Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Lactate plays a crucial role as an energy substrate, metabolite, and signaling molecule in cancer. Lactate has long been considered a byproduct of glycolysis. Still, the lactate shuttle hypothesis has changed the lactate paradigm, revealing the implications of lactate in cellular metabolism and cellular communications that can transcend the compartment barrier and occur within and between different cells, tissues, and organs. Due to the Warburg effect, the tumor produces a large amount of lactate, thus creating a low-nutrition, hypoxic, and low-pH tumor microenvironment (TME). Consequently, immunosuppressive networks are built to acquire immune evasion potential and regulate tumor growth. Lactylation is a newly discovered post-translational modification of lysine residues with the capacity for transcriptional regulation via histone modification and modulation of non-histone protein functions, which links gene regulation to cellular metabolism by aberrant metabolism activity and epigenetic modification. There is growing evidence that lactylation plays a crucial role in cancer progression and drug resistance. Targeting lactylation enzymes or metabolic pathways has shown promising effects in suppressing cancer progression and drug resistance, highlighting the therapeutic potential of this modification. Therefore, in this review, we offer a systematic overview of lactate homeostasis in physiological and pathological processes as well as discuss the influence of lactylation in cancer progression and drug resistance and underlying molecular mechanisms, providing a theoretical basis for further research.

Radiotherapy (RT) is the primary treatment modality for hepatocellular carcinoma (HCC). Inevitably, the X-ray exposure also increases the metabolic stress and energy demands in surviving tumor cells, which leads to metabolic reprogramming that reduces the sensitivity of HCC to clinical treatments including RT. Nevertheless, the current research in tumor metabolic therapy predominantly focuses on inhibiting glycolytic pathways, and the consequent metabolic compensation behavior of tumor cells exacerbates the risks of drug resistance and recurrence. To address this challenge, we innovatively proposed a tumor-specific multi-metabolic pathway regulation strategy navigated by tumor cell surface nutrient transporter (2-DG/BP MRs), which can be triggered by X-ray radiation to achieve dual blockade of glycolysis and glutamine metabolism pathways. Thus, this nanosystem reconfigured metabolic pathways within tumor cells to counteract RT-induced metabolic reprogramming through dual metabolic inhibition (glycolysis and glutamine metabolism). This approach disrupted the essential energy supply required for cancer cell proliferation without causing metabolic disorders in normal cells, thereby sensitizing HCC to RT. This tumor cell-specific metabolic intervention strategy provides a safe and effective approach for combination therapy in clinically RT-resistant tumors.

Respiratory viral infections, such as those caused by rhinoviruses (RVs) and human corona viruses (HCoV), result in a serious strain on healthcare systems and public health, underscoring an urgent need for inhaled broad-spectrum antiviral therapies. However, their development is challenging, as no standardized in vitro methodologies that can fully replicate the in vivo environment have been established. In this work, we aimed to investigate the antiviral and anti-inflammatory effect of three 2-deoxylated glucose analogues (2-DGA): 2-deoxy-D-glucose, 2-fluoro-2-deoxy-D-glucose and 2-fluoro-2-deoxy-D-mannose (2-FDM), by utilizing advanced in vitro air-liquid interface (ALI) airway models. We demonstrated that commonly used ALI models have variable susceptibility to RV, HCoV and influenza A virus (IAV) infection. Further, we showed that 2-DGA have an anti-inflammatory effect and suppress respiratory viral replication in models mimicking the upper and lower respiratory airways. Moreover, we confirmed that 2-DGA can be delivered via nebulization in vitro, highlighting their potential to be used as broad-spectrum inhaled antivirals. Finally, our results demonstrate the importance of incorporating complex in vitro methodologies, such as primary cell ALI cultures and aerosol exposure, at an early stage of drug development.

2-deoxy-D-glucose is a synthetic glucose analog and a potent inhibitor of glycolysis. Preclinical models demonstrated antiviral effects of 2-deoxy-D-glucose by inducing a glucose-deprived state in cells, which interferes with viral replication.

This was a phase I, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single (cohort 1: 100µl in one nostril, cohort 2: 200µl in one nostril, cohort 3: 200µl in both nostrils) and multiple (cohort 4: four-times 200µl/day in one nostril, cohort 5: four-times 200µl/day in both nostrils, cohort 6: six-times 200µl/day in both nostrils; all for seven days) ascending doses of intranasal 3.5% 2-deoxy-D-glucose in normal healthy volunteers with the primary objective of investigating safety and tolerability. Drug concentrations were measured in plasma and in nasal wash fluid.

Forty-five healthy volunteers participated in this study. Single and multiple doses of 2-deoxy-D-glucose were well-tolerated, with no safety signals or treatment-related serious or severe adverse events observed throughout the trial. Pharmacokinetics showed virtually absent systemic absorption of intranasal 2-deoxy-D-glucose, while intranasal maximum drug concentrations were comparable to those shown to have antiviral effects in vitro.

Intranasal 2-deoxy-D-glucose, a novel intranasal therapeutic treatment for acute viral infections was safe and well-tolerated in healthy volunteers. These data support the further clinical development of 2-deoxy-D-glucose for treating viral infections in the target population (NCT05314933).

Protein glycosylation plays a versatile role in regulating homeostasis, such as cell migration, protein sorting, and the immune response. Drugs aimed at targeting glycosylation have strong implications for immunity enhancement, diagnosis, and cancer regression. Programmed death-ligand 1 (PD-L1), expressed in cancer or antigen-presenting cells, binds to programmed cell death protein 1 (PD-1) and suppresses T cells. Glycosylation of PD-L1 at N35, N192, N200, and N219 stabilizes PD-L1 on the cancer cell surface, which contributes to immune evasion by inhibiting T cell activity. To date, at least six glycosyltransferases and four associate proteins are known to regulate PD-L1 glycosylation. Terminal modifications such as poly-N-acetyl-lactosamine (poly-LacNAC), sulfation, and sialylation are commonly found on PD-L1, acting as an immune recognition ligand and regulating certain immune responses. Studies have identified many mechanisms and potential therapeutic targets within the glycosylation pathways of PD-L1, revealing their involvement in cancer pathology, immune evasion, and resistance to immunotherapy. In this review, we covered the glycoforms, terminal moiety, binding lectin, glycosyltransferase, as well as sugar analogs focusing on glycosylated PD-L1. We present a mechanism that originates from the endoplasmic reticulum (ER)-Golgi apparatus (Golgi) and its subsequent translocation to the cell membrane. This pathway determines the immune suppression function of PD-L1 and therefore regulates the immune response such as T cells, monocytes, and macrophages. This collection of findings underscores the significance of glycosylation in the role of PD-L1 in cancer and highlights multiple potential targets and strategies for improving therapeutic intervention and diagnostic techniques.

It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells.

Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field.

Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.

The positron emission tomography (PET) tracer 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) is widely used to study diseases where glucose metabolism is dysregulated, including cancer and neurodegenerative disorders. Here we investigate the hypothesis that the 2-position deuterium-enriched analogue 2-deoxy-2-[2H2]-d-glucose (2-DG-d2) can also map glucose uptake using deuterium metabolic imaging (DMI) without ionizing radiation. To accomplish this, we used a spectrally selective multiband radiofrequency pulse and balanced steady-state free procession (bSSFP) technique, enabling rapid 2H imaging with high specificity and sensitivity to 2-DG-d2. Both in vitro and in vivo validations demonstrated the sequence's ability to suppress endogenous water signal. Mapping of 2-DG-d2 with high spatial resolution was achieved in healthy mouse brains, comparable to what might be obtained using [18F]FDG PET. The numerous applications of [18F]FDG PET, as well as recent clinical translation of the natural abundance 2-deoxy-d-glucose (2-DG) parent sugar, suggest that DMI using 2-DG-d2 may be applied to patients in the future.

Bladder cancer (BLCA) ranks among the most prevalent malignancies of the urinary system, with its clinical diagnosis predominantly reliant on invasive procedures. Traditional chemotherapy regimens exhibit significant limitations, underscoring the urgency of identifying novel diagnostic biomarkers and strategies to enhance chemotherapy efficacy. CDCA3 has been recognized as a facilitator of BLCA progression, activated by MYBL2. However, its precise regulatory mechanisms in BLCA pathogenesis remain incompletely elucidated.

To investigate the functional role of CDCA3 in BLCA, MTT and colony formation assays were employed to assess cellular proliferation, while flow cytometry was utilized to evaluate apoptosis and intracellular ROS levels. The expression of CDCA3, ENO1, TRIM28, and MYC was analyzed through WB and qRT-PCR, and Co-IP assays were conducted to delineate interactions among CDCA3, TRIM28, and MYC.

CDCA3, a key regulator of the cell cycle, facilitates BLCA glycolysis by modulating the transcriptional expression of α-Enolase (ENO1), thereby enhancing BLCA progression. Mechanistically, CDCA3 recruits TRIM28, which stabilizes MYC, while MYC transcriptionally upregulates CDCA3, establishing a self-reinforcing CDCA3-MYC feedback loop. A risk prediction model incorporating the expression profiles of CDCA3 and ENO1 was developed to evaluate the overall survival of patients with BLCA. This model provides a prognostic tool to predict survival outcomes in patients with BLCA based on CDCA3 and ENO1 expression levels.

This study delineates a novel role for CDCA3 in the regulation of BLCA glycolysis and identifies its interaction with MYC as a critical positive feedback mechanism, providing fresh insights into the molecular mechanisms underlying BLCA progression.

Normal tissues typically maintain partial oxygen pressure within a range of 3-10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism and resistance to therapy. Hypoxic tumor regions experience uneven oxygen distribution with severe hypoxia in the core due to poor vascularization and high metabolic oxygen consumption. Cancer cells adapt to these conditions through metabolic shifts, predominantly relying on glycolysis, and by upregulating antioxidant defenses to mitigate reactive oxygen species (ROS)-induced oxidative damage. Hypoxia-induced ROS, resulting from mitochondrial dysfunction and enzyme activation, exacerbates genomic instability, tumor aggressiveness, and therapy resistance. Overcoming hypoxia-induced ROS cancer resistance requires a multifaceted approach that targets various aspects of tumor biology. Emerging therapeutic strategies target hypoxia-induced resistance, focusing on hypoxia-inducible factors, ROS levels, and tumor microenvironment subpopulations. Combining innovative therapies with existing treatments holds promise for improving cancer outcomes and overcoming resistance mechanisms.

A cellulose nanocrystal (CNC)-annealed hydrogel (CAH) structure, including doxorubicin (DOX) and 2-deoxy-d-glucose (2DG), was developed for local chemo-metabolic therapy (LCMT) of melanoma. DOX has been used as a chemotherapeutic agent because of its intercalation into DNA and generation of free radicals. 2DG has been used as a glycolytic inhibitor in multiple metabolic therapies in combination with DOX. Covalent and non-covalent (i.e., ionic and hydrogen bonding) binding approaches between CNC and drug cargo (i.e., DOX and 2DG) were used to tune the rheological properties of the CAH structure to achieve sustained drug release. Reduction of reduced nicotinamide adenine dinucleotide phosphate, adenosine triphosphate, and mitochondrial membrane potential, and elevation of cellular reactive oxygen species and cleaved caspases 3 and 7 were observed following treatment with CNC/DOX/2DG in B16F10 cells. Glutathione depletion, enhanced lipid peroxidation, and decreased lactate levels were observed in the CNC/DOX/2DG group. After intratumoral injection of the CNC/DOX/2DG hydrogel into B16F10 tumor-bearing mice, stronger tumor growth suppression and anti-recurrence capabilities were observed. These findings imply that the viscoelastically modulated CAH system can be a strong candidate for LCMT of melanoma.

Breast cancer is a cancer with global prevalence and a surge in the number of cases with each passing year. With the advancement in science and technology, significant progress has been achieved in the prevention and treatment of breast cancer to make ends meet. The scientific intradisciplinary subject of "metabolomics" examines every metabolite found in a cell, tissue, system, or organism from different sources of samples. In the case of breast cancer, little is known about the regulatory pathways that could be resolved through metabolic reprogramming. Evidence related to the significant changes taking place during the onset and prognosis of breast cancer can be obtained using metabolomics. Innovative metabolomics approaches identify metabolites that lead to the discovery of biomarkers for breast cancer therapy, diagnosis, and early detection. The use of diverse analytical methods and instruments for metabolomics includes Magnetic Resonance Spectroscopy, LC/MS, UPLC/MS, etc., which, along with their high-throughput analysis, give insights into the metabolites and the molecular pathways involved. For instance, metabolome research has led to the discovery of the glutamate-to-glutamate ratio and aerobic glycolysis as biomarkers in breast cancer. The present review comprehends the updates in metabolomic research and its processes that contribute to breast cancer prognosis and metastasis. The metabolome holds a future, and this review is an attempt to amalgamate the present relevant literature that might yield crucial insights for creating innovative therapeutic strategies aimed at addressing metastatic breast cancer.

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.

Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

Oral squamous cell carcinoma (OSCC) is a prevalent oral malignancy, which poses significant health risks with a high mortality rate. Regulatory T cells (Tregs), characterized by their immunosuppressive capabilities, are intricately linked to OSCC progression and patient outcomes. The metabolic reprogramming of Tregs within the OSCC tumor microenvironment (TME) underpins their function, with key pathways such as the tryptophan-kynurenine-aryl hydrocarbon receptor, PI3K-Akt-mTOR and nucleotide metabolism significantly contributing to their suppressive activities. Targeting these metabolic pathways offers a novel therapeutic approach to reduce Treg-mediated immunosuppression and enhance anti-tumor responses. This review explores the metabolic dependencies and pathways that sustain Treg function in OSCC, highlighting key metabolic adaptations such as glycolysis, fatty acid oxidation, amino acid metabolism and PI3K-Akt-mTOR signaling pathway that enable Tregs to thrive in the challenging conditions of the TME. Additionally, the review discusses the influence of the oral microbiome on Treg metabolism and evaluates potential therapeutic strategies targeting these metabolic pathways. Despite the promising potential of these interventions, challenges such as selectivity, toxicity, tumor heterogeneity, and resistance mechanisms remain. The review concludes with perspectives on personalized medicine and integrative approaches, emphasizing the need for continued research to translate these findings into effective clinical applications for OSCC treatment.

Doxorubicin is limited in its therapeutic utility due to its life-threatening cardiovascular side effects. Here, we present an integrated drug discovery pipeline combining human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs), CRISPR interference and activation (CRISPRi/a) bidirectional pooled screens, and a small-molecule screening to identify therapeutic targets mitigating doxorubicin-induced cardiotoxicity (DIC) without compromising its oncological effects. The screens revealed several previously unreported candidate genes contributing to DIC, including carbonic anhydrase 12 (CA12). Genetic inhibition of CA12 protected iCMs against DIC by improving cell survival, sarcomere structural integrity, contractile function, and calcium handling. Indisulam, a CA12 antagonist, can effectively attenuate DIC in iCMs, engineered heart tissue, and animal models. Mechanistically, doxorubicin-induced CA12 potentiated a glycolytic activation in cardiomyocytes, contributing to DIC by interfering with cellular metabolism and functions. Collectively, our study provides a roadmap for future drug discovery efforts, potentially leading to more targeted therapies with minimal off-target toxicity.

Background/Objectives: Glycolysis and mitochondrial oxidative phosphorylation are the two major metabolic pathways for cellular ATP production. The metabolic plasticity displayed by cancer cells allows them to effectively shift between each of these pathways as a means of adapting to various growth conditions, thus ensuring their survival, proliferation and disease progression. Metabolic plasticity also provides cancer cells with the ability to circumvent many traditional monotherapies aimed at only one or the other of the major ATP-producing pathways. The purpose of this study was to determine the effectiveness of a dual treatment strategy aimed simultaneously at both pathways of ATP production in human breast cancer cells. It was hypothesized that concurrent exposure of these cells to the mitochondria-targeting chemotherapeutic agent, elesclomol, in combination with either of two glycolytic inhibitors, 2-deoxy-D-glucose or 3-bromopyruvate, would yield greater in vitro anticancer effects than those observed for any of the compounds used as a single agent. Methods: Cytotoxicity and clonogenic assays were employed to assess the survival and proliferation of MCF7 and MDA-MB-231 human breast adenocarcinoma cells exposed to the compounds alone and in combination. Results: The data obtained show that the cancer-cell-killing and antiproliferative effects of the dual treatment were significantly enhanced compared to those observed for any of the compounds alone. Conclusions: The results of this study are important in that they suggest the possibility of a novel and effective chemotherapeutic strategy for breast cancer cell killing.

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

Ischemic stroke is currently the second leading cause of mortality worldwide, with limited treatment options available. As resident immune cells, microglia promptly respond to cerebral ischemic injury, influencing neuroinflammatory damage and neurorepair. Studies suggest that microglia undergo metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis in response to ischemia, significantly impacting their function during ischemic stroke. Therefore, this study aims to investigate the roles and regulatory mechanisms involved in this process, aiming to identify a new therapeutic target or potential drug candidate.

We previously reported that metformin, a widely prescribed antidiabetic drug, induces the accumulation of triglyceride (TG) together with the apoptotic death of H4IIE via AMP-activated protein kinase (AMPK) in hepatocellular carcinoma (HCC) cells. However, the effect of cytoplasmic fat accumulation on the growth of HCCs remains controversial. Herein, we investigated the effect of fatty acid synthase (FASN) inhibitors on the basal- or metformin-induced changes including the content of cytoplasmic TG and the viability of HCC cells. Cerulenin and C75, inhibitors of FASN, did not significantly affect the basal TG content but dose-dependently suppressed the metformin-induced increase in the cytoplasmic TG content. Metformin-induced apoptosis of H4IIE cells was also significantly reduced by cerulenin and C75. Metformin enhanced the generation of reactive oxygen species which was suppressed by adding cerulenin or T75. Cerulenin also stimulated cell migration, which was suppressed by metformin. However, the degree of suppressive effect of metformin on TG synthesis, apoptosis, and cell migration was much more prominent by the inhibition of AMPK by compound C than cerulenin. In conclusion, our study found that excess fat accumulation is responsible for the apoptosis of H4IIE HCC cells and is informative for designing anti-tumor reagents, especially in HCC.

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.

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.

In this perspective, we highlight and reflect on the current knowledge with respect to serine/glycine metabolism in cancer, therapeutic resistance, and precision medicine opportunities for therapeutic targeting and treatment follow-up. Cancer subtypes with high mortality rates include lung cancer and glioblastomas. In order to improve future therapeutic opportunities, patient stratification need to be performed to select patients that might benefit from adjuvant serine/glycine targeting compounds. In an effort to identify the group of patients for stratification purposes, we analyzed publicly available TCGA patient datasets to test associations between serine/glycine metabolism enzyme expression and important cancer drivers in lung cancer and glioblastoma. These patients presenting serine/glycine pathway overexpression might benefit from adjuvant sertraline treatment in the future.

Objective This study aimed to evaluate the role of 2-Deoxy-D-Glucose (2-DG) in moderate to severe Coronavirus Disease 2019 (COVID-19) cases. Methodology This study retrospectively analyzed the effects of 2-DG alongside Standard of Care (SOC) for moderate to severe COVID-19 in 150 patients. Eligible patients were aged 18-65, with confirmed COVID-19, who met clinical criteria for moderate or severe illness. Data collected included demographics, clinical status, treatment details, and outcomes, evaluated using the WHO's 10-point scale. The primary outcome measured was time to clinical improvement, with secondary outcomes including duration of oxygen supplementation, length of hospital stay, and viral clearance. Data analysis employed the Cox proportional hazard model, with significance at p < 0.05. Results In the study, initial oxygen saturation levels upon admission were similar between groups, averaging 92.6% in the 2-DG with SOC group and 91.8% in the SOC-only group (p = 0.97). The WHO ordinal scores, pulse, and respiratory rates improved significantly in the 2-DG group across multiple intervals. Oxygen supplementation needs to be decreased notably, with 2-DG patients requiring an average of 5.1 L/min by Day 5, showing significant reductions compared to the SOC group. The time to clinical improvement and length of hospital stay were also shorter in the 2-DG group (5.2 days vs. 7.5 days; 8.5 days vs. 10.5 days, respectively; p < 0.001). Adverse events were less frequent in the 2-DG group (6.7% vs. 13.3%, p = 0.03). Conclusion In conclusion, 2-DG demonstrates significant efficacy as an adjunct therapy for moderate to severe COVID-19, reducing both time to clinical improvement (5.2 vs. 7.5 days, p < 0.001) and hospital stay duration. Additionally, fewer adverse events were reported, and viral clearance rates were higher in the 2-DG group. These findings highlight 2-DG's potential to improve clinical outcomes in COVID-19 care.

While fatty acid oxidation (FAO) in mitochondria is a primary energy source for quiescent lymphocytes, the impact of promoting FAO in activated lymphocytes undergoing metabolic reprogramming remains unclear. Here, we demonstrate that pemafibrate, a selective PPARα modulator used clinically for the treatment of hypertriglyceridemia, transforms metabolic system of T-cells and alleviates several autoimmune diseases. Pemafibrate suppresses Th17 cells but not Th1 cells, through the inhibition of glutaminolysis and glycolysis initiated by enhanced FAO. In contrast, a conventional PPARα agonist fenofibrate significantly inhibits cell growth by restraining overall metabolisms even at a dose insufficient to induce fatty acid oxidation. Clinically, patients receiving pemafibrate showed a significant decrease of Th17/Treg ratio in peripheral blood. Our results suggest that augmented FAO by pemafibrate-mediated selective activation of PPARα restrains metabolic programs of Th17 cells and could be a viable option for the treatment of autoimmune diseases.

The most destructive period the world has experienced seems to be behind us. Not a single nation was spared by this disease, and many continue to struggle today. Even after recovering from COVID, patient may continue to experience some post-COVID effects, such as heart irregularities or a decline in lung vitality. In the past three years (2019-2022), the world has witnessed the power of a small entity, a single peculiar virus. Science initially appeared to be helpless in this regard, but due to the emergence of disease, pharmaceutics (the development of anti-covid drugs), immunology (the rapid antigen test), microbiology (the isolation of viruses from infected people), biotechnology (the development of recombinant vaccines), biochemistry (the blood profile, the D-dimer test), and biochemistry (blood profile, D-dimer test), biophysics (PCR, RT-PCR, CT Scan, MRI) had worked together to fight the disease. The results of these efforts are the development of new diagnostic techniques, possible treatment and finally the availability of vaccines against COVID-19. However, it is not proven that the treatment through the traditional medical system is directly active on SARS-CoV-2 but is instead indirectly acting on SARS-CoV-2 effects by improving symptoms derived from the viral disease. In India, the traditional system of medicine and tradition knowledge together worked in the pandemic and proved effective strategies in prevention and treatment of SARS-CoV-2. The use of effective masks, PPE kits, plasma therapy, yoga, lockdowns and social seclusion, use of modern antiviral drugs, monoclonal antibodies, herbal remedies, homoeopathy, hygienic practice, as well as the willpower of people, are all contributing to the fight against COVID. Which methods or practices will be effective against COVID nobody is aware since medical professionals who wear PPE kits do not live longer, and some people in India who remained unprotected and roamed freely were not susceptible to infection. The focus of this review is on the mode of transmission, diagnosis, preventive measures, vaccines currently under development, modern medicine developed against SARS-CoV-2, ayurvedic medicine used during pandemic, homoeopathic medicine used during pandemic, and specific yoga poses that can be used to lessen COVID-related symptoms.

Acute myeloid leukemia (AML) is a malignant tumor with high recurrence and refractory rates and low survival rates. Increased glycolysis is characteristic of metabolism in AML blast cells and is also associated with chemotherapy resistance. The purpose of this study was to use gene expression and clinical information from The Cancer Genome Atlas (TCGA) database to identify subtypes of AML associated with lactate metabolism. Two different subtypes linked to lactate metabolism, each with specific immunological features and consequences for prognosis, were identified in this study. Using the TCGA and International Cancer Genome Consortium (GEO) cohorts, a prognostic model composed of genes (LMNA, RETN and HK1) for the prognostic value of the lactate metabolism-related risk score prognostic model was created and validated, suggesting possible therapeutic uses. Additionally, the diagnostic value of the prognostic model genes was explored. LMNA and HK1 were ultimately identified as hub genes, and their roles in AML were determined through immune infiltration, GeneMANIA, GSEA, methylation analysis and single-cell analysis. LMNA was upregulated in AML associating with a poor prognosis while HK1 was downregulated in AML associating with a favorable prognosis. The findings underscore the noteworthy impact of genes linked to lactate metabolism in AML and illustrate the possible therapeutic usefulness of the lactate metabolism-related risk score and the hub lactate metabolism-related genes in guiding AML patients' treatment choices.

Type 2 innate lymphoid cells (ILC2s) have emerged as pivotal regulators in the pathogenesis of diseases, with their roles in inflammation, metabolism, and tissue homeostasis becoming increasingly recognized. This review provides an overview of the current understanding of ILC2s in inflammation and metabolic disorders, including their functional contributions. Moreover, we will discuss how these cells adapt their metabolic processes to support their function and survival and how their metabolic requirements change under different physiological and pathological conditions. Lastly, we will review recent omics studies that have provided insights into the molecular and cellular characteristics of ILC2s. This includes transcriptomic, proteomic, and metabolomic analyses that have elucidated the gene expression profiles, protein interactions, and metabolic networks, respectively, associated with ILC2s. These studies have advanced our understanding of the functional diversity of ILC2s and their involvement in metabolic disease.

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.

Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells' pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms.

One defining feature of various aggressive cancers, including glioblastoma multiforme (GBM), is glycolysis upregulation, making its inhibition a promising therapeutic approach. One promising compound is 2-deoxy-d-glucose (2-DG), a d-glucose analog with high clinical potential due to its ability to inhibit glycolysis. Upon uptake, 2-DG is phosphorylated by hexokinase to 2-DG-6-phosphate, which inhibits hexokinase and downstream glycolytic enzymes. Unfortunately, therapeutic use of 2-DG is limited by poor pharmacokinetics, suppressing its efficacy.

To address these issues, we synthesized novel halogenated 2-DG analogs (2-FG, 2,2-diFG, 2-CG, and 2-BG) and evaluated their glycolytic inhibition in GBM cells. Our in vitro and computational studies suggest that these derivatives modulate hexokinase activity differently.

Fluorinated compounds show the most potent cytotoxic effects, indicated by the lowest IC50 values. These effects were more pronounced in hypoxic conditions. 19F NMR experiments and molecular docking confirmed that fluorinated derivatives bind hexokinase comparably to glucose. Enzymatic assays demonstrated that all halogenated derivatives are more effective HKII inhibitors than 2-DG, particularly through their 6-phosphates. By modifying the C-2 position with halogens, these compounds may overcome the poor pharmacokinetics of 2-DG. The modifications seem to enhance the stability and uptake of the compounds, making them effective at lower doses and over prolonged periods.

This research has the potential to reshape the treatment landscape for GBM and possibly other cancers by offering a more targeted, effective, and metabolically focused therapeutic approach. The application of halogenated 2-DG analogs represents a promising advancement in cancer metabolism-targeted therapies, with the potential to overcome current treatment limitations.

In 2019, a novel post-translational modification termed lactylation was identified, which established a connection among lactate, transcriptional regulation and epigenetics. Lactate, which is traditionally viewed as a metabolic byproduct, is now recognized for its significant functional role, including modulating the tumor microenvironment, engaging in signaling and interfering in immune regulation. While research on lactylation (KLA) is advancing, the focus has primarily been on histone lactylation. This paper aims to explore the less-studied area of nonhistone lactylation, highlighting its involvement in certain diseases and physiological processes. Additionally, the clinical relevance and potential implications of nonhistone lactylation will be discussed.

Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. We therefore investigated 2DG's effect on IFN-γ in activated human T cells from PBMCs, with 2DG treatment commenced either concurrently with activation or 48 h after activation. Concurrent 2DG treatment decreased IFN-γ secretion in a dose-dependent manner. However, 2DG treatment of pre-activated T cells had a hormetic effect on IFN-γ, with 0.15-0.6 mM 2DG (achievable in vivo) increasing and >2.4 mM 2DG reducing its secretion. In contrast, IL-2 levels declined monotonously with increasing 2DG concentration. Lower 2DG concentrations reduced PD-1 and increased CD69 expression regardless of treatment timing. The absence of increased T-bet or Eomes expression or IFNG transcription suggests another downstream mechanism. 2DG dose-dependently induced the unfolded protein response, suggesting a possible role in increased IFN-γ secretion, possibly by increasing the ER folding capacity for IFN-γ via increased chaperone expression. Overall, low-dose, short-term 2DG exposure could potentially improve the T cell anti-tumor response.

Autoimmune hepatitis (AIH) is a serious liver disease characterized by immune disorders, particularly effector T-cell overactivation. This study aimed to explore the therapeutic effect and underlying mechanism of mesenchymal stem cell-derived extracellular vesicle (MSC-EV) treatment on CD4+ T-cell overactivation and liver injury in AIH.

The metabolic changes of CD4+ T cells were assayed in human AIH and mouse hepatitis models. The liver protective effect of MSC-EVs was evaluated by transaminase levels, liver histopathology and inflammation. The effect of MSC-EVs on the metabolic state of CD4+ T cells was also explored.

Enhanced glycolysis (eg, ~1.5-fold increase in hexokinase 2 levels) was detected in the CD4+ T cells of AIH patient samples and mouse hepatitis models, whereas the inhibition of glycolysis decreased CD4+ T-cell activation (~1.8-fold decrease in CD69 levels) and AIH liver injury (~6-fold decrease in aminotransferase levels). MSC-EV treatment reduced CD4+ T-cell activation (~1.5-fold decrease in CD69 levels) and cytokine release (~5-fold decrease in IFN-γ levels) by reducing glycolysis (~3-fold decrease) while enhancing mitochondrial oxidative phosphorylation (~2-fold increase in maximal respiration) in such cells. The degree of liver damage in AIH mice was ameliorated after MSC-EV treatment (~5-fold decrease in aminotransferase levels). MSC-EVs carried abundant mitochondrial proteins and might transfer them to metabolically reprogram CD4+ T cells, whereas disrupting mitochondrial transfer impaired the therapeutic potency of MSC-EVs in activated CD4+ T cells.

Disordered glucose metabolism promotes CD4+ T-cell activation and associated inflammatory liver injury in AIH models, which can be reversed by MSC-EV therapy, and this effect is at least partially dependent on EV-mediated mitochondrial protein transfer between cells. This study highlights that MSC-EV therapy may represent a new avenue for treating autoimmune diseases such as AIH.

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders.