bims-glucam 2026-11-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–11–01
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolic interaction network reshapes tumor immunotherapy resistance.
Tip60-Mediated USP22 Lactylation Drives Glutamine Metabolic Reprogramming via SLC25A5 in TNBC.
Integrated targeted metabolomics and complementary [α-15N] glutamine tracing reveal glutamine metabolic remodeling associated with RA-ILD.
Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.
Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity.
Glutamine metabolic reprogramming in acute and chronic kidney diseases: mechanistic insights and therapeutic implications.
Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
Glutaminolysis Shapes Cardiac Resilience to Stress via Mitochondrial Glutathione.
Non-Canonical HIF2 Accumulation in Breast Cancer Cells.
Modulation of the Liver-Brain Axis by Ondansetron in Thio-Acetamide-Induced Acute Hepatic Encephalopathy.
The amino acid transporters SLC38A3-SLC38A5-SLC38A7 as novel anti-cancer therapeutic targets.
Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives.
Glutamine deprivation elevates EFNB3 and its potential link to macropinocytosis in glioblastoma.
Measuring Blood Plasma Glutamine Levels Using a Nanopore-Based Sensor.
Diminished nutrient supply stimulates endothelial metabolic rate turnover - impact of the cellular sex on glucose und glutamine metabolism.
T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.
Gene functions determine stochastic or adaptive futile transcription in cancers through deregulated start site deployments.
GABARAPL1 drives therapeutic differentiation of cancer cells by targeting epigenetic changes regulated by SFPQ.
Prognostic Significance of Amino Acid Transporters in Endometrial Cancer.
Repurposing the orphan drug nitisinone synergizes with sorafenib to sensitize immunotherapy-refractory MSS-CRC via metabolic stress-driven STING activation.

Trends Immunol. 2026 Oct 29. pii: S1471-4906(26)00287-5. [Epub ahead of print]

Glutamine metabolic interaction network reshapes tumor immunotherapy resistance.

Shao-Cheng Tang, Jiang-Xi Liu, Yi-Ming Wang, Hao Wang, Ling Lu.

  Glutamine metabolism is often viewed as a cancer cell dependency, but its biological consequences depend on how glutamine and its carbon- and nitrogen-derived metabolites are used across malignant, immune, and stromal compartments. In this article, we introduce the glutamine metabolic interaction network (GMIN) as an analytical framework that integrates nutrient partitioning, competition, metabolic cooperation, and metabolite-mediated regulation while distinguishing candidate associations from functionally supported interactions. We review the biochemical, spatial, and treatment-dependent determinants of GMIN states, including emerging evidence for metabolic remodeling during immunotherapy resistance. Current clinical evidence neither supports uniform glutaminase 1 dependence nor establishes a single preferred strategy for glutamine-directed intervention. GMIN may therefore provide a framework for identifying context-specific glutamine-centered interactions and prioritizing them for state-resolved therapeutic targeting.

Keywords:  glutamine metabolism; immunotherapy resistance; metabolic crosstalk; spatial metabolism; tumor immunometabolism

DOI:  https://doi.org/10.1016/j.it.2026.10.001
Adv Sci (Weinh). 2026 Oct 26. pii: e78486. [Epub ahead of print]

Tip60-Mediated USP22 Lactylation Drives Glutamine Metabolic Reprogramming via SLC25A5 in TNBC.

Fang Zhen, Hongyi Wang, Ningzhi Zhang, Le Wang, Huiyuan Tian, Luxi Kang, Zhanpeng Liu, Jing Hu.

  Glutamine metabolism promotes breast cancer progression and metastasis, though the underlying mechanisms are not fully understood. In this study, we identified a significant positive correlation between glutamine metabolism and ubiquitin-specific protease 22 (USP22)expression in breast cancer patients. USP22 drives glutamine reprogramming to promote lactate secretion, thereby supporting triple-negative breast cancer (TNBC) growth and survival. This process involves the lactyltransferase Tat-interactive protein, 60 kDa (Tip60), which catalyzes K134 lactylation of USP22. This post-translational modification (PTM) stabilizes USP22 protein levels and facilitates its mitochondrial location. Moreover, USP22 stabilizes the solute carrier family 25 member 5 (SLC25A5) through its de-ubiquitinase activity. Clinically, increased expression levels of both USP22 and SLC25A5 are significantly associated with a poor prognosis in patients with TNBC. Furthermore, USP22 regulates glutamine metabolism to promote α-ketoglutarate (α-KG) secretion, thereby activating M2 macrophages and suppressing the anti-tumor immune response. Importantly, targeting USP22 synergized with CB-839 in TNBC xenograft models. These findings underscore USP22 as a promising therapeutic target for TNBC.

Keywords:  USP22; glutamine metabolism; macrophages; metabolic reprogramming; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.78486
Anal Chim Acta. 2026 Dec 01. pii: S0003-2670(26)01249-3. [Epub ahead of print]1425 346299

Integrated targeted metabolomics and complementary [α-15N] glutamine tracing reveal glutamine metabolic remodeling associated with RA-ILD.

Li Jiang, Luna Shen, Shuting Fang, Fangyuan Sun, Guizhong Xin, Lifang Liu, Jiayi Zheng.

   BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe complication with limited therapeutic options, characterized by destructive joint lesions and pulmonary fibrosis involving excessive collagen deposition. Glutamine metabolism supplies precursors for collagen-related amino acid biosynthesis, which drives the fibrotic remodeling process, but its cross-organ redistribution and pathway-specific utilization remain difficult to resolve using conventional metabolomic readouts. An analytical strategy capable of integrating quantitative multi-matrix profiling with isotope-resolved nitrogen tracing is therefore needed to characterize alterations in glutamine-related amino acid metabolism associated with RA-ILD and its pharmacological modulation.
RESULTS: We established a complementary analytical framework in which 3-trimethylsilyl-1-propanaminium chloride (TSPC) derivatization-assisted UPLC-QqQ-MS/MS targeted metabolomics and intestinal amino acid transporter profiling were applied to an RA-ILD rat model, while [α-15N] glutamine tracing was independently performed in a TGF-β1-induced fibrotic cell model to examine pathway-specific glutamine nitrogen utilization. The validated method enabled sensitive quantification of glutamine-related amino acids in serum, lung tissue, and cells. In RA-ILD rats, cross-matrix profiling revealed a compartment-dependent disturbance of glutamine-related amino acid distribution, characterized by pulmonary accumulation coupled with altered circulating availability. Clematis triterpenoid saponins (CTSs) partially normalized this metabolic imbalance and were associated with coordinated regulation of intestinal glutamine transporters. Stable-isotope tracing in a fibrotic cell model further showed preferential incorporation of glutamine-derived nitrogen into the serine-glycine axis, which was supported by increased expression of ATF4-associated serine-glycine biosynthetic enzymes in lung tissue. CTSs treatment attenuated the corresponding lung transcriptional alterations.
SIGNIFICANCE: Together, invivo multi-matrix metabolomics characterized systemic glutamine-related metabolic redistribution and its response to CTSs in RA-ILD, whereas complementary in vitro isotope tracing provided pathway-level evidence for preferential glutamine-derived nitrogen utilization through the serine-glycine axis under fibrotic stimulation. Such a complementary framework also provides a transferable analytical strategy for investigating cross-organ diseases and multi-level interventions of traditional Chinese medicines.

Keywords:  Clematis triterpenoid saponins; Glutamine metabolism; Metabolomics; RA-ILD; [α-(15)N] glutamine tracing

DOI:  https://doi.org/10.1016/j.aca.2026.346299
Elife. 2026 Oct 29. pii: RP107627. [Epub ahead of print]14

Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling.

Sung Hoon Cho, Shawna K Brookens, Ariel L Raybuck, Kaylor Meyer, Yeeun Paik, Jennie Hamilton, Jingxin Li, Karel Kalecky, Chloe Park, Juyeon Lim, Sakeenah L Hicks, John Karijolich, Teodoro H Bottiglieri, Jeffrey C Rathmell, Denis Mogilenko, Christopher D Scharer, Mark R Boothby.

  The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis - a major metabolic use of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases if either glucose uptake into mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.

Keywords:  B lymphocyte; cytokine receptor signaling; immunology; immunometabolism; inflammation; mitochondria; mouse; plasma cell; regulation of antibodies

DOI:  https://doi.org/10.7554/eLife.107627
Sci Adv. 2026 Oct 30. 12(44): eaeh5903

Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity.

Rundi Song, Jinhong Li, Chaoyu Wang, Langston Tillman, Yibin Mao, Yuxuan Xiong, Xuan Li, Ralph R Weichselbaum, Wenbin Lin.

Aberrant glutamine metabolism undermines the efficacy of cancer radiotherapy (RT) by promoting DNA repair, increasing oxygen consumption, and imposing metabolic stress that compromises the viability and function of cytotoxic T lymphocytes (CTLs). Here, we report a mitochondria-enriched, metabolism-regulating monolayered metal-organic framework (MOF) nanoplatform, Hf-Ir/DON, constructed by incorporating the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) into a radiosensitizing hafnium-iridium (Hf-Ir) MOF to inhibit glutaminolysis. This design markedly sensitizes tumor cells to RT and, upon x-ray irradiation, enables mitochondria-targeted RT-radiodynamic therapy with substantially enhanced reactive oxygen species accumulation. The resulting oxidative stress induces extensive DNA damage, mitochondrial dysfunction, and immunogenic tumor cell pyroptosis. Concurrently, Hf-Ir/DON alleviates metabolic constraints on activated T cells, preserving CTL viability while sustaining effector and memory functions. In a murine colon cancer model, low-dose RT combined with Hf-Ir/DON achieved >95% tumor growth inhibition. Further combination with anti-PD-L1 therapy induced regression of bilateral triple-negative breast tumors and prevented lung metastasis. These results establish a radiometabolic MOF nanoplatform that potentiates RT while promoting durable antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.aeh5903
Front Immunol. 2026 ;17 1939528

Glutamine metabolic reprogramming in acute and chronic kidney diseases: mechanistic insights and therapeutic implications.

Ruotong Xu, Jin Zhao, Minna Liu, Yifan Qiao, Xiaoxuan Ning, Shiren Sun.

  Acute kidney injury (AKI) and chronic kidney disease (CKD) are common clinical disorders that have high incidence and mortality. Their pathogenesis and the mechanisms underlying AKI-to-CKD progression remain unclear. Metabolic reprogramming has emerged as a core mechanism driving the onset and progression of kidney diseases. Glutamine (Gln) metabolism, a central component of renal energy metabolism, not only maintains acid-base balance and cellular homeostasis but also actively participates in pathophysiological processes including ischemic injury, oxidative stress, inflammatory regulation and fibrosis. Multi-omics studies have revealed stage-specific alterations in Gln metabolism-associated signatures during kidney injury. In AKI, altered Gln levels and redox-related metabolites may suggest disturbances in metabolic pathways, whereas in CKD, elevated glutaminase 1 (GLS1) expression and glutaminolysis-associated metabolic reprogramming are associated with fibrosis. Gln, as an immunonutrient, also serves as a critical energy substrate to sustain the proliferation, activation, and effector functions of immune cells. Gln metabolism may reshape the immune microenvironment within the injured kidney, thereby modulating disease progression. Targeting the Gln metabolic axis may offer new therapeutic insights for AKI and CKD. However, the changes in Gln metabolism and its consequent immunometabolic effects during the AKI-to-CKD transition remain poorly understood. This narrative review aims to provide a comprehensive overview of the dynamic changes in Gln metabolism during acute and chronic kidney diseases, its stage-specific mechanisms, and its potential as a therapeutic target. We also seek to provide a theoretical basis for developing novel biomarkers and targeted therapies based on Gln metabolic reprogramming.

Keywords:  acute kidney injury; chronic kidney disease; fibrosis; glutaminase 1; glutamine metabolic reprogramming; immunometabolism; inflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1939528
Cancer Res. 2026 Oct 27.

Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.

Nathan J Coffey, Sara M Demczyszyn, Yizheng Xue, Zian Zhang, Nicolas Skuli, Nicholas P Lesner, Romain Riscal, Yanqing Jiang, Xu Han, Madeleine Carens, Morgan Brown, Laura C Kim, Brian Keith, Zoltan Arany, M Celeste Simon.

Metabolic reprogramming is a well-described hallmark of clear cell renal cell carcinoma (ccRCC). Gene copy number variation and altered gene expression data suggest enhanced branched-chain amino acid (BCAA) transamination and reduced BCAA oxidation are highly selected traits in ccRCC. Surprisingly, we found that genetic modulation of BCAA oxidation had little effect on experimental ccRCC cell growth in vitro and in vivo. In contrast, BCAA transamination in ccRCC cells was essential for the generation of glutamate-derived glutathione and cell viability when glutamine was limiting. Thus, BCAA transamination conferred resistance to states of low glutamine or treatment with the glutaminase inhibitor CB-839 by providing glutathione independent of glutamine breakdown. Targeting BCAA transamination in vitro and in vivo sensitized ccRCC to CB-839 mediated glutaminase inhibition by decreasing glutathione biosynthesis and redox homeostasis. These findings reveal that BCAA transamination maintains critical glutamate and glutathione levels in glutamine-deprived ccRCC, explaining why CB-839 treatment has been ineffective in ccRCC clinical trials and demonstrate an approach to treat ccRCC by targeting BCAA transamination to create a vulnerability to glutaminase inhibition.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0563
Circ Res. 2026 Oct 28.

Glutaminolysis Shapes Cardiac Resilience to Stress via Mitochondrial Glutathione.

Xinpei Wang, Jiaheng Zhou, Haomiao Bai, Zihan Wei, Lina Su, Changyang Xing, Guiling Wu, Min Li, Jiong An, Pengfei Zhang, Yi Zhang, Shifang Ding, Xing Zhang, Jingyi Ren, Feng Gao, Jia Li.

   BACKGROUND: Cardiac reserve is a strong predictor of cardiovascular morbidity and mortality, yet the metabolic mechanisms that enable the heart to mount an adaptive response to stress remain poorly understood. In this study, we sought to dissect the specific role of glutaminolysis, a key anaplerotic and redox-supporting pathway, in regulating cardiac reserve.
METHODS: Cardiac reserve was assessed by echocardiography under β-adrenergic stimulation in mice with cardiomyocyte-specific deletion of glutaminase and in wild-type controls. Stable isotope tracing with [U-13C] glutamine was performed in Langendorff-perfused hearts. A randomized, double-blind, placebo-controlled crossover trial of acute glutamine supplementation in healthy volunteers was conducted to evaluate translational relevance (ChiCTR2400082676).
RESULTS: During acute stress, such as exercise or β-adrenergic stimulation, glutaminolysis was rapidly mobilized to supply mitochondrial glutathione, preserving mitochondrial redox homeostasis and sustaining cardiac contractile reserve. Mice with cardiomyocyte-specific deletion of glutaminase exhibited marked impairments in both contractile reserve and exercise capacity, accompanied by a failure to elevate mitochondrial glutathione and consequent mitochondrial oxidative stress. Chronic exercise training upregulated cardiac glutaminase expression and expanded the mitochondrial glutathione pool, linking this adaptive mechanism to training-induced improvements in cardiac reserve. In humans, acute oral glutamine supplementation enhanced cardiac reserve, as assessed by exercise stress echocardiography, in a placebo-controlled crossover design.
CONCLUSIONS: These findings reveal a novel metabolic paradigm in which glutaminolysis functions as a dynamic pathway supporting mitochondrial health and cardiac resilience, and highlight glutamine supplementation as a potential therapeutic strategy to enhance cardiac reserve.

Keywords:  cardiac reserve; exercise; glutaminolysis; heart; mitochondrial GSH

DOI:  https://doi.org/10.1161/CIRCRESAHA.126.328900
Int J Mol Sci. 2026 Oct 20. pii: 9306. [Epub ahead of print]27(20):

Non-Canonical HIF2 Accumulation in Breast Cancer Cells.

Karolina Kozal, Aleksandra Opitz, Monika Jarosiewicz, Michał Juszczak, Anna Krześlak.

  Metabolic reprogramming drives cancer aggressiveness. While hypoxia-inducible factor 1 (HIF1) is commonly associated with glycolysis regulation, the under-investigated HIF2 isoform may also modulate the metabolic profile of breast cancer. We investigated the role of non-canonical HIF2 activation in metabolic adaptation to nutrient availability by culturing MDA-MB-231 and MCF-7 cells under normoxia with varying glucose and glutamine concentrations. Using RNA interference, we downregulated HIF2 and analyzed HIF isoforms and metabolic targets (GLUT1, HK2, PKM2, PDK1) at the transcriptional and protein levels. We observed a new, non-canonical accumulation of HIF2 in MDA-MB-231 cells associated with glucose and glutamine restriction, a phenomenon absent in MCF-7 cells. In MDA-MB-231 cells, silencing HIF2A under standard conditions significantly decreased PDK1 mRNA expression. At the protein level, HIF2 downregulation altered metabolic targets in a context-dependent manner under nutrient restriction. Adding a hypoxia-mimetic (CoCl2) did not fully restore the protein expression patterns, suggesting that HIF2 accumulation may contribute to these context-dependent shifts. HIF2 downregulation decreased glycolytic efficiency under low-glucose conditions. Our findings suggest that HIF2 might modulate the metabolic plasticity of MDA-MB-231 cells through distinct changes in gene expression and post-translational mechanisms. This provides support for investigating the HIF2 isoform while studying breast cancer metabolism and considering it as a potential target for treating triple-negative breast cancer.

Keywords:  Warburg effect; breast cancer; glycolytic efficiency; hypoxia-inducible factor; metabolic plasticity; metabolism

DOI:  https://doi.org/10.3390/ijms27209306
Int J Mol Sci. 2026 Oct 19. pii: 9265. [Epub ahead of print]27(20):

Modulation of the Liver-Brain Axis by Ondansetron in Thio-Acetamide-Induced Acute Hepatic Encephalopathy.

Fatih Mehmet Sari, Yasin Bilgin, Betul Cicek, Engin Kurt, Mustafa Ozkaraca, Ali Gungor, Nezahat Kurt, Asli Ozbek Bilgin.

  Hepatic encephalopathy (HE) is a severe neurological complication of liver failure characterized by hyperammonemia, oxidative stress, neuroinflammation, and progressive neuronal dysfunction. Ondansetron (OND), a selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, has reported anti-inflammatory and neuroactive properties, but its effects in HE remain poorly defined. This study evaluated OND in a thioacetamide (TAA)-induced acute HE model in female Sprague-Dawley rats. Animals were assigned to Control, TAA, OND, TAA+OND (0.5 mg/kg), and TAA+OND (1 mg/kg) groups. Serum and cerebral glutamine, oxidative and antioxidant parameters, histopathological alterations, and TLR2, NF-κB, IL-1β, GFAP, NLRP3, and caspase-1 immunoreactivity were assessed in liver and brain tissues. TAA increased glutamine accumulation, produced tissue injury, altered redox parameters, and increased several inflammation-related markers. OND significantly reduced cerebral glutamine and attenuated selected biochemical, histopathological, and immunohistochemical alterations, with generally more pronounced effects at 0.5 mg/kg. These findings indicate that OND administration is associated with partial modulation of metabolic, oxidative, inflammatory, and structural alterations in TAA-treated rats, warranting further receptor-specific and functional studies to clarify its mechanisms and therapeutic relevance.

Keywords:  glutamine metabolism; hepatic encephalopathy; liver-brain axis; neuroinflammation; ondansetron; oxidative stress

DOI:  https://doi.org/10.3390/ijms27209265
Front Mol Biosci. 2026 ;13 1959729

The amino acid transporters SLC38A3-SLC38A5-SLC38A7 as novel anti-cancer therapeutic targets.

Nektarios E Madenis, Martina Chiu, Massimiliano G Bianchi, Chiara Ughini, Mattia E Castellucchio, Ovidio Bussolati, Giuseppe Taurino.

  System N amino acid transporters SLC38A3 and SLC38A5 are carriers capable of mediating net inward or outward fluxes of substrates, such as glutamine, asparagine and histidine, coupled with Na+ symport and H+ antiport. The third member of the group, SLC38A7, principally exports glutamine and asparagine from lysosomes and its ion-coupling mechanism remains incompletely defined. Although historically less investigated than other amino acid transporters, emerging evidence reveals that System N carriers play diverse and context-dependent roles across several solid tumors and hematological malignancies. SLC38A3 can exert pro-tumor or tumor suppressive activities, displaying bidirectional transport and lineage-specific regulatory functions. SLC38A5 sustains macropinocytosis, pro-growth pathways, and antioxidant stress response conferring ferroptosis resistance. In addition, when expressed on stromal cells, it promotes amino acid exchanges within tumor microenvironment. SLC38A7 is expressed on lysosomal membranes to export proteolysis-derived amino acids and activates growth signaling. Together, evidence thus far available indicates that these transporters support metabolic plasticity, tumor progression, therapy resistance and microenvironmental remodeling in many types of cancers. This review summarizes recent advances in the comprehension of expression, regulation and functional relevance of System N transporters, highlighting their metabolic role in cancer and discussing their possible exploitation as emerging therapeutic targets.

Keywords:  amino acid transport system; asparagine; cancer; glutamine; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2026.1959729
Int J Mol Sci. 2026 Oct 15. pii: 9131. [Epub ahead of print]27(20):

Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives.

Da Ding, Jingyi Hu, Yitong Wang, Lei Jiang.

  Colorectal cancer (CRC) is one of the most prevalent malignancies of the gastrointestinal tract worldwide. Notably, most patients with microsatellite-stable (MSS) tumors show primary resistance to immune checkpoint inhibitors (ICIs), creating an unmet clinical need. The mechanisms underlying immune evasion and strategies to overcome therapeutic resistance have therefore become important topics in CRC immunology research. Recent studies indicate that mitochondrial metabolic reprogramming contributes to immune evasion in CRC. Tumor cells display metabolic plasticity through dynamic shifts between glycolysis and oxidative phosphorylation (OXPHOS), which can intensify the depletion of critical nutrients, particularly glucose and glutamine, within the tumor microenvironment (TME). These metabolic changes can also promote the accumulation of immunosuppressive metabolites, including lactate, thereby impairing the function of effector cells such as CD8+ T cells and dendritic cells (DCs) and supporting the expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Lactate may further reshape the immune landscape through hydroxycarboxylic acid receptor 1 (HCAR1) signaling and histone lactylation. In parallel, mitochondrial quality control can regulate tumor immunogenicity by influencing mtDNA availability and cGAS-STING signaling. Therapeutic approaches targeting glycolysis, glutamine metabolism, fatty acid oxidation, lactate transport, and mitochondrial dynamics have shown immune-sensitizing activity in preclinical models. Nanodelivery systems and gene-editing technologies may improve the spatial and cellular specificity of these interventions. This review summarizes how mitochondrial metabolic reprogramming contributes to immune evasion in CRC and evaluates mitochondria-directed strategies for improving treatment responsiveness, particularly in MSS CRC.

Keywords:  colorectal cancer; immune evasion; metabolic plasticity; mitochondrial metabolic reprogramming; mitochondrial quality control; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27209131
Biochim Biophys Acta Mol Basis Dis. 2026 Oct 30. pii: S0925-4439(26)00383-2. [Epub ahead of print] 168517

Glutamine deprivation elevates EFNB3 and its potential link to macropinocytosis in glioblastoma.

Bo Wang, Xuan Yao, Yuanping Su, Guo-QiangYuan, YaWen Pan.

  Glioblastoma (GBM) is the most common malignant brain tumor with a poor prognosis and prominent therapeutic resistance. l-glutamine (Gln) is crucial for cancer cell survival, and the microenvironment of GBM is often accompanied by Gln deficiency. To explore the molecular mechanisms by which GBM adapts to Gln deprivation, we performed proteomic profiling of clinical GBM tissues and established a Gln-deprived cell model. Our results showed that EFNB3 was significantly upregulated under Gln deprivation. Our data suggest a potential association between EFNB3 and Rac1-GTP, which may contribute to macropinocytosis through the Cdc42/PAK1 related signaling pathway. Knockdown of EFNB3 suppressed proliferation and macropinocytosis in GBM cells. Notably, the p38 MAPK pathway may correlate with sustained Rac1-GTP abundance and macropinocytosis, whereas blocking p38 MAPK signaling appears to attenuate Rac1-GTP levels and impair macropinocytosis without affecting EFNB3 expression. Collectively, our findings reveal a potential regulatory network involving the p38 MAPK/Rac1-GTP axis linked to EFNB3, indicating that EFNB3 may act as an important modulator of metabolic adaptation in GBM.

Keywords:  EFNB3; Glioblastoma; Glutamine deprivation; Macropinocytosis; p38 MAPK

DOI:  https://doi.org/10.1016/j.bbadis.2026.168517
Adv Healthc Mater. 2026 Oct 30. pii: e71825. [Epub ahead of print]

Measuring Blood Plasma Glutamine Levels Using a Nanopore-Based Sensor.

Sofia B Relvas, Iris M Kormelink, Sandra Michel-Souzy, Florian L R Lucas, Nieck J van der Heide, Hans R Waterham, Ramon Versteeg, Judith Jans, Loes I Segerink, Carsten Wloka.

  Measuring blood glutamine (GLN) levels is valuable for managing urea cycle disorders. Currently, patients visit the hospital to have their GLN levels checked using analytical techniques that, despite being highly accurate and reliable, lead to long waiting times and delay clinical decisions. A point-of-care device would enable patients to monitor GLN levels at home, allowing for greater control over the condition. Here, we made use of a highly sensitive GLN biosensor system based on dodecameric Cytolysin A variant AS (ClyA-AS) nanopore coupled with the GLN-specific protein, the substrate-binding domain 2 (SBD2). Measurements are performed on a single ClyA-AS nanopore embedded into an artificial lipid bilayer, where the application of a small voltage generates ionic currents that report on the binding and unbinding of GLN (added in the trans side of ClyA-AS) to SBD2 (added in cis). We demonstrate that the ClyA-AS and SBD2 biosensor pair can quantify GLN levels in patients' blood plasma. To facilitate the use of this sensor in clinical and point-of-care settings, we also developed a dedicated algorithm that accelerates signal processing and data analysis. Together, these advances represent a significant step toward a point-of-care device for GLN monitoring, both at the hospital and home-care levels.

Keywords:  OTC deficiency; biosensors; glutamine; nanopore; nanotechnology

DOI:  https://doi.org/10.1002/adhm.71825
Am J Physiol Cell Physiol. 2026 Oct 09.

Diminished nutrient supply stimulates endothelial metabolic rate turnover - impact of the cellular sex on glucose und glutamine metabolism.

Mario Lorenz, Janine Wiebach, Angelika Vietzke, Cornelia Bartsch, Verena Stangl, Karl Stangl, Wolfgang Henrich, Jennifer A Kirwan, Raphaela Fritsche.

  Endothelial cells must be able to maintain metabolic activity during angiogenesis. At impaired energy levels they have to form new blood vessels to supply the surrounding tissue with oxygen and nutrients. This requires modifications of intracellular metabolism to provide the necessary energy for migration and proliferation. Studies on metabolic adaptions of endothelial cells to diminished energy supply are sparse and investigation of potential sex differences are lacking. We therefore performed a metabolic flux analysis with 13C-glucose or 13C-glutamine labeling for different time points with female and male human umbilical vein endothelial cells (HUVECs) from dizygotic twin pairs. Labeling was performed at basal conditions and after serum starvation for an early and late time point for each labeling. Overall, a much faster label incorporation was found in serum-starved cells. Central carbon metabolites showed a significantly higher label incorporation at both early and late time points for 13C-glucose and 13C-glutamine after serum starvation, independent of the sex of the cells. However, a non-significant but consistent sex-specific pattern was observed. After labeling with 13C-glucose, a higher label incorporation was seen in male cells after serum starvation. In contrast, labeling with 13C-glutamine resulted in a faster label incorporation in female cells, both at basal conditions and after serum starvation. The observed sex differences were coherent throughout the analyzed metabolites. Although not significant and rather small, they could point to subtle sex differences in glucose versus glutamine metabolism in cellular metabolic adaptions to reduced energy supply.

Keywords:  endothelial metabolism; glucose; glutamine; serum starvation; sex differences

DOI:  https://doi.org/10.1152/ajpcell.00336.2026
Front Immunol. 2026 ;17 1961063

T-cell metabolic reprogramming in systemic lupus erythematosus: linking intracellular metabolism to effector differentiation and senescent-like/exhausted-like states.

Yi Zou, Zhichu Ren, Yuki Kudo, Michihito Kono.

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and multiorgan inflammation. T-cell metabolic reprogramming has recently emerged as an active area of investigation in the pathogenesis of SLE. This metabolic reprogramming, which involves glycolysis, mitochondrial oxidative phosphorylation, glutamine metabolism, and lipid metabolism, is associated not only with functional alterations in SLE T cells but also with changes in their differentiation and proliferation, potentially contributing to disease pathogenesis and progression. Moreover, metabolic alterations, including mitochondrial dysfunction and reactive oxygen species accumulation, in the context of persistent T-cell activation may contribute to phenotypic transitions toward senescent-like or exhausted-like states. These two partially overlapping but biologically distinct cellular phenotypes may represent divergent cellular responses to chronic inflammatory stimulation. Rather than representing mutually exclusive states or a simple loss of function, both may contribute to the perpetuation of chronic inflammation, immune imbalance and disease activity. This review summarizes recent advances in T-cell metabolic reprogramming in SLE and its potential relationship to senescent-like and exhausted-like T-cell states.

Keywords:  exhausted-like T cells; immunometabolism; metabolic reprogramming; senescent-like T cells; systemic lupus erythematosus

DOI:  https://doi.org/10.3389/fimmu.2026.1961063
Front Bioinform. 2026 ;6 1883461

Gene functions determine stochastic or adaptive futile transcription in cancers through deregulated start site deployments.

Aditi Lakshmi Satish, Praveen Kumar, Ishani Morbia, Umashankar Singh.

  Cancers display near-universal hallmarks, including energy addiction, aerobic glycolysis, and biosynthesis. In addition to glucose (and glutamine) addiction, cancers display futile transcription. Discretely measurable futile transcription occurs between transcription start sites (TSSs) and start codons of protein-coding genes. Multiple TSSs for each gene offer various combinations of futile transcription with no effect on the encoded proteins. The relationship between proximal and distal TSS deployment, futile transcription, and energy addiction of cancers remains unclear. By analyzing CAGE and PRO-cap data, we show that TSS deployment dysregulation in cancers increases the energy cost coefficients of cancer transcriptomes. We define the bases of the altered energy cost coefficients of cancer transcriptomes by comparing TSS deployment frequencies, associated entropies, and futile transcription distances across heterogeneous pools of cancers and non-cancers. We show that TSS deployment entropies differ between cancers and non-cancers. It leads to an overall higher distal TSS deployment in cancers but selectively favors an energy-economical proximal TSS deployment for cancer hallmark genes involved in cell proliferation and biosynthesis. We show that the frequency of TSS deployment is linked differently to futile transcription distance and gene function in cancers and non-cancers. This work lays out a theoretical framework describing the stochasticity of TSS deployment in the context of cancerogenesis and the energetics of transcription. It also suggests that the current human TSS landscape has evolved to minimize futile transcription, an outcome favored by stochastic TSS deployment. Under normal conditions of energy metabolism, it forms a threshold that incipient cancer cells breach.

Keywords:  TSS distance; alternative TSS; cancer; gene function; stochastic; transcriptional cost

DOI:  https://doi.org/10.3389/fbinf.2026.1883461
Pharmacol Res. 2026 Oct 24. pii: S1043-6618(26)01621-X. [Epub ahead of print]233 109706

GABARAPL1 drives therapeutic differentiation of cancer cells by targeting epigenetic changes regulated by SFPQ.

Lin Zhou, Jiawen Yang, Di Zhou, Jian Gao, Liwei Wang, Ying Huang, Guoyu Li, Xiaofeng Liu, Xiaoning Wang, Hui Ye, Peipei Xu, Qiang Xu, Yan Shen.

  Differentiation-based cancer therapy is a potentially low-toxicity approach with demonstrated clinical benefits. However, the therapeutic efficacy of differentiation therapy remains limited in tumor types other than acute promyelocytic leukemia (APL). Our previous studies reported that diptoindonesin G (Dip G), a natural compound, can induce differentiation in both acute myeloid leukemia (AML) cells and basal-like breast cancer cells. In this study, we report a crucial role of GABAA receptor-associated protein-like 1 (GABARAPL1) in driving cancer cell differentiation. By utilizing myeloid cell differentiation models and primary leukemic cells, we demonstrate that upregulation of GABARAPL1 expression was crucial for Dip G-induced differentiation and that Dip G upregulated GABARAPL1 expression by targeting nucleolin (NCL). Also, GABARAPL1 promoted differentiation independent of its autophagic function. Both pharmacological and genetic upregulation of GABARAPL1 expression effectively overcame the differentiation blockade in various tumor models, including AML cells. Mechanistically, GABARAPL1 interacted with splicing factor proline and glutamine rich (SFPQ) and recruited MDM2 to promote the degradation of SFPQ by the proteasome. Upon SFPQ depletion, the transcription of linker histone H1.2 gene was repressed, which in turn rescued the transcription of the differentiation-related pathway. Our study not only highlights the contribution of GABARAPL1 to differentiation but also provides a potential therapeutic strategy aimed at expanding the scope of application of differentiation-based cancer therapy.

Keywords:  AML; Cell differentiation; Diptoindonesin G; GABARAPL1; Histone H1.2; SFPQ

DOI:  https://doi.org/10.1016/j.phrs.2026.109706
Cancers (Basel). 2026 Oct 21. pii: 3404. [Epub ahead of print]18(20):

Prognostic Significance of Amino Acid Transporters in Endometrial Cancer.

Mikołaj Piotr Zaborowski, Łukasz Ciecierski, Piotr Tyburski, Magdalena Nadolna, Marta Brygida Szczygieł, Jędrzej Sikora, Mateusz Szot, Stefan Malewski, Marcin Iwanicki, Kinga Piątek-Bajan, Jarosław Lewandowski, Cezary Miedziarek, Michał Potograbski, Nikodem Horst, Ewa Nowak-Markwitz.

  Background: Identification of high-risk patients with endometrial cancer (EC) remains challenging despite advances in molecular profiling. Methods: We comprehensively analyzed the RNA expression of 18 amino acid transporters (AATs) in 373 EC samples from The Cancer Genome Atlas (TCGA). Results: Our clustering analysis based on AAT expression identified a patient group with a significantly worse prognosis. Sideroflexin family (SFXN1, SFXN5), glutamine (SLC38A1, SLC38A3), glycine (SLC6A9) transporters, and the heavy-chain subunit of heteromeric AATs (SLC3A2) were elevated in poorly differentiated tumors. In contrast, the transporter of small neutral amino acids (SLC1A4) and proline/imino-acid transporter (SLC6A20) were enriched in lower-grade disease. SFXN1 and SLC38A1 were also higher in advanced (III/IV) FIGO stages. AAT expression differed across molecular subtypes, with SFXN5, SLC38A1, SLC38A3, and SLC3A2 associated with the copy-number-high profile. In survival analysis, we demonstrated that SLC38A3, SFXN4, and SLC3A2 were associated with shorter disease-free survival, and SLC38A1, SLC38A3, and SFXN1 with worse overall survival, whereas SLC1A4, SLC6A20, and the taurine transporter (SLC6A6) were related to favorable outcomes. Conclusions: These findings highlight AAT expression as a potential marker of EC aggressiveness and prognosis and suggest that integrating metabolic features with molecular classification may improve risk stratification and identify potential therapeutic targets.

Keywords:  SFXN1; SLC1A4; SLC38A1; SLC38A3; endometrial carcinoma; mRNA expression; molecular subtypes; solute carrier transporters; survival analysis; the cancer genome atlas

DOI:  https://doi.org/10.3390/cancers18203404
Pharmacol Res. 2026 Oct 30. pii: S1043-6618(26)01639-7. [Epub ahead of print] 109724

Repurposing the orphan drug nitisinone synergizes with sorafenib to sensitize immunotherapy-refractory MSS-CRC via metabolic stress-driven STING activation.

Minshan Wu, Guannan Tang, Minghui Liu, Xiaoshu Wang, Yumo Xie, Yuanhui Wu, Jinxin Lin, Jingrong Weng, Xiaolin Wang, Huichuan Yu, Meijin Huang, Shaochun Yuan, Yanxin Luo, Xiaoxia Liu.

  Microsatellite-stable colorectal cancer (MSS-CRC) remains broadly refractory to immune checkpoint blockade, underscoring the need for strategies that convert immunologically "cold" tumors into therapy-responsive states. Here, we identify 4-hydroxyphenylpyruvate dioxygenase (HPD), the rate-limiting enzyme in tyrosine catabolism, as a modulator of sorafenib sensitivity in MSS-CRC. Pharmacological inhibition of HPD by the FDA-approved orphan drug nitisinone synergized with sorafenib across patient-derived organoids, human PBMC-tumor co-cultures, and immunocompetent orthotopic models. Mechanistically, nitisinone imposes strict glutaminolysis dependency, whereas sorafenib disrupts cRaf-MEK-ERK signaling to trigger proteasomal cMYC degradation and transcriptional repression of GLS1, thereby ablating compensatory glutamine anaplerosis. This dual metabolic blockade creates a synthetic lethal trap, provoking irreversible mitochondrial collapse and mtDNA release, which activates the cGAS-STING pathway and drives intratumoral infiltration of cytotoxic NK and CD8+ T cells. Critically, ρ⁰ cells and STING-deficient models confirm mitochondrial damage as the "trigger" of cell death and STING as the "amplifier" of antitumor immunity. In TCGA MSS-CRC cohorts, a double-low glutamine/tyrosine metabolic signature was associated with prolonged survival, enhanced cGAS-STING signaling, and immune-hot tumor features, findings corroborated by single-cell RNA-seq analyses. Finally, the triple combination of nitisinone, sorafenib, and anti-PD-1 therapy achieved superior antitumor efficacy with favorable tolerability in vivo. Collectively, our findings delineate a metabolic-mitochondrial-STING axis and support repurposing nitisinone as a promising translational strategy to sensitize MSS-CRC to immunotherapy.

Keywords:  Orphan drug nitisinone; Sorafenib; cGAS-STING; immunotherapy; microsatellite-stable colorectal cancer (MSS CRC)

DOI:  https://doi.org/10.1016/j.phrs.2026.109724