bims-glucam 2026-09-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–09–13
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase contributes to MYC-induced cell-autonomous autophagy and to Ras V12 -dependent non-autonomous autophagy in the Drosophila wing disc epithelium.
A novel glutamine metabolism-based classification system for characterizing the heterogeneity of hepatocellular carcinoma.
Enhanced SIRT3 activity potentiates germinal center epigenetic modulation through α-ketoglutarate.
Mitochondrial Raf1 regulates glutamine catabolism.
Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.
Differential metabolic and cellular brain regional susceptibility in adult rats with chronic liver disease.
Correlations between cerebrospinal fluid and plasma levels of GABA, glutamate, dopamine, and related metabolites, and their concentrations across neurological disorders.
Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation.
Untargeted metabolomics reveals differential metabolic pathways and biomarkers in the acute phase of Kawasaki disease.
Circulating metabolite signatures mediating the association between minerals in domestic water and incident MASLD: a prospective cohort study.
Neural-Metabolic Crosstalk Governing Cell Death and Therapy Resistance in Tumors.
Sarcopenia in Pediatric Intoxication Type Inborn Errors of Metabolism: A Frequent and Underrecognized Condition.
NRF2 activation is required for chemotherapy resistance acquisition in medulloblastoma via metabolic and redox adaptation.
Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.
Corrigendum to "Glutamine alleviates lead-induced neuroinflammation via αKG-JMJD3-H3K27me3 pathway: Population, animal, and in vitro evidence" [Ecotoxicol. Environ. Saf. 323 (2026) 120721].
Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.

bioRxiv. 2026 Sep 02. pii: 2026.08.31.748041. [Epub ahead of print]

Glutaminase contributes to MYC-induced cell-autonomous autophagy and to Ras V12 -dependent non-autonomous autophagy in the Drosophila wing disc epithelium.

Francesca Destefanis, Lorenzo Conci, Shivani Bajaj, Valeria Manara, Paola Bellosta.

MYC-driven metabolic reprogramming supports rapid cell growth but also creates metabolic demands that require adaptive mechanisms to maintain cellular homeostasis. Here, combining clonal analysis in Drosophila wing imaginal discs with studies in Schneider S2 cells, we identify glutamine metabolism as a component of Myc-induced autophagy. Myc increased the expression of genes involved in glutamine utilization, including glutaminase (GLS), and enhanced ammonia production, a metabolic by-product of glutaminolysis. Genetic depletion of GLS in clones suppressed the accumulation of Myc-induced Atg8a-positive structures and reduced autophagic flux, demonstrating that glutaminase contributes to the autophagic response elicited by Myc. Exogenous NH₄Cl was sufficient to induce Atg8a-positive structures and partially restored their accumulation following GLS depletion, supporting ammonia as a downstream contributor to this response. Mechanistically, Myc-induced autophagy in clones required the core autophagy factor Atg5 but was not suppressed by activation of Rheb/TOR signaling or Atg1 depletion, indicating reduced dependence on canonical TOR-Atg1 regulation. We further found that Myc activity is required for Ras V12 -driven epithelial overgrowth and that Ras V12 cells induce a pronounced non-cell-autonomous accumulation of Atg8a-positive structures in wild-type cells surrounding Ras V12 clones. Depletion of either Myc or Gls in Ras V12 cells strongly reduced this neighboring autophagic response. Together, our findings identify Gls-dependent glutamine metabolism as a previously unrecognized component of Myc-induced autophagy and extend this relationship to Ras-transformed epithelia, linking the metabolic state of transformed cells to autophagy in the surrounding tissue.
Graphical abstract: Myc increases glutaminase (Gls)-dependent glutamine catabolism, promoting ammonia production and Atg5-dependent autophagy in Drosophila epithelial cells. In Ras V12- transformed epithelia, Myc and Gls are also required for the induction of autophagy in neighboring wild-type cells, suggesting that metabolic signals generated by transformed cells can elicit a non-cell-autonomous autophagic response. Solid arrows indicate experimentally supported relationships, whereas the dashed arrow denotes a proposed metabolic signal whose identity remains to be established.

DOI: https://doi.org/10.64898/2026.08.31.748041
J Gastrointest Oncol. 2026 Aug 31. 17(4): 258

A novel glutamine metabolism-based classification system for characterizing the heterogeneity of hepatocellular carcinoma.

Meijun Li, Zhiyi Chen, Xudong Shen, Zhenyu Feng, Shaohua Wei, Yecheng Li, Minjian Zhang, Zhenyu Ye.

   Background: Glutamine dependence is a hallmark of tumor cell metabolism, and further molecular classification based on glutamine metabolism in patients with hepatocellular carcinoma (HCC) may provide clinical value. This study thus comprehensively examined the patterns of HCC-specific alterations in glutamine metabolism.
Methods: Consensus clustering analysis was conducted on samples from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset based on glutamine metabolism-related genes, which was validated in the GSE76427, the Liver Cancer-France (LICA-FR) cohort, and the Liver Cancer-Japan (LIRI-JP) cohort from the ICGC. Somatic mutation features were evaluated with the Maftools package in R. The activity of oncogenic pathways was estimated via gene set enrichment analysis (GSEA) or single-sample GSEA (ssGSEA). The tumor microenvironment was analyzed using both the CIBERSORT algorithm (for immune cell infiltration estimation) and the ESTIMATE algorithm (for stromal and immune score calculation). Drug sensitivity and immune checkpoint blockade (ICB) response were also analyzed, for which a classifier was built via least absolute shrinkage and selection operator (LASSO). Immunohistochemistry (IHC) was performed to validate the protein expression levels of key differentially expressed genes (DEGs). Intracellular glutamine content under different glutamine concentrations was measured. The viability of HCC cell lines under varying glutamine concentrations was assessed via Cell Counting Kit-8 (CCK-8) assays. Cell migration and invasion were evaluated through Transwell assays, and protein expression was analyzed via Western blotting.
Results: HCC samples were classified into two glutamine metabolism-based clusters, with cluster 1 having a more advanced stage of disease and shorter survival than cluster 2. A higher frequency of genetic mutations and stronger activation of oncogenic pathways was found in cluster 1. There were substantial differences in immune cell infiltration and stromal scores between clusters 1 and 2. Cluster 1 exhibited significantly higher infiltration of immunosuppressive cells and lower stromal scores compared to cluster 2. Cluster 1 had a stronger response to ICB due as indicated by a higher tumor mutation burden (TMB) and T cell-inflamed gene expression profile score, immune checkpoints, and Tumor Immune Dysfunction and Exclusion (TIDE)-predicted data. Moreover, the LASSO classifier accurately differentiated the two clusters. The DEGs between the two clusters were validated in clinical samples. IHC confirmed the differential expression of glutamine metabolism-related genes in HCC samples. CCK-8 assays showed no significant effect of glutamine concentration on cell proliferation. However, Transwell assays revealed that glutamine deprivation (0.2 mM) reduced migration and invasion, while high-glutamine conditions (10 mM) promoted them. Western blotting showed increased expression of metabolism-related proteins under high-glutamine conditions and reduced expression under deprivation.
Conclusions: Altogether, these findings indicate the involvement of glutamine metabolism in HCC and may help inform patient stratification and the formulation of precision therapeutics for this population.

Keywords:  Hepatocellular carcinoma (HCC); classification; glutamine metabolism; heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.21037/jgo-2026-0706
J Biol Chem. 2026 Sep 11. pii: S0021-9258(26)02424-5. [Epub ahead of print] 113552

Enhanced SIRT3 activity potentiates germinal center epigenetic modulation through α-ketoglutarate.

Xinyu Yang, Guoyuan Peng, Qian Hao, Kexin Liu, Zhengcao Xin, Mingming Zhang, Innocent Agida, Yong Zuo, Leng-Siew Yeap, Tianshi Wang, Jianli He, Hongsheng Tan, Jinke Cheng.

  Germinal center (GC) B cells depend on sustained epigenetic modulation to maintain transcriptional identity and support affinity maturation; however, whether mitochondrial metabolism directly enhances this chromatin state remains unclear. Here, we show that enhanced SIRT3 activity promotes glutamine-derived α-ketoglutarate (αKG) accumulation and is associated with reduced H3K27me3 enrichment at the Bcl6 locus. Using SIRT3 K223R gain-of-function mice, metabolomic profiling, and stable isotope tracing, we show that SIRT3 activation increases glutamine-derived αKG accumulation without a uniform increase in downstream tricarboxylic acid (TCA) cycle labeling. Elevated αKG was associated with reduced H3K27me3 at tested Bcl6 regulatory regions, reinforced BCL6 and AID expression, sustained B cell proliferation, and qualitatively enhanced antibody affinity maturation. Glutamine supplementation partially phenocopied these effects, whereas inhibition of glutamine metabolism attenuated them. Importantly, sustained activation of this metabolic-epigenetic axis was associated with enhanced GC expansion accompanied by increased autoantibody levels and renal IgG deposition in a pristane-induced lupus model. Collectively, our findings indicate that enhanced SIRT3 activity potentiates a glutamine-αKG-chromatin axis that links mitochondrial glutamine metabolism to germinal center epigenetic modulation and humoral immune output.

Keywords:  Antibody affinity maturation; B cells; Epigenetic regulation; Germinal center; Glutaminolysis; SIRT3; α-Ketoglutarate

DOI:  https://doi.org/10.1016/j.jbc.2026.113552
Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01053-3. [Epub ahead of print]45(9): 117975

Mitochondrial Raf1 regulates glutamine catabolism.

Ronald L Shanderson, Ian D Ferguson, Luca Ducoli, Weili Miao, Suhas Srinivasan, Zurab Siprashvili, Albert M Li, Mary Grace Velasco, Yang Li, Christine N Hoang, Jiangbin Ye, Paul A Khavari.

  Raf kinases are central to mitogenic signaling and cancer, yet the full complement of functionally important Raf-proximal proteins across subcellular compartments remains undefined. Here, proximity-dependent biotinylation (BioID) of Raf1 in Raf1-dependent cancer cells recovered proteins localized to the mitochondrial matrix. Mitochondrial purification and super-resolution microscopy confirmed that a pool of Raf1 resides within mitochondria. There, Raf1 associated with glutaminase (GLS) across diverse human cancers and enabled glutaminolysis, a major source of biosynthetic precursors in tumor cells. These effects required Raf1 kinase activity but were independent of canonical MAP kinase pathway signaling, and matrix-targeted kinase-dead Raf1 impaired both glutaminolysis and in vivo tumorigenesis. Raf1 therefore acts inside mitochondria, where it engages GLS to drive glutamine catabolism and support tumor growth, revealing a non-canonical, metabolic arm of Raf signaling.

Keywords:  CP: metabolism; MAPK; Raf1; glutaminase; metabolic reprograming

DOI:  https://doi.org/10.1016/j.celrep.2026.117975
JCI Insight. 2026 Sep 08. pii: e200076. [Epub ahead of print]11(17):

Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.

Mohammad Adeel Zafar, Charlotte N Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Haigis, Louis-Marie Charbonnier.

  Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy or for intermediate metabolite biosynthesis responsible for immunomodulation. Here, we demonstrate that glutamine utilization for biosynthetic pathways supported autoimmune inflammation in the settings of Foxp3 deficiency and dextran sodium sulfate-induced colitis. By employing a model of autoimmunity driven by Treg-specific loss of Foxp3, we showed that this effect is independent of pathogenic Foxp3-deficient Treg reprogramming. Mechanistically, glutamine biosynthetic pathways sustained conventional T cell activation and proinflammatory cytokine production by preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production relied on glutamine-dependent asparagine availability, which we identified as a targetable vulnerability for autoantibody formation. These findings highlighted glutamine-driven biosynthetic processes as critical drivers of autoimmunity and revealed distinct metabolic vulnerabilities in autoreactive T and B cells that could be targeted for therapeutic intervention.

Keywords:  Autoimmune diseases; Autoimmunity; Inflammation; Metabolism; Mouse models; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.200076
Metab Brain Dis. 2026 Sep 11. pii: 215. [Epub ahead of print]41(1):

Differential metabolic and cellular brain regional susceptibility in adult rats with chronic liver disease.

Dunja Simicic, Katarzyna Pierzchala, Olivier Braissant, Dario Sessa, Valérie McLin, Cristina Cudalbu.

  Patients with type C hepatic encephalopathy (HE) present diverse symptoms, indicating disease-associated effects in multiple brain regions. While identifying the distinct metabolic and cellular changes in these regions could help explain the clinical variability of HE, this remains challenging. By leveraging the non-invasive capabilities of in-vivo 1H-MR Spectroscopy (9.4T) and complementary ex-vivo histological assessments, we analyzed, longitudinal neurometabolic and morphological changes in the hippocampus, striatum, and cerebellum during the progression of chronic liver disease, induced type C HE in the bile duct ligated rat model (n = 41). We showed that while brain regions share common metabolic and cellular responses such as acute glutamine increase, glial activation, and neuronal alterations, they also display unique characteristics. The most striking difference was in the cerebellum, where the highest glutamine load (+ 134%) was associated with elevated lactate and reduced Purkinje soma surface, while the striatum showed the strongest osmolyte decrease despite having the lowest glutamine increase among the studied regions. Based on the early rise of glutamine across regions, we highlight glutamine as one of the molecular drivers of a cascade of metabolic and cellular abnormalities, together with 1H-MRS as a valuable modality to investigate region-specific brain alterations in HE both in animal models and humans.

Keywords:  Bile duct ligation; Central nervous system; Glutamine; Proton magnetic resonance spectroscopy; Type C hepatic encephalopathy

DOI:  https://doi.org/10.1007/s11011-026-01954-1
Clin Chim Acta. 2026 Sep 05. pii: S0009-8981(26)00507-3. [Epub ahead of print]594 121325

Correlations between cerebrospinal fluid and plasma levels of GABA, glutamate, dopamine, and related metabolites, and their concentrations across neurological disorders.

Yuhang Deng, Wenqing Wu, Sumei Han, Haoqin Jiang, Ming Guan.

   BACKGROUND: Neurotransmitters play critical roles in both central and peripheral nervous system function. However, the correlation between cerebrospinal fluid (CSF) and plasma levels of neurotransmitters remains incompletely understood, limiting the interpretation of peripheral measurements as surrogates for central neurochemical changes. This study aimed to investigate the correlations between CSF and plasma levels of GABA, glutamate, dopamine, and related metabolites, and to explore their expressions across common neurological disorders in a real-world clinical setting.
METHODS: A total of 181 paired CSF and plasma samples from patients with neurological disorders and 67 plasma samples from healthy controls were analyzed. Concentrations of GABA, betaine, L-DOPA, histamine, glutamine, glutamate, dopamine, and choline were quantified using LC-MS/MS. Correlations between CSF and plasma concentrations were assessed using Pearson correlation analysis. Age- and sex-related effects were evaluated in healthy controls, and differences among disease groups were analyzed after classifying patients into neurodegenerative diseases (NDDs), CNS demyelinating diseases (CNS DDs), CNS tumors, and CNS infections.
RESULTS: GABA, histamine, betaine, glutamate, and choline exhibited higher concentrations in plasma than in CSF, whereas glutamine concentrations were higher in CSF. Except for betaine and glutamate, all other neurotransmitters showed statistically significant but weak CSF-plasma correlations (r = 0.15-0.7, p < 0.05). In healthy controls, plasma histamine, betaine, glutamate, and choline levels were higher in males. Plasma GABA levels in all disease groups were consistently lower than controls, and plasma glutamine levels in NDDs, CNS DDs, and CNS tumors were significantly higher than those in controls. By contrast, there were no significant differences in CSF levels among different disease groups, except that glutamate was higher in the CNS tumor group than in the other disease groups.
CONCLUSIONS: Most plasma neurotransmitters and their metabolites do not reliably reflect their CSF levels, which may provide important context for interpreting peripheral neurotransmitter biomarkers in CNS diseases.

Keywords:  Cerebrospinal fluid (CSF); LC–MS/MS; Neurodegenerative diseases; Neurotransmitters; Plasma

DOI:  https://doi.org/10.1016/j.cca.2026.121325
JCI Insight. 2026 Sep 08. pii: e203626. [Epub ahead of print]

Type 3 Inflammation-Specific Keratinocyte Glutaminolysis Promotes Skin Inflammation.

Yongfei Hu, Hai Yu, Kaiyu Liang, Liyan Yuan, Wenjun Zhang, Zhe Zhuang, Suyun Ji, Xichun Xia.

  Inflammatory cytokines reprogram keratinocyte metabolism, but the metabolic pathways that couple immune signals to pathological epidermal growth remain incompletely defined. Here, we identify GLS1-mediated glutaminolysis as a metabolic program preferentially induced in keratinocytes under type 3 inflammatory conditions. Integrated transcriptomic, metabolomic, genetic, and functional analyses showed that IL-17A induced GLS1 expression and glutaminolysis in keratinocytes. Keratinocyte-specific Gls1 deletion reduced the intracellular availability of arginine, proline, and methionine, impaired amino acid-dependent mTORC1 activation, disrupted redox homeostasis, and limited keratinocyte proliferation. Amino acid or antioxidant supplementation partially rescued these defects, whereas rapamycin blocked the amino acid-mediated proliferative rescue. Gls1 deletion did not impair steady-state skin development or homeostasis and did not alter MC903-induced type 2 dermatitis, but it delayed wound re-epithelialization and attenuated IMQ-induced psoriasiform inflammation. Loss of keratinocyte GLS1 also reduced epidermal chemokine expression and the accumulation of neutrophils and IL-17A-producing γδ T cells, revealing a role for glutaminolysis in amplifying epithelial-immune crosstalk. These findings define GLS1-mediated glutaminolysis as a context-specific metabolic checkpoint linking type 3 inflammation to keratinocyte proliferation and cutaneous immune amplification, and support locally or temporally controlled GLS1 inhibition as a potential therapeutic strategy for psoriasis.

Keywords:  Autoimmunity; Dermatology; Metabolism; Skin; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.203626
Front Med (Lausanne). 2026 ;13 1907194

Untargeted metabolomics reveals differential metabolic pathways and biomarkers in the acute phase of Kawasaki disease.

Hanqi Dai, Qianwen Wang, Yi Zhan.

   Introduction: Kawasaki disease (KD) is one of the most common rheumatic diseases in children and manifests with multisystem clinical features. Using untargeted metabolomics, our study investigated alterations in small-molecule metabolites in plasma of children with acute KD. Our study aimed to identify differential metabolic pathways and potential biomarkers.
Methods: Plasma samples were collected from 30 children diagnosed with KD and 30 age-matched healthy controls (HC) at Jinhua Maternal and Child Health Hospital between January 2025 and December 2025. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to analyse plasma samples. Enriched pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and differential metabolic pathways were determined using MetaboAnalyst 5.0. Differential metabolites were screened using the nonparametric Mann-Whitney U-test and receiver operating characteristic curve area (AUC). The conservative average AUC from nested cross-validation was reported as the primary performance metric. Pearson correlation analysis was conducted to evaluate correlations between metabolites and clinical parameters.
Results: In total, 261 differential metabolites were identified between the KD and HC groups, including 87 lipids and lipid-like molecules, 69 organic heterocyclic compounds, 38 benzenoids, 34 organic acids, 14 phenylpropanoids, and 19 other compounds. Pathway analysis of these differential metabolites revealed 30 putatively enriched metabolic pathways for exploratory analysis. Of these pathways, primary bile acid biosynthesis, arginine biosynthesis, histidine metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis were nominally associated with KD. Six metabolites with exploratory discriminatory performance (AUC > 0.8) were further identified: L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid. A combined model incorporating these metabolites achieved an apparent AUC of 0.984 in the full dataset; nested cross-validation yielded a more conservative AUC of 0.889 (95% CI 0.798-0.968), indicating promising exploratory discriminatory performance.
Conclusion: Untargeted metabolomics enables identification of metabolically perturbed pathways during the acute phase of KD. L-tyrosine, L-tryptophan, glutamine, histidine, histamine, and taurocholic acid may serve as candidate biomarkers for acute phase of KD.

Keywords:  Kawasaki disease; biomarkers; differential metabolites; plasma; untargeted metabolomics

DOI:  https://doi.org/10.3389/fmed.2026.1907194
Front Nutr. 2026 ;13 1866771

Circulating metabolite signatures mediating the association between minerals in domestic water and incident MASLD: a prospective cohort study.

Keyang Li, Yincheng Liu, Wenlong Li, Li Qin, Danrui Zhang, Hong Chen, Zhiyu Yin, Hanwen Zhou, Biao Xie, Xiaoni Zhong.

   Background: Epidemiological evidence on minerals in domestic water and incident metabolic dysfunction-associated steatotic liver disease (MASLD) remains limited, particularly regarding potential mediating roles of circulating metabolites. We evaluated the association between minerals and incident MASLD and characterized metabolomic biomarkers that may mediate this association.
Methods: We included 218,339 UK Biobank participants without MASLD or other liver disease at baseline. Domestic water hardness (DWH), including calcium (Ca), magnesium (Mg), and calcium carbonate (CaCO3), was obtained from water-utility outputs. MASLD was ascertained using linked health records. One hundred sixty-eight plasma biomarkers were measured using nuclear magnetic resonance profiling. We used Cox models to quantify associations between minerals and MASLD risk, while causal mediation analyses were used to evaluate mediation by these biomarkers.
Results: During a median follow-up of 13.7 years, 3,004 participants developed MASLD. Higher Ca in domestic water was positively associated with incident MASLD (Hazard ratio 1.087, 95% confidence interval 1.013-1.166), whereas Mg (1.042, 0.993-1.094) and CaCO3 (1.006, 0.939-1.078) showed no significant associations with MASLD. In mediation analyses, Glutamine, Lactate, and Alanine may mediated the association, with proportions mediated of 21.42, 7.53, and 5.38%, respectively.
Conclusion: Ca in domestic water was positively associated with incident MASLD, with partial mediation by metabolites including glutamine, lactate, and alanine. These findings provide insight into the metabolic pathways of minerals-MASLD association and support prevention strategies.

Keywords:  MASLD; alanine; epidemiology; glutamine; lactate; minerals

DOI:  https://doi.org/10.3389/fnut.2026.1866771
Pharmacol Res. 2026 Sep 09. pii: S1043-6618(26)00357-9. [Epub ahead of print] 108442

Neural-Metabolic Crosstalk Governing Cell Death and Therapy Resistance in Tumors.

Yiming Yan, Haojie Sun, Ziqiang Liu, Chandra Sekhar Bhol, Gautam Sethi, Wenhua Xue, Lifeng Li.

  Metabolic reprogramming and resistance to regulated cell death (RCD) are central features of the tumor microenvironment (TME) that drive therapeutic failure. Emerging evidence indicates that neurotransmitter signaling networks-including glutamate, dopamine, 5-hydroxytryptamine (5-HT), and norepinephrine-extend beyond neural communication to function as critical regulators of tumor metabolism, immune modulation, and cell fate. These neurotransmitters influence multiple RCD modalities, such as ferroptosis, cuproptosis, and PANoptosis, through interconnected metabolic and signaling mechanisms. Glutamate is explicitly resolved by compartment and route: high extracellular glutamate inhibits System Xc⁻, restricts cystine uptake and glutathione synthesis, and promotes ferroptosis, whereas intracellular glutamate production, glutaminolysis, SLC7A11-coupled glutamate export, and receptor-mediated signaling have distinct, context-dependent consequences. Dopamine and 5-HT exert context-dependent effects through receptor subtype-specific metabolic rewiring. Sympathetic neurotransmitters, including norepinephrine, enhance glycolysis and lactate-driven immunosuppression through β₂-adrenergic signaling. In parallel, the gut-brain axis modulates tumor susceptibility to RCD by shaping the availability of microbiota-derived neurotransmitter precursors and metabolites. Mechanistically, neurotransmitter signaling converges on RCD programs by regulating redox homeostasis, lipid peroxidation, mitochondrial vulnerability, and inflammatory signaling. Integrating these observations, this review proposes a conceptual framework termed the "Neurotransmitter-Novel Cell Death-Gut-Brain Axis," which links neural signaling, microbial metabolism, and tumor cell death decisions. Building on this framework, we highlight therapeutic strategies combining receptor-subtype-specific neurotransmitter modulation with selective induction of RCD pathways to overcome metabolic plasticity, immune evasion, and therapy resistance. Targeting this integrated neuro-metabolic-death network may offer a clinically actionable avenue to enhance tumor sensitivity to existing and emerging anticancer therapies.

Keywords:  Neurotransmitter metabolism; PANoptosis; clinical translation; cuproptosis; ferroptosis; gut-brain axis; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2026.108442
J Inherit Metab Dis. 2026 Sep;49(5): e70250

Sarcopenia in Pediatric Intoxication Type Inborn Errors of Metabolism: A Frequent and Underrecognized Condition.

Silvio Veraldi, Maria Sole Basso, Giovanna Soglia, Riccardo Cirelli, Gionata Spagnoletti, Silvia Maria Bernabei, Alessia Esposito, Cristiano Rizzo, Sara Cairoli, Diego Martinelli, Lidia Monti, Marco Spada, Andrea Pietrobattista, Carlo Dionisi-Vici.

  Sarcopenia is increasingly recognized in pediatric chronic diseases, yet its prevalence and determinants in children with intoxication-type inborn errors of metabolism (IEM) have never been investigated. This study aimed to evaluate sarcopenia in this population and to investigate associated metabolic alterations. We conducted a retrospective single-center study including 45 pediatric patients (0-18 years) with maple syrup urine disease (MSUD, 11 pts.), organic acidurias (OA, 22 pts.), or urea cycle defects (UCD, 12 pts.) considered for liver transplantation. Sarcopenia was defined as total psoas muscle area z-score ≤ -2 on CT scan. Anthropometric, dietary, and laboratory parameters were analyzed. Forty percent of patients exhibited sarcopenia, most frequently among OA (54.5%) and UCD (33.3%), and only occasionally in MSUD (18.2%). Sarcopenic children showed lower weight, height, and were more likely to require enteral nutritional support. Plasma levels of essential amino acids, particularly branched-chain amino acids (leucine, isoleucine, valine), histidine, and glutamine, were significantly reduced in sarcopenic patients. Leucine emerged as an independent predictor of sarcopenia (p = 0.016). FGF21 levels were elevated in sarcopenic OA and UCD patients, whereas MSUD patients with higher branched-chain amino acids levels showed lower FGF21, suggesting a role beyond mitochondrial stress signaling. Sarcopenia is common in pediatric patients with severe intoxication-type IEM and is closely linked to essential amino acid deficiencies and altered FGF21 signaling. These monogenic diseases provide unique pathophysiological models for better understanding of sarcopenia. Our findings highlight the need for targeted nutritional and metabolic strategies to preserve muscle mass in these vulnerable patients.

Keywords:  branched‐chain amino acids; fibroblast growth factor 21; insulin; intoxication type inborn errors of metabolism; leucine; sarcopenia

DOI:  https://doi.org/10.1002/jimd.70250
Redox Biol. 2026 Sep 03. pii: S2213-2317(26)00379-4. [Epub ahead of print]97 104380

NRF2 activation is required for chemotherapy resistance acquisition in medulloblastoma via metabolic and redox adaptation.

Lorenzo Manfreda, Fatlum Rruga, Arianna Zanolli, Bryan P Marzullo, Lisa Vettore, Martina Mozzo, Martina Canton, Chiara Marchioro, Elena Rampazzo, Elena Mariotto, Serena Filiberti, Marta Turati, Roberto Ronca, Daniel A Tennant, Luca Persano, Giampietro Viola, Roberta Bortolozzi.

  This study explores the pivotal role of NRF2 signaling in conferring resistance to chemotherapy and ferroptosis in medulloblastoma (MB), a highly malignant pediatric brain tumor. Using newly developed in vitro models of MB cells, resistant to standard chemotherapeutics (vincistine, etoposide, cisplatin, and cyclophosphamide), we observed that chemotolerant cells exhibit an enhanced antioxidant response. Specifically, we found higher levels of glutathione, compared to sensitive cells, and increased thioredoxin reductase activity, both key components in maintaining redox homeostasis. Furthermore, we identified a metabolic shift in resistant cells, marked by increased flux through the pentose phosphate pathway (PPP), which boosts NADPH production and supports the antioxidant defense mechanisms. This adaptive antioxidant response is largely mediated by hyperactivation of the NRF2 transcription factor and the consequent upregulation of a set of antioxidant genes, thus effectively reducing intracellular reactive oxygen species (ROS) levels and enhancing cells' ability to tolerate oxidative stress. Intriguingly, our results suggest that NRF2 activation not only supports the acquisition of chemotherapy resistance but also confers protection against ferroptosis induction. Indeed, resistant cells upregulate iron sequestration proteins and ferroptosis-suppressing genes, directly controlled by NRF2, thereby reducing vulnerability to lipid peroxidation-induced cell death. Inhibition of NRF2 in resistant cells increased their sensitivity to both chemotherapy and ferroptosis inducers and, more interestingly, its knockdown prevented sensitive cells from acquiring resistance. Overall, our study underscores the crucial role of NRF2-controlled redox homeostasis in mediating resistance mechanisms in MB, highlighting the therapeutic potential of targeting this pathway. Targeting NRF2 signaling may provide a novel approach to overcome therapy resistance and improve treatment outcomes for patients with this challenging cancer.

Keywords:  Chemotherapy resistance; Ferroptosis resistance; Medulloblastoma; NRF2 signaling; Redox homeostasis

DOI:  https://doi.org/10.1016/j.redox.2026.104380
iScience. 2026 Sep 18. 29(9): 117325

Differential activation of TCA cycle activity and PDH flux by dichloroacetate in skeletal muscle measured by hyperpolarized [2-13C,3-2H3]pyruvate.

Sung-Han Lin, Andrew Cho, Mai T Huynh, Zohreh Erfani, Blanka Kucejova, Sasanka Wathukara Dewage, Thomas Jue, Xiaorong Fu, Zoltán Kovács, Shawn C Burgess, Jae Mo Park.

  Despite the central role of skeletal muscle bioenergetics in whole-body metabolic health, assessing mitochondrial oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity in vivo remains a major challenge. While hyperpolarized [1-13C]pyruvate has been used to probe pyruvate dehydrogenase (PDH) flux to approximate TCA cycle activity, this approach relies on the unreliable assumption that PDH and TCA cycle fluxes are tightly coupled. Here, we demonstrate that hyperpolarized [2-13C,3-2H3]pyruvate can track label-incorporation into TCA cycle-derived glutamate in rat skeletal muscle. Following intravenous dichloroacetate administration, we observed a greater increase in hyperpolarized [1-13C]acetyl-L-carnitine relative to [5-13C]glutamate, suggesting disproportionately increased PDH flux relative to TCA cycle flux. A similar trend was also observed in ex vivo GC-MS analysis of skeletal muscle tissue collected from rats injected with [U-13C3]pyruvate. Together, these findings highlight the complex interplay between PDH and TCA cycle fluxes and establish hyperpolarized [2-13C,3-2H3]pyruvate as a robust agent for assessing mitochondrial metabolism in skeletal muscle.

Keywords:  TCA cycle; acetyl-L-carnitine; dichloroacetate; hyperpolarized; oxidative phosphorylation; pyruvate; pyruvate dehydrogenase; skeletal muscle

DOI:  https://doi.org/10.1016/j.isci.2026.117325
Ecotoxicol Environ Saf. 2026 Sep 10. pii: S0147-6513(26)01105-X. [Epub ahead of print] 120775

Corrigendum to "Glutamine alleviates lead-induced neuroinflammation via αKG-JMJD3-H3K27me3 pathway: Population, animal, and in vitro evidence" [Ecotoxicol. Environ. Saf. 323 (2026) 120721].

Meitao Tan, Kaiju Chen, Gang Zheng, Tao Wang, Anfei Liu, Yunting Li, Lifan Li, Ying Li, Bin Wang, Xingmei Zhang, Fei Zou, Xiaojing Meng.

DOI: https://doi.org/10.1016/j.ecoenv.2026.120775
J Inherit Metab Dis. 2026 Sep;49(5): e70244

Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in TMEM70 and MT-ATP6-Related Mitochondrial ATP Synthase Defects.

Barbara Siri, Diego Martinelli, Rosalba Carrozzo, Sara Boenzi, Sara Cairoli, Cristiano Rizzo, Teresa Giovanniello, Johannes Häberle, Carlo Dionisi-Vici.

  ATP synthase defects, including TMEM70 and MT-ATP6 deficiencies, cause severe mitochondrial encephalo-(cardio)-myopathies complicated by acute metabolic decompensations (AMDs) often associated with hyperammonaemia. However, detailed biochemical characterisation of these events remains limited. The aim of the study was to evaluate the metabolic profiles associated with TMEM70 and MT-ATP6 deficiencies during AMDs in comparison to stable metabolic conditions, assessing frequency and severity of hyperammonaemia, and exploring the mechanisms linking impaired mitochondrial ATP production to the urea cycle by in vivo ureagenesis studies, using [15N] ammonium chloride as stable isotope and assessed by high-resolution mass-spectrometry coupled with liquid chromatography. We retrospectively analysed clinical and biochemical profiles from two genetically confirmed cohorts. Patients with TMEM70 deficiency experienced more frequent AMDs, often with hyperammonaemia and requiring extracorporeal detoxification, while the MT-ATP6 cohort had more prominent neurological symptoms and a lower incidence of hyperammonaemia. Biochemically, both groups showed elevated lactate, alanine and glutamine, with orotic aciduria and abnormalities in purine/pyrimidine metabolism. Plasma citrulline levels were divergent in the two cohorts, with a consistent reduction in patients with MT-ATP6 deficiency and normal or borderline elevated levels in the TMEM70 cohort. In vivo stable isotope studies pointed to the differential impact of TMEM70 and MT-ATP6 deficiency on ureagenesis and on the enrichment of individual urea cycle-related amino acids. This study reveals that TMEM70 and MT-ATP6 deficiencies share features of mitochondrial dysfunction but present distinct metabolic profiles, highlighting a different impact on the urea cycle and its related metabolites, and providing novel insights on our understanding of mitochondrial pathophysiology.

Keywords:  ATP synthase defects; MT‐ATP6; TMEM70‐related encephalo‐(cardio)‐myopathy; acute metabolic decompensation; urea cycle

DOI:  https://doi.org/10.1002/jimd.70244