Prostate cancer (PCa) is the most prevalent cancer among men globally. Although, there are various therapeutic methods for the localized or advanced cancers, there is still a high rate of mortality among PCa patients that is mainly associated with bone metastasis in advanced tumors. There are few options available for treating bone metastasis in PCa, which only provide symptom relief without curing the disease. Therefore, it is crucial to evaluate the molecular mechanisms associated with bone metastasis of PCa cells to suggest the novel diagnostic and therapeutic approaches that could lower the morbidity and mortality rates in PCa patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological processes such as tumor growth and osteoblasts/osteoclasts formation. Since, miRNA deregulation has been also frequently observed in PCa patients with bone metastasis, we discussed the role of miRNAs in bone metastasis during PCa progression. It has been reported that miRNAs mainly reduced the ability of PCa tumor cells for the bone metastasis through the regulation of WNT, NF-kB, PI3K/AKT, and TGF-β signaling pathways. They also affected the EMT process, transcription factors, and structural proteins to regulate the bone metastasis during PCa progression. This review paves the way to suggest the miRNAs as the reliable markers not only for the non-invasive early diagnosis, but also for the targeted therapy of PCa tumors with bone metastasis.

Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

Leukemia is driven by complex interactions within the inherently hypoxic bone marrow microenvironment, impacting both disease progression and therapeutic resistance. Co-cultivation of leukemic cells with feeder cells has emerged as a valuable tool to mimic the bone marrow niche. This study explores the interplay between human commercial SD-1 and patient-derived UPF26K leukemic cell lines with feeders - human fibroblasts (NHDF) and mesenchymal stem cells (hMSCs) under normoxic and hypoxic conditions.

Co-cultivation with feeders significantly enhances proliferation and glycolytic activity in the SD-1 cells, improving their viability, while this interaction inhibits the growth and glucose metabolism of the feeders, particularly NHDF. In contrast, UPF26K cells show reduced proliferation when co-cultivated with the feeders while this interaction stimulates NHDF and hMSCs proliferation and glycolysis but reduce their mitochondrial metabolism with hypoxia amplifying these effects.

Cells that switch to glycolysis during co-cultivation, particularly under hypoxia, benefit most from these low oxygen conditions. Due to this leukemic cells' response heterogeneity, targeting microenvironmental interactions and oxygen levels is crucial for personalized leukemia therapy. Advancing co-cultivation models, particularly through innovations like spheroids, can further enhance in vitro studies of primary leukemic cells and support the testing of novel therapies.

Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Circadian rhythms orchestrate physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day (TOD). This study identifies an interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We reveal that the SC clock triggers TOD-dependent inflammatory gene transcription after injury, particularly genes related to neutrophil activity and chemotaxis. These responses are driven by cytosolic regeneration of the signaling metabolite nicotinamide adenine dinucleotide (oxidized form) (NAD+), as enhancing cytosolic NAD+ regeneration in SCs is sufficient to induce inflammatory responses that influence muscle regeneration. Mononuclear single-cell sequencing of the regenerating muscle niche further implicates the cytokine CCL2 in mediating SC-neutrophil cross-talk in a TOD-dependent manner. Our findings highlight the intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.

Virus-derived small interfering RNAs (vsiRNAs) play an important role in viral infection by regulating the expression of host genes. At present, research on the regulation of plant primary metabolic pathways by vsiRNAs is very limited. TvsiRNA24 derived from tobacco curly shoot virus (TbCSV) was amplified by reverse transcription polymerase chain reaction, and its target gene NbTPI (triosephosphate isomerase) was verified using reverse transcription quantitative polymerase chain reaction and GFP fluorescence observation. The effect of the interaction between TvsiRNA24 and NbTPI on TbCSV infection was analyzed by virus mediated, genetic transformation, western blotting, and quantitative detection. The expression of TvsiRNA24 retards the growth of Nicotiana benthamiana and enhances TbCSV accumulation within N. benthamiana. The overexpression of NbTPI attenuates the accumulation of TbCSV, and the silencing of NbTPI leads to the growth retardation of N. benthamiana and intensifies symptoms post-TbCSV infection. Moreover, the expression of some genes related to photosynthesis, primary metabolism and immune response is regulated by NbTPI. Our results unveil the specific role of TvsiRNA24-NbTPI in the pathogenicity of TbCSV, resulting in hindrance to plant growth and facilitation of viral infection. The identification of this regulatory pathway provides valuable insights that can be utilized to devise novel antiviral approaches targeting the reduction of viral pathogenicity.

Cancer remains a significant global challenge, and despite the numerous strategies developed to advance cancer therapy, an effective cure for metastatic cancer remains elusive. A major hurdle in treatment success is the ability of cancer cells, particularly cancer stem cells (CSCs), to resist therapy. These CSCs possess unique abilities, including self-renewal, differentiation, and repair, which drive tumor progression and chemotherapy resistance. The resilience of CSCs is linked to certain signaling pathways. Tumors with pathway-dependent CSCs often develop genetic resistance, whereas those with pathway-independent CSCs undergo epigenetic changes that affect gene regulation. CSCs can evade cytotoxic drugs, radiation, and apoptosis by increasing drug efflux transporter activity and activating survival mechanisms. Future research should prioritize the identification of new biomarkers and signaling molecules to better understand drug resistance. The use of cutting-edge approaches, such as bioinformatics, genomics, proteomics, and nanotechnology, offers potential solutions to this challenge. Key strategies include developing targeted therapies, employing nanocarriers for precise drug delivery, and focusing on CSC-targeted pathways such as the Wnt, Notch, and Hedgehog pathways. Additionally, investigating multitarget inhibitors, immunotherapy, and nanodrug delivery systems is critical for overcoming drug resistance in cancer cells.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrate enhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for their malignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus, has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits.

This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors.

This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways.

In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.

Deep understanding of sugar metabolite-protein interactions should provide implications on sugar metabolic reprogramming in human physiopathology. Although tremendous efforts have been made for determining individual event, global profiling of such interactome remains challenging. Here we describe thermal proteome profiling of glycolytic metabolite fructose-1,6-bisphosphate (FBP)-interacting proteins. Our results reveal a chemical signaling role of FBP which acts as a phosphate donor to activate phosphoglycerate mutase 1 (PGAM1) and contribute an intrapathway feedback for glycolysis and cell proliferation. At molecular level, FBP donates either C1-O-phosphate or C6-O-phosphate to the catalytic histidine of PGAM1 to form 3-phosphate histidine (3-pHis) modification. Importantly, structure-activity relationship studies facilitate the discovery of PGAM1 orthostatic inhibitors which can potentially restrain cancer cell proliferation. Collectively we have profiled a spectrum of FBP interactome, and discovered a unique covalent signaling function of FBP that supports Warburg effect via histidine phosphorylation which inspires the development of pharmacological tools targeting sugar metabolism.

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

Pyruvate kinase (PK), as a key rate-limiting enzyme in glycolysis, has been widely used to assess the stress tolerance and sensitivity of organisms. However, its phosphorylation regulatory mechanisms mainly focused on human cancer research, with no reports in marine organisms. In this study, we firstly reported a conserved PK Ser11 phosphorylation site in mollusks, which enhanced enzyme activity by promoting substrate binding, thereby regulating divergent thermal metabolism of two allopatric congeneric oyster species with differential habitat temperature. It was phosphorylated by ERK kinase, and regulated by the classical MAPK pathway. The MAPK/ERK-PK signaling cascade responded to increased environmental temperature and exhibited stronger activation pattern in the relatively thermotolerant species (Crassostrea angulata), indicating its involvement in shaping temperature adaptation. These findings highlight the presence of complex and unique phosphorylation-mediated signaling transduction mechanisms in marine organisms, and provide new insights into the evolution and function of the crosstalk between classical pathways.

Immunosuppressive tumor microenvironment (TME) contributes to tumor progression and causes major obstacles for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme involved in cancer metabolism while its role in remodeling TME remains unclear. In this study, we reported that PGAM1 suppression in breast cancer (BC) cells led to a decrease in M2 polarization, migration, and interleukin-10 (IL-10) production of macrophages. PGAM1 regulation on CCL2 expression was essential to macrophage recruitment, which further mediated by activating JAK-STAT pathway. Additionally, the CCL2/CCR2 axis was observed to participate in PGAM1-mediated immunosuppression via regulating PD-1 expression in macrophages. Combined targeting of PGAM1 and the CCL2/CCR2 axis led to a reduction in tumor growth in vivo. Furthermore, clinical validation in BC tissues indicated a positive correlation between PGAM1, CCL2 and macrophage infiltration. Our study provides novel insights into the induction of immunosuppressive TME by PGAM1 and propose a new strategy for combination therapies targeting PGAM1 and macrophages in BC.

The intersection of metabolic processes and epigenetic regulation during embryogenesis is crucial yet not fully understood. Through a candidate RNAi screen in Caenorhabditis elegans , we identified metabolic enzymes ALDO-2 and PDHB-1 as potential epigenetic regulators. Mild alteration of the chromatin remodeler LET-418 /Mi2 activity rescues embryonic lethality induced by suppressing aldo-2 or pdhb-1 , suggesting a critical role for glucose and pyruvate metabolism in chromatin remodeling during embryogenesis. Given the conservation of central metabolic pathways and chromatin modifiers across species, our findings lay the foundation for future mechanistic investigations into the interplay between epigenetics and metabolism during development and upon disease.

Phosphoglycerate mutase 1 (PGAM1) is a key node enzyme that diverts the metabolic reactions from glycolysis into its shunts to support macromolecule biosynthesis for rapid and sustainable cell proliferation. It is prevalent that PGAM1 activity is upregulated in various tumors; however, the underlying mechanism remains unclear. Here, we unveil that pyruvate kinase M2 (PKM2) moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, that is essential for PGAM1 activity. Moreover, monomeric and dimeric but not tetrameric PKM2 are efficient to phosphorylate and activate PGAM1. In response to epidermal growth factor signaling, Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and the subsequent PGAM1 H11 phosphorylation, which constitutes a discrepancy between tumor and normal cells. A PGAM1-derived pY119-containing cell-permeable peptide or Y119 mutation disrupts the interaction of PGAM1 with PKM2 and PGAM1 H11 phosphorylation, dampening the glycolysis shunts and tumor growth. Together, these results identify a function of PKM2 as a histidine kinase, and illustrate the importance of enzyme crosstalk as a regulatory mode during metabolic reprogramming and tumorigenesis.

Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect metabolic reprogramming, enabling the identification of biomarkers and anticancer targets for diagnosis and treatment. In this study, two genome-scale metabolic models (GSMMs) were reconstructed by employing RNA sequencing expression patterns of hepatocellular carcinoma (HCC) and their healthy counterparts. An anticancer target discovery (ACTD) framework was integrated with the two models to identify HCC targets for anticancer treatment. The ACTD framework encompassed four fuzzy objectives to assess both the suppression of cancer cell growth and the minimization of side effects during treatment. The composition of a nutrient may significantly affect target identification. Within the ACTD framework, ten distinct nutrient media were utilized to assess nutrient uptake for identifying potential anticancer enzymes. The findings revealed the successful identification of target enzymes within the cholesterol biosynthetic pathway using a cholesterol-free cell culture medium. Conversely, target enzymes in the cholesterol biosynthetic pathway were not identified when the nutrient uptake included a cholesterol component. Moreover, the enzymes PGS1 and CRL1 were detected in all ten nutrient media. Additionally, the ACTD framework comprises dual-group representations of target combinations, pairing a single-target enzyme with an additional nutrient uptake reaction. Additionally, the enzymes PGS1 and CRL1 were identified across the ten-nutrient media. Furthermore, the ACTD framework encompasses two-group representations of target combinations involving the pairing of a single-target enzyme with an additional nutrient uptake reaction. Computational analysis unveiled that cell viability for all dual-target combinations exceeded that of their respective single-target enzymes. Consequently, integrating a target enzyme while adjusting an additional exchange reaction could efficiently mitigate cell proliferation rates and ATP production in the treated cancer cells. Nevertheless, most dual-target combinations led to lower side effects in contrast to their single-target counterparts. Additionally, differential expression of metabolites between cancer cells and their healthy counterparts were assessed via parsimonious flux variability analysis employing the GSMMs to pinpoint potential biomarkers. The variabilities of the fluxes and metabolite flow rates in cancer and healthy cells were classified into seven categories. Accordingly, two secretions and thirteen uptakes (including eight essential amino acids and two conditionally essential amino acids) were identified as potential biomarkers. The findings of this study indicated that cancer cells exhibit a higher uptake of amino acids compared with their healthy counterparts.

Cancer cells undergo metabolic reprogramming in response to hostile microenvironments, such as energy stress; however, the underlying mechanisms remain largely unclear. It is also unknown whether energy stress-responsive circular RNA (circRNA) is involved in the regulation of glucose metabolism. Here we report that circDDX21 is upregulated in response to glucose deprivation by the transcription factor c-Myc. Functionally, circDDX21 is shown to promote glycolysis by increasing PGAM1 expression. Mechanistically, circDDX21 interacts with the RNA binding protein PABPC1, disrupting its association with the ubiquitin E3 ligase MKRN3. This disassociation attenuates MKRN3-mediated PABPC1 ubiquitination and enhances the binding of PABPC1 to PGAM1 mRNA, thereby leading to PGAM1 mRNA stabilization. The ability of the circDDX21-PGAM1 axis to promote hepatocellular carcinogenesis is validated in a xenograft mouse model. Additionally, in clinical hepatocellular carcinoma tissues, there is a positive correlation between circDDX21 and PGAM1 expression. These findings establish circDDX21 as an important regulator of glycolysis and suggest circDDX21 as a potential therapeutic target for hepatocellular carcinoma.

Metabolic reprogramming is an important coordinator of tumor development and resistance to therapy, such as the tendency of tumor cells to utilize glycolytic energy rather than oxidative phosphorylation, even under conditions of sufficient oxygen. Therefore, targeting metabolic enzymes is an effective strategy to overcome therapeutic resistance.

We explored the differential expression and growth-promoting function of MDH2 by immunohistochemistry and immunoblotting experiments in lung cancer patients and lung cancer cells. Pentose phosphate pathway-related phenotypes (including ROS levels, NADPH levels, and DNA synthesis) were detected intracellularly, and the interaction of malate and proteinase 6PGD was detected in vitro. In vivo experiments using implanted xenograft mouse models to explore the growth inhibitory effect and pro-chemotherapeutic function of dimethyl malate (DMM) on lung cancer.

We found that the expression of malate dehydrogenase (MDH2) in the tricarboxylic acid cycle (TCA cycle) was increased in lung cancer. Biological function enrichment analysis revealed that MDH2 not only promoted oxidative phosphorylation, but also promoted the pentose phosphate pathway (PPP pathway). Mechanistically, it was found that malate, the substrate of MDH2, can bind to the PPP pathway metabolic enzyme 6PGD, inhibit its activity, reduce the generation of NADPH, and block DNA synthesis. More importantly, DMM can improve the sensitivity of lung cancer to the clinical drug cisplatin.

We have identified malate as a natural inhibitor of 6PGD, which will provide new leads for the development of 6PGD inhibitors. In addition, the metabolic enzyme MDH2 and the metabolite malate may provide a backup option for cells to inhibit their own carcinogenesis, as the accumulated malate targets 6PGD to block the PPP pathway and inhibit cell cycle progression.

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.

Glycolysis is a universal metabolic process that breaks down glucose to produce adenosine triphosphate (ATP) and biomass precursors. The Entner-Doudoroff (ED) pathway is a glycolytic pathway that parallels textbook glycolysis but yields half as much ATP. Accordingly, in organisms that possess both glycolytic pathways (for example, Escherichia coli), its raison d'être remains a mystery. In this study, we found that the ED pathway provides a selective advantage during growth acceleration. Upon carbon and nitrogen upshifts, E. coli accelerates growth faster with than without the ED pathway. Concurrent isotope tracing reveals that the ED pathway flux increases faster than that of textbook glycolysis. We attribute the fast response time of the ED pathway to its strong thermodynamic driving force and streamlining of glucose import. Intermittent nutrient supply manifests the evolutionary advantage of the parallel glycolysis; thus, the dynamic nature of an ostensibly redundant pathway's role in promoting rapid adaptation constitutes a metabolic design principle.

Renewed interest in tumor metabolism sparked an enthusiasm for dietary interventions to prevent and treat cancer. Changes in diet impact circulating nutrient levels in the plasma and the tumor microenvironment, and preclinical studies suggest that dietary approaches, including caloric and nutrient restrictions, can modulate tumor initiation, progression, and metastasis. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources and can be addicted to glucose, fructose, amino acids, or lipids for survival and growth. This dependence is influenced by tumor type, anatomical location, tissue of origin, aberrant signaling, and the microenvironment. This review summarizes nutrient dependencies and the related signaling pathway activations that provide targets for nutritional interventions. We examine popular dietary approaches used as adjuvants to anticancer therapies, encompassing caloric restrictions, including time-restricted feeding, intermittent fasting, fasting-mimicking diets (FMDs), and nutrient restrictions, notably the ketogenic diet. Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations. Further research is needed to determine the optimal duration, timing, safety, and efficacy of dietary restrictions for different cancers and treatments. In addition, well-designed human trials are necessary to establish the link between specific metabolic vulnerabilities and targeted dietary interventions. However, low patient compliance in clinical trials remains a significant challenge.

Phosphoglycerate mutase 1 (PGAM1) is a key enzyme regulating cancer glycolysis. However, the expression and function of PGAM1 in uveal melanoma (UVM) are unknown and systematic analysis is lacking. This study performed a comprehensive analysis of PGAM1 expression across 33 cancer types in multiple public databases. Results demonstrated PGAM1 is aberrantly overexpressed in most tumors compared to normal tissues, and this overexpression is associated with poor prognosis, advanced tumor staging, and aggressive clinical phenotypes in multiple cancers including UVM, lung, breast and bladder carcinomas. In addition, PGAM1 expression positively correlated with infiltration levels of tumor-promoting immune cells including macrophages, NK cells, myeloid dendritic cells, etc. Further experiments showed that PGAM1 was overexpressed in UVM cell lines and tissues, and it was positively associated with a poor prognosis of UVM patients. And knockdown of PGAM1 inhibited migration/invasion and induced apoptosis in UVM cells, followed by decreased levels of PD-L1, Snail, and BCl-2 and increased levels of E-cadherin. Additionally, the correlation analysis and molecular docking results suggest that PGAM1 could interact with PD-L1, Snail and BCl-2. Thus, PGAM1 may promote UVM pathogenesis via modulating immune checkpoint signaling, EMT and apoptosis. Collectively, this study reveals PGAM1 as a valuable prognostic biomarker and potential therapeutic target in aggressive cancers including UVM.

Aerobic glycolysis is a pivotal hallmark of cancers, including colorectal cancer. Evidence shows glycolytic enzymes are regulated by post-translational modifications (PTMs), thereby affecting the Warburg effect and reprograming cancer metabolism. Lysine lactylation is a PTM reported in 2019 in histones. In this study, we identified protein lactylation in FHC cells and SW480 colon cancer cells through mass spectrometry. Totally, 637 lysine lactylation sites in 444 proteins were identified in FHC and SW480 cells. Lactylated proteins were enriched in the glycolysis pathway, and we identified lactylation sites in phosphofructokinase, platelet (PFKP) lysine 688 and aldolase A (ALDOA) lysine 147. We also showed that PFKP lactylation directly attenuated enzyme activity. Collectively, our study presented a resource to investigate proteome-wide lactylation in SW480 cells and found PFKP lactylation led to activity inhibition, indicating that lactic acid and lactylated PFKP may form a negative feedback pathway in glycolysis and lactic acid production.

The human brain utilizes ∼20% of all of the body's metabolic resources, while chimpanzee brains use <10%. Although previous work shows significant differences in metabolic gene expression between the brains of primates, we have yet to fully resolve the contribution of distinct brain cell types. To investigate cell type-specific interspecies differences in brain gene expression, we conducted RNA-seq on neural progenitor cells, neurons, and astrocytes generated from induced pluripotent stem cells from humans and chimpanzees. Interspecies differential expression analyses revealed that twice as many genes exhibit differential expression in astrocytes (12.2% of all genes expressed) than neurons (5.8%). Pathway enrichment analyses determined that astrocytes, rather than neurons, diverged in expression of glucose and lactate transmembrane transport, as well as pyruvate processing and oxidative phosphorylation. These findings suggest that astrocytes may have contributed significantly to the evolution of greater brain glucose metabolism with proximity to humans.

Moonlighting proteins have more than one physiologically significant role within one polypeptide chain. The multifunctionality of proteins was first described in 1987 by Joram Piatigorsky and Graeme Wistow. Cells can benefit from involvement of these proteins in biological processes in several ways, e.g. at the energy level. Furthermore, cells have developed a number of mechanisms to change these proteins' functions. Moonlighting proteins are found in all types of organisms, including prokaryotes, eukaryotes, and even viruses. These proteins include a variety of enzymes that serve as receptors, secreted cytokines, transcription factors, or proteasome components. Additionally, there are many combinations of functions, e.g. among receptors and transcription factors, chaperones and cytokines, as well as transcription factors within the ribosome. This work describes enzymes involved in several important metabolic processes in cells, namely cellular respiration, gluconeogenesis, the urea cycle, and pentose phosphate metabolism.

Viral infections can result in metabolism rewiring of host cells, which in turn affects the viral lifecycle. Phosphoenolpyruvate (PEP), a metabolic intermediate in the glycolytic pathway, plays important roles in several biological processes including anti-tumor T cell immunity. However, whether PEP might participate in modulating viral infection remains largely unknown. Here, we demonstrate that PEP generally inhibits viral replication via upregulation of apoptosis-associated tyrosine kinase (AATK) expression. Targeted metabolomic analyses have shown that the intracellular level of PEP was increased upon viral infection. PEP treatment significantly restricted viral infection and hence declined subsequent inflammatory response both in vitro and in vivo. Besides, PEP took inhibitory effect on the stage of viral replication and also decreased the mortality of mice with viral infection. Mechanistically, PEP significantly promoted the expression of AATK. Knockdown of AATK led to enhanced viral replication and consequent increased levels of cytokines. Moreover, AATK deficiency disabled the antiviral effect of PEP. Together, our study reveals a previously unknown role of PEP in broadly inhibiting viral replication by promoting AATK expression, highlighting the potential application of activation or upregulation of the PEP-AATK axis in controlling viral infections.

Objective: The aim of this study was to analyze and compare the differential expression of peptides within the follicular fluid of polycystic ovary syndrome (PCOS) patients versus normal women by using peptidomics techniques. The underlying mechanisms involved in PCOS pathogenesis will be explored, together with screening and identification of potential functional peptides via bioinformatics analysis. Materials and methods: A total of 12 patients who underwent in vitro fertilization and embryo transfer (IVF-ET) at the Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from 1 September 2022 to 1 November 2022 were included in this study. The follicular fluid of PCOS patients (n = 6) and normal women (n = 6) were collected. The presence and concentration differences of various peptides were detected by the LC-MS/MS method. GO and KEGG analysis were performed on the precursor proteins of the differentially-expressed peptides, and protein network interaction analysis was carried out to identify functionally-relevant peptides among the various peptides. Results: A variety of peptides within the follicular fluid of PCOS versus normal patients were detected by peptidomics techniques. Altogether, 843 upregulated peptides and 236 downregulated peptides were detected (absolute fold change ≥2 and p < 0.05). Of these, 718 (718 = 488 + 230) peptides were only detected in the PCOS group, while 205 (205 = 174 + 31) were only detected in the control group. Gene Ontology enrichment and pathway analysis were performed to characterize peptides through their precursor proteins. We identified 18 peptides from 7 precursor proteins associated with PCOS, and 4 peptide sequences were located in the functional domains of their corresponding precursor proteins. Conclusion: In this study, differences in the follicular development of PCOS versus normal patients were revealed from the polypeptidomics of follicular development, which thus provided new insights for future studies on the pathological mechanisms of PCOS development.

Chronic inflammatory diseases (CIDs), including inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are thought to emerge from an impaired complex network of inter- and intracellular biochemical interactions among several proteins and small chemical compounds under strong influence of genetic and environmental factors. CIDs are characterised by shared and disease-specific processes, which is reflected by partially overlapping genetic risk maps and pathogenic cells (e.g., T cells). Their pathogenesis involves a plethora of intracellular pathways. The translation of the research findings on CIDs molecular mechanisms into effective treatments is challenging and may explain the low remission rates despite modern targeted therapies. Modelling CID-related causal interactions as networks allows us to tackle the complexity at a systems level and improve our understanding of the interplay of key pathways. Here we report the construction, description, and initial applications of the SYSCID map (https://syscid.elixir-luxembourg.org/), a mechanistic causal interaction network covering the molecular crosstalk between IBD, RA and SLE. We demonstrate that the map serves as an interactive, graphical review of IBD, RA and SLE molecular mechanisms, and helps to understand the complexity of omics data. Examples of such application are illustrated using transcriptome data from time-series gene expression profiles following anti-TNF treatment and data from genome-wide associations studies that enable us to suggest potential effects to altered pathways and propose possible mechanistic biomarkers of treatment response.

Myofibrillar protein degradation is primarily related to meat tenderness through protein phosphorylation regulation. Pyruvate kinase M2 (PKM2), a glycolytic rate-limiting enzyme, is also regarded as a protein kinase to catalyze phosphorylation. The objective of this study was to investigate the relationship between myofibrillar protein degradation and phosphorylation induced by PKM2. Myofibrillar proteins were incubated with PKM2 at 4, 25, and 37 °C. The global phosphorylation level of myofibrillar proteins in the PKM2 group was significantly increased, but it was sensitive to temperature (P < 0.05). Compared with 4 and 25 °C, PKM2 significantly increased the myofibrillar protein phosphorylation level from 0.5 to 6 h at 37 °C (P < 0.05). In addition, the degradation of desmin and actin was inhibited after they were phosphorylated by PKM2 when incubated at 37 °C. These results demonstrate that phosphorylation of myofibrillar proteins catalyzed by PKM2 inhibited protein degradation and provided a possible pathway for meat tenderization through glycolytic enzyme regulation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.

Nonhydrolysable stable analogues of τ-phosphohistidine (τ-pHis) and π-pHis have been designed, aided by electrostatic surface potential calculations, and subsequently synthesized. The τ-pHis and π-pHis analogues (phosphopyrazole 8 and pyridyl amino amide 13, respectively) were used as haptens to generate pHis polyclonal antibodies. Both τ-pHis and π-pHis conjugates in the form of BSA-glutaraldehyde-τ-pHis and BSA-glutaraldehyde-π-pHis were synthesized and characterized by 31 P NMR spectroscopy. Commercially available τ-pHis (SC56-2) and π-pHis (SC1-1; SC50-3) monoclonal antibodies were used to show that the BSA-G-τ-pHis and BSA-G-π-pHis conjugates could be used to assess the selectivity of pHis antibodies in a competitive ELISA. Subsequently, the selectivity of the pHis antibodies generated by using phosphopyrazole 8 and pyridyl amino amide 13 as haptens was assessed by competitive ELISA against His, pSer, pThr, pTyr, τ-pHis and π-pHis. Antibodies generated by using phosphopyrazole 8 as a hapten were found to be selective for τ-pHis, and antibodies generated by using pyridyl amino amide 13 were found to be selective for π-pHis. Both τ- and π-pHis antibodies were shown to be effective in immunological experiments, including ELISA, western blot, and immunofluorescence. The τ-pHis antibody was also shown to be useful in the immunoprecipitation of proteins containing pHis.

Fertility rates in developing countries have declined over the past decades, and the trend of delayed fatherhood is rising as societies develop. The reasons behind the decline in male fertility with advancing age remain mysterious, making it a compelling and crucial area for further research. However, the limited number of studies dedicated to unraveling this enigma poses a challenge. Thus, our objective is to illuminate some of the upregulated and downregulated mechanisms in the male testis during the aging process.

Herein, we present a critical overview of the studies addressing the alterations of testicular proteome through the aging process, starting from sexually matured young males to end-of-life-expectancy aged males. The comparative studies of the proteomic testicular profile of men with and without spermatogenic impairment are also discussed and key proteins and pathways involved are highlighted.

The difficulty of making age-comparative studies, especially of advanced-age study subjects, makes this topic of study quite challenging. Another topic worth mentioning is the heterogeneous nature and vast cellular composition of testicular tissue, which makes proteome data interpretation tricky. The cell type sorting and comorbidities testing in the testicular tissue of the studied subjects would help mitigate these problems.

The involvement of glucose metabolic reprogramming in breast cancer progression, metastasis, and therapy resistance has been increasingly appreciated. Studies in recent years have revealed molecular mechanisms by which glucose metabolic reprogramming regulates breast cancer. To date, despite a few metabolism-based drugs being tested in or en route to clinical trials, no drugs targeting glucose metabolism pathways have yet been approved to treat breast cancer. Here, we review the roles and mechanisms of action of glucose metabolic reprogramming in breast cancer progression and drug resistance. In addition, we summarize the currently available metabolic inhibitors targeting glucose metabolism and discuss the challenges and opportunities in targeting this pathway for breast cancer treatment.

Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.

Neuropathic pain is a common type of chronic pain, primarily caused by peripheral nerve injury. Different T-cell subtypes play various roles in neuropathic pain caused by peripheral nerve damage. Peripheral nerve damage can lead to co-infiltration of neurons and other inflammatory cells, thereby altering the cellular microenvironment and affecting cellular metabolism. By elaborating on the above, we first relate chronic pain to T-cell energy metabolism. Then we summarize the molecules that have affected T-cell energy metabolism in the past five years and divide them into two categories. The first category could play a role in neuropathic pain, and we explain their roles in T-cell function and chronic pain, respectively. The second category has not yet been involved in neuropathic pain, and we focus on how they affect T-cell function by influencing T-cell metabolism. By discussing the above content, this review provides a reference for studying the direct relationship between chronic pain and T-cell metabolism and searching for potential therapeutic targets for the treatment of chronic pain on the level of T-cell energy metabolism.

Hesperidin and narirutin are the major citrus flavanones. Several studies have associated these compounds with pancreatic β-cell survival through their capacity to reduce oxidative stress, inflammation, and inhibit apoptosis. However, the molecular mechanisms of action of flavanones in pancreatic β-cells under high-glycemic stress is still largely unknown. Therefore, this study aimed to decipher molecular mechanisms of flavanone metabolites in pancreatic β-cells treated with high glucose concentration using untargeted shotgun proteomics. We identified 569 proteins differentially expressed in cells exposed to hesperetin 7-glucuronide (H7G) and 265 in cells exposed to 3-(4'-hydroxyphenyl) propanoic acid (PA). Comparison of global proteomic profiles suggest that these metabolites could counteract changes in protein expression induced by high glucose stress. The bioinformatic analyses suggested that H7G and PA modulated the expression of proteins involved in cell adhesion, cell signaling, metabolism, inflammation, and protein processing in endoplasmic reticulum (ER) pathways. Taken together, this study suggests that H7G and PA can modulate the expression of proteins that may prevent dysfunction of pancreatic β-cells under stress induced by high glucose.