Rheumatoid arthritis (RA) has been associated with an elevated risk of developing disorders related to glucose metabolism, including decreased insulin secretion, impaired glucose tolerance, and type 2 diabetes mellitus. The previse mechanisms underlying this association remain incompletely elucidated. In this study, we utilized a cohort of fifty Wistar female rats, establishing a type II collagen-induced arthritis (CIA) model (n = 30). Out observations indicated abnormal glucose and inulin levels in the CIA rats, accompanied by diminished β cell function. Additionally, we detected elevated cytokines levels and increased apoptosis within the pancreatic tissue of the CIA rats. It is hypothesized that the heightened apoptosis may be induced by cytokines, potentially leading to reduced insulin synthesis and dysregulated glucose metabolism. Through transcriptomic and proteomic analyses, we identified differential expression of genes and proteins involved in pathways that directly or indirectly regulate glycolysis in the CIA rats. Notably, we discovered novel differentially expressed enzymes implicated in the glycolysis pathway, such as hexokinase and fructose-bisphosphate aldolase, within the CIA rat model, which may serve as new markers for the diagnosis of RA or provide new perspectives to treat RA or RA-related glucose metabolism disorder.

Cellular respiration is the primary metabolic process for producing the energy (ATP) needed for survival. Disruptions in this process can lead to various diseases, including colon cancer. This paper reviews the current understanding of how excess fatty acids (FAs) and glucose (Glc) alter metabolic pathways. We focused on the impact of unsaturated fatty acids (UFAs) (eicosapentaenoic acid (EPA), linoleic acid (LA)), saturated fatty acid (SFA) (palmitic acid (PA)), and glucose on healthy human colon cells (CCD-18 Co) and cancerous colon cells (Caco-2) using Raman microspectroscopy. Our study examined the metabolic abnormalities in mitochondria and lipid droplets caused by the external intake of FAs and glucose. The results indicate that the peaks at 750 cm-1, 1004 cm-1, 1256 cm-1, 1444 cm-1, and 1656 cm-1 can serve as Raman biomarkers for monitoring metabolic pathways in colon cancer. We proved that oxidative metabolism towards glycolysis allows maintaining redox homeostasis and enables the survival and proliferation of cancer cells in hypoxic conditions. Our findings show that comparing control cells with cells supplemented with UFAs, SFA, and glucose can help detect metabolic abnormalities. Specifically, supplementation with UFAs reduces the intensity of the bands at 750 cm-1 and 1004 cm-1, while SFA and glucose increase their intensity. For the bands at 1256 cm-1, 1444 cm-1, and 1656 cm-1, palmitic acid and glucose decrease the intensity, whereas linoleic acid increases it. This paper introduces new experimental techniques, such as Raman microspectroscopy and imaging, to track and understand the metabolic changes in colon cells caused by FAs and glucose under hypoxic conditions.

Breast cancer (BC) is the primary cause of cancer-related deaths in women. Currently, the discovery of biomarkers primarily relies on single platform, which might overlook other potential biomarkers and lead to inaccurate diagnoses. This study aims to: (1) expand the detection range of biomarkers through multiple analytical techniques, thereby improving the accuracy of BC diagnosis, and (2) analyze the metabolic pathways of the biomarkers to explore the metabolic mechanisms underlying BC. Urine samples from BC patients and healthy controls were analyzed using two techniques: Ultra-high performance liquid chromatography combined with Quadrupole-Exactive-Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap-MS), and headspace solid-phase microextraction combined with gas chromatography-high resolution mass spectrometry (HS-SPME/GC-HRMS). Data from each platform was analyzed independently using both univariate and multivariate statistical approaches to identify candidate biomarkers. Subsequently, a mid-level data fusion approach was applied to integrate the candidate biomarkers identified by each platform. The fused data were used to construct orthogonal partial least squares discriminant analysis (OPLS-DA) models and random forest (RF) models, which were then compared against models based on individual platform. The fused RF and OPLS-DA models demonstrated enhanced diagnostic accuracy compared to the individual model. Integrating GC-HRMS and UPLC-Q-Exactive Orbitrap-MS achieved the best performance, with an AUC value of 0.967, sensitivity of 86.37 %, and specificity of 89.19 %. Metabolic pathway analysis revealed that 10 metabolic pathways exert an impact on BC. Four pathways-pyruvate metabolism, sulfur metabolism, taurine and hypotaurine metabolism, and tyrosine metabolism-were found to be associated with BC in both metabolomics and volatolomics studies, indicating that these pathways play pivotal roles in BC. This study confirmed the potential of merging multi-platforms to enhance the accuracy of BC diagnosis, offering new avenues for understanding the metabolic mechanisms of BC.

The detection and imaging of cysteine (Cys) are vital for clinical applications, given its critical role as a biomarker in various diseases. In this study, a cationic fluorescent probe (probe T) was synthesized, featuring benzothiazole as a fluorescent group and acrylate as a Cys recognition site. Compared to other biothiols, probe T specifically detects Cys while targeting mitochondria and nuclei. In addition, probe T has low cytotoxicity and successfully imaged mitochondria and nuclei in MCF-7 cells. The fluorescence intensity ratio (F560 nm/F500 nm) of probe T was linearly correlated with the Cys concentration under 360 nm excitation, and the limit of detection was 60.4 nM. When quantifying Cys in complex biological samples, background interferences often lead to biased quantitative results. To mitigate this, chemometric method based on spectral shape deformation (SSD) theory was used to correct the spectral shape and intensity changes caused by background signals. By combining the SSD model with the ratiometric fluorescence sensing method, it was able to accurately quantify Cys in cell lysate, and the quantitative results were consistent with the kit. Therefore, this method not only provides a new diagnostic tool for the study of Cys-related diseases, but also provides an effective solution for background interference correction.

This review article offers a literature search of the most active, new copper (II) anticancer complexes based on nitrogen-containing ligands, reported in the literature over the past 5 years: from the beginning of 2019, until mid-2024. In the modern world, cancer remains one of the deadliest diseases of all. Although years of the ongoing research allowed us to better understand its nature, and thus aim more precisely at specific molecular targets and pathways, many of its aspects remain unclear. Today, chemotherapy still remains at the forefront of cancer treatment. With the ever-growing struggles to overcome chemoresistance and occurrence of serious side effects, the discovery of new, more selective and active drugs is a task of an utmost importance. At the same time, copper (II)-based compounds offer a wide array of biological activities and valuable biochemical properties. This review article provides the update on the recent advances in the discovery of new potential anticancer drugs among copper (II)-based compounds in the recent five years.

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

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

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

The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodrugs were designed. In this review, we underscore the synergistic relationship among the various organelles and advocate for a holistic view of organelle-targeting design. Through the integration of biology and material science, recent advancements in organelle targeting, escaping, and collaborating are consolidated to offer fresh perspectives for the development of antitumor nanomedicines.

Radioresistance in tumors, driven by the insufficiency and rapid depletion of reactive oxygen species (ROS), limits the efficacy of radiotherapy (RT). This study introduces an Ir@Au nanozyme that enhances tumor radiosensitivity by disrupting energy homeostasis and inducing ferroptosis in tumor cells. The Ir@Au nanozyme mimics glucose oxidase to block the tumor's energy supply, continuously produces hydrogen peroxide (H2O2), and lowers the pH to optimize Fenton reactions. Acting as a peroxidase (POD), it generates additional ROS for chemodynamic therapy (CDT), depletes glutathione (GSH), and perturbs the tumor's antioxidant defenses. Upon exposure to ionizing radiation, the nanozyme absorbs photons and emits electrons, interacting with water to amplify ROS production. This ROS accumulation, combined with radiation, enhances DNA damage and lipid peroxidation, reversing radioresistance and promoting ferroptosis. Additionally, Ir@Au serves as a contrast agent for computed tomography, enabling precise RT through the delineation of tumor boundaries. In summary, the Ir@Au nanozyme effectively disrupts tumor energy homeostasis, initiating ROS-based cascades that inhibit tumor growth. It thus offers a promising strategy for overcoming radioresistance during cancer therapy.

The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.

The brain naturally synthesizes hydrogen sulfide (H2S) via enzymes such as cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), cysteine aminotransferase (CAT), and cystathionine-γ-lyase (CSE). From a physiological point of view, H2S serves as a neuromodulator with antioxidant and neuroprotective properties. Recent research suggests that H2S is crucial in regulating learning and memory, as its downregulation is commonly observed in cognitive impairment diseases. Preclinical studies suggest that external supplementation, through donors like sodium hydrosulfide (NaHS), can improve cognitive impairment in various cognitive disorder models. Moreover, numerous molecular mechanisms have been proposed to explain the effects of these H2S donors. This review aims to detail the roles of H2S in various models of cognitive impairment and in human subjects, highlighting its potential mechanisms and providing experimental support for its use as a novel therapeutic approach in treating cognitive disorders. Overall, H2S plays a significant role in the treatment of cognitive impairment diseases, but further large-scale studies are still required to support the results of current research.

Cancer poses a significant threat to human life and health. Cancers treated with cisplatin invariably develop drug resistance. This challenge can be overcome by identifying and exploiting the vulnerabilities acquired by drug-resistant cancer cells, paving the way for finding effective novel treatment options for cisplatin-resistant cancers. Our previous study revealed that cisplatin resistance in cancer cells comes at the cost of increased intracellular hypoxia. In this study, we used 2-nitroimidazole modified hyaluronic acid (HA-NI) as the carrier. The cisplatin-resistant tumor cell specific intracellular hypoxia programmed activation nanomedicine (T/C@HN NPs) was constructed by the hypoxic toxic drug tirapazamine (TPZ) and encapsulating chlorin e6 (Ce6) into HA-NI using polymer assembly technology. The amphiphilic carrier could release free Ce6 molecules under the stimulation of intracellular hypoxic environment, and exhibit specific "activated state" photodynamic properties in cisplatin-resistant tumor cells. Upon irradiation, Ce6-mediated photodynamic therapy further intensifies hypoxia, amplifying its cytotoxicity. This project systematically evaluated the effects of T/C@HN NPs on the identification and recognition of cisplatin-resistant tumors using drug-resistant patient-derived xenograft (PDX) models. This study provides a promising avenue for the development of novel treatment of cisplatin-resistant tumors.

Pampus argenteus, a species distributed throughout the Indo-West Pacific, plays a significant role in the yield of aquaculture species. However, cultured P. argenteus has always been characterised by unbalanced growth synchronisation among individuals, slow growth rate, and lack of excellent germplasm resources. Therefore, we conducted mass selection for fast-growing strain P. argenteus for several consecutive years. Various genetic improvement programs have modified its genome sequence through selective pressure, leaving nucleotide signals that can be detected at the genomic level. In the present study, we combined bulked segregant analysis and transcriptome sequencing to identify candidate single nucleotide polymorphisms (SNPs) and key genes for growth-related traits in P. argenteus. A total of 7,280,936 SNPs and 2,212,379 insertions/deletions were identified in the extreme phenotypes of the fast-growing and slow-growing groups. Based on the examination of SNP frequency differences and sliding-window analysis, 42 SNPs were identified as candidate markers. Moreover, 14 of the 42 SNPs linked to growth-related traits were confirmed to be credible SNPs, and eight growth-related genes were screened, namely myb-binding protein 1 A, insulin A/B chains, α-1B adrenoceptor, engulfment and cell motility protein 3, myosin light chain kinase family member 4, insulin receptor located, unconventional myosin-9b, and matrilin-1. An optimal three-factor model (SNP4&SNP12&SNP14) was constructed using the generalized multifactor dimensionality reduction method, and its accuracy was verified as 67.72 %. These results may benefit genetic studies and accelerate genetic improvement of fast-growing strains of P. argenteus.

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

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

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

Oxidative stress, metabolism, and epigenetics are deeply interconnected processes that collectively influence cellular function, health status, and contribute to disease progression. This review highlights the critical role of metabolic intermediates in epigenetic regulation, focusing on lactate, glutathione (GSH), and S-adenosylmethionine (SAM). Beyond its traditional role in energy metabolism, lactate modulates epigenetic mechanisms, influencing gene expression and cellular adaptation. Meanwhile, GSH and SAM serve as key regulators of DNA methylation and histone post-translational modifications, maintaining epigenetic homeostasis. These processes are tightly controlled by redox balance and oxidative stress, underscoring the intricate interplay between metabolism and epigenetic regulation. GSH depletion disrupts methylation homeostasis, while oxidative post-translational modifications (oxPTMs) on histones-including S-glutathionylation, carbonylation, and nitrosylation-alter chromatin architecture and transcriptional regulation. Additionally, we focus on histone lactylation, particularly its role in regulating innate and adaptive immune responses. We also explore how GSH and oxidative stress influence lactate levels, potentially inducing histone lactylation or S-glutathionylation through S,D-lactoylglutathione (LGSH), thereby impacting epigenetic regulation. By integrating insights into metabolic-epigenetic crosstalk, this review underscores the role of oxidative stress and central metabolic pathways in regulating epigenetic mechanisms, a concept known as "redox epigenetics." Understanding these intricate interactions offers new perspectives for therapeutic strategies aimed at restoring redox homeostasis and metabolic integrity to counteract disturbances in the epigenetic landscape.

Lipid metabolism has been increasingly recognized to play an influencing role in tumor initiation, progression, metastasis, and therapeutic drug resistance. Targeting lipid metabolic reprogramming represents a promising therapeutic strategy. Despite their structural complexity and poor targeting efficacy, lipid-metabolizing drugs, either used alone or in combination with chemotherapeutic agents, have been employed in clinical practice. The advent of nanotechnology offers new approaches to enhancing therapeutic effects, includingthe targeted delivery and integration of lipid metabolic reprogramming with chemotherapy, photodynamic therapy (PDT), and immunotherapy. The integrated nanoformulation, nanomedicine, could significantly advance the field of lipid metabolism therapy. In this review, we will briefly introduce the concept of cancer lipid metabolism reprogramming, then elaborate the latest advances in engineered nanomedicine for targeting lipid metabolism during cancer treatment, and finally provide our insights into future perspectives of nanomedicine for interference with lipid metabolism in the tumor microenvironment.

Cellular metabolism is a dynamic and essential process, with alterations in metabolic pathways serving as hallmark features of cancer. In this study, we developed a chip-based solid-phase extraction mass spectrometry (Chip-SPE-MS) platform for high-sensitivity, high-throughput analysis of cellular metabolites and real-time tracking of metabolic fluxes. The system achieved detection limits ranging from 0.10 to 9.43 μmol/mL for various amino acids and organic acids, with excellent linearity (r ≥ 0.992). By incorporating isotope tracing, the platform enabled derivatization-free, real-time monitoring of 13C-labeled metabolites, such as lactic acid. Our analysis revealed significant metabolic differences between normal (L02) and cancerous (HepG2, HCT116) cells, including enhanced glycolytic activity and elevated lactate production in cancer cells. Furthermore, treatment with 1,25-dihydroxyvitamin D3 was shown to suppress glucose uptake and modulate metabolic activity in HCT116 cells, highlighting the regulatory effects of vitamin D3 on cancer metabolism. This study not only provides novel insights into the metabolic reprogramming associated with cancer but also demonstrates the potential of the Chip-SPE-MS platform as a powerful tool for real-time monitoring of dynamic metabolic processes. The findings have broad implications for cancer therapy and the study of metabolic diseases.

Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.

Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer 13C6-glucose, the Nalm6/DOX cells showed an increase in the abundance of 13C-alanine and a decrease in the levels of 13C-lactate, indicating impaired utilization of 13C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.

A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.

The serine hydrolase LYPLAL1 is a poorly characterised enzyme with emerging roles in hepatic metabolism. A multitude of association studies have shown links between variants of this gene locus and metabolic conditions such as obesity and insulin resistance. However, the enzyme's function is still largely unknown. Recent biochemical studies have revealed that it may play a role in hepatic glucose metabolism and that its activity is allosterically regulated. Herein, we use a selective activity-based probe to delineate LYPLAL1's involvement in hepatic metabolism. We show that the enzyme's activity is modulated during metabolic stress, specifically pointing to a putative role in negatively regulating gluconeogenesis and upregulating glycolysis. We also determine that knock-out of the enzyme does not affect liver lipid profiles and bring forth evidence for insulin-mediated control of LYPLAL1 in HepG2 cells. Furthermore, LYPLAL1 activity appears to be largely post-translationally regulated as gene expression levels remain largely constant under insulin and glucagon treatments. Taken together these data point to an enzymatic role in regulating glucose metabolism that may be part of a feedback mechanism of signal transduction.

Cellular metabolic reprogramming supports tumor proliferation, invasion, and metastasis by enhancing resistance to stress and immune clearance. Understanding these metabolic changes within the tumor microenvironment is vital to developing effective therapies. We conducted single-cell RNA sequencing on 11 gastric cancer (GC) samples and eight metastatic lesions, analyzing 92,842 cells across eight cell types, including cancer cells, stromal cells, and immune cells. Our findings highlight that the mitochondrial ATP synthase subunit ATP5MC2 uniquely alters during early GC metastasis. Experiments and clinical data confirmed that ATP5MC2 upregulation facilitates cancer cell proliferation, invasion, and metastasis. Constructing a single-cell atlas revealed significant immune cell heterogeneity associated with GC metastasis and its molecular subtypes. This study underscores the role of ATP5MC2-driven metabolic changes and diverse immune landscapes in promoting GC metastasis, offering new avenues for anti-metastatic treatment development.

AARS2, an alanyl-tRNA synthase, is essential for protein translation, but its function in mouse hearts is not fully addressed. Here, we found that cardiomyocyte-specific deletion of mouse AARS2 exhibited evident cardiomyopathy with impaired cardiac function, notable cardiac fibrosis, and cardiomyocyte apoptosis. Cardiomyocyte-specific AARS2 overexpression in mice improved cardiac function and reduced cardiac fibrosis after myocardial infarction (MI), without affecting cardiomyocyte proliferation and coronary angiogenesis. Mechanistically, AARS2 overexpression suppressed cardiomyocyte apoptosis and mitochondrial reactive oxide species production, and changed cellular metabolism from oxidative phosphorylation toward glycolysis in cardiomyocytes, thus leading to cardiomyocyte survival from ischemia and hypoxia stress. Ribo-Seq revealed that Aars2 overexpression increased pyruvate kinase M2 (PKM2) protein translation and the ratio of PKM2 dimers to tetramers that promote glycolysis. Additionally, PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency. Thus, this study demonstrates that AARS2 plays an essential role in protecting cardiomyocytes from ischemic pressure via fine-tuning PKM2-mediated energy metabolism, and presents a novel cardiac protective AARS2-PKM2 signaling during the pathogenesis of MI.

Hepatocellular carcinoma (HCC) is prevalent globally, and the discovery of new targets is vital for the treatment of HCC. Mitochondrial pyruvate carrier 1 (MPC1) has been found to exhibit reduced expression and promote tumour progression in some cancers, although its role in HCC needs to be explored. Using GEO datasets and Kaplan‒Meier plotter, the clinicopathological features and patient prognosis were analysed by assessing the expression levels of MPC1 in HCC tissues. After MPC1-knockdown and MPC1-overexpressing cell lines were constructed, the effects of modulating MPC1 expression on the malignant phenotype of HCC cells were tested via CCK8, colony formation, and scratch assays and flow cytometry. The effects of MPC1 on HCC cells and mitochondria were examined via MitoTracker Red CMXRos staining, cytoskeleton staining and cellular energy metabolism assays. MPC1 expression was found to be reduced in HCC patients and correlated with prognosis and clinicopathological features. It was found that low expression of MPC1 promotes the malignant phenotype of HCC cells and affects the mitochondrial energy metabolism of HCC cells to support the tumour microenvironment, and that MPC1 may act through signal transducer and activator of transcription 3 (STAT3). MPC1 might play a tumor-suppressing role in HCC through its interaction with STAT3, and this discovery could offer novel perspectives for HCC treatment.

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

Abnormalities in glucose metabolism have been shown to characterize malignant tumors. Glucose depletion by glucose oxidase (GOD) has shown great potential in tumor therapy by causing tumor starvation. Since 2017, nanomedicines have been designed and utilized to deliver GOD for more precise and effective glucose modulation, which can overcome intrinsic limitations of different cancer therapeutic modalities by remodeling the tumor microenvironment to enhance antitumor therapy. To date, the topic of GOD-delivering nanomedicines for enhancing tumor therapy has not been comprehensively summarized. Herein, this review aims to provide an overview and discuss in detail recent advances in GOD delivery and directly involved starvation therapy strategies, GOD-sensitized various tumor therapy strategies, and GOD-mediated multimodal antitumor strategies. Finally, the challenges and outlooks for the future progress of the emerging tumor therapeutic nanomedicines are discussed. This review provides intuitive and specific insights to a broad audience in the fields of nanomedicines, biomaterials, and cancer therapy.

Multi-drug resistance and immunosuppressive triple-negative breast cancer (TNBC) is triggered by the Warburg effect, which promotes homologous recombination repair (HRR) and upregulates expression of P-glycoprotein (P-gp), in turn preventing DNA damage from chemotherapy and creating an immunosuppressive microenvironment. It is therefore of clinical relevance to develop an effective delivery system that targets metabolic reprogramming and DNA damage response pathways for the treatment of drug-resistant TNBC. Herein, a P-gp-inhibiting and GSH-responsive multifunctional drug carrier targeting integrin αvβ3 was synthesised for the delivery of Lonidamine-prodrug (M1, glycolysis inhibitor) and Senaparib (Se, Poly [ADP-ribose] polymerase inhibitor). The nanodrug delivery system (iPR@M1/Se nanoparticles) exhibit effective tumour penetration and P-gp inhibition, effectively inducing DNA damage and apoptosis in Olaparib-resistant TNBC cells in vitro, as well as a higher tumour inhibitory rate compared with that of Se (81.82 % ± 2.31 % vs 43.91 % ± 4.65 %) in vivo. Mechanistically, iPR@M1/Se nanoparticles not only reshaped the immunosuppressive microenvironment resulting from tumour glycolysis, but also downregulated the expression of HRR-related protein, fostering the cytoplasmic accumulation of DNA damage fragments, which induced activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway. Experimental results show that iPR@M1/Se nanoparticles effectively promote dendritic cell maturation and T lymphocyte activation, which elicits long-term immune memory responses, and prevents tumour recurrence and lung metastasis. Therefore, these multifunctional nanoparticles have great potential and provide a clinically relevant and valuable option for Olaparib-resistant TNBC.

Recent studies have demonstrated that PLEKHA4 promotes tumor growth in some cancers, such as small-cell lung cancer, melanoma, and hepatic carcinomas; however, the underlying mechanism in glioblastoma remains ambiguous. Bioinformatic was used to analysis PLEKHA4 expression. In vitro and in vivo experiments were conducted to detect the effect of PLEKHA4 on glioblastoma cell glycolytic reprogramming and progression. GSEA was used to analyze the signal pathways related to PLEKHA4. Pharmacological methods further validated the role of activation pathways. We evaluated the effects of PLEKHA4 knockdown combined with temozolomide (TMZ) on glioblastoma cell proliferation and apoptosis in vitro and in vivo. We observed an overexpression of PLEKHA4 in GBM cell lines, resulting in enhanced cell proliferation, inhibited apoptosis, and promoted glycolysis. Mechanistically, our study demonstrated that PLEKHA4 mediates cell proliferation, apoptosis, and glycolysis via the STAT3/SOCS1 signaling pathway. Additionally, HOXD9 was predicted using Jasper, which is a transcription factor that binds to the PLEKHA4 promoter region. Knocking down PLEKHA4 combined with TMZ inhibited cell proliferation and promoted cell apoptosis in vitro and in vivo. Our results indicated that HOXD9-medicated PLEKHA4 regulates glioblastoma cell proliferation and glycolysis via activation of the STAT3/SOCS1 pathway.

Retinoblastoma (RB) is a type of intraocular tumor in childhood with a high lethality rate. N4-acetylcytosine (ac4C) modification is known to regulate multiple cancers, which is mediated by the only known ac4C writer N-Acetyltransferase 10 (NAT10). In this study, the authors aimed to reveal the mechanism of RB progression regulated by ac4C modification.

Phenotypically, dot blot assay and quantitative real-time PCR were used to detect the ac4C levels and NAT10 expression in clinical samples and RB cell lines. Then, NAT10 was knocked down to assess its effect on glycolysis. Mechanically, RNA immunoprecipitation assay, immunofluorescence assay, and dual luciferase report were used to explore the mRNA modified by NAT10-mediated ac4C modification. Mice xenograft model was used to determine the effect of NAT10 on tumor growth in vivo.

The present results demonstrated that the levels of ac4C and NAT10 were increased in cancer tissues and RB cell lines. Furthermore, NAT10 knockdown inhibited the glycolysis in RB cell lines. Moreover, the authors revealed that NAT10 knockdown decreased the ac4C modification and mRNA stability of HK1, while the inhibition of glycolysis by NAT10 knockdown was reversed by HK1 overexpression. Finally, NAT10 knockdown relieved the growth of tumors in mice models.

The authors illustrated that NAT10 plays an important role in the progression of RB by regulating the ac4C modification on HK1 mRNA and affects its stability, which may provide a novel theoretical basis for the treatment of RB.

For steady transgenic expression, lentiviral vector-mediated gene delivery is a commonly used technique. One question that needs to be explored is how external lentiviral vectors and overexpressed genes perturb cellular homeostasis, potentially altering transcriptional networks. In this study, two Human Embryonic Kidney 293T (HEK293T)-derived cell lines were established via lentiviral transduction, one overexpressing green fluorescent protein (GFP) and the other co-overexpressing GFP and ADORA3 following puromycin selection to ensure stable genomic integration. Genes with differentially transcript utilization (gDTUs) and differentially expressed genes (DEGs) across cell lines were identified after short-read and long-read RNA-seq. Only 31 genes were discovered to have changed in expression when GFP was expressed, although hundreds of genes showed variations in transcript use. In contrast, even when co-overexpression of GFP and ADORA3 alters the expression of more than 1000 genes, there are still less than 1000 gDTUs. Moreover, DEGs linked to ADORA3 overexpression play a major role in RNA splicing, whereas gDTUs are highly linked to a number of malignancies and the molecular mechanisms that underlie them. For the analysis of gene expression data from stable cell lines derived from HEK293T, our findings provide important insights into changes in gene expression and alternative splicing.

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

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

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

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

Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody-drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.

Understanding cancer etiology requires replicating the tumor microenvironment (TME), which significantly differs from standard in vitro cultures due to nutrient limitations, acidic pH, and oxidative stress. To address this, a microfluidic bioreactor (µBR) with an expanded culture surface was designed to optimize exosome enrichment and glioblastoma cell behavior. Using response surface methodology (RSM), key parameters-including medium exchange volume and interval time-were optimized, leading to about a six-fold increase in exosome concentration without artificial inducers. Characterization techniques (SEM, AFM, DLS, RT-qPCR, and ELISA) confirmed significant alterations in exosome profiles, cancer stemness, and epithelial-mesenchymal transition (EMT)-related markers. Notably, EMT was induced in the µBR system, with a six-fold increase in HIF-1α protein despite normoxic conditions, suggesting activation of compensatory signaling pathways. Molecular analysis showed upregulation of SOX2, OCT4, and Notch1, with SOX2 protein reaching 28 ng/mL, while it was undetectable in traditional culture. Notch1 concentration tripled in the µBR system, correlating with enhanced stemness and phenotypic heterogeneity. Immunofluorescent microscopy confirmed nuclear SOX2 accumulation and co-expression of SOX2 and HIF-1α in dedifferentiated CSC-like cells, demonstrating tumor heterogeneity. These findings highlight the µBR's ability to enhance stemness and mimic glioblastoma's aggressive phenotype, establishing it as a valuable platform for tumor modeling and therapeutic development.

Lactate metabolism and signaling intricately intertwine in the context of cancer and immunity. Basigin, working alongside monocarboxylate transporters MCT1 and MCT4, orchestrates the movement of lactate across cell membranes. Despite their potential in treating formidable tumors, the mechanisms by which basigin antibodies affect basigin and MCTs remain unclear. Our research demonstrated that basigin positively modulates MCT activity. We subsequently developed a basigin antibody that converts basigin into a negative modulator, thereby suppressing lactate transport and enhancing anti-tumor immunity. Additionally, the antibody alters metabolic profiles in NSCLC-PDOs and T cells. Cryo-EM structural analysis and molecular dynamics simulations reveal that the extracellular Ig2 domain and transmembrane domain of basigin regulate MCT1 activity through an allosteric mechanism. The antibody decreases MCT1 transition rate by reducing the flexibility of basigin's Ig2 domain and diminishing interactions between basigin's transmembrane domain and MCT1. These findings underscore the promise of basigin antibodies in combating tumors by modulating metabolism and immunity, and the value of a common therapeutic subunit shared by multiple transporter targets.

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

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

Hypoxia results in a wide range of adaptive physiological responses, including metabolic reprogramming, erythropoiesis, and angiogenesis. The response to hypoxia at the cellular level is mainly regulated by hypoxia-inducible factors (HIFs): HIF1α and HIF2α isoforms. Although structurally similar and overlapping gene targets, both isoforms can exhibit distinct expression patterns and functions in some conditions of hypoxia. The interaction between these isoforms, known as the "HIF switch", determines their coordinated function under varying oxygen levels and exposure time. In angiogenesis, HIF-1α is rapidly stabilized under acute hypoxia, prompting a metabolic shift from oxidative phosphorylation to glycolysis and initiating angiogenesis by activating endothelial cells and extracellular matrix remodeling. Conversely, HIF-2α regulates cell responses to chronic hypoxia by sustaining genes critical for vascular remodeling and maturation. The current review highlights the different roles and regulatory mechanisms of HIF-1α and HIF-2α isoforms, focusing on their involvement in cell metabolism and the multi-step process of angiogenesis. Tuning the specific targeting of HIF isoforms and finding the right therapeutic window is essential to obtaining the best therapeutic effect in diseases such as cancer and vascular ischemic diseases.

Excessive glycogen deposition is a common feature of liver enlargement, liver adenoma, and liver cancer, yet the underlying mechanisms remain poorly understood. In this study, we found that NUMB, a well-known cell fate determinant, is downregulated in glycogen-rich adenomas and hepatocellular carcinoma (HCC). NUMB-deficient livers developed excessive glycogen accumulation and adenoma formation particularly in aged mice. Surprisingly, the Alb-Cre:Trp53loxP/loxP liver displayed no similar defective morphology and function, although p53 is considered an important downstream target of NUMB and closely related to glucose metabolism. Instead, we observed a synergistic interaction between NUMB and p53 in regulating glycogen metabolism in HCC tissues and cell lines. Combined knockout of NUMB and p53 in mice significantly enhances glycogen accumulation and hepatomegaly, particularly when mice are subjected to a high sugar diet (HSD), leading to higher cancer incidence. Mechanistically, NUMB deficiency disrupts the PTEN-PI3K/AKT signaling pathway, promoting glycogen accumulation. Subsequently, successive glycogen deposition triggers hepatomegaly and tumorigenesis via the Hippo signaling pathway. Our results suggest that NUMB plays a crucial role in maintaining the homeostasis of glucose metabolism and suppressing the development of liver tumors associated with glycogen deposition.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.