hemoglobin, utilization of oxygen by the mitochondrial respiratory chain machinery, and oxygen sensing by hypoxia-inducible factor proteins, may provide a target for future therapeutic interventions. Antioxid. Redox Signal. 42, 730-750.

The word "cancer" evokes myriad emotions, ranging from fear and despair to hope and determination. Cancer is aptly defined as a complex and multifaceted group of diseases that has unapologetically led to the loss of countless lives and affected innumerable families across the globe. The battle with cancer is not only a physical battle, but also an emotional, as well as a psychological skirmish for patients and for their loved ones. Cancer has been a part of our history, stories, and lives for centuries and has challenged the ingenuity of health and medical science, and the resilience of the human spirit. From the early days of surgery and radiation therapy to cutting-edge developments in chemotherapeutic agents, immunotherapy, and targeted treatments, the medical field continues to make significant headway in the fight against cancer. However, even after all these advancements, cancer is still among the leading cause of death globally. This urges us to understand the central hallmarks of neoplastic cells to identify novel molecular targets for the development of promising therapeutic approaches. Growing research suggests that stress mediators, including epinephrine, play a critical role in the development and progression of cancer by inducing neoplastic features through activating adrenergic receptors, particularly β-adrenoreceptors. Further, our experimental data has also shown that epinephrine mediates the growth of T-cell lymphoma by inducing proliferation, glycolysis, and apoptosis evasion via altering the expression levels of key regulators of these vital cellular processes. The beauty of receptor-based therapy lies in its precision and higher therapeutic value. Interestingly, the enhanced expression of β-adrenergic receptors (ADRBs), namely ADRB2 (β2-adrenoreceptor) and ADRB3 (β3-adrenoreceptor) has been noted in many cancers, such as breast, colon, gastric, pancreatic, and prostate and has been reported to play a pivotal role in facilitating cancer growth mainly by promoting proliferation, evasion of apoptosis, angiogenesis, invasion and metastasis, and chemoresistance. The present review article is an attempt to summarize the available findings which indicate a distinct relationship between stress hormones and cancer, with a special emphasis on epinephrine, considered as a key stress regulatory molecule. This article also discusses the possibility of using beta-blockers for cancer therapy.

The KIT receptor is a transmembrane protein found on the surface of many different cell types. Mutant forms of KIT are drivers of myeloid neoplasms, including systemic mastocytosis. The KIT D816V mutation is the most common, leading to constitutive activation of the receptor and its downstream targets, and it is highly resistant to c-KIT inhibitors. Metabolic rewiring is a common trait in cancer. We analyzed the metabolic profile induced by the KIT D816 mutation, measuring mitochondrial parameters in two myeloid cell lines. We found that the KIT D816V mutation causes a significant increase in mitochondrial abundance and activity associated with superoxide production, which could promote DNA instability. Functional and morphologic changes in mitochondria were associated with reduced levels of BNIP3 protein expression. We also detected low BNIP3 levels in clinical acute myeloid leukemia samples harboring D816V mutations. In addition, we have found constitutive mTOR activation in mutated cells, a pathway that has been shown to regulate autophagy. Our data suggest that KIT D816V increases mitochondrial activity through downregulation of BNIP3 expression, which increases mitochondrial number through the autophagy pathway. Alterations in the cellular metabolism induced by the KIT D816V mutation could be therapeutically exploited.

Abnormal metabolism is a characteristic of malignant tumors. Numerous factors play roles in the regulation of tumor metabolism. As epigenetic regulators, enhancers, especially the super-enhancers (SEs), serve as platforms for transcription factors that regulate the expression of metabolism-related enzymes or transporters at the gene level. In this study, we review the effects of enhancer/ SE-driven genes on tumor metabolism and immunity. Enhancers/SEs play regulatory roles in glucose metabolism (glycolysis, gluconeogenesis, tricarboxylic acid (TCA) cycle, pyruvate, and pentose phosphate pathway, lipid metabolism (cholesterol, fatty acid, phosphatide, and sphingolipid), and amino acid metabolism (glutamine, tryptophan, arginine, and cystine). By regulating tumor metabolism, enhancers and SEs can reprogram tumor microenvironment, especially the status of various immune cells. Therefore, interfering enhancers/SEs that regulate the tumor metabolism is likely to enhance the effectiveness of immunotherapy.

A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.

A novel exopolysaccharide AVP-214-1was isolated and purified from the metabolites of a Mariana Trench-derived fungus Aspergillus versicolor SCAU214. AVP-214-1 exhibited a heteropolysaccharide architecture composed of mannose, galactose, and glucose residues. The linear backbone adopted α-(1 → 4)-linked d-galactopyranose and d-glucopyranose units with the following sequence: →[4,6)-α-D-Glcp-(1 → 4)-α-D-Glcp-(1]4 → [4)-α-D-Glcp-(1 → 6)-α-D-Glcp-(1 → 3)-α-D-Glcp-(1]3 → [4,6)-α-D-Glcp-(1 → 4)-α-D-Glcp-(1]2 → [4)-α-D-Glcp-(1]19 → [4)-α-D-Glcp-(1 → 4)-α-D-Galp-(1]2→. Structural complexity arose from two distinct branching motifs: single α-d-glucopyranosyl and an α-D-mannopyranosyl, both attached via C-6 positions of the backbone residues 1,4,6-α-D-Glcp. The molecular weight of AVP-214-1 was determined to be 8277 Da. In functional assays, AVP-214-1 was found to significantly enhance the proliferation of RAW 264.7 macrophage cells and promote the secretion of cytokines, such as IL-6, TNF-α and IL-1β. Metabolomic analysis revealed that AVP-214-1 primarily influences pyrimidine metabolism and amino acid-related metabolic pathways, these metabolic pathways were likely related to immune regulation. These results suggest that AVP-214-1 from a Mariana Trench-derived fungus was a novel immune-stimulating polysaccharide, opening up new avenues for the development of bioactive polysaccharides from deep-sea organisms for potential biotechnological applications.