bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–06–08
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge



  1. Biochem J. 2025 May 30. pii: BCJ20253033. [Epub ahead of print]
      Arginine is a conditionally essential amino acid with known roles in protein production, nitric oxide synthesis, biosynthesis of proline and polyamines, and regulation of intracellular signaling pathways. Arginine biosynthesis and catabolism have been linked to TGF-β-induced activation of fibroblasts in the context of pulmonary fibrosis; however, a thorough study on the metabolic and signaling roles of arginine in the process of fibroblast activation has not been conducted. Here, we examined the regulation and role of arginine metabolism in lung fibroblasts activated with TGF-β. We found that TGF-β increases the expression of arginine metabolic biosynthetic and catabolic enzymes in lung fibroblasts. Surprisingly, using metabolic tracers of arginine and its precursors, we found little evidence of arginine synthesis or catabolism in lung fibroblasts treated with TGF-β. Despite this, arginine remained crucial for TGF-β-induced expression of collagen and α-smooth muscle actin. We found that arginine limitation leads to activation of GCN2 while inhibiting TGF-β-induced mTORC1 activation and collagen protein production. Extracellular citrulline could rescue the effect of arginine deprivation in an ASS1-dependent manner. Our findings suggest that the major role of arginine in lung fibroblasts is for charging of arginyl-tRNAs and promotion signaling events which are required for fibroblast activation.
    Keywords:  Arginine; Fibroblast; Metabolism; Pulmonary Fibrosis; Transforming Growth Factor-β
    DOI:  https://doi.org/10.1042/BCJ20253033
  2. Endocrinology. 2025 Jun 03. pii: bqaf101. [Epub ahead of print]
      Expression of the activating transcription factor 4 (ATF4) in thermogenic adipocytes is required to maintain core body temperature and systemic metabolic homeostasis in models of mitochondrial stress. We have recently shown that ATF4 is required for thermoregulation in response to cold stress in mice, establishing a role for ATF4 in regulating BAT function during physiological stress. In the present study, we investigated the role of ATF4 in thermogenic adipocytes in regulating glucose metabolism and energy homeostasis during diet-induced obesity (DIO). To this end, we generated mice with selective Atf4 deletion in brown adipose tissue (ATF4 BKO). After 12 weeks of high-fat-feeding, ATF4 BKO mice had similar weight gain and total fat mass relative to WT mice. Accordingly, no changes in food intake, locomotor activity or energy expenditure were detected between genotypes. Nonetheless, diet-induced glucose intolerance and insulin resistance were attenuated in ATF4 BKO mice, which correlated with reduced markers of inflammation and increased levels of glucose transporters in BAT. Taken together, our results indicate that Atf4 deficiency in BAT during DIO improves glucose homeostasis and insulin sensitivity in mice without affecting energy homeostasis. Mechanistically, our data suggest ATF4 deletion leads to repressed inflammation in BAT of obese mice, while likely increasing glucose uptake and utilization, thereby contributing to overall improvement in glucose homeostasis.
    Keywords:  ATF4; brown adipose tissue; diet-induced obesity; glucose homeostasis; insulin resistance
    DOI:  https://doi.org/10.1210/endocr/bqaf101
  3. Cell Death Discov. 2025 Jun 04. 11(1): 266
      Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.
    DOI:  https://doi.org/10.1038/s41420-025-02544-3
  4. Sci Rep. 2025 Jun 03. 15(1): 19368
      Caloric restriction and ketogenic diets may modify the progression of neurological disorders, including HIV-associated neurological disorders and Alzheimer's disease, in part by influencing astrocyte function. This study examines how metabolic substrate availability affects metabolic processes and gene expression in human astrocytes. We exposed astrocytes to the glycolysis inhibitor 2-deoxyglucose (2-DG), to mimic caloric restriction, prior to stimulation with interleukin-1β and measured extracellular flux using the Seahorse ® platform. We next analyzed gene expression and chromatin accessibility changes using RNA-sequencing and ATAC-sequencing, respectively. Finally, we tested the effects of glucose deprivation and the ketone body β-hydroxybutyrate (BHB) on inflammatory gene expression. 2-DG reduced oxygen consumption rate and extracellular acidification rate in the presence of IL-1β, while concomitantly decreasing expression of pro-inflammatory cytokines TNF, IL-6, and C3. These changes were linked to altered chromatin structure. The metabolic substrate β-hydroxybutyrate was associated with reduced cytokine expression compared to glucose. Inhibition of glycolysis attenuated IL-1β-induced inflammation and gene expression changes and altered chromatin architecture. Both glucose deprivation and BHB treatment reduced inflammatory cytokine expression, with additive effects when combined with 2-DG. These results suggest that targeting glycolysis could provide therapeutic strategies for treating neurological diseases through modulation of astrocyte-driven inflammation.
    Keywords:  Astrocytes; Caloric restriction; Chromatin accessibility; Glycolysis; Immunometabolism; Neuroinflammation
    DOI:  https://doi.org/10.1038/s41598-025-03796-w
  5. Cancer Metab. 2025 Jun 05. 13(1): 27
       BACKGROUND: Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.
    METHODS: Analyses of RNA sequencing data from murine cachexia models and comprehensive, unbiased open approach proteomics analyses of skeletal myotubes was performed. In vitro techniques were employed to evaluate mitochondrial function and capacity in skeletal muscle cells and cardiomyocytes. Functional bioassays were used to measure autophagy activity. ARG1 level in patients' plasma was evaluated using ELISA, and the association between ARG1 level and patient survival, across multiple types of cancer, was examined using the online database Kaplan-Meier plotter.
    RESULTS: In line with arginine-degrading activity of ARG1, we found signs of arginine restriction in atrophic muscles. In response to arginine restriction, mitochondrial functions and ATP generation was severely compromised in both skeletal muscle cells and in cardiomyocytes. In skeletal muscle cells, arginine restriction enhanced the expression of autophagic proteins, suggesting autophagic degradation of cellular content. Reduction in mitochondria marker TIMM23 supports selective autophagic degradation of mitochondria (mitophagy). In arginine starved cardiomyocytes, mitochondrial dysfunction is accompanied by both increased bulk autophagy and mitophagy. In cancer patients, we found an association between ARG1 expression and accelerated weight loss and reduced survival, further supporting a role of ARG1-producing cells in cachexia pathogenesis.
    CONCLUSION: Together, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.
    Keywords:  ARG1; Arginine; Autophagy; Cachexia; Cancer; Mitochondria; Mitophagy; Muscle; Myeloid-derived suppressor cell; Neutrophil
    DOI:  https://doi.org/10.1186/s40170-025-00396-0
  6. J Leukoc Biol. 2025 Jun 04. pii: qiaf080. [Epub ahead of print]
      Trained immunity, also termed innate immune memory, is supported by metabolic rewiring of innate immune cells, altering their bioenergetic profile and ultimately their functions. While amino acids such as arginine are known to possess immunomodulatory properties, their role in trained immunity remains largely unexplored. Primary human monocytes were trained with β-glucan in a medium enriched with or deprived of arginine or supplemented with an arginase inhibitor. After a resting period, trained cells were restimulated with LPS. Arginine deprivation or arginase inhibition during β-glucan-training impaired the amplification of IL-6 and TNF cytokine response to LPS, while they did not affect the cells' phagocytotic capacity. Arginine deprivation also significantly reduced the oxygen consumption rate of trained cells, without affecting glycolysis. Genetic studies revealed polymorphisms near genes coding for arginine-metabolizing enzymes modulated induction of trained immunity, highlighting the role of arginine-derived metabolites in trained immunity. These findings demonstrate that arginine and its metabolites are involved in the induction of trained immunity. Understanding metabolic mechanisms involved in trained immunity could provide insights into new therapeutic strategies for harnessing arginine deprivation to modulate inflammatory disorders.
    Keywords:  arginine; metabolism; monocytes; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiaf080
  7. bioRxiv. 2025 May 20. pii: 2025.05.15.654370. [Epub ahead of print]
      Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26). We found no difference in whole-body lipolysis and proteolysis, ketogenesis, or fatty acid and ketone oxidation by tissues between the two groups. In contrast, compared to ncxC26 mice ad libitum, glucose turnover flux decreased in food intake-controlled ncxC26 mice but not in cxC26 mice. Similarly, sustained glucose turnover flux was observed in two autochthonous cancer cachexia models despite reduced food intake. We identified glutamine and alanine as responsible for sustained glucose production and tissues with altered use of glucose and lactate in cxC26 mice. We provide a comprehensive view of metabolic alterations in cancer cachexia revealing those distinct from decreased nutrient intake.
    Highlights: Quantitative fluxomics of cancer cachexia under matched food intake and body weightIntact lipolysis, proteolysis, ketogenesis, and lipid oxidation in cachectic miceSustained glucose consumption in cachectic mice despite reduced food intakeIncreased glucose production from glutamine and alanine in cachectic mice.
    DOI:  https://doi.org/10.1101/2025.05.15.654370
  8. J Biol Chem. 2025 May 29. pii: S0021-9258(25)02163-5. [Epub ahead of print] 110313
      Impairments in protein glycosylation, including O-GalNAc-type glycosylation, are linked to severe developmental disorders with prominent neurological involvement. However, the role of this glycosylation pathway at a cellular level is not yet fully understood. Here, we report a comprehensive map of GalNAc-type O-glycoproteins (>800) and O-glycosites (>4,000) from neuronal tissues and cell lines and identify abundant O-glycosites within major classes of proteins involved in neuroplasticity including axon guidance, membrane remodeling, and regulated vesicular secretion. Applying the map, we demonstrate that the regulated secretory pathway constitutes highly O-glycosylated proteins including Chromogranin A, a key player in dense core granulogenesis, and that correct O-glycosylation is important for its multimerization. Concurrently, genetically engineered neuronal cell lines deficient in O-glycosylation exhibit altered capacity for storing neurotransmitter noradrenaline and present enlarged neurotransmitter-containing dense core granules. Collectively, this map provides the foundation for uncovering critical roles for O-glycosylation in regulating neuroplasticity and provides evidence that dense core granule content is regulated by this pathway. Subjects: Granin, glycosylation, glycosaminoglycans, dense core granules (DCG), perineuronal net (PNN), mucin, central nervous system (CNS), neuron, neuroplasticity, neurotransmitter.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110313
  9. Gut. 2025 Jun 04. pii: gutjnl-2024-334361. [Epub ahead of print]
       BACKGROUND: Pancreatic cancer exhibits limited clinical responses to immunotherapy, highlighting the need for new strategies to counteract its immunosuppressive microenvironment. Although metabolic reprogramming and epigenetic changes contribute to malignancy, the impact of lactate-driven histone lactylation on the tumour microenvironment (TME) has not been fully explored.
    OBJECTIVE: This study aims to investigate the role of histone lactylation in pancreatic cancer, focusing on its effects on cholesterol metabolism and antitumour immunity.
    DESIGNS: Global lactylome profiling was conducted to identify novel epigenetic mechanisms driven by lactate-induced histone lactylation. Mechanisms were investigated via RNA sequencing, CUT&Tag, immunoprecipitation-mass spectrometry and GST-pull down. Mass cytometry by time-of-flight, in vitro co-culture system, orthotopic pancreatic cancer models and flow cytometry were used to explore Acetyl-CoA acetyltransferase (ACAT2) functions. A proteolysis-targeting chimaera (PROTAC) was developed to degrade ACAT2.
    RESULTS: Global lactylome profiling revealed that lactate-driven histone lactylation, particularly H3K18la, promotes the transcriptional activation of ACAT2. ACAT2 acetylates mitochondrial carrier homolog 2 (MTCH2), stabilising it and disrupting oxidative phosphorylation, which increases lactate production and fuels a positive feedback loop in pancreatic cancer. This loop facilitates the delivery of cholesterol via small extracellular vesicles (sEVs), polarising tumour-associated macrophages toward an immunosuppressive M2 phenotype. Additionally, the PROTAC targeting ACAT2 enhanced the efficacy of immune checkpoint blockade therapy in vivo.
    CONCLUSIONS: Our findings highlight the critical role of the H3K18la/ACAT2/sEV-cholesterol axis in TME reprogramming. Targeting this pathway may improve anti-PD-1 therapy response in pancreatic cancer, providing a novel therapeutic strategy by linking histone lactylation, cholesterol metabolic reprogramming and immune modulation.
    Keywords:  GENE TARGETING; IMMUNE RESPONSE; LIPID METABOLISM; MACROPHAGES; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2024-334361