Antiproliferative effects of glucosamine, a glucose derivative with a similar structure to glucose, have been discovered, but the molecular mechanisms are not yet fully understood. Since glucosamine and glucose not only have similar structures but also are catalyzed by the same enzyme, hexokinase (HK), the present study delved into determining whether the antiproliferative effect of glucosamine involved the inhibition of glycolysis by competition with glucose. Whole‑genome screening analysis showed that a number of the gene pathways controlled by glucosamine were directly and indirectly involved in glycolysis. In vitro experiments revealed that as more glucose was added, the antiproliferative effect of glucosamine decreased. Also, it was found that glucosamine was transported into cells mainly through glucose transporter (GLUT) 2 which was responsible for the antiproliferative effects of glucosamine. In addition, the present study found that cancer cell lines with low expression level of HKII show high sensitivity to glucosamine and a HK inhibitor, 3‑bromopyruvate, enhanced the antiproliferative effect of glucosamine. Under hypoxic conditions, activated hypoxia‑inducible factor 1α (HIF‑1α) inducing glucose uptake and glycolysis hampered glucosamine‑induced cell death and HIF1A knockdown or HK inhibitors restored the antiproliferative effects of glucosamine. These findings demonstrated that glucosamine is an efficient glycolysis inhibitor and that GLUT2 and HKII play important roles as biomarkers for determining sensitivity to glucosamine. Moreover, the results suggested that the antiproliferative effect of glucosamine may be more efficient when administered in combination with other glycolytic agents or inhibitors targeting HIF‑1α.

Acute myeloblastic leukemia (AML) is one of the most common and life-threatening forms of leukemia. Treatment remains challenging due to its high heterogeneity, drug resistance, and metabolic flexibility. Targeting specific metabolic pathways has emerged as a promising therapeutic approach. The ability to monitor treatment response is crucial for disease management. Here, we utilized hyperpolarized 13C nuclear magnetic resonance (NMR) spectroscopy to evaluate the therapeutic effects of 2-deoxy-D-glucose (2-DG), a glucose analog known to inhibit glycolysis and induce cell death in leukemic cell lines. Hyperpolarized 13C NMR spectroscopy, biochemical assays, and respirometry were used to assess the metabolic effects of 2-DG treatment at various concentrations on the AML cell line ML-1 in vitro. Significant metabolic alterations were observed following 2-DG treatment at 2 mM and 5 mM for 24 h, as revealed by multiple analytical approaches. The concentration-dependent effects of 2-DG treatment were clearly detected using hyperpolarized NMR, demonstrating substantial inhibition of glycolytic pathways in ML-1 cells. This study supports the potential of 2-DG for enhancing chemosensitivity in AML treatment and highlights hyperpolarized NMR as a valuable tool for therapy evaluation.

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 intricate multi-scale phenomenon of entropy generation, resulting from the inhomogeneous and anisotropic rearrangement of cells during their collective migration, is examined across three distinct regimes: (i) convective, (ii) conductive (diffusion), and (iii) sub-diffusion. The collective movement of epithelial monolayers on substrate matrices induces the accumulation of mechanical stress within the cells, which subsequently influences cell packing density, velocity, and alignment. Variations in these physical parameters affect cell-cell interactions, which play a crucial role in the storage and dissipation of energy within multicellular systems. The internal dynamics of entropy generation, as a consequence of energy dissipation, are characterized in each regime using viscoelastic constitutive models and the surface properties at the cell-matrix biointerface. The focus of this theoretical review is to clarify how cells can modulate their rate of energy dissipation by altering cell-cell and cell-matrix adhesion interactions, undergoing changes in shape, and re-establishing polarity due to the contact inhibition of locomotion. We approach these questions by discussing the physical aspects of these complex phenomena.

A library of 50 indolyl sulfonamides and 9 amide analogs based upon the 4-indolyl and 5-indolyl frameworks has been synthesized to target the metabolic processes of pancreatic cancer. Thirteen of the 50 compounds are identified as cytotoxic at 50 μM using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 noncancerous cell line. The potential role of the compounds as metabolic inhibitors of adenosine triphosphate (ATP) production is then evaluated using a rapid screening (1-2 h compound exposure) assay developed within our laboratories. The rapid assay identifies ten compounds as strong or moderate hits at 3 μM against the panel of pancreatic and noncancerous cell lines. The IC50 values of the active compounds are determined using the rapid assay in the absence of glucose and four of the compounds display an IC50 value <1 μM against one or more pancreatic cancer cell lines. A comparison of IC50 values of the active compounds in the presence of glucose implicates the potential role of the compounds as oxidative phosphorylation inhibitors of ATP production. Finally, a series of amide analogs are synthesized and screened for activity to determine the structural importance of the sulfonamide functionality.

Coenzyme Q10 (Q10) plays a critical role in cellular energy conversion within the mitochondrial respiratory chain and offers protective effects against oxidative and metabolic stress. In this study, we investigated the impact of Q10 on the spatio-temporal patterns of cellular energetics in keratinocyte-derived HaCaT cells, utilizing the genetically-encoded FRET sensor AMPfret. Engineered from the AMP-activated protein kinase (AMPK), this sensor leverages endogenous affinities of the kinase that evolved to detect energy stress, specifically decreases in ATP/ADP and ATP/AMP ratios that pose a threat to cell survival. We successfully established HaCaT cells stably expressing AMPfret, validated their functionality by inducing energy stress with 2-deoxy-D-glucose, and demonstrated that Q10, together with high glucose conditions in culture, can enhance cellular energetics compared to low glucose controls. We then employed AMPfret to analyze the spatio-temporal response of HaCaT keratinocytes to Luperox (tert-butyl peroxide), a potent organic prooxidant, in the presence of varying intracellular levels of Q10. Preloading cells with Q10 was protective, slowing the speed and reducing the extend of the energy stress response. In contrast, preincubation with Simvastatin, an inhibitor of the mevalonate Q10 biosynthesis pathway, depleted cellular Q10 levels, accelerated the onset of energy stress, and led to early cell death as compared to controls. Under all conditions, AMPfret revealed cell-to-cell heterogeneity in energy stress at baseline and in the response to Luperox. Overall, tracking changes in energy state in time and at single-cell level allows further insights into the beneficial role of Q10 in enhancing cellular bioenergetics in skin cells, and a potential role of AMPK in mediating responses to altered Q10 levels.

Platinum(II) complexes such as cisplatin, among a few others, are well-known anticancer metal-based drugs approved for clinical use. In spite of their wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks, the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and to further improve its pharmacological properties. Among the recently introduced multiaction prodrugs is the Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, glycolysis in cancer cells. While platinum-based multiaction prodrugs exhibit increased levels of activity toward cancer cells and, thus, are considered potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteome. These are challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work, we performed these analyses for 8-azaguanine and the experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780 employing both mechanism- and compound-centric ultrafast chemical proteomics approaches. These approaches were based on protein expression analysis and thermal proteome profiling, respectively. Data obtained for the Pt(IV)-lonidamine complex revealed regulation of proteins involved in the glucose metabolic process associated with lonidamine, further supporting the multiaction mechanism of this prodrug action.

Abnormal cellular respiration plays a critical role in carcinogenesis. However, the molecular mechanisms underlying dysregulation of respiratory gene expression across different cancer types remain unclear. Here, we developed a computational framework that provides an analytical approach for exploring the molecular alterations and clinical relevance of respiratory genes in pan-cancer. We identified a total of 53 gene signatures in the three stages of respiration (including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation) through this framework and found that they were broadly differentially expressed and genetically altered across 33 cancer types. Pathway analysis manifested that the expression levels of almost all respiratory gene signatures were remarkably associated with the activation or inhibition of numerous oncogenic pathways, such as metabolism, angiogenesis, cell proliferation, and apoptosis. Survival analysis highlighted the oncogenic or tumor suppressor potential of the respiratory gene signatures. In particular, VCAN has shown significant oncogenic features in multiple cancer types. Finally, we identified a number of respiratory gene signatures that could be potential therapeutic targets, including VCAN. We also predicted small-molecule compounds targeting respiratory gene signatures or components of pathways regulated by them. Overall, our comprehensive analysis has greatly enhanced the understanding of molecular alterations of respiratory genes in tumorigenesis and progression, and provided insights into developing new therapeutic strategies.

Glycolysis provides tumors with abundant nutrients through glucose (Glu) metabolism. As a therapeutic target, precise targeting and effective inhibition of the glycolysis process remains a major challenge in anti-metabolic therapy. In this study, a novel dual-template molecularly imprinted polymer (D-MIP), capable of specifically recognizing glucose transporter member 1 (GLUT1) and hexokinase-2 (HK2) was prepared for anti-glycolytic tumor therapy. The imprinting factors of D-MIP for the recognition of the template molecules, the GLUT1 epitope and the HK2 epitope, were 2.1 and 2.5, respectively, enabling specific recognition of the entire target protein. Targeting GLUT1 with D-MIP could impede its Glu uptake, while simultaneously inhibiting the activity of cytoplasmic HK2, thereby reducing the metabolic rate of Glu. Cell experiments demonstrated that inhibition of HK2 resulted in downregulation of the downstream, products glucose-6-phosphate (6PG) and lactate (LA). In vitro and in vivo experimental results indicated that D-MIP exhibited significant targeting and inhibitory effects on GLUT1 and HK2, respectively, which suppressed tumor glycolysis and induced apoptosis in MCF-7 cells. Furthermore, mouse tumor models and hematoxylin-eosin (H&E) staining confirmed the excellent anti-tumor efficacy and favorable biocompatibility of D-MIP. This work represents the first design and development of a dual-template imprinted polymer targeting key transport channels and metabolic enzymes involved in glycolysis, advancing the research and application of anti-glycolytic tumor therapy.

Breast cancer is one of the most common cancers among women. Tumor cell proliferation is highly dependent on aerobic glycolysis, so regulating aerobic glycolysis in breast cancer cells is a promising therapeutic strategy. Resveratrol (Res), as a potential new anti-breast cancer drug, has been shown to regulate the glycolysis of cancer cells and inhibit the metastasis and recurrence of breast cancer. The nano drug delivery system can regulate the aerobic glycolysis metabolism by targeting the signaling factors and reaction products of the tumor aerobic glycolysis process to enhance the anti-tumor effect.

A new albumin-modified layered double hydroxide resveratrol dosage form (BSA@LDHs-Res) was synthesized by hydrothermal co-precipitation. Characterization was carried out to determine the successful synthesis of the nanocarrier system. The bioactivity, glycolytic activity and biocompatibility were examined by in vitro cellular assays; in vivo experiments were performed to further evaluate the anti-tumor effects of the BSA@LDHs-Res dosage form for breast cancer.

In this study, we obtained for the first time a bovine serum albumin-modified BSA@LDHs-Res loaded dosage form, which was able to enter breast cancer cells SKBR3 and MDA-MB-231 via endocytosis and successfully escaped from lysosomal capture. BSA@LDHs-Res inhibited the proliferation, migration, and invasion of two types of breast cancer cells, induced apoptosis, and promoted the reduction of mitochondrial membrane potential and ROS. BSA@LDHs-Res inhibited the expression and viability of the key enzymes of glycolysis, hexokinase 2 (HK2), pyruvate kinase (PK), and lactate dehydrogenase, resulting in decreased glucose consumption, decreased lactate accumulation, and decreased intracellular ATP levels. BSA@LDHs-Res was examined in the mouse model with good anti-tumor effects.

BSA@LDHs-Res is an efficient nanoreagent for the treatment of breast cancer. The albumin-modified resveratrol layered double hydroxide delivery system developed in this study will provide some theoretical references for further research and clinical application of tumor aerobic glycolysis.

Cuproptosis, a newly identified programmed cell death form, is characterized by excessive copper accumulation in cells, resulting in mitochondria damage and toxic protein stress, ultimately causing cell death. Given the considerable therapeutic promise of copper toxicity in cancer treatment, copper-based nanomaterials that induce copper death have attracted interest as a promising approach for tumor therapy. This review comprehensively introduces the mechanisms of cuproptosis and the associated regulatory genes, including both positive and negative regulatory regulators, and systematically summarizes the application of various nanoparticles in inducing cuproptosis, ranging from inorganic copper compounds to delivery systems. These nanoparticles offer significant advantages, such as improving copper absorption, extending the duration of effectiveness, enhancing the precision of copper release, increasing biocompatibility, and serving as enhancers in combination therapy. In conclusion, the authors present a detailed overview and insights into the current research directions of nanoplatforms that facilitate copper-induced cancer treatment, establishing a foundation for the future development of effective nanomedicines that induce cuproptosis and offering new possibilities and treatment strategies for tumor therapy.

Acute liver failure (ALF) has a high mortality rate, and despite treatment advancements, long-term outcomes remain poor.

This study explores the therapeutic targets and pathways of Sini Decoction plus Ginseng Soup (SNRS) in ALF using bioinformatics and network pharmacology, focusing on its impact on macrophage polarization through glucose metabolism reprogramming. The efficacy of SNRS was validated in an LPS/D-GalN-induced ALF model, and its optimal concentration was determined for in vitro macrophage intervention.

Differentially expressed genes (DEGs) in HBV-induced and acetaminophen-induced ALF were identified from GEO datasets. The correlation between target gene expression and immune cell infiltration in ALF liver tissue was analyzed. AST, ALT, TNF-α, HMGB1, IL-1β, IL-6, and IL-10 levels were measured, and liver histopathology was assessed. Macrophage polarization was analyzed via immunofluorescence, flow cytometry, and Western blot. Glycolysis-related enzymes and metabolites, including HK2, PFK-1, PKM2, and LDHA, were quantified. Cellular ultrastructure was examined by transmission electron microscopy.

Five key glycolysis-regulating genes (HK2, CDK1, SOD1, VEGFA, GOT1) were identified, with significant involvement in the HIF-1 signaling pathway. Immune infiltration was markedly higher in ALF liver tissue. SNRS improved survival, reduced ALT/AST levels, alleviated liver injury, and modulated macrophage polarization by decreasing CD86 and increasing CD163 expression. In vitro, SNRS inhibited LPS-induced inflammatory cytokine release, lactate production, p-mTOR/mTOR ratio, and HIF-1α expression.

SNRS modulates macrophage polarization and glucose metabolism reprogramming via the mTOR/HIF-1α pathway, showing promise as a treatment for ALF.

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.

Real-time monitoring of molecular transformations is crucial for advancements in biotechnology. In this study, we introduce a novel self-assembling 19F-labeled nuclear magnetic resonance (NMR) probe that disassembles upon interaction with various nucleotides. This interaction not only activates the 19F signals but also produces distinct signatures for each specific component, thereby enabling precise identification and quantification of molecules in evolving samples. We demonstrate the capability of this probe for real-time monitoring of adenosine triphosphate (ATP) hydrolysis and screening potential enzyme inhibitors. These applications highlight the probe's significant potential in enzyme analysis, drug development, and disease diagnostics.

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC50 value <5 μM against one or more pancreatic cancer cell lines.

Colorectal cancer (CRC) is the second most common cause of cancer-related death and represents a serious worldwide health problem. CRC metastasis decreases the survival rate of cancer patients, underscoring the need to identify novel anticancer agents and therapeutic targets. Here, we introduce Plectalibertellenone A (B) as a promising agent for the inhibition of CRC cell motility and glucose metabolism and explore its mechanism of action in CRC cells. Plectalibertellenone A suppressed TGF-β gene expression and the activation of the TGF-β/Smad signaling pathway, leading to reverse epithelial to mesenchymal transition (EMT) by modulating the expressions of EMT markers and transcriptional factors such as E-cadherin, N-cadherin, vimentin, Slug, Snail, Twist, and ZEB1/2. Furthermore, disruption of Wnt signaling inhibited CRC motility and glucose metabolism including glycolysis and oxidative phosphorylation, primarily affecting glycolytic enzymes, GLUT1, HK2, PKM2, LDHA, and HIF-1α under hypoxic condition. Therefore, Plectalibertellenone A is a potential drug candidate that can be developed into a promising anticancer treatment to prevent CRC metastasis and inhibit glucose metabolism.

The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.

Rising cancer care costs are becoming cost prohibitive for lower income people worldwide. We developed the Warburg protocol as a low-cost option for the treatment of cancer that was inspired. It was developed to exploit an Achilles heel which is a hallmark of cancer cells; the metabolic requirement for higher levels of glucose than normal cells.

The purpose of this report is to assess the clinical safety and affordability of the Warburg therapy as an option for patients with advanced cancers.

Between 2021 and 2023, 251 patients with advanced cancers received a total of 8542 treatments with the Warburg therapy. To restrict the supply of blood glucose to cancerous tumors, regular human insulin was administered (IV) sufficient to reduce blood glucose concentrations to hypoglycemic levels for 40-60 min. Subroutine doses of fluorouracil and cyclophosphamide were administered intravenously during this hypoglycemic period. Food or intravenous glucose was given as needed to return blood glucose to euglycemic levels after treatment. Patient symptoms, status, vitals, blood glucose, and hypoglycemic symptoms were monitored throughout treatment. Various blood parameters were measured before and after patients' course of treatment.

There were no irreversible adverse reactions in advanced tumor patients of different ages and different cancer types after treatment. There was no significant fluctuation in blood glucose levels in diabetic and non-diabetic patients after treatment, and the weight, vital index and blood biochemical index of patients before and after multiple treatments exhibited little variation.

Warburg therapy for the treatment of advanced tumors is clinically feasible, and safe for multiple treatments. It is inexpensive and widely applicable to different patient groups.

Around the world, non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths among all cancers. Despite advancements in new therapeutic approaches over the past few decades, the five-year survival rate still remains disappointing. The lack of effective anti-angiogenic and anti-migration drugs is the biggest obstacle to the treatment of metastatic lung cancer. Therefore, there is a need to develop new and effective therapeutic compounds targeting anti-angiogenic and anti-migration pathways for the treatment of lung cancer. Ornidazole is a nitroimidazole agent widely used in the treatment of parasitic infections such as trichomonas vaginalis, amebiasis and giardiasis. This study aimed to investigate the anti-proliferative, anti-angiogenic and anti-mitotic activities of the anti-parasitic drug Ornidazole in two human lung cancer cell lines (A549, H1299).

We determined the effects of Ornidazole, on cell viability, apoptosis, migration, angiogenesis and metastatic ability against NSCLC in lung cancer cell lines. Its action on the mRNA and protein expression levels of VEGFA, VEGFR2, NRP1, Casp9, Casp3, Bax, Bcl-2, PIK3CA, AKT, MTOR, PTEN and FOX3A was assessed. Furthermore, in this study the effects on cell migration, cell viability and proliferation was evaluated through wound healing, MTT and Crystal violet assays.

This study demonstrated that Ornidazole effectively reduces cell viability and migration ability, inhibits angiogenesis and metastatic abilities in NSCLC cells.

In conclusion, these results may shed light on the treatment of NSCLC, and we suggest the anti-parasitic drug Ornidazole as a new agent with potential anti-angiogenic and anti-mitotic activity by interfering with the molecular pathways that trigger tumor angiogenesis and migration.

Cellular death evasion is a defining characteristic of human malignancies and a significant contributor to therapeutic inefficacy. As a result of oncogenic inhibition of cell death mechanisms, established therapeutic regimens seems to be ineffective. Mitochondria serve as the cellular powerhouses, but they also function as repositories of self-destructive weaponry. Changes in the structure and activities of mitochondria have been consistently documented in cancer cells. In recent years, there has been an increasing focus on using mitochondria as a targeted approach for treating cancer. Considerable attention has been devoted to the development of delivery systems that selectively aim to deliver small molecules called "mitocans" to mitochondria, with the ultimate goal of modulating the physiology of cancer cells. This review summarizes the rationale and mechanism of mitochondrial targeting with small molecules in the treatment of cancer, and their impact on the mitochondria. This paper provides a concise overview of the reasoning and mechanism behind directing treatment towards mitochondria in cancer therapy, with a particular focus on targeting using small molecules. This review also examines diverse small molecule types within each category as potential therapeutic agents for cancer.

Lactate, once viewed as a byproduct of glycolysis and a metabolic "waste", is now recognized as an energy-providing substrate and a signaling molecule that modulates cellular functions under pathological conditions. The discovery of histone lactylation in 2019 marked a paradigm shift, with subsequent studies revealing that lactate can undergo lactylation with both histone and non-histone proteins, implicating it in the pathogenesis of various diseases, including cancer, liver fibrosis, sepsis, ischemic stroke, and acute kidney injury. Aberrant lactate metabolism is associated with disease onset, and its levels can predict disease outcomes. Targeting lactate production, transport, and lactylation may offer therapeutic potential for multiple diseases, yet a systematic summary of the small molecules modulating lactate and its metabolism in various diseases is lacking. This review outlines the sources and clearance of lactate, as well as its roles in cancer, liver fibrosis, sepsis, ischemic stroke, myocardial infarction, and acute kidney injury, and summarizes the effects of small molecules on lactate regulation. It aims to provide a reference and direction for future research.

Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.

Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors.

To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA.

Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested.

In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through "starvation therapy", cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H2O2). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H2O2, while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future.

This study investigates the expression and functional roles of SUGT1 in ovarian cancer, utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Our analyses reveal that SUGT1 is significantly upregulated in ovarian cancer tissues compared to normal controls. We further explore the prognostic value of SUGT1, where elevated expression correlates with poorer patient outcomes, particularly in ovarian cancer. The functional implications of SUGT1 in cancer biology were assessed through in vitro and in vivo experiments. Gene Set Enrichment Analysis (GSEA) indicates a significant association between high SUGT1 expression and the activation of glycolytic pathways, suggesting a potential role in metabolic reprogramming. Inhibition of SUGT1 via siRNA in ovarian cancer cell lines results in decreased proliferation and increased apoptosis, along with reduced migration and invasion capabilities. Additionally, our study identifies the transcription factor ELF1 as a significant regulator of SUGT1 expression. Through promoter analysis and chromatin immunoprecipitation, we demonstrate that ELF1 directly binds to the SUGT1 promoter, enhancing its transcription. This regulatory mechanism underscores the importance of transcriptional control in cancer metabolism, providing insights into potential therapeutic targets. Our findings establish SUGT1 as a crucial player in the oncogenic processes of ovarian cancer, influencing both metabolic pathways and transcriptional regulation. This highlights its potential as a biomarker and therapeutic target in managing ovarian cancer.

Gliomas are malignant tumors originating from both neuroglial cells and neural stem cells. The involvement of neural stem cells contributes to the tumor's heterogeneity, affecting its metabolic features, development, and response to therapy. This review provides a brief introduction to the importance of metabolism in gliomas before systematically categorizing them into specific groups based on their histological and molecular genetic markers. Metabolism plays a critical role in glioma biology, as tumor cells rely heavily on altered metabolic pathways to support their rapid growth, survival, and progression. Dysregulated metabolic processes, involving carbohydrates, lipids, and amino acids not only fuel tumor development but also contribute to therapy resistance and metastatic potential. By understanding these metabolic changes, key intervention points, such as mutations in genes like RTK, EGFR, RAS, and IDH can be identified, paving the way for novel therapeutic strategies. This review emphasizes the connection between metabolic pathways and clinical challenges, offering actionable insights for future research and therapeutic development in gliomas.

Well-controlled metabolism is associated with high-quality oocytes and optimal development of a healthy embryo. However, the metabolic framework that controls mammalian oocyte growth remains unknown. In the present study, we comprehensively depict the temporal metabolic dynamics of mouse oocytes during in vivo growth through the integrated analysis of metabolomics and proteomics. Many novel metabolic features are discovered during this process. Of note, glycolysis is enhanced, and oxidative phosphorylation capacity is reduced in the growing oocytes, presenting a Warburg-like metabolic program. For nucleotide biosynthesis, the salvage pathway is markedly activated during oocyte growth, whereas the de novo pathway is evidently suppressed. Fatty acid synthesis and channeling into phosphoinositides are specifically elevated in oocytes accompanying primordial follicle activation; nevertheless, fatty acid oxidation is reduced in these oocytes simultaneously. Our data establish the metabolic landscape during in vivo oocyte growth and serve as a broad resource for probing mammalian oocyte metabolism.

Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing ∆ubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in ∆ubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic flux-dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.

The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells, and extracellular matrix (ECM). However, the specific role of neutrophils during tumor development, and their interactions with other immune cells is still not well understood. Here, we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated ECM bridge to elucidate how naive primary neutrophils respond to tumor cells. Our data demonstrated that tumor cells trigger cluster formation in neutrophils accompanied with the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) release. Using label-free optical metabolic imaging (OMI), we observed changes in the metabolic activities of primary neutrophils during the different clustering phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities compared to non-contact neutrophils.

Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field.

Studies have indicated that RAB17 expression levels are associated with tumor malignancy, and RAB17 is more highly expressed in endometrial cancer (EC) tissues than in peritumoral tissues. However, the roles and potential mechanisms of RAB17 in EC remain undefined. The present study confirmed that the expression of RAB17 facilitates EC progression by suppressing cellular ferroptosis-like alterations. Mechanistically, RAB17 attenuated ferroptosis in EC cells by inhibiting transferrin receptor (TFRC) protein expression in a ubiquitin proteasome-dependent manner. Because EC is a blood-deprived tumor with a poor energy supply, the relationship between RAB17 and hypoglycemia was investigated. RAB17 expression was increased in EC cells incubated in low-glucose medium. Moreover, low-glucose medium limited EC cell ferroptosis and promoted EC progression through the RAB17-TFRC axis. The in vitro results were corroborated by in vivo studies and clinical data. Overall, the present study revealed that increased RAB17 promotes the survival of EC cells during glucose deprivation by inhibiting the onset of TFRC-dependent ferroptosis.

Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.

Diacylglycerol O-acyltransferase 2 (DGAT2) synthesizes triacylglycerol (TG) from diacylglycerol; therefore, DGAT2 is considered as a therapeutic target for steatosis. However, the consequence of inhibiting DGAT2 is not fully investigated due to side effects including lethality and lipotoxicity. In this article, we observed the role of DGAT2 in hepatocarcinoma.

The role of DGAT2 is analyzed via loss-of-function assay. DGAT2 knockdown (KD) and inhibitor treatment on HepG2 cell line was analyzed. Cumulative analysis of cell metabolism with bioinformatic data were assessed, and further compared with different cohorts of liver cancer patients and non-alcoholic fatty liver disease (NAFLD) patients to elucidate how DGAT2 is regulating cancer metabolism.

Mitochondrial function is suppressed in DGAT2 KD HepG2 cell along with the decreased lipid droplets. In the aspect of the cancer, DGAT2 KD upregulates cell proliferation. Analyzing transcriptome of NAFLD and hepatocellular carcinoma (HCC) patients highlights negatively correlating expression patterns of 73 lipid-associated genes including DGAT2. Cancer patients with the lower DGAT2 expression face lower survival rate. DGAT2 KD cell and patients' transcriptome show downregulation in estrogen- related receptor alpha (ESRRA) via integrated system for motif activity response analysis (ISMARA), with increased dimerization with corepressor prospero homeobox 1 (PROX1).

DGAT2 sustains the stability of mitochondria in hepatoma via suppressing ESRRA-PROX1 transcriptional network and hinders HCC from shifting towards glycolytic metabolism, which lowers cell proliferation.

Cancer cells exhibit altered metabolic pathways, prominently featuring enhanced glycolytic activity to sustain their rapid growth and proliferation. Dysregulation of glycolysis is a well-established hallmark of cancer and contributes to tumor progression and resistance to therapy. Increased glycolysis supplies the energy necessary for increased proliferation and creates an acidic milieu, which in turn encourages tumor cells' infiltration, metastasis, and chemoresistance. Circular RNAs (circRNAs) have emerged as pivotal players in diverse biological processes, including cancer development and metabolic reprogramming. The interplay between circRNAs and glycolysis is explored, illuminating how circRNAs regulate key glycolysis-associated genes and enzymes, thereby influencing tumor metabolic profiles. In this overview, we highlight the mechanisms by which circRNAs regulate glycolytic enzymes and modulate glycolysis. In addition, we discuss the clinical implications of dysregulated circRNAs in cancer glycolysis, including their potential use as diagnostic and prognostic biomarkers. All in all, in this overview, we provide the most recent findings on how circRNAs operate at the molecular level to control glycolysis in various types of cancer, including hepatocellular carcinoma (HCC), prostate cancer (PCa), colorectal cancer (CRC), cervical cancer (CC), glioma, non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer (GC). In conclusion, this review provides a comprehensive overview of the significance of circRNAs in cancer glycolysis, shedding light on their intricate roles in tumor development and presenting innovative therapeutic avenues.

Gastrointestinal stromal tumor (GIST) is the most prevalent mesenchymal tumor of the digestive tract. Its growth is primarily influenced by mutations in KIT or PDGFRA. Surgery is the primary treatment option for GIST; however, KIT inhibitors, such as imatinib, are used for inoperable cases. Resistance to imatinib is an upcoming challenge, especially because the effectiveness of alternative drugs is limited. Enhancement of the glycolysis pathway in cancer cells has been identified as a key feature in cancer. This unique metabolic activity has implications on tumor growth, prognosis, and resistance to therapy, even in GIST. Members of the glucose transporter (GLUT) family (particularly GLUT-1) play a significant role in GIST progression and response to treatment. Diagnostic imaging using 18F-fluorodeoxyglucose positron emission tomography/computed tomography, which enables visualization of glucose metabolism, can aid in GIST diagnosis and risk assessment. The interplay between glycolysis and GIST can lead to the development of various therapeutic strategies, especially those involving glycolysis-related molecules, such as hexokinase and lactate dehydrogenase. However, further research is required to understand the full spectrum of glycolysis in GIST and its therapeutic potential. Herein, we present an exhaustive overview and analysis of the role of glycolysis in GIST, especially as a therapeutic target.

Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1Δ mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1Δ strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1Δ strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin ® A as a compound restoring growth on glucose of the yeast tps1Δ mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin ® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin ® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1Δ cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin ® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism.