Cancer cells are considered the most adaptable for their metabolic status, which supports growth, survival, rapid proliferation, invasiveness, and metastasis in a nutrient-deficient microenvironment. Since the discovery of altered glucose metabolism (aerobic glycolysis), which is generally known as a part of metabolic reprogramming and an innate trait of cancer cells, in 1930 via Dr. Otto Warburg, numerous studies have endeavored to recognize various aspects of cancer cell metabolism and find new methods for efficiently eradicating described cells by targeting their energy metabolism. In this way, the outcomes have mainly been promising. Accordingly, outlining the related results will indeed assist us in making a definitive path for developing targeted therapy strategies based on cancer cell-altered metabolism. The present study reviews the key features of cancer cell metabolism and treatment strategies based on them. It emphasizes the importance of targeting cancer cell dysregulated metabolic pathways that influence the cell energy supply and manage cancer cell growth and survival. This trial also introduces a multimodal therapeutic strategy hypothesis, a potential next-generation combination therapy approach, and suggests interdisciplinary research to recognize the complexities of cancer metabolism and exploit them for designing more efficacious cancer therapeutic strategies.

Nrf2 plays a critical role in regulating cytoprotective transcriptional responses and glucose metabolism while also preventing inflammation-induced carcinogenesis. However, Nrf2 can paradoxically promote carcinogenesis. Here, we aimed to elucidate the role of Nrf2 in ATL associated with HTLV-1. HTLV-1-infected T-cell lines exhibited nuclear accumulation of Nrf2. Nrf2 knockdown along with the inhibition of its activity using ML385, decreased cell proliferation and survival. Furthermore, ML385-induced G1 arrest by enhancing γH2AX and p53 expression while downregulating CDK4/6, cyclin D2/E, and c-Myc. Additionally, ML385 triggered caspase-mediated apoptosis by downregulating the expression of anti-apoptotic proteins while upregulating pro-apoptotic proteins. The compound also induced necroptosis, promoted JNK phosphorylation, and inhibited the NF-κB, AP-1, and STAT3/5 signaling. Moreover, ML385 was found to reduce the expression of LDHA, glucose uptake, and the levels of lactate derived from glycolysis. Overall, these results suggest that Nrf2 functions as an oncogene in ATL and may represent a promising therapeutic target.

The tumor suppressor p53, long known for its roles in maintaining genomic integrity and suppressing tumorigenesis, has recently been recognized as a key regulator of cellular metabolism. Here, we review p53's emerging metabolic functions, highlighting its ability to orchestrate glucose, amino acid, and lipid metabolism. By promoting oxidative phosphorylation while inhibiting glycolysis and anabolic pathways, wild-type p53 counters metabolic reprogramming characteristic of cancer cells, such as the Warburg effect, and protects cells from mild cellular stresses. In contrast, mutant p53 disrupts these processes, fostering metabolic adaptations that support tumor progression. These findings pave the way for therapeutic approaches targeting p53-driven metabolic vulnerabilities in cancer.

The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.

Protein glycosylation as a common post-translational modification that has significant impacts on protein folding, enzymatic activity, and interfering with receptor functioning. In recent years, with the rapid development of glycopeptide enrichment and analysis technology and the deepening of glycosylation research, glycosylation has gradually become a sign of disease occurrence and development. Multiple investigations suggest that protein glycosylation affect the advances of diabetes and aging.

This review was focused on the action mechanisms of glycosylated proteins production, permanent abnormalities in extracellular matrix component function, inflammatory and reactive oxygen species production, as well as the glycosylated characterizations of diabetes and aging. Further, advances in glycosylation analysis and detection methods are presented for the first time, highlighting for needed future developments. All literatures were gathered from PubMed and Google Scholar.

Herein, we review how protein glycosylation impacts the progression of diabetes and aging. Specifically, we focus on various types of glycosylation, including N-linked glycosylation, O-linked glycosylation, C-glycosylation, S-glycosylation, and glycophosphatidylinositol (GPI) anchors. N-linked glycosylation and O-linked glycosylation are commonly observed glycosylation forms, wherein O-GlcNAcylation plays a significant role in diabetes, while N-glycan could serve as biomarkers for identifying inflammation and aging.

Protein glycosylation produces a vastly larger number of core glycan structures through utilizing at least 173 glycosyltransferases and repeated common scaffolds. Single protein may contain multiple glycosylation sites, and the structure and occupancy of glycan at each site may be different, resulting in the macro heterogeneity of protein glycosylation. This review will contribute to how protein glycosylation impacts the life progress of cells and its association with diseases.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impact of key factors leading to cellular senescence on tumorigenesis. In addition, this review summarizes the current intervention strategies targeting nutrient sensing pathways, as well as the clinical cases of treating tumors targeting the characteristics of senescence with the existing nanodelivery research strategies. Finally, it also suggests sensible dietary habits for those who wish to combat aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota-gut-brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments.

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.

Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy characterized by dysregulated energy and stromal metabolism. It is strongly supported by activated pancreatic stellate cells (PSC) which drive excessive desmoplasia and tumor growth via metabolic crosstalk. Herein, a programmed nanosystem is designed to dual rectify the metabolism abnormalities of the PDAC cells, which overexpress glucose transporter 1(GLUT1) and CD71, and the PSC for oncotherapy. The nanosystem is based on a tumor microenvironment-responsive liposome encapsulating an NF-κB inhibitor (TPCA-1) and a CD71 aptamer-linked Glut1 siRNA. TPCA-1 reverses the activated PSC to quiescence, which hampers metabolic support of the PSC to PDAC cells and bolsters the PDAC cell-targeting delivery of the siRNA. Aerobic glycolysis and the following enhancement of oxidative phosphorylation are restrained by the nano-modulation so as to amplify anti-PDAC efficacy in an orthotopic xenograft mouse model, which implies more personalized PDAC treatment based on different energy metabolic profiles.

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.

The protein p53, encoded by the most frequently mutated gene TP53 in human cancers, has diverse functions in tumor suppression. As a best known transcription factor, p53 can regulate various fundamental cellular responses, ranging from the cell-cycle arrest, DNA repair, senescence to the programmed cell death (PCD), which includes autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis and disulfidoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N6-methyladenosine (m6A) modification and diverse PCD are important for the progression, proliferation and metastases of cancers.

This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m6A Modification and diverse PCD.

TME, a crucial local homeostasis environment, influences every step of tumorigenesis and metastasis. m6A, the most prevalent and abundant endogenous modification in eukaryotic RNAs, plays an essential role in various biological processes, containing the progression of cancers. Additionally, PCD is an evolutionarily conserved mechanism of cell suicide and a common process in living organisms. Some forms of PCD contribute to the occurrence and development of cancer. However, the complex roles of p53 within the TME, m6A modification and diverse PCD mechanisms are still not completely understood. Presently, the function roles of p53 including the wild-type and mutant p53 in different context are summarized. Additionally, the interaction between the cancer immunity, cancer cell death and RNA m6A methylation and the p53 regulation during the development and progress of cancers were discussed. Moreover, the key molecular mechanisms by which p53 participates in the regulation of TME, m6A and diverse PCD are also explored. All the findings will facilitate the development of novel therapeutic approaches.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

Esophageal squamous cell carcinoma (ESCC) is a common fatal malignant tumor of the digestive tract; however, its pathogenic mechanism is unknown and lacks specific molecular diagnosis and treatment. Therefore, it is particularly important to identify new tumor biomarkers to enhance the early diagnosis and molecular-targeted therapy of ESCC. Here, we found that the E3 ubiquitin ligase Tripartitemotif-containing33 (TRIM33) is highly expressed in ESCC tissues and cell lines, and is associated with adverse clinical outcomes. We determined that TRIM33 drives aerobic glycolysis to promote tumor growth in vivo and in vitro. In terms of mechanism, TRIM33 binds to p53 to inhibit its stability and promote the expression of downstream glycolysis target genes GLUT1, HK2, PKM2, and LDHA. In addition, TRIM33 promotes the polyubiquitination of P53 K48-linked and proteasome degradation. Further studies have shown that the K351 site of P53 is the key site mediating the ubiquitination of P53 K48-linked to promote aerobic glycolysis in ESCC and tumor cell growth. Our results reveal that the TRIM33-P53 signal axis regulates glycolysis during ESCC and may provide a new perspective for the diagnosis and treatment of ESCC.

The problem of copper (Cu) intoxication and deficiency continues to impact economic gains and animal welfare in sheep husbandry. This study investigated the ovine genome for regions and potential genes under selection for Cu accretion between sheep breeds. For this, we compared ovine single nucleotide polymorphism (SNP) data of three Cu-susceptible breeds with three Cu-tolerant breeds. After merging SNP data of breeds and removal of related individuals, a total of 229 sheep and 45 640 autosomal SNPs were left. Then, we selected 14 individuals per breed into two datasets (datasets 1 and 2) for analysis of selection signatures using the Fixation index, cross-population extended haplotype homozygosity and haplotype-based FLK methods. Selection regions shared by both datasets detected by at least two methods revealed regions on OAR 4, 8 and 11 containing 54 candidate genes under selection for Cu accretion. Enrichment analysis revealed that 19 gene ontologies and 1 enriched Kyoto encyclopaedia of genes and genomes pathway terms were associated with the candidate genes under selection. Genes such as TP53, TNFSF13, TNFSF12, ALOX15, ALOX12, EIF5A and PREP are associated with the regulation of Cu homeostasis, programmed cell death or inflammatory response. We also found an enrichment of arachidonate 15-lipoxygenase activity, arachidonate 12-lipoxygenase activity and ferroptosis that influence cellular inflammation and cell death. These results shed light on ovine genomic regions under selection for Cu accretion and provide information on candidate genes for further studies on breed differences in ovine Cu accretion.

The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.

A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.

Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).

These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

The importance of post-translational modifications (PTMs), particularly O-GlcNAcylation, of cytoplasmic proteins in apoptosis has been neglected for quite a while. Modification of cytoplasmic proteins by a single N-acetylglucosamine sugar is a dynamic and reversible PTM exhibiting properties more like phosphorylation than classical O- and N-linked glycosylation. Due to the sparse information existing, we have only limited understanding of how GlcNAcylation affects cell death. Deciphering the role of GlcNAcylation in cell fate may provide further understanding of cell fate decisions. This review focus on the modulation of extrinsic apoptotic pathway via GlcNAcylation carried out by O-GlcNAc transferase (OGT) or by other bacterial effector proteins.

Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player. Yet, the molecular mechanisms remain elusive. This study introduces a comprehensive mathematical model, integrating essential p53 targets, offering insights into how p53 orchestrates its targets to redirect cancer metabolism towards an OXPHOS-dominant state. Simulation outcomes align closely with experimental data comparing glucose metabolism in colon cancer cells with wild-type and mutated p53. Additionally, our findings reveal the dynamic capability of elevated p53 activation to fully reverse the Warburg effect, highlighting the significance of its activity levels not just in triggering apoptosis (programmed cell death) post-chemotherapy but also in modifying the metabolic pathways implicated in treatment resistance. In scenarios of p53 mutations, our analysis suggests targeting glycolysis-instigating signalling pathways as an alternative strategy, whereas targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support mitochondrial respiration but may not effectively suppress the glycolysis pathway, potentially boosting the energy production and cancer cell viability.

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general.

For its vital role in maintaining cellular activity and survival, mitochondrion is highly involved in various diseases, and several strategies to target mitochondria have been developed for specific imaging and treatment. Among these approaches, theranostic may realize both diagnosis and therapy with one integrated material, benefiting the simplification of treatment process and candidate drug evaluation. A variety of mitochondria-targeting theranostic agents have been designed based on the differential structure and composition of mitochondria, which enable more precise localization within cellular mitochondria at disease sites, facilitating the unveiling of pathological information while concurrently performing therapeutic interventions. Here, progress of mitochondria-targeting theranostic materials reported in recent years along with background information on mitochondria-targeting and therapy have been briefly summarized, determining to deliver updated status and design ideas in this field to readers.

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of BC globally necessitates continued research into novel diagnostic and therapeutic strategies. Metabolomics, a burgeoning field, offers a comprehensive analysis of all metabolites within a cell, tissue, system, or organism, providing crucial insights into the dynamic changes occurring during cancer development and progression. This review focuses on the metabolic alterations associated with BC, highlighting the potential of metabolomics in identifying biomarkers for early detection, diagnosis, treatment and prognosis. Metabolomics studies have revealed distinct metabolic signatures in BC, including alterations in lipid metabolism, amino acid metabolism, and energy metabolism. These metabolic changes not only support the rapid proliferation of cancer cells but also influence the tumour microenvironment and therapeutic response. Furthermore, metabolomics holds great promise in personalized medicine, facilitating the development of tailored treatment strategies based on an individual's metabolic profile. By providing a holistic view of the metabolic changes in BC, metabolomics has the potential to revolutionize our understanding of the disease and improve patient outcomes.

The p53 tumor suppressor protein has a plethora of cell-intrinsic functions and consequences that impact diverse cell types and tissues. Recent studies are beginning to unravel how wild-type and mutant p53 work in distinct ways to modulate tumor immunity. This sets up a disequilibrium between tumor immunosurveillance and escape therefrom. The ability to exploit this emerging knowledge for translational approaches may shape immunotherapy and targeted therapeutics in the future, especially in combinatorial settings.

We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway.

Cell proliferation, viability, cycle, and apoptosis were analyzed using WST-8 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti-ATL effects of DHODH knockdown and inhibition, RT-PCR and immunoblotting were conducted.

HTLV-1-infected T-cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV-1-infected T-cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti-proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c-Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase-mediated apoptosis by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, BAY2402234 induced caspase-independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, IκBα, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF-κB and Akt signaling is involved in its anti-ATL action.

These findings highlight DHODH as a potential therapeutic target for treating ATL.

The circadian clock regulates biological cycles across species and is crucial for physiological activities and biochemical reactions, including cancer onset and development. The interplay between the circadian rhythm and cancer involves regulating cell division, DNA repair, immune function, hormonal balance, and the potential for chronotherapy. This highlights the importance of maintaining a healthy circadian rhythm for cancer prevention and treatment. This article investigates the complex relationship between the circadian rhythm and cancer, exploring how disruptions to the internal clock may contribute to tumorigenesis and influence cancer progression. Numerous databases are utilized to conduct searches for articles, such as NCBI, MEDLINE, and Scopus. The keywords used throughout the academic archives are "circadian rhythm", "cancer", and "circadian clock". Maintaining a healthy circadian cycle involves prioritizing healthy sleep habits and minimizing disruptions, such as consistent sleep schedules, reduced artificial light exposure, and meal timing adjustments. Dysregulation of the circadian clock gene and cell cycle can cause tumor growth, leading to the need to regulate the circadian cycle for better treatment outcomes. The circadian clock components significantly impact cellular responses to DNA damage, influencing cancer development. Understanding the circadian rhythm's role in tumor diseases and their therapeutic targets is essential for treating and preventing cancer. Disruptions to the circadian rhythm can promote abnormal cell development and tumor metastasis, potentially due to immune system imbalances and hormonal fluctuations.

STAT3 is constitutively activated in many cancer types, including lung cancer, and can induce cancer cell proliferation and cancer stem cell (CSC) maintenance. STAT3 is activated by tyrosine kinases, such as JAK and SRC, but the mechanism by which STAT3 maintains its activated state in cancer cells remains unclear. Here, we show that PRMT5 directly methylates STAT3 and enhances its activated tyrosine phosphorylation in non-small cell lung cancer (NSCLC) cells. PRMT5 expression is also induced by STAT3, suggesting the presence of a positive feedback loop in cancer cells. Furthermore, methylation of STAT3 at arginine 609 by PRMT5 is important for its transcriptional activity and support of tumour growth and CSC maintenance. Indeed, NSCLC cells expressing the STAT3 mutant which R609 was replaced to alanine (R609K) show significantly impaired tumour growth in nude mice. Overall, our study reveals a mechanism by which STAT3 remains activated in NSCLC and provides a new target for cancer therapeutic approaches.

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.

Cancer cells reprogram their metabolism to become "glycolysis-dominant," which enables them to meet their energy and macromolecule needs and enhancing their rate of survival. This glycolytic-dominancy is known as the "Warburg effect", a significant factor in the growth and invasion of malignant tumors. Many studies confirmed that members of the GLUT family, specifically HK-II from the HK family play a pivotal role in the Warburg effect, and are closely associated with glucose transportation followed by glucose metabolism in cancer cells. Overexpression of GLUTs and HK-II correlates with aggressive tumor behaviour and tumor microenvironment making them attractive therapeutic targets. Several studies have proven that the regulation of GLUTs and HK-II expression improves the treatment outcome for various tumors. Therefore, small molecule inhibitors targeting GLUT and HK-II show promise in sensitizing cancer cells to treatment, either alone or in combination with existing therapies including chemotherapy, radiotherapy, immunotherapy, and photodynamic therapy. Despite existing therapies, viable methods to target the glycolysis of cancer cells are currently lacking to increase the effectiveness of cancer treatment. This review explores the current understanding of GLUT and HK-II in cancer metabolism, recent inhibitor developments, and strategies for future drug development, offering insights into improving cancer treatment efficacy.

Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers.

The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.

Aerobic glycolysis also known as the Warburg effect, remains a hallmark of various cancers, including ovarian cancer. Cancer cells undergo metabolic changes to sustain their tumorigenic properties and adapt to environmental conditions, such as hypoxia and nutrient starvation. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, develop resistance to chemotherapy, maintain cancer stem cell phenotype, and escape anti-tumor immune responses. Glucose transporters (GLUTs), which play a pivotal role as the rate-limiting step in glycolysis, are frequently overexpressed in a variety of tumors, including ovarian cancer. Multiple oncoproteins can regulate GLUT proteins, promoting tumor proliferation, migration, and metastasis, either dependent or independent of glycolysis. This review examines the alteration of GLUT proteins, particularly GLUT1, in ovarian cancer and its impact on cancer initiation, progression, and resistance to treatment. Additionally, it highlights the role of these proteins as biomarkers for diagnosis and prognosis in ovarian cancer, and delves into novel therapeutic strategies currently under development that target GLUT isoforms.

Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells.

Cancer development and progression of cancer are closely associated with the activation of oncogenes and loss of tumor suppressor genes. Nucleic acid drugs (e.g., siRNA, mRNA, and DNA) are widely used for cancer therapy due to their specific ability to regulate the expression of any cancer-associated genes. However, nucleic acid drugs are negatively charged biomacromolecules that are susceptible to serum nucleases and cannot cross cell membrane. Therefore, specific delivery tools are required to facilitate the intracellular delivery of nucleic acid drugs. In the past few decades, a variety of nanoparticles (NPs) are designed and developed for nucleic acid delivery and cancer therapy. In particular, the polymeric NPs in response to the abnormal redox status in cancer cells have garnered much more attention as their potential in redox-triggered nanostructure dissociation and rapid intracellular release of nucleic acid drugs. In this review, the important genes or signaling pathways regulating the abnormal redox status in cancer cells are briefly introduced and the recent development of redox-responsive NPs for nucleic acid delivery and cancer therapy is systemically summarized. The future development of NPs-mediated nucleic acid delivery and their challenges in clinical translation are also discussed.

The dynamic changes between glycolysis and oxidative phosphorylation (OXPHOS) for adenosine triphosphate (ATP) output, along with glucose, glutamine, and fatty acid utilization, etc., lead to the maintenance and selection of growth advantageous to tumor cell subgroups in an environment of iron starvation and hypoxia. Iron plays an important role in the three major biochemical reactions in nature: photosynthesis, nitrogen fixation, and oxidative respiration, which all require the participation of iron-sulfur proteins, such as ferredoxin, cytochrome b, and the complex I, II, III in the electron transport chain, respectively. Abnormal iron-sulfur cluster synthesis process or hypoxia will directly affect the function of mitochondrial electron transfer and mitochondrial OXPHOS. More research results have indicated that iron metabolism, oxygen availability and hypoxia-inducible factor mutually regulate the shift between glycolysis and OXPHOS. In this article, we make a perspective review to provide novel opinions of the regulation of glycolysis and OXPHOS in tumor cells.

Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.

The therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in myocardial infarction (MI) is hindered by poor cell survival. This study explored the role of N6-methyladenosine (m6A) regulation, specifically YTHDC1, in improving BMSC transplantation for MI. By screening m6A-related regulators in hypoxia and serum deprivation (HSD)-induced BMSC apoptosis, YTHDC1 was found to be downregulated. Overexpression of Ythdc1 in BMSCs reduced apoptosis markers, reactive oxygen species (ROS) release, and improved cell survival under HSD conditions. Conversely, Ythdc1 knockdown enhanced apoptosis. In rat MI models, transplantation of Ythdc1-overexpressing BMSCs improved cardiac function and reduced myocardial fibrosis. Mechanistically, YTHDC1 interacts with nuclear factor kappa B (NF-κB) inhibitor-alpha mRNA, suggesting its involvement in BMSC survival pathways. This study identifies YTHDC1 as a potential target to enhance BMSC efficacy in MI therapy.