bims-glucam 2026-08-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–08–16
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic crosstalk between c-Myc and glutamine utilization sustains IgM+ B-cell immunity in teleosts.
Hypoxia drives ferroptosis resistance and immunosuppression in hepatocellular carcinoma by inducing UBASH3B-mediated glutamine metabolism reprogramming and CXCL8 expression.
Renal glycosuria triggers a coordinated mannose and glutamine metabolic program to maintain glucose homeostasis.
Glutaminase regulates alveolar regeneration through autophagy-YAP/TAZ in pulmonary fibrosis.
GLUD1 Inhibition Disrupts Glutamate Homeostasis and Induces Metabolic and Redox Stress in Gliomas.
Human M1-macrophages secrete glutamine: a role for the transporters ASCT2 and SNAT5.
Molecular Mechanisms and Therapeutic Targeting of the Macrophage Metabolic-Epigenetic Interaction Network in Chronic Obstructive Pulmonary Disease.
Glutamine synthetase deficiency triggers mitochondrial oxidative stress and a ribotoxic stress response during acute hepatic metabolic crisis.
Dysregulated BCR repertoire and metabolic state of HBsAg-specific B cells in chronic hepatitis B revealed by integrated single-cell analysis.
Metabolomic Analysis of Intracellular Amino Acid Profile Differences Between Cisplatin-Resistant and Cisplatin- Sensitive CALU-1 Lung Cancer Cells.
Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.
Amino acid metabolic regulatory network in tumor immune escape: mechanistic exploration and intervention directions.
Dietary Fatty Acids Differentially Modulate Hippocampal Glutamate-Related Gene Expression in Mice: Sex-Specific in Vivo and in Vitro Effects.
Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones.
Metabolic Reprogramming at the Tumor-Immune Interface in Hepatocellular Carcinoma.
OmrA sRNA inhibits translation of phosphoenolpyruvate carboxylase to impair TCA-cycle flux.
Metabolic danger signals: TCA cycle metabolites regulate immunity and disease.

J Immunol. 2026 Aug 04. pii: vkag227. [Epub ahead of print]215(8):

Metabolic crosstalk between c-Myc and glutamine utilization sustains IgM+ B-cell immunity in teleosts.

Xinying Jiao, Yating Zhu, Kang Li, Ming Geng, Jiansong Zhang, Yuying Zheng, Qiqi Jiang, Haokai Chen, Jialong Yang, Xiumei Wei.

  B-cell responses rely on a tightly coordinated interplay between transcriptional programs and metabolic reprogramming. Upon activation, B cells remodel their metabolic profiles, with enhanced glutamine metabolism supporting biomass synthesis and proliferation. However, whether and how glutaminolysis underpins B-cell responses in early vertebrates remains largely unexplored. Here, using the Nile tilapia (Oreochromis niloticus) as a model, we demonstrate that IgM+ B cells markedly increase glutamine utilization upon activation. Glutamine deprivation impaired B-cell activation and proliferation, whereas glutamine supplementation promoted these processes. During Edwardsiella piscicida infection, pharmacological inhibition of glutamine metabolism significantly reduced the expansion of IgM+ B cells and compromised antibody secretion. Mechanistically, glutamine metabolism in tilapia IgM+ B cells was governed by the transcription factor c-Myc. Inhibition of c-Myc disrupted glutaminolysis, leading to diminished B-cell proliferation and antibody production. Upon activation, IgM+ B cells coordinated c-Myc expression and downstream glutamine metabolism through the mTORC1 and ERK signaling pathways, thereby coordinating metabolic and immune functions. Notably, this regulatory mechanism operated in a B cell-intrinsic manner and was independent of T-cell help. Collectively, our findings reveal that teleost B cells possess evolutionarily conserved and sophisticated immunometabolic regulatory programs. This study provides new insights into how metabolic pathways are integrated with immune signaling to control B-cell function, highlighting coordinated immunometabolic regulation as a fundamental mechanism underlying vertebrate B-cell immunity.

Keywords:  IgM+ B cell; c-Myc; glutamine metabolism; immunometabolism

DOI:  https://doi.org/10.1093/jimmun/vkag227
Redox Biol. 2026 Aug 06. pii: S2213-2317(26)00341-1. [Epub ahead of print]96 104342

Hypoxia drives ferroptosis resistance and immunosuppression in hepatocellular carcinoma by inducing UBASH3B-mediated glutamine metabolism reprogramming and CXCL8 expression.

Guo-Qiang Pan, Shao-Peng Zhang, Xi Wang, Ying Qu, Xue-Feng Liu, Yu-Chuan Yan, Tao Li, Zhao-Ru Dong.

Hypoxia-induced reprogramming of glutamine metabolism and ferroptosis resistance serve as pivotal factors that drive the progression of solid tumors and contribute to therapeutic resistance. However, the potential interaction between these processes remains inadequately understood. Elucidating the regulatory mechanisms linking these pathways is essential for developing effective therapies for solid tumors. This study demonstrated that HIF-1α promotes the expression of UBASH3B in hepatocellular carcinoma (HCC), resulting in ferroptosis resistance mediated by glutamine metabolism. Mechanistically, HIF-1α-driven UBASH3B dephosphorylated MYBL2 at Y15, leading to MYBL2 stabilization and a reprogramming of glutamine metabolism that modulates ferroptosis resistance. Specifically, MYBL2 augmented the transcriptional activity of SPSB4, which facilitated the K48-linked polyubiquitination and degradation of GLUD1, a key enzyme in glutamine metabolism, at residue K191. This degradation inhibited glutamine-driven oxidative phosphorylation (OXPHOS). Furthermore, UBASH3B played a crucial role in macrophage polarization and T-cell inhibition by promoting CXCL8 expression, which contributed to immunosuppression. Finally, we found that targeting UBASH3B in HCC cells using ZIF-8-Cu@siRNA@HA nanoparticles (ZCSH NPs) enhanced the efficacy of anti-PD-1 in combination with lenvatinib treatment. In summary, our study uncovers a novel interaction between hypoxia, glutamine metabolic reprogramming, and immune suppression in HCC progression, positioning UBASH3B as a promising therapeutic target for overcoming hypoxia-induced treatment resistance.

DOI: https://doi.org/10.1016/j.redox.2026.104342
Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00882-X. [Epub ahead of print]45(8): 117804

Renal glycosuria triggers a coordinated mannose and glutamine metabolic program to maintain glucose homeostasis.

Nadia Rashid, Moses Otunla, Nazmul Hasan, Michael J Hodges, Heba H Qaissi, Tumininu S Faniyan, Pontiana Ritika Clement, Penghui Lin, Mohamed M Y Kaddah, Teresa A Cassel, Donald A Morgan, Kamal Rahmouni, Kavaljit H Chhabra.

  Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and showed increased incorporation of mannose-derived carbon into oxidative metabolism while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, consistent with reliance on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-coordinated metabolic program associated with maintenance of systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.

Keywords:  CP: metabolism; dapagliflozin; glucose metabolism; glycosuria; mannose-6-phosphate isomerase; metabolic reprogramming; mouse model; proximal tubule; stable isotope-resolved metabolomics

DOI:  https://doi.org/10.1016/j.celrep.2026.117804
Am J Respir Cell Mol Biol. 2026 Aug 11. pii: aanag145. [Epub ahead of print]

Glutaminase regulates alveolar regeneration through autophagy-YAP/TAZ in pulmonary fibrosis.

Morgan A Pantuck, Xiaoying Zhang, Fatemeh Meshkini, Yinfei Tan, Adam Karami, Adam Chatoff, Nathaniel Snyder, Walter J Koch, Beata Kosmider, Ying Tian.

   RATIONALE: Impaired alveolar regeneration is a central feature of chronic lung diseases. Type 2 alveolar epithelial cells (AT2) serve as lung stem/progenitor cells that differentiate into type 1 cells (AT1) to restore gas exchange following injury. However, the metabolic determinants governing this regenerative process remain poorly understood.
OBJECTIVES: This study aimed to determine the role of glutamine metabolism via glutaminase 1 (GLS1) in regulating AT2-to-AT1 differentiation and alveolar regeneration after lung injury.
METHODS: We used primary murine AT2 cells, alveolar organoids, and lineage-tracing mouse models of bleomycin-induced lung injury. The effects of AT2-specific GLS1 deletion on epithelial differentiation were assessed in vitro and in vivo. Chloroquine and bafilomycin A1, two autophagy inhibitors with distinct molecular mechanisms of action, were used for mechanistic rescue experiments.
MEASUREMENTS AND MAIN RESULTS: GLS1 expression increased during AT2-to-AT1 differentiation and was accompanied by metabolic reprogramming characterized by enhanced glycolysis and increased glutamine entry into the TCA cycle. AT2-specific GLS1 deletion impaired differentiation in vitro and in vivo, resulting in defective alveolar repair and exacerbated pulmonary fibrosis. Mechanistically, GLS1 deficiency induced excessive autophagy and promoted degradation of the Hippo pathway effectors YAP and TAZ, key regulators of epithelial cell fate decisions. Inhibition of autophagy with either chloroquine or bafilomycin A1 restored YAP/TAZ levels, rescued AT2-to-AT1 differentiation, reduced fibrosis, and improved lung function.
CONCLUSIONS: GLS1-mediated glutaminolysis is essential for alveolar stem/progenitor cell differentiation through regulation of autophagy and YAP/TAZ stability. Modulation of autophagy may represent a therapeutic strategy to enhance lung regeneration in fibrotic lung diseases.

Keywords:  AT2-to-AT1 differentiation; alveolar epithelial cells; glutaminolysis; lung regeneration; pulmonary fibrosis

DOI:  https://doi.org/10.1093/ajrcmb/aanag145
Cells. 2026 Aug 03. pii: 1401. [Epub ahead of print]15(15):

GLUD1 Inhibition Disrupts Glutamate Homeostasis and Induces Metabolic and Redox Stress in Gliomas.

Malgorzata Trybula, Małgorzata Łysiak, Emilia Wiechec, Annika Malmström, Peter Söderkvist.

  Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma.

Keywords:  GLUD1; cancer metabolism; glioma; glutamate dysregulation; redox

DOI:  https://doi.org/10.3390/cells15151401
Am J Physiol Cell Physiol. 2026 Aug 10.

Human M1-macrophages secrete glutamine: a role for the transporters ASCT2 and SNAT5.

Giuseppe Taurino, Martina Chiu, Chiara Ughini, Chiara Maccari, Roberta Andreoli, Giulia Longhi, Marco Ventura, Ovidio Bussolati, Massimiliano G Bianchi.

  Previous results indicated that LPS treatment of human macrophages is associated with the induction of glutamate-ammonia-ligase (GLUL)GLUL, the enzyme that synthesizes glutamine, although the effects on cell Gln level were not assessed by those studies. Here, we show that M1 polarization of human THP-1 macrophage-like cells with LPS and IFNγ induces not only GLUL but also the exchange Gln transporter ASCT2 and the bidirectional carrier SNAT5. Consequently, Gln influx markedly increases, with ASCT2 and SNAT5 inhibitors suppressing the effect. Notwithstanding these changes, cell Gln is comparable in human M0 and M1 macrophages. However, under Gln-free conditions, Gln efflux is three-fold faster in M1 macrophages. With the same approach, we have demonstrated that cell glutamate mostly derives from extracellular Gln. Furthermore, Glu efflux is markedly higher in M1 macrophages, consistent with the induction of the Glu-cystine exchanger xCT. Induction of GLUL, SNAT5 and xCT, along with SNAT5-dependent stimulation of Gln transport, are clearly detectable also in primary human macrophages, derived from monocytes of peripheral blood and M1-polarized with LPS/IFNγ. These data indicate that, through a stimulation of Gln and Glu efflux, M1-polarized human macrophages can increase the concentration of both amino acids in the extracellular microenvironment.

Keywords:  GLUL; LPS; SLC38A5; glutamate; glutamine synthetase

DOI:  https://doi.org/10.1152/ajpcell.00055.2026
Cell Biochem Biophys. 2026 Aug 13.

Molecular Mechanisms and Therapeutic Targeting of the Macrophage Metabolic-Epigenetic Interaction Network in Chronic Obstructive Pulmonary Disease.

Qi Liu, Weiying Liu.

  Pulmonary macrophages serve as one of the primary mediators of the complex and persistent inflammation in chronic obstructive pulmonary disease (COPD). While driven by multiple mechanisms-including oxidative stress pathways, macrophage heterogeneity, microbiome interactions, and the dynamics of acute exacerbations-the intrinsic drivers promoting continuous inflammatory amplification remain incompletely defined. Recent findings point to a bidirectional relationship between cellular metabolism and epigenetic regulation as a driver of this abnormal activation. This review outlines the biochemical components of this crosstalk, linking shifts in glucose, lipid, and glutamine metabolism to chromatin remodeling events. We detail four major molecular axes: α-ketoglutarate-dependent DNA methylation, NAD⁺/SIRT1-mediated deacetylation, the acetyl-CoA-fueled histone acetylation feedback loop, and the regulatory influence of non-coding RNAs (ncRNAs). Together, these pathways create a self-sustaining cycle where altered metabolic fluxes reshape the epigenetic landscape, which subsequently reinforces the initial metabolic abnormalities. This loop helps establish a stable "functional memory" in macrophages, accelerating alveolar damage. Finally, we discuss current gaps, including the need for spatial mapping and multi-omics integration, and evaluate how emerging targeted therapies-such as dual-inhibitors, PROTACs, and RNA-based treatments-could disrupt this pathogenic loop to provide novel preclinical strategies for COPD management.

Keywords:  COPD; Epigenetic; Macrophage; Metabolic; Molecular mechanisms; Targeting potential

DOI:  https://doi.org/10.1007/s12013-026-02124-x
Metabolism. 2026 Aug 13. pii: S0026-0495(26)00243-X. [Epub ahead of print]184 156730

Glutamine synthetase deficiency triggers mitochondrial oxidative stress and a ribotoxic stress response during acute hepatic metabolic crisis.

Guihua Jin, Chengcheng Lin, Yamei Wei, Lujia Zhu, Donghan Zhang, Miaotong Lin, Zhenghui Wu, Xiaorong Chen, Longwang Chen, Aifang Sun, Zhongqiu Lu.

   BACKGROUND & AIMS: Chlorfenapyr (CHL) is associated with high acute lethality in humans, with a case fatality rate exceeding 80%. However, the mechanisms underlying its hepatotoxicity remain poorly understood.
METHODS: Transcriptomic, proteomic, and metabolomic analyses were combined with assessments of mitochondrial morphology and function in cultured hepatocytes. Rescue experiments were performed using MitoTEMPO, glutamine, and GSH. Glutamine synthetase (GLUL) function was investigated through overexpression of wild-type and catalytically inactive mutants, and CRISPR knockout. ZAKα siRNA and c-Jun N-terminal kinase (JNK) inhibitors were used to examine downstream signaling mechanisms. In vivo, the effects of MitoTEMPO treatment and hepatocyte-specific GLUL reconstitution were evaluated in mice.
RESULTS: Multi-omics profiling identified mitochondria and ribosomes as the primary organelles affected by CHL. CHL induced mitochondrial damage and oxidative stress; MitoTEMPO restored viability, confirming mtROS causality. GLUL emerged as a key downregulated target. CHL destabilized GLUL, thereby disrupting the glutamine-glutamate axis, and supplementation with glutamine or GSH restored cell viability and redox homeostasis. Wild-type GLUL overexpression restored viability and suppressed mtROS, whereas the inactive mutant or knockout did not. Mechanistically, mtROS activated the ribotoxic stress response (RSR) through the ZAKα-JNK pathway. Critically, ZAKα depletion abolished CHL-induced JNK phosphorylation and apoptosis, an effect mirrored by JNK inhibition. In vivo, both MitoTEMPO treatment and GLUL reconstitution alleviated hepatic injury and attenuated RSR signaling.
CONCLUSION: These findings delineate a GLUL-mtROS-RSR signaling axis driving CHL hepatotoxicity and positioning GLUL stabilization as a potential therapeutic strategy for this highly lethal poisoning.

Keywords:  Chlorfenapyr; Glutamine synthetase; Hepatotoxicity; Mitochondrial reactive oxygen species; Ribotoxic stress response

DOI:  https://doi.org/10.1016/j.metabol.2026.156730
Hepatol Commun. 2026 Sep 01. pii: e0994. [Epub ahead of print]10(9):

Dysregulated BCR repertoire and metabolic state of HBsAg-specific B cells in chronic hepatitis B revealed by integrated single-cell analysis.

Mengying He, Liangjun Shen, Yaming Li, Menghan Hao, Bing Wang, Yi Zhang, Min Wu, Zhanqing Zhang, Zhong Fang, Zhenghong Yuan, Jieliang Chen.

   BACKGROUND: Humoral immunity targeting hepatitis B virus (HBV) surface antigen (HBsAg) is critical for viral clearance. However, the phenotypic, repertoire, and metabolic features of HBsAg-specific B cells in chronic hepatitis B (CHB) remain incompletely defined.
METHODS: HBsAg-specific B cells were enriched using oligonucleotide-tagged antigen probes and profiled by integrated single-cell RNA sequencing (scRNA-seq) and single-cell B cell receptor sequencing (scBCR-seq) in HBeAg-positive CHB patients, convalescent individuals, and vaccinated healthy controls. Key findings were further evaluated in an independent cohort. Recombinant monoclonal antibodies (mAbs) were generated for functional validation, and ex vivo assays were performed to assess the effects of glutamine modulation on B cell responses.
RESULTS: CHB patients exhibited expansion of unswitched memory (USW) and double-negative 1 (DN1) B cell subsets, characterized by impaired immunoglobulin class switching, altered co-stimulatory molecule expression, and increased clonal expansion. B cell receptor (BCR) repertoire analysis revealed biased immunoglobulin heavy chain variable (IGHV) gene usage and elevated somatic hypermutation in specific isotypes. Single-cell metabolic analysis demonstrated increased oxidative phosphorylation (OXPHOS) and reduced glutamine metabolism in CHB HBsAg-specific B cells. Recombinant mAbs showed heterogeneous and conformation-dependent antigen binding, with limited neutralizing activity. In ex vivo assays, glutamine supplementation enhanced antibody production and was associated with reduced OXPHOS signatures and increased interferon signaling, with similar effects observed in total immunoglobulin secretion.
CONCLUSIONS: HBsAg-specific B cells in CHB display coordinated alterations in subset composition, BCR repertoire, and metabolic state. These findings identify reproducible features of B-cell dysregulation and suggest a potential link between immunometabolic imbalance and impaired humoral responses, providing a framework for further mechanistic investigation.

Keywords:  B-cell exhaustion; B-lymphocyte subsets; glutamine; hepatitis B virus; oxidative phosphorylation

DOI:  https://doi.org/10.1097/HC9.0000000000000994
Cell Biochem Biophys. 2026 Aug 12.

Metabolomic Analysis of Intracellular Amino Acid Profile Differences Between Cisplatin-Resistant and Cisplatin- Sensitive CALU-1 Lung Cancer Cells.

Ismail Koyuncu, Mehmet Ali Tapsık, Ozgur Yuksekdag, Murat Tiken, Ebru Temiz, Hale Güler Kara.

  Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and resistance to cisplatin remains a major limitation in the treatment of non-small cell lung cancer (NSCLC). Accumulating evidence indicates that cancer cells reprogram amino acid metabolism to support proliferation, stress adaptation, redox balance, and therapeutic resistance. In this context, defining the amino acid-related metabolic alterations associated with cisplatin resistance may help identify potential metabolic vulnerabilities and biomarker candidates. In this study, intracellular free amino acid profiles were compared between cisplatin-sensitive parental human lung squamous cell carcinoma cells (CALU-1) and their cisplatin-resistant counterpart (cr-CALU-1) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analysis revealed marked differences in the intracellular amino acid profiles of cr-CALU-1 cells compared with parental CALU-1 cells. Several amino acids, including proline, glutamine, glutamate, arginine, and alanine, were detected at higher levels in parental CALU-1 cells, whereas their intracellular levels were significantly lower in cr-CALU-1 cells. In contrast, cystine and phosphoethanolamine were increased in resistant cells. Multivariate and pathway analyses indicated that arginine and proline metabolism, histidine metabolism, and glutathione metabolism were among the most prominently affected pathways. These findings suggest that cisplatin resistance in CALU-1 cells is associated with broad remodeling of intracellular amino acid homeostasis. However, because targeted LC-MS/MS provides static metabolite pool-size information, further isotope-tracing and functional validation studies are required to determine whether these alterations reflect changes in amino acid uptake, biosynthesis, catabolism, or downstream utilization.

Keywords:  CALU-1 cells; Cisplatin resistance; Intracellular amino acid profiling; LC-MS/MS; Lung cancer; Metabolomics; cr-CALU-1 cells

DOI:  https://doi.org/10.1007/s12013-026-02134-9
Cells. 2026 Aug 05. pii: 1422. [Epub ahead of print]15(15):

Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.

Jianing Zhang, Zimei Tang, Yiran Wang, Jiaying Wan, Yajing Zhou, Jiexiao Li, Jie Ming.

  Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of "metabolic siege" on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites-such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids-function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the "metabolism-epigenetics-immunity" axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.

Keywords:  T cell exhaustion; epigenetic remodeling; immunotherapy; metabolic reprogramming; oncometabolites; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15151422
Front Immunol. 2026 ;17 1871598

Amino acid metabolic regulatory network in tumor immune escape: mechanistic exploration and intervention directions.

Zhaoxia Liu, Lin He, Yu Tian, Shipin Feng, Xiongtao Yang, Hui Wu, Qiaoshuang Pu, Yan Wang, Xiaoli Yuan.

  Tumor immune escape is not determined solely by immune checkpoints, suppressive cytokines, or changes in immune-cell composition; it is also organized by the metabolic architecture of the tumor microenvironment. Reprogrammed amino acid metabolism contributes to this process by redistributing nutrients, generating immunoregulatory metabolites, and reshaping immune-cell states. Rather than viewing individual amino acid pathways as independent mechanisms, this review proposes a network framework in which nutrient competition, metabolite-mediated communication, and immune-state stabilization are mechanistically coupled across tumor, immune, stromal, vascular, and microbiota-associated compartments. We define four properties of this network: cross-pathway convergence on shared immune outcomes, division of metabolic labor among cell populations, spatial and temporal context dependence, and compensatory feedback that sustains immune suppression. Within this framework, we examine how tryptophan, glutamine, methionine, arginine, and emerging pathways such as asparagine regulate T-cell dysfunction, regulatory T-cell persistence, myeloid polarization, dendritic-cell impairment, and resistance to immune checkpoint blockade. We further discuss how network-level understanding may improve biomarker development and guide cell-selective, temporally optimized, and rational combination strategies. Conceptualizing amino acid metabolism as an interconnected regulatory system may better explain the context-dependent effects of metabolic interventions and support precision immunometabolic therapy.

Keywords:  amino acid metabolism; immunometabolism; immunotherapy resistance; tumor immune escape; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1871598
Mol Nutr Food Res. 2026 Aug;70(15): e70580

Dietary Fatty Acids Differentially Modulate Hippocampal Glutamate-Related Gene Expression in Mice: Sex-Specific in Vivo and in Vitro Effects.

Laura Romero-Muñoz, Beatriz Merino, Enrique Sánchez-Hita, Ana Belén Sanz-Martos, María E Casado, Mónica Domingo-Martínez, Adrián Plaza, Lidia Morales, Antonia García, Constanza Fernández-Hernández, Jesús Fernández-Felipe, Nuria Del Olmo, Alberto Marcos, Julie A Chowen, Mariano Ruiz-Gayo, Victoria Cano.

  High-fat diets (HFDs) disrupt hippocampal (HIP) glutamatergic transmission, reducing synaptic plasticity and contributing to cognitive decline. While excessive dietary fat is known to alter glutamate (Glu) homeostasis, the specific effects of saturated versus unsaturated fatty acids and the role of sex remain unclear. We examined two HFDs, one enriched in oleic acid (OA) (UOLF, unsaturated) and another in palmitic and lauric acids (LAs) (SOLF, saturated), in young adult male and female mice. In males, both diets increased HIP Glu and glutamine (Gln) levels; however, only UOLF upregulated genes linked to Glu/Gln uptake and synthesis, suggesting an adaptive metabolic response. These changes were absent in females, indicating marked sex-dependent effects. In cultured HIP neurons and astrocytes, OA caused milder alterations than palmitic acid (PA) and selectively activated pathways that may lower extracellular Glu and enhance recycling. Lauric acid (LA) failed to activate protective mechanisms, implying it is a major driver of HIP dysfunction in males consuming saturated fats. Both diets disrupted the HIP Glu-Gln cycle in males, but only unsaturated fats triggered compensatory mechanisms that mitigate Glu accumulation. These findings emphasize the critical role of dietary fat composition and biological sex in shaping HIP Glu metabolism and glutamatergic function.

Keywords:  astrocyte; glutamate metabolism; high‐fat diets; lauric acid; neuron; oleic acid; palmitic acid

DOI:  https://doi.org/10.1002/mnfr.70580
J Am Chem Soc. 2026 Aug 12. 148(31): 33905-33912

Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones.

Xingyu Ma, Anne A Leaman, Zeng Lin, Huapeng Li, Zhengjun Cai, Qianyue Wang, Kaiwaan Dalal, Md Shahadat Hossain, Venkatesh P Thirumalaikumar, Zhihong Wang, Valerie P O'Brien, W Andy Tao, Qingfei Zheng.

Histamine is a key signaling molecule in pathophysiology that can exhibit significant regulatory roles in diverse health and disease states. Besides the well-studied noncovalent interactions between histamine and its receptors, protein histaminylation is a recently discovered mechanism of action through which histamine regulates cellular signaling pathways in a covalent modification manner. Histaminylation is an emerging protein post-translational modification (PTM), where an isopeptide bond is formed between the histamine primary amine and the γ-carboxyl group of glutamine through a transamidation reaction catalyzed by transglutaminase 2 (TGM2). However, due to the lack of efficient pan-specific antibodies targeting histaminylated glutamine, the histaminylation proteome in cells remains poorly explored. Here, we report the design and development of a novel Nτ-propargylated histamine (Nτ-PH) probe as well as its successful application in chemical proteomic profiling of the histaminylation proteome in cancer cells. Notably, new TGM2-catalyzed epigenetic marks on core histones, e.g., H2AX-Q84 and Q104 histaminylation, have been identified from cancer cells and verified. Lastly, the crosstalk between H2AX histaminylation and γH2AX formation was discovered in this study, suggesting that TGM2-mediated histaminylation plays a critical role in DNA damage responses.

DOI: https://doi.org/10.1021/jacs.6c11677
Cells. 2026 Jul 28. pii: 1357. [Epub ahead of print]15(15):

Metabolic Reprogramming at the Tumor-Immune Interface in Hepatocellular Carcinoma.

Weiming Zhao, Ping Li.

  Hepatocellular carcinoma (HCC) arises predominantly in chronic liver disease with a uniquely tolerogenic microenvironment. Immune checkpoint inhibitors (ICIs) have improved the prognosis of advanced HCC, yet most patients exhibit low response rates or therapeutic resistance due to the highly immunosuppressive tumor microenvironment. Metabolic reprogramming is not only a core hallmark of HCC but also a key regulatory axis connecting tumor cells and the immune system. HCC cells exhibit pronounced Warburg glycolysis, upregulated glutaminolysis, aberrant lipid storage and oxidation, enhanced ketone metabolism, and altered polyamine flux. These metabolic alterations lead to nutrient competition, lactate accumulation, amino acid depletion, and oncometabolite signaling, resulting in T cell exhaustion, macrophage polarization, T cell expansion, and impaired dendritic cell function, thereby influencing tumor progression, immune escape, and therapeutic resistance. Targeting metabolic-immune crosstalk represents a promising strategy for reversing immunosuppression and enhancing the efficacy of immunotherapy. In this review, we systematically summarize the core patterns of metabolic reprogramming in HCC, dissect the molecular mechanisms of metabolic crosstalk at the tumor-immune interface, and discuss the role of immunometabolic remodeling in therapeutic resistance. This review aims to provide a comprehensive theoretical basis and new research directions for improving the efficacy of HCC treatment by targeting the metabolic-immune regulatory axis.

Keywords:  hepatocellular carcinoma; immune; interface; metabolic reprogramming

DOI:  https://doi.org/10.3390/cells15151357
Nucleic Acids Res. 2026 Aug 10. pii: gkag804. [Epub ahead of print]54(15):

OmrA sRNA inhibits translation of phosphoenolpyruvate carboxylase to impair TCA-cycle flux.

Thomas Stenum, Kim Boi Le Huyen, Jonas Kjellin, Sanna Koskiniemi, E Gerhart H Wagner, Erik Holmqvist.

Small RNAs (sRNAs) rarely cause strong growth phenotypes upon overexpression, complicating efforts to link regulatory interactions to physiological outcomes. Here, we report that high levels of the Escherichia coli sRNA OmrA, but not its sibling OmrB, severely inhibit growth in glucose minimal medium. Genetic, biochemical, and physiological analyses indicate that OmrA-dependent toxicity results from reduced flux through the tricarboxylic acid (TCA) cycle. A UV-based suppressor screen identified mutations in the gene encoding Hfq, the RNA-chaperone that aids sRNA-mRNA interactions. Secondly, three independent mutations clustered in the ribosome-binding site of ppc, encoding phosphoenolpyruvate carboxylase, a key anaplerotic enzyme. OmrA directly inhibits Ppc translation via Hfq-dependent base-pairing in the ppc 5' UTR, including the mutated nucleotides obtained in the genetic screen. OmrA is significantly more effective than OmrB in ppc repression in vivo and in vitro, consistent with sequence divergence in their central regions. Supplementation with glutamate, glutamine, or downstream TCA cycle metabolites fully restores growth, linking reduced Ppc levels to metabolic limitation. These results identify ppc as a physiologically relevant OmrA target and suggest how RNA toxicity can uncover central metabolic nodes used by sRNAs to modulate bacterial physiology.

DOI: https://doi.org/10.1093/nar/gkag804
Cell Chem Biol. 2026 Aug 04. pii: S2451-9456(26)00275-8. [Epub ahead of print]

Metabolic danger signals: TCA cycle metabolites regulate immunity and disease.

Tristram A J Ryan, Ivan Zanoni.

  Mitochondrial tricarboxylic acid (TCA) cycle metabolites have emerged as critical regulators of immunity and inflammation beyond their canonical metabolic functions. During inflammatory responses, these metabolites accumulate to millimolar concentrations in immune cells and act as endogenous damage-associated molecular patterns (DAMPs), linking metabolic state to immune regulation through receptor-dependent and receptor-independent mechanisms. Here, we characterize the inflammatory roles of TCA cycle metabolites as immunometabolites in infections, inflammatory and autoimmune diseases, and cancers. We discuss how their anti-microbial functions must be balanced against their capacity to drive and sustain inflammation. To capture the pleiotropic functions of immunometabolites, we introduce the concept of metabolic DAMPs (metaDAMPs), a class of metabolically derived danger signals that orchestrate immune responses. We highlight key metaDAMPs, including itaconate, succinate, and fumarate, and emerging immunometabolites such as malate and oxaloacetate. Finally, we highlight technological advances redefining our understanding of metabolite signaling and consider how targeting immunometabolite signaling may enable therapeutic intervention.

Keywords:  TCA cycle; cancer; immunometabolism; inflammation; metaDAMPs; metabolic damage-associated molecular patterns; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.chembiol.2026.07.004