This study describes the development of a pyruvate kinase (PyK)-biosensor for the evaluation of PyK activity, as a diagnostic tool for early cancer screening and detection of kinase inhibitors used in cancer treatment, with the evaluation of the inhibition mechanism. The biosensor was constructed by co-immobilizing the enzymes PyK and pyruvate oxidase (PyOx) on Au film electrodes by crosslinking with glutaraldehyde (GA) and evaluated electrochemically by cyclic voltammetry (CV) and fixed potential amperometry (CA). First, the experimental conditions were optimized in terms of applied potential, enzyme ratio PyK:PyOx and enzyme substrate concentration: phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP). The biosensor sensitivity towards PEP detection was 2.11 ± 0.08 μA mM-1 cm-2, with very high reproducibility and repeatability, which made it suitable for inhibition studies of PyK inhibitor. The inhibition mechanism of shikonin was determined in relation to both PEP and ADP, with the calculation of IC50 values and binding constants (Ki). Detection of shikonin was possible at very low concentrations in the linear range of 0.1-4.0 pM. The electrochemical results were validated by UV-Vis spectrophotometry. The developed biosensor is a valuable tool for drug screening by enabling enzyme catalytic function examination with applicability to identify inhibitors, estimate their affinity, inhibition mechanism linked to their molecular mechanisms of action and evaluate selectivity, of great interest in both pharmaceutical and medical domains.

The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

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.

Ubiquitin-specific peptidase 13 (USP13) has emerged as a key regulator of proteins critical to the hallmarks of cancer, playing an essential role in cellular regulation. This deubiquitinating enzyme, often overexpressed in malignancies, wields its molecular scissors precisely, snipping ubiquitin tags to rescue oncoproteins from degradation. Our review highlights the dual role of USP13 in cancer biology: while it predominantly fuels tumor growth and metastasis, USP13 occasionally functions as a tumor suppressor. USP13 is as a formidable factor in cancer therapy, fortifying tumors against an arsenal of treatments. It bolsters DNA repair mechanisms, ignites prosurvival autophagy, and even reprograms cell lineages to evade targeted therapies. However, USP13 is also a promising target in the treatment of cancer. We highlight burgeoning strategies to neutralize USP13, from small molecule inhibitors to innovative protein degraders, which may disarm cancer resistance mechanisms. We also offer suggestions for future USP13 research, emphasizing the need for structural insights and more potent inhibitors. This review highlights the critical role of USP13 in cancer and underscores its potential as a therapeutic target for advancing cancer treatment.

Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer.

In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism.

In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Mitochondria are key regulators of inflammatory responses and mitochondrial dysfunction is closely linked to various inflammatory diseases. Increasing genetic and experimental evidence suggests that mitochondria play a critical role in inflammatory bowel disease (IBD). In the complex environment of the intestinal tract, intestinal epithelial cells (IECs) and their mitochondria possess unique phenotypic features, shaping each other and regulating intestinal homeostasis and inflammation through diverse mechanisms. Here, we focus on intestinal inflammation in IBD induced by mitochondrial damage-associated molecular patterns (mtDAMPs), which comprise mitochondrial components and metabolic products. The pathogenic mechanisms of mtDAMP signaling pathways mediated by two major mtDAMPs, mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), are discussed.

Assessment of liver function is essential before partial hepatectomy to predict the risk of post hepatectomy liver failure, a severe and life-threatening complication. Traditional methods have focused on expected future liver remnant (FLR) volume estimation. However, liver volume does not always correlate with function. We suggest that metabolism might be a better surrogate for function than volume. Therefore, we aimed to investigate the metabolic changes in a porcine model of partial portal vein ligation (PVL) using hyperpolarized magnetic resonance imaging (HP-MRI). Specifically, we sought to quantify and compare the pyruvate metabolism in the FLR and the deportalized liver (DL).Six pigs underwent PVL. HP-MRI with [1-13C] pyruvate was performed at baseline, post-surgery, and 1 week after surgery. Metabolic conversion was quantified with kinetic modelling of the rate constants of pyruvate to lactate (kPL) and pyruvate to alanine (kPA). Mean kPL was increased in FLR compared to DL at post-surgery and 1 week after surgery (P = 0.002), while kPA was unaltered (P = 0.761). These findings indicate a metabolic shift towards glycolysis in the FLR. This non-invasive metabolic imaging technique could serve as a powerful tool for evaluation of regional liver function prior to partial hepatectomy and consequently improve patient outcomes.

Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC). Elucidating the molecules that influence fatty acid metabolism in HCC is important for developing precise therapy. However, elucidating its molecular mechanisms in tumour cells is challenging. In this study, we aimed to determine the characteristics and differences of fatty acid metabolism in HCC.

We employed organoid models, single-cell RNA sequencing, and spatial transcriptomics to identify key genes involved in tumour fatty acid metabolism. Metabolomics, proteomics, metabolic flux analysis, and transmission electron microscopy were utilized to evaluate this metabolic process. Tumour malignancy was characterized using multi-species models. Changes in the immune microenvironment were analyzed by time-of-flight mass cytometry and multiplexed immunohistochemistry. Gene knockdown targeting the liver was achieved using lipid nanoparticles.

Eukaryotic translation initiation factor 3 subunit f (eIF3f) is upregulated in HCC tissues and is associated with poor prognosis. eIF3f directly interacted with and stabilised long chain acyl CoA synthetase 4 (ACSL4) through K48-linked deubiquitination, promoting fatty acid biosynthesis (FAB) and tumour malignancy. The increased fatty acid levels in the tumour microenvironment indirectly reduced CD8+ T-cell infiltration. In addition, phosphorylated eIF3f enhanced the interaction between eIF3f and ACSL4.

Targeting the eIF3f-ACSL4-FAB axis could decelerate HCC malignancy and enhance anti-programmed cell death-1 efficacy, suggesting that eIF3f is a potential target for precision therapy in HCC.

Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.

High-grade serous cancer (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. In this study, we utilized liquid chromatography and mass spectrometry analysis to investigate metabolic alterations in HGSC. Among the 1353 metabolites identified, 140 were significantly differed between HGSC and normal ovarian tissue. KEGG pathway enrichment analysis revealed 23 distinct metabolic pathways, including the alanine/aspartate/glutamate metabolism, pyruvate metabolism, biosynthesis of amino acids, and citrate cycle, etc. Of the significantly differentiated metabolites, malic acid, fumarate, and phosphoenolpyruvate were found in the citrate cycle and glycolysis. In further analysis, 22 differentially expressed genes (DEGs) of glucose metabolism were found between HGSC and normal controls. Multivariate Cox analysis of the 22 DEGs showed that ME1, ALDOC, and RANBP2 were associated with overall survival in the TCGA cohort.Bioinformatic analysis indicated WTAP is strongly correlated to the expression of ME1, which is a rate-limiting enzyme that regulates the shuttle of malic acid in mitochondria and cytoplasm. After the knockdown of WTAP in A2780 and OVCAR-3 cells, the activity of the malic enzyme decreased which led to the accumulation of malic acid and citric acid, and the reduction of pyruvate and lactic acid. In A2780 and OVCAR-3 cells, the IC50 to platinum was increased after the knockdown of WTAP. After the knockdown of WTAP, the expression of ME1 was down-regulated and the m6A modification was down-regulated in ovarian cell lines. On the SRAMP website, there were two binding sites with high m6A scores at the 5 '-UTR 177 and 970 of ME1 mRNA. WTAP contributes to the platinum resistance through regulating the conversion from aerobic glycolysis to OXPHOS by upregulating the expression of ME1.

Hypoxic stress causes cell damage and serious diseases in organisms, especially in aquatic animals. It is important to elucidate the changes in metabolic function caused by hypoxia and the mechanisms underlying these changes. This study focuses on the low oxygen tolerance feature of a new blunt snout bream strain (GBSBF1). Our data show that GBSBF1 has a different lipid and carbohydrate metabolism pattern than wild-type bream, with altering glycolysis and lipid synthesis. In GBSBF1, the expression levels of phd2 and vhl genes are significantly decreased, while the activation of HIF-3α protein is observed to have risen significantly. The results indicate that enhanced HIF-3α can positively regulate gpd1ab and gpam through PPAR-γ, which increases glucose metabolism and reduces lipolysis of GBSBF1. This research is beneficial for creating new aquaculture strains with low oxygen tolerance traits.

Low-grade gliomas (LGGs) are notorious for their difficult early-stage diagnosis, limited treatment options, and poor prognosis, making them a focal point in cancer research. Long noncoding RNAs (lncRNAs) have been identified as regulators of metabolic reprogramming in tumor cells, offering new directions for LGG treatment.

This study employed data from The Cancer Genome Atlas, focusing on key fatty acid metabolism-related lncRNA. A risk scoring model was developed using univariate/multifactorial and least absolute shrinkage and selection operator Cox regression. Additionally, the study evaluated the role of these prognostic lncRNAs in LGG progression by assessing associations between LGG immune markers and tumor drug resistance. Finally, functional enrichment analysis highlighted the molecular roles of these lncRNAs.

In this study, a total of 14 prognostic lncRNAs were obtained. The risk model demonstrated excellent validity and reliability, making it a superior predictor of prognosis among patients with varying LGG risks. Among the identified lncRNAs, GHET-1 was notably associated with LGG sensitivity to current chemotherapy options and might be a crucial lncRNA affecting LGG progression. High-risk patients exhibited T-helper cell-mediated immunosuppression, potentially paving new paths for future LGG immunotherapy.

Focusing on lncRNA regulation and fatty acid metabolism reprogramming, this study established an innovative prognostic prediction model for LGGs, showing outstanding validity and reliability. The findings offer new molecular and cellular targets for the future development of LGG treatments.

The most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse. These patients urgently need other options. This study shows how calcium/calmodulin-dependent protein kinase II delta (CAMKIIδ) is pivotal for BCL development. In BCL cells, ablation of CAMKIIδ inhibits both lipolysis from lipid droplets and oxidative phosphorylation (OXPHOS). With lipolysis blocked, BCL progression is markedly suppressed in two distinct BCL mouse models: MYC-driven EµMyc mice and Myc/Bcl2 double-expressed mice. When CAMKIIδ is present, it destabilizes transcription factor Forkhead Box O3A (FOXO3A) by phosphorylating it at Ser7 and Ser12. This then permits transcription of downstream gene IRF4 - a master transcription factor of lipid metabolism. The CAMKIIδ/FOXO3A axis bolsters lipid metabolism, mitochondrial respiration, and tumor fitness in BCL under metabolic stress. This study also evaluates Tetrandrine (TET), a small molecule compound, as a potent CAMKIIδ inhibitor. TET attenuates metabolic fitness and elicits therapeutic responses both in vitro and in vivo. Collectively, this study highlights how CAMKIIδ is critical in BCL progression. The results also pave the way for innovative therapeutic strategies for treating aggressive BCL.

Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA levels caused by genetic or pharmacological inhibition of VLCFA degradation reduced the activity of two major kinases involved in MM pathogenesis, MET proto-oncogene (MET) and insulin-like growth factor 1 receptor (IGF1R). Mechanistically, inhibition of ACOX1 promoted the accumulation of VLCFA-containing cerebrosides, altered MET and IGF1R interaction with a cerebroside analog, and selectively inhibited the association of these kinases with the plasma membrane signaling platforms, importantly, without disrupting the platforms' integrity. Our study revealed a specific metabolic vulnerability of MM cells and identified a targetable axis linking VLCFA metabolism to the regulation of MET and IGF1R activity.

Cancer cachexia is a multifaceted metabolic syndrome characterized by muscle wasting, fat redistribution, and metabolic dysregulation, commonly associated with advanced cancer but sometimes also evident in early-stage disease. More subtle body composition changes have also been reported in association with cancer, including sarcopenia, myosteatosis, and increased fat radiodensity. Emerging evidence reveals that body composition changes including sarcopenia, myosteatosis, and increased fat radiodensity, arise from distinct biological mechanisms and significantly impact survival outcomes. Importantly, these features often occur independently, with their combined presence exacerbating poor prognoses. Tumor plays a pivotal role in driving these host changes, either by acting as a metabolic parasite or by releasing mediators that disrupt normal tissue function. This review explores the diversity of tumor metabolism. It highlights the potential for tumor-specific metabolic phenotypes to influence systemic effects, including fat redistribution and sarcopenia. Addressing this tumor-host metabolic interplay requires personalized approaches that disrupt tumor metabolism while preserving host health. Promising strategies include targeted pharmacological interventions and anticachexia agents like growth differentiation factor 15 (GDF-15) inhibitors. Nutritional modifications such as ketogenic diets and omega-3 fatty acid supplementation also merit further investigation. In addition to preserving muscle, these therapies will need to be evaluated for their capability to improve survival and quality of life. This review underscores the need for further research into tumor-driven metabolic effects on the host and the development of integrative treatment strategies to address the interconnected challenges of cancer progression and cachexia.

Progression of lung adenocarcinoma (LUAD) is frequently associated with alterations in epithelial-mesenchymal transition (EMT) and cell cycle. Our study analyzed the Cancer Genome Atlas (TCGA) database and identified a positive correlation between high expression of SSBP1 in LUAD tumor tissues and poor prognosis (p < 0.05), with an AUC of 0.853, suggesting that SSBP1 could serve as a prognostic biomarker. In vitro experiments, including siRNA-mediated SSBP1 knockdown and subsequent cell cloning and Transwell assays, revealed significant inhibition of proliferation, migration, and cell cycle progression in LUAD cells (p < 0.05). In vivo mouse model experiments further confirmed that SSBP1 knockdown inhibits tumor burden (p < 0.05). Mechanistic investigations, integrating pathway enrichment analysis with molecular biology techniques, identified RRM2 as a downstream target of SSBP1, and RRM2 knockdown similarly suppressed LUAD cell proliferation, migration, and cell cycle progression (p < 0.05). These findings indicate that SSBP1 promotes EMT and cell cycle progression in LUAD cells by positively regulating RRM2, thereby accelerating disease progression. Collectively, our study not only confirms the potential role of SSBP1 in LUAD but also provides a theoretical foundation for therapeutic strategies targeting the SSBP1/RRM2 axis, potentially offering new therapeutic targets for LUAD patients.

The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.

Proliferative vitreoretinopathy (PVR) is a major cause of rhegmatogenous retinal detachment repair failure. Despite many attempts to find therapeutics for PVR, no pharmacotherapy has been proven effective. Steroids, as the epitome, show uncertain clinical effectiveness, which lacks an explanation and hints at unappreciated mechanisms of PVR. In this study, we investigated the involvement of metabolic reprogramming, mitochondrial impairment, and their association with steroid effectiveness in PVR using dexamethasone (Dex) as an example. Proteomics of vitreous samples from PVR patients demonstrated an upregulation in the glycolysis pathway. Transcriptomics of PVR tissues (dataset GSE179603) revealed downregulations in oxidative phosphorylation (OXPHOS), mitochondrial respiration, and mitochondrial quality control-related pathways. Transcriptomics of TGFβ and TNFα (TNT)-induced retinal pigment epithelial (RPE) cell model (GSE176513) confirmed the changes in glycolysis, OXPHOS, and mitochondria and also revealed downregulation of Dex response pathway with increased duration of TNT exposure. Transcriptomics of mouse RPE/choroid following Dex intravitreal injections (GSE49872) showed that glycolysis decreased at 1-week postinjection but increased at 1-month postinjection; OXPHOS increased but gradually decreased with treatment duration. The dispase-induced mouse PVR model revealed that a simultaneous Dex injection could alleviate PVR severity rather than an injection 5 days after the PVR induction. The TGFβ2-induced RPE cell model demonstrated the enhancement of EMT, oxidative stress, and mitochondrial impairment, which could be alleviated by Dex: Cellular ROS were accumulated; the mRNA expressions of antioxidases (GPX, SOD1 and TXN2) were decreased; mitochondrial morphology and dynamics were impaired, exhibiting decreases in mitochondrial heterogeneity, mitochondrial length and MFN2 expression; Mitochondrial membrane potential showed an elevation; and mitophagy was decreased, related to reduced Parkin recruitment. These results demonstrate the essential roles of metabolic reprogramming and mitochondrial dysfunction in PVR pathology, which is associated with the therapeutic effect of steroids. Steroid intervention might benefit the treatment of PVR in the early rather than late stages.

Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

Metabolic pathways play a critical role in driving differentiation but remain poorly understood in the development of kidney organoids. In this study, parallel metabolite and transcriptome profiling of differentiating human pluripotent stem cells (hPSCs) to multicellular renal organoids revealed key metabolic drivers of the differentiation process. In the early stage, transitioning from hPSCs to nephron progenitor cells (NPCs), both the glutamine and the alanine-aspartate-glutamate pathways changed significantly, as detected by enrichment and pathway impact analyses. Intriguingly, hPSCs maintained their ability to generate NPCs, even when deprived of both glutamine and glutamate. Surprisingly, single cell RNA-Seq analysis detected enhanced maturation and enrichment for podocytes under glutamine-deprived conditions. Together, these findings illustrate a novel role of glutamine metabolism in regulating podocyte development.

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

Hepatocellular carcinoma features extensive metabolic reprogramming. This includes alterations in major biochemical pathways such as glycolysis, the pentose phosphate pathway, amino acid metabolism and fatty acid metabolism. Moreover, there is a complex interplay among these altered pathways, particularly involving acetyl-CoA (coenzyme-A) metabolism and redox homeostasis, which in turn influences reprogramming of other metabolic pathways. Understanding these metabolic changes and their interactions with cellular signaling pathways offers potential strategies for the targeted treatment of hepatocellular carcinoma and improved patient outcomes. This review explores the specific metabolic alterations observed in hepatocellular carcinoma and highlights their roles in the progression of the disease.

Metabolic reprogramming in tumor cells plays a crucial role in promoting cell proliferation and metastasis, and is currently recognized as a significant marker of tumor progression. Interleukin-10 receptor subunit alpha (IL-10RA), a member of the type II cytokine receptor family, is predominantly expressed on macrophages and T cells and plays a crucial role in regulating immune cell metabolism and immune response. However, its role in the energy metabolic pathways of tumor cells remains unclear. In this study, we found increased expression of IL-10RA in human non-small cell lung cancer (NSCLC), and a correlation between increased IL-10RA expression and tumor stage, tumor size, and short overall survival of patients with NSCLC. IL-10RA overexpression significantly promoted the proliferation of NSCLC cell lines and enhanced glycolysis and fatty acid oxidation (FAO), thereby boosting energy production. Correspondingly, the downregulation of IL-10RA inhibited proliferation, glycolysis, and FAO in NSCLC cell lines. Bioinformatic analyses indicated that IL-10RA upregulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. STAT3 inhibitor effectively blocked the increase in FAO levels and cell proliferation induced by IL-10RA overexpression. These findings suggest that IL-10RA accelerates NSCLC cell proliferation by increasing FAO levels via the STAT3 pathway, highlighting IL-10RA as a potential therapeutic target for NSCLC.

Given the inherent complexity and heterogeneity of tumors, current therapeutic approaches often fall short in meeting prognostic requirements. Starvation therapy (ST) utilizing glucose oxidase (GOx) has emerged as a promising strategy, specifically targeting tumor glucose consumption to disrupt nutrient supply. However, the therapeutic potential of GOx is significantly hampered by its inherent limitations as a protein, particularly its poor stability and short in vivo half-life. In recent years, the development of nanocarriors has provided an effective platform for intravenous and local tumor delivery of GOx. This review systematically examines three key strategies in GOx delivery: stimulus-response, biofilm modification, and local delivery. The progress in various carrier systems for GOx-mediated tumor therapy is comprehensively summarized, providing valuable insights for nanocarrier design. Furthermore, the existing challenges and future directions to advance the development of GOx-based tumor therapies are critically analyzed.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression.

RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis in vivo.

High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. In vivo, USP19 knockdown controlled HCC growth by modulating c-Myc.

E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.

Cervical cancer is one of the most prevalent malignant tumors affecting women worldwide, and affected patients often face a poor prognosis due to its high drug resistance and recurrence rates. β-lapachone, a quinone compound originally extracted from natural plants, is an antitumor agent that specifically targets NQO1.

CC cells were treated with varying concentrations of β-lapachone to examine its effects on glucose metabolism, proliferation, metastasis, angiogenesis, and EMT in vitro. The targets and action pathways of β-lapachone were identified using network pharmacology and molecular docking, with KEGG pathway enrichment analysis. Its effects and toxicity were verified in vivo using a nude mouse xenograft model.

β-lapachone significantly inhibited the proliferation and metastasis of cervical cancer cells by regulating glucose metabolism, reducing tumor angiogenesis, and suppressing epithelial-mesenchymal transition (EMT) in cells with high NQO1 expression. Furthermore, we identified the inactivation of the PI3K/AKT/mTOR pathway as the key mechanism underlying these effects. AKT1 was identified as a potential target of β-lapachone in modulating glucose metabolism and EMT in cervical cancer cells.

These findings suggest that β-lapachone inhibits the malignant progression of cervical cancer by targeting AKT1 to regulate glucose metabolism in NQO1-overexpressing cells, providing a theoretical basis for developing novel therapeutic strategies for cervical cancer.

KRAS mutations can cause metabolic reprogramming in ovarian cancer, leading to an increased metastatic capacity. This study investigated the metabolic reprogramming changes induced by KRAS mutations in ovarian cancer and the mechanism of action of metformin combined with a glutaminase 1 inhibitor (CB-839). KRAS-mutant ovarian cancer accounted for 14% of ovarian cancers. The expression of glucose metabolism-related (PFKFB3, HK2, GLUT1, and PDK2) and glutamine metabolism-related enzymes (GLS1 and ASCT2) was elevated in KRAS-mutant ovarian cancer cells compared with that in wild-type cells. KRAS-mutant cells had a higher aerobic oxidative capacity than did wild-type cells. Metformin inhibited proliferation, the expression of glucose metabolism-related enzymes, and the aerobic oxidative capacity of KRAS-mutant cells compared with those of control cells. Furthermore, it enhanced the expression of glutamine metabolism-related enzymes in KRAS-mutant cells. Metformin combined with CB-839 inhibited the proliferation and aerobic oxidation of KRAS-mutant cells to a greater extent than that observed in wild-type cells. Additionally, the inhibitory effects of metformin and CB-839 in the KRAS-mutant ovarian cancer NOD-SCID mouse model were significantly stronger than those in the drug-alone group. KRAS mutations lead to enhanced glucose and glutamine metabolism in ovarian cancer cells, which was inhibited by metformin combined with CB-839.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Black soybeans have numerous health benefits owing to their high polyphenolic content, antioxidant activity, and antitumor effects. We previously reported that the Korean black soybean cultivar 'Soman' possesses higher anthocyanin and isoflavone contents and superior antioxidant potential than other Korean black soybean cultivars and landraces (Seoritae) do. Here, we investigated and compared the antitumor effects of Soman and Seoritae and aimed to elucidate the possible mechanisms of action. Soman inhibited cancer cell proliferation and was more potent than Seoritae. Mechanistically, Soman inhibited the phosphorylation of the signal transducer and activator of transcription (STAT1, 3, and 5) in a reactive oxygen species (ROS)-independent manner, subsequently decreasing glycolytic enzyme expression and the activities of pyruvate kinase and lactate dehydrogenase. Thus, Soman suppressed glucose uptake, lactate production, and ATP production in cancer cells. Additionally, it inhibited tumor growth in a B16F10 murine melanoma syngeneic model, accompanied by reduced STAT1 phosphorylation and decreased proliferation in Soman-treated mice, more potently than observed in Seoritae-treated mice. These findings showed that Soman exerted superior antitumor activities by suppressing STAT-mediated aerobic glycolysis and proliferation. Overall, our findings demonstrate the potent, tumor-suppressive role of Soman in human cancer and uncover a novel molecular mechanism for its therapeutic effects in cancer treatment.

PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.

Nasopharyngeal carcinoma (NPC) initially responds well to platinum-based therapy but often develops resistance. Combining therapies may offer a viable approach to address this resistance. Heat shock protein 90 (Hsp90) has shown promising anticancer activity in various cancer types. This study aimed to investigate the efficacy of an Hsp90 inhibitor, luminespib (AUY922), and evaluate the synergistic effect of combining AUY922 with cisplatin on two cisplatin-resistant human NPC cell lines. The response of cisplatin-resistant NPC cells to AUY922 and/or cisplatin was assessed through proliferation assay, cell cycle analysis, Annexin V apoptosis detection, Western blot analysis, in vivo investigation, and histological analysis. Our results indicated that AUY922/cisplatin combination significantly inhibited the proliferation of both non-resistant and resistant NPC cells. Moreover, Annexin V analysis indicated apoptosis when AUY922 was administered alone or in combination with cisplatin. Consistently, Western blot analysis revealed increased cleavage of PARP. Most importantly, the combination treatment demonstrated enhanced tumor growth inhibition in nude mice xenograft models, without notable adverse effects. These findings highlight the antiproliferative effects and anticancer activity of the AUY922/cisplatin combination in cisplatin-resistant NPC cells. The combination treatment of AUY922 and cisplatin holds promise as a strategy to overcome drug resistance in NPC patients.

Colon Cancer (CC) is a common malignant tumor. The aim of this study was to investigate the role and regulatory mechanism of circular RNA pappalysin-1 (circ-PAPPA; hsa_circ_0088233) in CC.

In cancer tissues from CC patients, circ-PAPPA expression was measured and its relationship with patients' clinical features was analyzed. Plasmid vectors or oligonucleotides interfering with the expression of circ-PAPPA, microRNA (miR)-656-3p or G-protein subunit Gamma-5 (GNG5) were transfected into CC cells. Cell viability was detected by MTT and colony formation assay; apoptosis was detected by flow cytometry; and cell migration and invasion were detected by wound healing assay and Transwell. Glycolytic capacity of CC cells was assessed by measuring glucose uptake and lactate production using commercial kits. The targeting relationship between miR-656-3p and circ-PAPPA or GNG5 was verified by bioinformatics website starBase and dual luciferase reporter gene assay assays.

Circ-PAPPA was upregulated in CC and was negatively correlated with benign pathological features and 5-year survival rates of CC patients. Circ-PAPPA silencing inhibited the growth and glycolysis of CC cells through upregulating miR-656-3p. GNG5, a target of miR-656-3p, could reverse the impacts of silencing circ-PAPPA on CC cells.

Circ-PAPPA may play an oncogenic role in CC by promoting cell growth and glycolysis through the miR-656-3p/GNG5 axis.

Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.