bims-glucam 2026-09-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–09–27
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.
SUCLG2 contributes to platinum resistance in lung adenocarcinoma through enhancing succinylation of GAC and glutamine metabolism.
Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.
Exploiting Metabolic Vulnerabilities in Acute Myeloid Leukemia: Rationale and Evidence for Combining Metabolic Modulators with Conventional Chemotherapy.
Ginsenoside Rk3 modulates glutamine metabolism and inhibits Th17 cell differentiation via gut microbiota regulation to ameliorate psoriasis.
Crosstalk Between Nrf2 and Metabolic Pathways: Redox Regulation, Glutaminolysis, and Cellular Proliferation.
Glutamine and Pediatric Intestinal Barrier Function: A Scoping Review of Clinical Evidence and Research Gaps.
Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering.
Perfluorooctanesulfonate (PFOS) precursor biotransformation drives shared lipidomic remodeling in HepaRG cells.
Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.
Real-Time Neurofeedback Training to Modulate Glutamate-Glutamine Concentration Using Functional Magnetic Resonance Spectroscopy.
ALKBH5-Dependent m6A Demethylation Promotes Cardiac Aging Through SLC38A3 Reduction and Glutamine Metabolic Alteration.
Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.
FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
Live-Cell Optical Redox Imaging Reveals Metabolic Heterogeneity and Context-Dependent Responses to Metabolic Perturbation in TNBC Cells.
Lactate and lactylation in cancer: metabolic regulation, immune modulation, and therapeutic opportunities.
Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.

Cells. 2026 Sep 09. pii: 1630. [Epub ahead of print]15(18):

In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.

Marjorie Anne Layosa, Keigo Tomoo, Madeline P Sheeley, Michael F Coleman, Chaylen Andolino, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.

  Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells that metastasize to the lungs (metM-WntLung) or liver (metM-WntLiver). Methods: The metastatic cell lines were exposed to varying in vitro glutamine concentrations (0.5, 2, and 4 mM). Cell viability, migration, 14C-glutamine uptake, mRNA abundance of metabolic enzymes, and 13C5-glutamine cellular flux, were measured. Results: At an intermediate level of in vitro glutamine supplementation (2 mM), metM-WntLung cells exhibited greater glutamine uptake, catabolic enzyme expression, and flux of glutamine-derived carbon into the TCA cycle compared with metM-WntLiver cells. Despite this, metM-WntLiver cells were more viable and migratory than metM-WntLung cells under both higher (4 mM) and lower (0.5 mM) glutamine levels, suggesting metabolic adaptability. Exposure to ammonia upregulated ammonia-assimilating enzymes in metM-WntLiver, but not metM-WntLung cells, plausibly mitigating ammonia toxicity in higher glutamine conditions. In glutamine-deprived conditions, the metM-WntLung cells maintained higher glutamine oxidation, but the metM-WntLiver cells had higher total glutathione and GSH/GSSG ratios and enhanced resistance to oxidative stress, suggesting glutamate utilization toward glutathione synthesis. Additionally, metM-WntLiver cells utilized glucose-derived carbons through pyruvate carboxylase (PC) to maintain TCA cycle activity, with elevated PC expression and M+3-labeled oxaloacetate enrichment to a greater extent than metM-WntLung cells. PC silencing in metM-WntLiver cells enhanced cell viability under glutamine deprivation, which was reversed by inhibiting phosphoglycerate dehydrogenase (PHGDH, a key enzyme in de novo serine synthesis). We propose that PC activity compensates for low glutamine levels, including diverting glucose to adaptive pathways such as de novo serine synthesis. Conclusions: Overall, our findings demonstrate that metM-WntLiver cells, but not metM-WntLung cells, exhibit glutamine-specific metabolic plasticity, characterized by the modulation of glutamine catabolism, enhanced ammonia metabolism and antioxidant defense, and support of glucose metabolism, which are associated with better cell survival and migration under glutamine excess and deprivation.

Keywords:  TNBC; breast cancer; glutamine; glutathione; metabolic adaptation; metabolic plasticity; metastasis; organotropic metastasis; pyruvate carboxylase

DOI:  https://doi.org/10.3390/cells15181630
Apoptosis. 2026 Sep 23. pii: 231. [Epub ahead of print]31(10):

SUCLG2 contributes to platinum resistance in lung adenocarcinoma through enhancing succinylation of GAC and glutamine metabolism.

Zuorui Wang, Hui Wang, Lei Wang, Jiayuan Chen, Lei Jiang, Wenxin Deng, Jing Xu, Yaoguang Hua, Yifan Shi, Yi Yuan, Menglin Huang, Xiangpei Cui, Lanxi Bai, Defu Li, Bentong Yu, Qifan Hu.

  Platinum-based drugs constitute first-line chemotherapy for lung adenocarcinoma (LUAD), yet resistance emerges in 50-70% of patients, representing a major clinical challenge. Synthetase GDP-forming subunit β (SUCLG2), the beta subunit of succinyl-CoA synthetase, is a key enzyme in the tricarboxylic acid (TCA) cycle. Using untargeted proteomic profiling, we identified SUCLG2 as a potential contributor of platinum resistance in LUAD. Further knockout of SUCLG2 significantly enhanced cellular sensitivity to platinum-based drugs. Mechanistically, using targeted metabolomics, we found that SUCLG2 conferred platinum resistance by promoting glutamine metabolism and facilitating the succinylation of glutaminase (GAC). This post‑translational modification enhanced GAC activity, thereby reducing ROS generation and suppressing apoptosis in LUAD cells. SUCLG2 was found to be highly expressed in both LUAD tissues and platinum-resistant cell lines. Consistent with cellular findings, animal experiments confirmed that elevated SUCLG2 expression critically contributes to platinum resistance in vivo. Our findings provide new insights into the molecular mechanisms underlying platinum resistance in LUAD and suggest novel therapeutic strategies.

Keywords:  GAC; Glutamine metabolism; Lung adenocarcinoma; Platinum resistance; SUCLG2

DOI:  https://doi.org/10.1007/s10495-026-02443-7
Cancer Treat Res Commun. 2026 Sep 19. pii: S2468-2942(26)00287-X. [Epub ahead of print]49 101376

Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.

Jiaoyu Zhang, Rui Yang.

  As key immune cells in the tumor microenvironment (TME), macrophages polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, with their functional states tightly linked to metabolic pathway dynamics. This review comprehensively examines macrophage metabolic reprogramming in glycolysis, lipid metabolism, glutamine metabolism, the pentose phosphate pathway (PPP), mitochondrial function, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, while exploring their implications for breast cancer's immune microenvironment and therapeutic approaches. In M1 macrophages, glycolysis is significantly enhanced, promoting the inflammatory response through lactate accumulation and reactive oxygen species (ROS) production. Simultaneously, the TCA cycle is disrupted at the citrate and succinate nodes, leading to the accumulation of metabolic intermediates and further strengthening the pro-inflammatory phenotype. On the other hand, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They regulate epigenetic modifications through metabolites such as alpha-ketoglutarate (α-KG) to maintain anti-inflammatory and tissue repair functions. Breast cancer cells reprogram macrophages via glutamine competition and exosome secretion, driving M2 polarization to support tumor progression. Different molecular subtypes exhibit distinct metabolic features: triple-negative breast cancer (TNBC) shows high glycolytic activity and glutamine addiction, whereas hormone receptor-positive breast cancer relies more on exogenous amino acid uptake. Targeting glycolysis or glutamine metabolism can revert tumor-associated macrophages (TAMs) to an anti-tumor M1-like state, boosting immunity. Although metabolic intervention strategies (such as inhibiting key enzymes hexokinase 2 (HK2), glutaminase (GLS), or fatty Acid Binding Protein 4 (FABP4)) show therapeutic potential, existing studies still have limitations: the compensatory effects between metabolic pathways, tumor heterogeneity, and insufficient clinical translation. Emerging strategies, including metabolic checkpoint targeting, CAR-macrophages (CAR-M), and biomimetic nanocarrier-based delivery systems, hold promise for overcoming these challenges. In summary, in-depth elucidation of the molecular mechanisms underlying macrophage metabolic reprogramming and their metabolic crosstalk with breast cancer cells will provide new insights and novel therapeutic targets for the precise immunometabolic therapy of breast cancer.

Keywords:  Breast cancer; Macrophage; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctarc.2026.101376
Pharmaceuticals (Basel). 2026 Sep 01. pii: 1384. [Epub ahead of print]19(9):

Exploiting Metabolic Vulnerabilities in Acute Myeloid Leukemia: Rationale and Evidence for Combining Metabolic Modulators with Conventional Chemotherapy.

Usman Ali Shams, Fawad Inayat, Muhammad Asif Zeb, Maryam, Sulaiman Shams, Muhammad Jawad Ullah, Silvia Jiménez-Morales.

  Acute myeloid leukemia (AML) represents a heterogeneous group of hematological malignancies characterized by uncontrolled proliferation of myeloid progenitors and accumulation of immature blasts in the bone marrow. Metabolic reprogramming is now recognized as a core hallmark of AML, generating dependencies that distinguish leukemic cells from normal hematopoietic stem and progenitor cells and that can be exploited therapeutically. In this review we follow a single connected line of argument: we first place metabolic rewiring within the broader hallmarks of cancer, then describe the principal metabolic programs altered in AML and the specific features that distinguish AML from other malignancies. We next examine the inhibitors and drugs that target each of these pathways, linking every drug class to its mechanism of synergy with chemotherapy, the preclinical and clinical evidence available, and its association with outcome in AML. We then consider multi-target (combination) therapy as a distinct opportunity, and finally the principal challenges that remainsafety and tolerability, the metabolic heterogeneity and plasticity of AML, and the design of biomarker-guided trials. Multiple classes of metabolic drugs are discussed, including glycolysis inhibitors, oxidative phosphorylation inhibitors, glutamine metabolism antagonists, fatty acid oxidation modulators, and redox-active compounds. Despite significant challenges, targeting cellular metabolism represents a promising strategy to enhance therapeutic outcomes in patients with AML.

Keywords:  acute myeloid leukemia; chemotherapy; drug combination; glutamine metabolism; glycolysis; metabolic reprogramming; oxidative phosphorylation; targeted therapy

DOI:  https://doi.org/10.3390/ph19091384
J Nat Med. 2026 Sep 21.

Ginsenoside Rk3 modulates glutamine metabolism and inhibits Th17 cell differentiation via gut microbiota regulation to ameliorate psoriasis.

Yuan Liu, Xiaoqi Wang, Liang Shi, Jiani Jiang, Zhiguang Duan, Chenhui Zhu, Rongzhan Fu.

  Dysbiosis of the gut microbiota has been demonstrated to trigger immune responses that may heighten psoriasis susceptibility. However, conventional therapies for psoriasis are often limited by significant side effects. Ginsenoside Rk3 (Rk3), a bioactive triterpenoid glycoside compound derived from natural ginseng, has shown promise as a potent immunomodulator and gut regulator. Therefore, this study aims to investigate the potential protective effect of Rk3 against psoriasis, with a focus on the gut microbiota modulation and immune response regulation. Network pharmacology was first employed to predict potential targets for the action of Rk3 on psoriasis and an imiquimod (IMQ)-induced psoriasis mice model was used to investigate the palliative effect of Rk3 on psoriasis. Our results reveal that Rk3 restores gut microbiota homeostasis, especially modulating the abundance of Akkermansia muciniphila and Parabacteroides distasonis, and effectively alleviates IMQ-induced psoriasis through gut microbiota-dependent mechanisms. Furthermore, Rk3 exerts a regulatory effect on aberrant amino acid metabolism, suppressing glutamine catabolism while enhancing short-chain fatty acids (SCFAs) biosynthesis. Rk3-mediated regulation of glutamine metabolism exerts an inhibition effect on the conversion of glutamine to glutamate, suppresses Th17 cell differentiation and alleviates psoriasis via the IL-6/JAK1-STAT3 signaling axis. Overall, our research elucidates Rk3's mechanism of action in ameliorating psoriasis and highlights its potential as a gut microbiota modulator for psoriasis treatment.

Keywords:  Ginsenoside Rk3; Glutamine metabolism; Gut microbiota; Psoriasis; Th17 cell differentiation

DOI:  https://doi.org/10.1007/s11418-026-02073-y
Cell Biochem Biophys. 2026 Sep 25.

Crosstalk Between Nrf2 and Metabolic Pathways: Redox Regulation, Glutaminolysis, and Cellular Proliferation.

Rademene Sunday Oria, Amarachukwu Vivian Umeano, Victoria Onyemachi Chukwu, Happiness Ochi Inyang, Saviour God'swealth Usin.

  The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was first described as a cytoprotective regulator that switches on antioxidant and detoxification genes through the antioxidant response element (ARE). That view is accurate but incomplete. Nrf2 also controls metabolic genes governing the pentose phosphate pathway, glutamine catabolism, regeneration of reduced nicotinamide adenine dinucleotide phosphate (NADPH), fatty acid handling, purine synthesis and iron storage, placing it where antioxidant defence and biosynthesis draw on shared pools of carbon, nitrogen and reducing equivalents. This critical narrative review, assembled purposively from PubMed, MEDLINE and Google Scholar rather than systematically, examines the Nrf2/Keap1 axis and then the point where Nrf2 partitions glutamate between anaplerotic entry into the tricarboxylic acid cycle and glutathione synthesis. Stable-isotope tracing shows this partitioning to be measurable as flux: Nrf2 activation raises both glutamate consumption for glutathione and glutamate export through system xc⁻, limiting the carbon available to central metabolism and creating dependency on exogenous glutamine. The same arithmetic accounts for tanshinone IIA starving proliferating myofibroblasts in pulmonary fibrosis and, in the diabetic heart, for Nrf2 repressing thioredoxin-interacting protein at an ARE to protect cardiomyocytes. We argue that the contested dual role of Nrf2 in tumour progression follows from this logic: Nrf2 supplies substrate rather than a proliferative instruction, so the direction of its effect is set by whether the cell carries demand able to consume that substrate and a checkpoint able to restrain its use. We close on tissue context and on matching Nrf2-directed compounds to tissue metabolic state.

Keywords:  Glutaminolysis; Glutathione; Nrf2; Pentose phosphate pathway; Redox metabolism

DOI:  https://doi.org/10.1007/s12013-026-02185-y
Children (Basel). 2026 Sep 11. pii: 1231. [Epub ahead of print]13(9):

Glutamine and Pediatric Intestinal Barrier Function: A Scoping Review of Clinical Evidence and Research Gaps.

Dejan Dobrijević, Nataša Nastić, Kristian Pastor.

  Background/Objectives: Glutamine has been proposed as a nutritional modulator of intestinal epithelial integrity, but its effects on intestinal barrier function in children remain uncertain. This scoping review mapped the available human evidence on glutamine in relation to pediatric intestinal permeability, mucosal injury, microbial translocation, and intestinal adaptation. Methods: The review followed Joanna Briggs Institute methodology and PRISMA-ScR guidance. PubMed, Scopus, and Web of Science Core Collection were searched. Eligible studies included participants aged <18 years and assessed glutamine supplementation or endogenous glutamine status in relation to predefined barrier-related outcomes. Data were charted using a standardized form and synthesized descriptively according to clinical population, study design, glutamine exposure, and barrier domain. Results: Of 598 records identified, 434 unique records were screened. Eighteen publications representing 15 distinct or partially overlapping studies/cohorts were included. Functional intestinal permeability was the most frequently investigated domain. Findings were heterogeneous, with favorable, partial, transient, and null effects reported across different pediatric populations. Evidence for microbial translocation was limited and showed no clear benefit. Positive findings related to intestinal adaptation were mainly derived from uncontrolled or combined interventions, limiting attribution to glutamine. Direct mechanistic evidence in children was sparse, and no consistent major safety signal emerged, although the available safety evidence was limited. Conclusions: Current evidence does not support a uniform beneficial effect of glutamine on pediatric intestinal barrier function. Observed effects vary across populations, intervention characteristics, and outcome assessment methods.

Keywords:  glutamine; intestinal barrier; intestinal permeability; necrotizing enterocolitis; pediatrics; scoping review; short bowel syndrome

DOI:  https://doi.org/10.3390/children13091231
Res Sq. 2026 Sep 15. pii: rs.3.rs-10832865. [Epub ahead of print]

Metabolic profiling of CAR T-cells in patients reveals a shift toward amino acid-supported OXPHOS and informs transporter engineering.

Naomi Taylor, Josquin Moraly, Taisuke Kondo, King Chan, Sooraj Achar, Makoto Ando, Marie Pouzolles, Bonnie Yates, Alexandra Dreyzin, Mehdi Benzaoui, Alka Dwivedi, Saliha Majdoul, Justin Mirazee, Jaehyun Suh, Angela Su, Cedric Mongellaz, Hannah Dada, Swapna Vidhur Dautalabad, Krithikha Bhuvaneshwar, Mina O Seedhom, Valerie Zimmermann, Sandrina Kinet, Daniel Crooks, Hannah Song, Jonathan Yewdell, Christopher Chien, Olivier Hermine, Valerie Dardhalon, Steven Highfill, Thorkell Andresson, Grégoire Altan-Bonnet, Nirali Shah.

CAR T-cell efficacy requires post-infusion expansion and persistence, yet metabolic programs supporting T-cells in patients remain poorly defined. Here, we developed a high-throughput single-cell immunometabolic profiling pipeline and applied it across pediatric leukemia trials, revealing a conserved post-infusion CAR T-cell shift from glycolysis toward amino acid-driven oxidative phosphorylation (OXPHOS). Within this remodeling, OXPHOS-dependent stem-like CAR T-cell subsets were enriched in patients achieving complete remission. Longitudinal plasma metabolomics revealed cytokine release syndrome-associated depletion of multiple amino acids, including glutamine and arginine, during CAR T-cell expansion, creating a nutrient-restricted environment. Analysis of public CAR T-cell datasets showed that responders upregulated amino-acid solute carrier transporters, whereas disrupting uptake impaired translation, OXPHOS, stemness, and cytotoxicity. Guided by these findings, we screened amino-acid transporters for CAR T-cell engineering. SLC1A5-, SLC7A1-, and SLC38A9-armored CAR T-cells emerged as the most promising, with enhanced oxidative capacity and anti-leukemic efficacy, establishing amino acid transport as a targetable metabolic checkpoint.

DOI: https://doi.org/10.21203/rs.3.rs-10832865/v1
Environ Pollut. 2026 Sep 24. pii: S0269-7491(26)01574-5. [Epub ahead of print]410 129204

Perfluorooctanesulfonate (PFOS) precursor biotransformation drives shared lipidomic remodeling in HepaRG cells.

Yu-Ting Chang, Ren-Yan Ying, Yu-Jia Yeh, Yu-Syuan Luo.

  Perfluorooctanesulfonate (PFOS) is a persistent legacy per- and polyfluoroalkyl substance (PFAS) associated with hepatic metabolic disruption, whereas PFOS precursors remain less characterized despite their potential to generate PFOS through biotransformation. This study investigated whether PFOS precursors induce PFOS-like or precursor-specific metabolic perturbations in HepaRG cells. Cells were exposed to PFOS, perfluorooctanesulfonamide (PFOSA), or N-methylperfluorooctanesulfonamidoethanol (N-MeFOSE-M) for 48 h, followed by paired intracellular and extracellular metabolomics and lipidomics analyses. Intracellular PFOS-related signals were detected after PFOSA and N-MeFOSE-M exposure, particularly at the highest exposure concentration, consistent with potential precursor biotransformation. Intracellular samples showed broader differential feature distributions than extracellular samples. Overlapping responses across PFOS and precursor exposures were dominated by putatively annotated lipid-related classes, while pathway-associated features mapped to fatty acid transport and metabolism, SREBP-related lipid regulation, glucose homeostasis, urea cycle-related metabolism, and amino acid transport. Paired intracellular and extracellular profiling unraveled divergent changes in glutamine and phenylalanine between compartments, suggesting altered amino acid handling following PFAS exposure. These findings indicate that PFOS precursors could undergo intracellular biotransformation while producing both overlapping and compound-specific hepatometabolic perturbations. Complementary intracellular and extracellular profiling provides a useful strategy to capture intracellular metabolic remodeling and extracellular metabolite or lipid redistribution.

Keywords:  Biotransformation; HepaRG cells; Lipid metabolism; Lipidomics; N-MeFOSE-M; PFOS; PFOSA

DOI:  https://doi.org/10.1016/j.envpol.2026.129204
Oncol Res. 2026 ;34(10): 10

Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications.

Xiangyang Wang, Ying Wu, Yutong Fu, Ejakpovi Emmanuel Oghenefejiro, Zakari Shaibu, Cunxi Li, Qi Zhou, Liang Yin.

  Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.

Keywords:  Gastric cancer (GC); immunometabolism; immunotherapy; metabolic reprogramming; tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2026.087144
NMR Biomed. 2026 Nov;39(11): e70399

Real-Time Neurofeedback Training to Modulate Glutamate-Glutamine Concentration Using Functional Magnetic Resonance Spectroscopy.

Zhiyan Wang, Savanna Babu, Nina Beck, Sebastian M Frank.

  Neurofeedback training is a procedure in which participants learn to modulate brain activity through their own efforts. Here, we designed a real-time neurofeedback training using functional magnetic resonance spectroscopy (fMRS) to modulate the concentration of glutamate, a major excitatory neurotransmitter, and its precursor glutamine (collectively referred to as Glx) in a volume-of-interest (VOI) located in the occipital lobes. During an induction phase participants employed a self-selected strategy to increase or decrease Glx concentration relative to a reference concentration measured prior to neurofeedback training. Participants were informed about their performance after the induction phase by displaying a disk in green for success or red for failure. The disk size indicated the magnitude of success or failure. The procedure was repeated over the course of 30 trials. Participants were randomly assigned to experimental and control groups (15 participants per group). The experimental group received veridical feedback about their success or failure in the induction phase. The control group received random feedback. Glx concentration in the VOI was measured using 2-s-long consecutive Point RESolved Spectroscopy (PRESS) scans in a 3-Tesla MRI scanner. The results showed that depending on group assignment, participants in the experimental group learned to increase or decrease Glx concentration over the course of training. No significant changes in Glx concentration were observed in the control group. These findings suggest that, with the help of veridical performance feedback, participants learned to modulate Glx concentration in the VOI in the desired direction over a relatively short period of time. fMRS-based neurofeedback training may complement existing neurofeedback approaches by targeting neurotransmitter-related processes.

Keywords:  Glx; excitatory processing; functional magnetic resonance spectroscopy; glutamate; glutamine; human participants; neurofeedback; occipital lobes; point resolved spectroscopy; training

DOI:  https://doi.org/10.1002/nbm.70399
Circulation. 2026 Sep 22.

ALKBH5-Dependent m6A Demethylation Promotes Cardiac Aging Through SLC38A3 Reduction and Glutamine Metabolic Alteration.

Kun Liu, Chi-Qian Liang, Hong-Ji Li, Cheng Li, Qian-Yu Huang, Jin-Hua Lin, Jia-Xuan Chen, Ze-Bing Ye, Hui Zhao, Kyu-Sang Park, Shuang Liu, Meng Wang, Qing-Hua Zhou, Yan-Mei Li, Hao Wang, Zhen-Yu Ju, Xu-Feng Qi.

   BACKGROUND: N6-methyladenosine (m6A) modification has been linked to various types of physiological and pathological bioprocesses. However, the exact role of m6A mRNA methylation in cardiac aging is largely unknown. Here, we show that ALKBH5 (alpha-ketoglutarate-dependent dioxygenase AlkB homolog 5), an m6A demethylase, plays a critical role in regulating cardiac aging.
METHODS: Physiologically aged and paraquat-induced mouse models of cardiac aging as well as senescent cardiomyocyte cell cultures were used to evaluate the expression and function of ALKBH5 in cardiac aging. The adeno-associated virus serotype 9 and small interfering RNAs were used to modulate ALKBH5 expression in vivo and in vitro, respectively. Cardiac aging and function were evaluated by histological analysis, immunostaining, and echocardiography. Methylated RNA immunoprecipitation sequencing and functional screening were performed to identify potential targets of ALKBH5 in regulating cardiac aging.
RESULTS: ALKBH5 expression was increased in aged hearts and in senescent-like cardiomyocyte models, accompanied by reduced m6A levels. ALKBH5 knockdown attenuated senescence-associated phenotypes in cardiomyocytes and reduced aging-associated cardiac remodeling and dysfunction in physiological aging and paraquat-challenged mouse models when adeno-associated virus serotype 9-short hairpin RNA targeting ALKBH5 gene was delivered beginning in young adulthood, whereas ALKBH5 knockdown initiated in already aged hearts did not reverse established phenotypes. Mechanistically, ALKBH5-dependent m6A demethylation reduced the expression of SLC38A3 (solute carrier family 38-member 3), which suggested a YTHDC2 (YTH domain-containing protein 2)-dependent mechanism, thereby contributing to reduced glutamine accumulation, impaired mitochondrial homeostasis, and increased oxidative stress. SLC38A3 overexpression attenuated aging-associated cardiac phenotypes in vivo. In addition, glutamine supplementation reduced senescence-associated and cardiac aging-related phenotypes.
CONCLUSIONS: Our study demonstrates that ALKBH5-SLC38A3 axis is an important regulator of m6A-linked, glutamine-associated pathways in aging-related cardiac phenotypes. These findings support a role for ALKBH5 as a contributor to cardiac aging-associated remodeling and dysfunction and suggest this pathway as a candidate target for further mechanistic and translational investigation.

Keywords:  AlkB homolog 5; RNA methylation; SLC38A3 protein; aging; heart

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.079193
Curr Issues Mol Biol. 2026 Sep 10. pii: 926. [Epub ahead of print]48(9):

Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.

Yufei Liu, Yutong Zhou, Huiwen Xue, Ruiru Xu, Yujiao Liu.

  Lysine lactylation (Kla) is a lactate-driven post-translational modification that covalently links lactyl groups to lysine residues, directly coupling cellular metabolic states to gene expression regulation and protein functional remodeling. Since its first report in 2019, extensive studies have confirmed that lactylation is broadly present on histones and thousands of non-histone substrates. In the context of tumor biology, lactylation reinforces glycolysis through positive feedback loops, suppresses oxidative phosphorylation, remodels lipid and glutamine metabolism, and exerts regulatory functions in autophagy, pyroptosis, ferroptosis, and apoptosis, thereby comprehensively participating in tumor cell proliferation, metabolic adaptation, cell death resistance, and invasion and metastasis. Within the tumor microenvironment, lactylation constructs an immune evasion barrier by upregulating immune checkpoints, including programmed death-ligand 1 (PD-L1), driving tumor-associated macrophage polarization toward the M2 phenotype, inducing CD8+ T cell exhaustion, and enhancing regulatory T cell suppressive function. Strategies targeting lactate production (lactate dehydrogenase A (LDHA) inhibitors), lactate transport (monocarboxylate transporter (MCT) inhibitors), and the lactylation enzymatic machinery (p300/CBP inhibitors, histone deacetylase (HDAC) inhibitors) have shown promising results in preclinical models, and a limited number of agents, including the MCT1 inhibitor AZD3965 and the p300/CBP inhibitor CCS1477, have entered early-phase clinical trials primarily for safety and tolerability assessment. This review systematically summarizes the molecular mechanisms and enzymatic basis of lactylation, as well as its regulatory functions in core cancer hallmarks and the immune microenvironment, evaluates the translational prospects of targeting the lactate-lactylation axis, and discusses the key scientific questions and future research directions currently facing the field.

Keywords:  lactate; lactylation; post-translational modification; targeted therapy; tumor immune microenvironment; tumor metabolic reprogramming

DOI:  https://doi.org/10.3390/cimb48090926
Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01107-1. [Epub ahead of print]45(10): 118029

FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.

Manas Kohli, Aurélien Tripp, Anastasiia Shcherbakova, George Poulogiannis.

  Metabolic reprogramming is a hallmark of cancer, yet dynamic metabolic flux has been difficult to study systematically. Here, we present FluxAtlas, a pan-cancer atlas of metabolic flux generated from genome-scale metabolic modeling of over 10,000 tumors across 28 The Cancer Genome Atlas (TCGA) cancer types. By integrating enzyme constraints and nutrient diffusion limits, we reveal conserved and tissue-specific metabolic rewiring, including alterations in bile acid recycling, urea metabolism, and amino acid biosynthesis. We identify a bile acid-associated program that remodels glutathione homeostasis and drives gastrointestinal-specific lipid metabolism. Comparisons with matched normal models uncover tumor-selective metabolic dependencies, such as increased reliance of renal cancers on de novo purine synthesis. Under nutrient limitation, modeling predicts convergence on glutamine-dependent aspartate synthesis while preserving tissue-specific metabolic states. Machine learning models based on fluxomics predict patient survival and highlight biotin uptake as a prognostic biomarker. FluxAtlas defines the functional metabolic landscape of human cancer and is accessible at https://software.icr.ac.uk/app/flux-atlas.

Keywords:  CP: cancer; CP: metabolism; FluxAtlas; cancer; genome-scale metabolic modeling; metabolic flux; metabolic reprogramming; prognostic biomarkers; therapeutic targets

DOI:  https://doi.org/10.1016/j.celrep.2026.118029
Metabolites. 2026 Aug 27. pii: 613. [Epub ahead of print]16(9):

Live-Cell Optical Redox Imaging Reveals Metabolic Heterogeneity and Context-Dependent Responses to Metabolic Perturbation in TNBC Cells.

He N Xu, Jack Kollmar, Allison Podsednik, Mihiar Wannousse, Alexander Shestov, Roddy S O'Connor, Joseph A Baur, Julia Tchou, Rong Zhou, Lin Z Li.

  Background/Objectives: Triple-negative breast cancer (TNBC) exhibits substantial metabolic heterogeneity and plasticity, contributing to variable therapeutic responses. We investigated whether optical redox imaging (ORI) could characterize metabolic phenotypes, monitor responses to metabolic perturbation, and relate these responses to functional outcomes in TNBC cells. Methods: Four TNBC cell lines were treated with the lactate dehydrogenase A inhibitor FX11 or the glutaminase inhibitor CB-839, alone or in combination with paclitaxel. Intensity-based label-free ORI was performed and followed by imaging of fluorescent probes to assess mitochondrial membrane potential (MMP), re-active oxygen species (ROS), and cell number in the same dishes. Seahorse assays were used to evaluate mitochondrial respiration and glycolytic flux. Results: TNBC cell lines exhibited distinct basal redox phenotypes and differential responses to acute glycolytic and glutaminolytic perturbation. HCC1806 cells showed the strongest acute ORI responses to both FX11 and CB-839. Acute FX11 treatment induced a rapid reductive shift accompanied by ROS accumulation and loss of MMP, whereas CB-839 produced a more modest early reductive response without detectable ROS accumulation or MMP loss. Prolonged treatment revealed distinct temporal redox trajectories in HCC1806 cells: FX11-treated cells evolved from an acute reductive response toward a more oxidized state, while CB-839-treated cells transitioned from an early reductive shift to a sustained oxidized redox state accompanied by marked reductions in OCR and ECAR. Functionally, in two representative models (HCC1806 and MDA-MB-231), CB-839 reduced cell numbers and enhanced the anti-proliferative effect of paclitaxel, whereas FX11 had no significant effect on cell number despite inducing pronounced acute redox perturbations. Conclusions: Integrating ORI with metabolic flux assays and imaging-based functional measurements enables characterization of multiple dimensions of metabolic behavior, including basal phenotype, pathway-specific responsiveness, temporal redox responses, and treatment-associated outcomes. These findings support intensity-based wide-field ORI as a practical and accessible tool for probing metabolic heterogeneity and characterizing context-dependent metabolic responses in TNBC cells.

Keywords:  ECAR; FAD; NADH; OCR; ORR; ROS; glutaminolysis; glycolysis; mitochondrial redox state; wide-field metabolic imaging microscopy

DOI:  https://doi.org/10.3390/metabo16090613
J Pathol. 2026 Sep 22.

Lactate and lactylation in cancer: metabolic regulation, immune modulation, and therapeutic opportunities.

Jiayi Chen, Anqi He, Siyi Zhu, Yong Xia, Lin Yang.

  Lactate has emerged from being viewed as a glycolytic byproduct to a central metabolic and signaling hub that coordinates tumor evolution and therapeutic adaptation. This review integrates current evidence on how lactate production, transport, and accumulation reshape cancer biology, with particular emphasis on the lactate-lactylation axis. In tumors, lactate is generated not only by malignant cells through aerobic glycolysis, hypoxia-driven metabolic rewiring, and glutamine-derived carbon flow, but also by stromal cells, immune cells, adipocytes, and tumor-associated microbiota. Through monocarboxylate transporter-mediated shuttling, lactate supports metabolic symbiosis, extracellular acidification, matrix remodeling, angiogenesis, invasion, and immune escape. Beyond these metabolic and signaling functions, lactate acts as a substrate for lysine lactylation, linking altered metabolism to epigenetic and post-translational regulation. Histone and nonhistone lactylation, governed by emerging writers, erasers, and putative readers, regulates transcription, DNA damage repair, cancer stemness, ferroptosis resistance, immune checkpoint expression, and resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We further discuss the biomarker potential of lactate-related enzymes, transporters, site-specific lactylation marks, and therapeutic strategies targeting lactate production, transport, sensing, depletion, and lactylation machinery. A deeper understanding of lactate flux and lactylation-dependent vulnerabilities may enable biomarker-guided combinations that integrate metabolic intervention, epigenetic modulation, and immuno-oncology for precision cancer therapy. © 2026 The Pathological Society of Great Britain and Ireland.

Keywords:  cancer therapy; combination therapy; lactate; lactylation; therapeutic targets; translational potential; treatment resistance; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1002/path.70132
Eur J Cell Biol. 2026 Sep 21. pii: S0171-9335(26)00046-4. [Epub ahead of print]105(4): 151575

Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.

Shaojie Liu, Jiaqi Zhang, Zihan Zhang, Shilong Yan, Wenyu Di, Jie Yang, Wei Su, Na Song, Haijun Wang.

  Mitochondria integrate bioenergetics, redox homeostasis, calcium signaling, metabolite synthesis, organelle quality control, innate immune sensing, and regulated cell death. In colorectal cancer (CRC), mitochondrial function is not simply suppressed by aerobic glycolysis; rather, tumor cells dynamically redistribute flux between glycolysis, oxidative phosphorylation, glutaminolysis, fatty-acid metabolism, and the mevalonate pathway to meet stage- and treatment-specific demands. This metabolic plasticity determines whether mitochondrial stress is buffered or converted into a lethal signal. Here, we critically synthesize recent evidence linking mitochondrial bioenergetics, reactive oxygen species (ROS), mitophagy, fusion-fission dynamics, mitochondrial DNA (mtDNA) damage and release, mitochondrial biogenesis, and oncogenic signaling to apoptosis and non-apoptotic forms of programmed cell death, including ferroptosis, pyroptosis, necroptosis, PANoptosis, and cuproptosis. We further discuss mtDNA sensors-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Toll-like receptor 9 (TLR9), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and Z-DNA-binding protein 1 (ZBP1)-as links between mitochondrial injury, tumor-cell death, and antitumor immunity. Particular attention is given to B-cell lymphoma 2 (BCL-2) homology 3 (BH3) mimetics, metabolic inhibitors, patient-derived organoids (PDO), patient-derived organoid xenografts (PDOX), and immunocompetent models. Current evidence supports mitochondria as a therapeutically actionable network, but also reveals major context dependencies related to tumor genotype, cell state, treatment schedule, immune competence, and normal-tissue mitochondrial requirements. Biomarker-guided combinations and model systems that preserve patient heterogeneity will therefore be essential for clinical translation.

Keywords:  Apoptosis; Colorectal cancer; Ferroptosis; Metabolic plasticity; Mitochondria; PANoptosis

DOI:  https://doi.org/10.1016/j.ejcb.2026.151575