bims-glucam 2026-05-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–05–24
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.
Mycobacterium tuberculosis reinforces M2 polarization of macrophages by activating glutamine metabolism.
ALDH18A1 regulates glutamine metabolism and tumor microenvironment in the attenuation of clear cell renal cell carcinoma.
Potentiated Tumor Photo-immunotherapy Based on Glutamine Starvation and Interferon Stimulatory DNA-Activated cGAS-STING Pathway.
Explore the Heterogeneity of Glioblastoma Based on Genes Related to Glutamine Metabolism.
TP53 mutations in triple-negative breast cancer cells confer sensitivity to ASCT2 inhibition via arginine uptake.
Introduction to Cancer Metabolism.
Taurine and glutamine supplementation in aging: systemic mechanisms, exercise interactions, and modulation of muscular and neurobiological pathways.
Metabolic Reprogramming in Cancer Stem Cells.
Glutamine-dependent downregulation of FLT3-ITD is a mechanism of FLT3 inhibitor resistance in FLT3-ITD AML in hypoxia.
Metabolic crosstalk in the bladder tumor microenvironment: lactate shuttling, amino acid dependency, and immunosuppression.
Targeting Metabolism in Cancer Therapy: Inhibitors and Approaches.
Metabolotheranostics of pancreatic cancer by targeting choline, glutamine, and glucose transporters with photoimmunotherapy.
Atomic elementary flux modes explain the steady state flow of metabolites in large-scale flux networks.
ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.
Checkpoint kinase 2 coordinates autophagy activation and Aurora kinase A degradation to regulate primary cilia for cell invasion.
Nutrition and pharmacologic support to address metabolic demands following trauma: a narrative review.
The Glutamate-Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers.
Conserved principles of central carbon partitioning in Hippo-Yorkie-driven Drosophila gut tumors.
xCT (Slc7a11) Regulation: Lessons from Cancer Research.

Cancer Treat Res. 2026 ;195 45-78

Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.

Aganta Chakraborty, Sanket Pramanik, Shrabasti Mullick, Rajarshi Nath, Mohini Mondal, Radheshyam Pal, Sumel Ashique, Mayukh Jana.

  Glutamine is crucial for cancer cell proliferation and survival because it fuels the TCA cycle, provides building blocks for macromolecules, and helps maintain redox balance by supporting antioxidant pathways like glutathione production. Cancer cells often become dependent on glutamine, a phenomenon known as glutaminolysis, and use it to produce energy and essential molecules for rapid growth. This metabolic addiction makes glutamine metabolism a significant target for cancer therapies. In recent years, some therapeutic drugs targeting glutamine metabolism to treat cancer have been developed. However, such drugs are not sufficiently effective. Targeting metabolic reprogramming may be an effective strategy to enhance cancer treatment efficacy. Glutamine serves as a vital nutrient for cancer cells. Inhibiting glutamine metabolism has shown promise in preventing tumor growth both in vivo and in vitro through various mechanisms.

Keywords:  Cancer microenvironment; Glutamine metabolism; Redox balance; Signaling pathways; TCA cycle; Therapeutic targets; Tumor proliferation

DOI:  https://doi.org/10.1007/978-3-032-21861-2_3
Braz J Microbiol. 2026 May 18. pii: 146. [Epub ahead of print]57(1):

Mycobacterium tuberculosis reinforces M2 polarization of macrophages by activating glutamine metabolism.

Yijuan Yu, Liqin Lai, Songtao Yu, Weili Lu, Hong Yang.

   BACKGROUND: Tuberculosis, a predominant health issue worldwide caused by Mycobacterium tuberculosis (Mtb), is refractory due to drug resistance. This study aims to explore whether Mtb reinforces M2 polarization of macrophages by modulating glutamine metabolism, thereby offering novel perspectives into its pathogenic mechanisms and potential therapeutic targets.
METHODS: This research established an in vivo model of C57BL/6 mice infected with Mtb H37Rv, and an in vitro infection model based on RAW264.7 macrophages. The expression of M2 polarization markers and activation of the key signaling molecule STAT6 were detected via flow cytometry, immunohistochemistry, RT-qPCR, Western blot (WB), and ELISA. The levels and activity of key enzymes in glutamine metabolism were evaluated by WB and enzyme activity assays, respectively. Furthermore, intervention experiments utilizing the glutamine metabolism inhibitor BPTES were conducted to validate the function of glutamine metabolism in Mtb-induced M2 polarization.
RESULTS: In vivo assay revealed that Mtb infection markedly promoted M2 polarization of macrophages in murine lung tissues. Flow cytometry detected an increased proportion of CD206 + macrophages, and immunohistochemical staining further confirmed elevated expression of the M2 markers Arg1 and Ym-1. In vitro experiments further confirmed that Mtb infection induced macrophage transition to the M2 phenotype and activated the glutamine metabolism pathway. Critically, the glutamine metabolism inhibitor BPTES substantially reversed Mtb-induced M2 polarization of macrophages, as evidenced by suppressed levels of M2 markers' expression and STAT6 phosphorylation. These results confirmed that glutamine metabolism was a key driver of Mtb-induced M2 macrophage polarization.
CONCLUSION: This study demonstrates that Mtb drives the polarization of host macrophages toward an M2 phenotype favorable for pathogen survival by activating the host glutamine metabolic pathway, revealing a novel mechanism by which pathogens exploit host metabolism to achieve immune evasion.

Keywords:   Mycobacterium tuberculosis ; Drug-resistant tuberculosis; Glutamine metabolism; Macrophages

DOI:  https://doi.org/10.1007/s42770-026-01960-6
Cancer Cell Int. 2026 May 22.

ALDH18A1 regulates glutamine metabolism and tumor microenvironment in the attenuation of clear cell renal cell carcinoma.

Yang Fu, Xuzhong Liu, Qing Sun, Zhiwang Tang, Zongyuan Xu, Kun Liu.

   OBJECTIVES: To assess the potential role of glutamine metabolism-related genes (GMRGs) in the progression, prognosis, and immune microenvironment of clear cell renal cell carcinoma (ccRCC).
METHODS: Publicly available single-cell RNA sequencing dataset was obtained, and differential gene expression analysis across tumors were performed. A cross scale disease driver gene validation chain and spatial transcriptome analysis with glutamine metabolism was further analyzed. 17 gene sets (M10295) correlated with glutamine metabolism were derived. The prognostic model of ccRCC constructed according to the differentially expressed GMRGs (DEGMRGs). GO and KEGG data were applied and the "GSVA" R package was used to analyze the characteristics of immune cells infiltration. In vitro validation study was performed in various RCC cell lines. Two shRNA plasmids were independently transfected into cells and examined by Transwell migration assay, proliferation assays and colony information tests. Glutamine levels and its related metabolism genes were also detected.
RESULTS: ALDH18A1 may serve as a tumor-specific glutamine metabolic marker in epithelial-derived malignancies, and spatial transcriptome analysis reveals enhanced glutamine metabolic activity in the tumor boundary region. The DEGMRGs-based prognostic model tailored for ccRCC delineated a stark contrast in the prognosis of high-risk group and low-risk group. Patients exhibiting high ALDH18A1 TPM demonstrating poorer prognosis compared to those with low levels. The in vitro study validated the high expression of ALDH18A1 in RCC cell lines. ALDH18A1 could significantly inhibit the proliferation and migration of RCC cells, suppress the glutamine metabolism in RCC cells. Additionally, subcutaneous tumor experiments in mice further confirmed the oncogenic-promoting effects of ALDH18A1 on RCC with the crosstalk of M2 macrophages.
CONCLUSIONS: ALDH18A1 could serve as a crucial role in precise classification, treatment response, and prognosis of patients with ccRCC by suppressing the proliferation and glutamine metabolisms in tumor cells and constructing tumor microenvironment.

Keywords:  ALDH18A1; Glutamine metabolism; Single-cell RNA sequencing; Tumor microenvironment; ccRCC

DOI:  https://doi.org/10.1186/s12935-026-04343-x
ACS Med Chem Lett. 2026 May 14. 17(5): 1138-1144

Potentiated Tumor Photo-immunotherapy Based on Glutamine Starvation and Interferon Stimulatory DNA-Activated cGAS-STING Pathway.

Jinwen Zhu, Zhenzhen Guo, Renpeng Xia, Peng Miao.

  Photo-immunotherapy combines phototherapy and immunotherapy, which can eliminate primary tumors and induce host immunity to control distant metastases. However, the effectiveness may be attenuated by the tumor defense mechanisms associated with glutamine metabolism regulation. In this work, a self-assembled stimulator was prepared for glutamine-starvation-potentiated photo-immunotherapy, which is composed of telaglenastat as the glutaminase inhibitor, chlorin e6 (Ce6) as the photosensitizer, and interferon stimulatory DNA (ISD). Ce6 transfers energy from light to molecular oxygen, generating reactive oxygen species (ROS). Telaglenastat assists in the downregulation of endogenous glutathione. Thus, ROS neutralization can be prevented, and the photodynamic therapy effect is enhanced. Additionally, the cGAS-STING signaling pathway activated by ISD remodels the tumor microenvironment by polarizing M2-type tumor-associated macrophages into M1, which finally enhances immunogenic cell death. The prepared nanomedicine combines glutamine starvation and a photo-immunotherapy strategy, offering new insights into cancer treatment.

Keywords:  Glutaminase inhibitor; Photodynamic therapy; Reactive oxygen species; Synergistic effect; cGAS-STING

DOI:  https://doi.org/10.1021/acsmedchemlett.6c00074
Cancer Inform. 2026 ;25 11769351261449032

Explore the Heterogeneity of Glioblastoma Based on Genes Related to Glutamine Metabolism.

Ling Wang, Tong Chen, Jiajia Chen, Yiwen Yang, Linglin Sun, Chao Gu, Chenliang Cao.

   Objectives: To establish a glutamine metabolism (GM)-based classification for glioblastoma (GBM) and evaluate its prognostic and immunotherapeutic implications.
Methods: A total of 237 GBM patients from the Chinese Glioma Genome Atlas (CGGA) database were included as the training set, and 219 patients from the Gene Expression Omnibus (GEO) database served as the validation set. Consensus clustering was performed based on the expression profiles of 13 GM-associated genes to identify robust subgroups. Differences between clusters were analyzed using clinical indices, genomic and transcriptomic biomarkers. Tumor response to immune checkpoint inhibitors (ICIs) was predicted using the tumor immune dysfunction and exclusion (TIDE) algorithm, tumor microenvironment (TME) score, T cell inflammation score, and SubMap algorithm. A GM-based classifier was subsequently developed and validated.
Results: Consensus clustering of the training set revealed 2 distinct subgroups (cluster 1 and cluster 2) with significant prognostic differences; cluster 2 exhibited poorer overall survival. Immunotherapy response prediction indicated that cluster 2 had a lower likelihood of benefiting from ICIs. The newly developed GM-based classifier demonstrated high accuracy (AUC > 0.9) and maintained strong consistency with the original clustering in terms of subtype classification and immunotherapy prediction across both datasets.
Conclusion: This study establishes a robust classification system for GBM based on glutamine metabolism-related genes, which effectively stratifies patients into prognostic subgroups and predicts immunotherapy response. The GM-based classifier offers a valuable tool for guiding clinical prognosis and treatment decisions in GBM.

Keywords:  classification; classifier; glioblastoma; glutamine metabolism; heterogeneity

DOI:  https://doi.org/10.1177/11769351261449032
Cell Death Dis. 2026 May 21.

TP53 mutations in triple-negative breast cancer cells confer sensitivity to ASCT2 inhibition via arginine uptake.

Xiaodan Lyu, Yuancheng Wei, Ziyi Chen, Qianlin Zou, Jia Wang, Yi Han, Chenxi Xu, Haolin Hu, Zizhang Zhou, Shengtao Yuan, Mei Yang, Li Sun.

Targeting dysregulated glutamine metabolism via ASCT2 inhibition has therapeutic potential in cancer, but its clinical translation is hindered by tumor metabolic heterogeneity and the lack of predictive biomarkers. This study aims to define genetic determinants of ASCT2 inhibitor sensitivity and uncover compensatory resistance mechanisms to enable precision therapeutic strategies. We systematically evaluated ASCT2 inhibitor responses across molecular subtypes of breast cancer via in vitro and in vivo models. Mechanistic studies integrated transcriptomics, metabolomics, and functional validation of candidate pathways. Using genetic and pharmacological tools, including TP53 isogenic lines and ASCT2 inhibitors, we mapped the metabolic compensation networks. This approach revealed that TP53-mutant triple-negative carcinomas were more sensitive to ASCT2 monotherapy than any other subtype. In TP53 wild-type tumors, ASCT2 inhibition triggered SLC7A3-mediated arginine uptake, destabilizing the CASTOR1-GATOR2 complex to sustain mTORC1-driven proliferation. Cotargeting ASCT2 and SLC7A3 overcame resistance in TP53 wild-type models, inducing metabolic collapse and tumor reduction. This work establishes the TP53 mutational status as a potential predictive biomarker for ASCT2 inhibitor responsiveness and defines the SLC7A3-arginine-mTORC1 axis as a targetable compensatory pathway. Therefore, we propose a genotype-guided therapeutic strategy, recommending ASCT2 monotherapy for TP53-mutant tumors and combined ASCT2 and SLC7A3 inhibition for TP53 wild-type cancers. These findings advance precision in targeting glutamine metabolism while providing a blueprint to counter adaptive resistance through rational drug combinations.

DOI: https://doi.org/10.1038/s41419-026-08814-x
Cancer Treat Res. 2026 ;195 1-20

Introduction to Cancer Metabolism.

Gomathi Mohan, Mukesh Meena, Manzer H Siddiqui, Gaurav Raturi, Pracheta Janmeda, Priya Chaudhary.

  The fact that tumor cells have a distinct metabolic phenotype from their normal equivalents is becoming more widely recognized. Tumor metabolism exhibits a complex ecological network due to the presence of multiple metabolic compartments interconnected through the transfer of catabolites. Tumor cells exhibit markedly elevated rates of metabolism for fatty acids, glutamine, acetate, hydroxybutyrate, pyruvate, lactate, and glucose compared to nontumor cells. Tumor cells can generate adenosine triphosphate (ATP) as the fundamental energy unit due to their metabolic flexibility and unpredictability, which aids in maintaining the redox balance and distributing resources to essential biosynthetic activities necessary for cell proliferation, growth, and survival. Experimental data indicate that cancer growth may be induced by metabolic cross talk between cell populations exhibiting distinct, synergistic metabolic characteristics. Thus, emphasizing the metabolic variations between tumor and normal cells presents a suitable approach for anticancer strategies. Cancer cells adapt their metabolism and influence the metabolic processes of surrounding cells within the microenvironment of the tumor to ensure their proliferation and survival. This process drives disease progression; specifically, we identify targetable metabolic weaknesses that can be intervened upon.

Keywords:  ATP; Cancer cells; Disease progression; Metabolic cross talk; Tumor metabolism

DOI:  https://doi.org/10.1007/978-3-032-21861-2_1
Front Physiol. 2026 ;17 1809107

Taurine and glutamine supplementation in aging: systemic mechanisms, exercise interactions, and modulation of muscular and neurobiological pathways.

Zhigang Chen, Zhiwei Niu.

  The senescence of the neuro-skeletal muscle system is typified by a gradual deterioration in muscle mass, strength, neuromuscular efficacy, and cognitive capabilities, which is further exacerbated by metabolic dysregulation and heightened vulnerability to fatigue. The identification of efficacious strategies aimed at reversing or mitigating these deficits is paramount for the promotion of healthy aging. Taurine, glutamine, and physical exercise emerge as promising modulators of cellular homeostasis, exhibiting synergistic potential to address multiple pathways implicated in age-associated decline. This review amalgamates mechanistic insights into the effects of taurine and glutamine supplementation, in conjunction with exercise regimens, on protein metabolism, mitochondrial functionality, muscle fatigue biomarkers, neuroinflammation, redox equilibrium, and body composition throughout the aging process. We examine the role of taurine in preserving calcium homeostasis, enhancing mitochondrial stability, and mitigating oxidative stress; the function of glutamine in sustaining nitrogen balance, regulating immune responses, and facilitating energy metabolism; and the ability of exercise to stimulate critical signaling cascades and antioxidant networks. The integration of taurine and glutamine supplementation with systematically designed exercise regimens may yield a holistic, multi-faceted strategy for counteracting neuro-skeletal muscle aging and augmenting overall functional capacity in the elderly population.

Keywords:  aging; exercise; glutamine; protein metabolism; taurine

DOI:  https://doi.org/10.3389/fphys.2026.1809107
Cancer Treat Res. 2026 ;195 155-174

Metabolic Reprogramming in Cancer Stem Cells.

Gaurav Ranjan, Srijani Dasgupta, Uttam Kumar Mishra, Priyashree Sunita, Shakti Prasad Pattanayak.

  Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal, differentiation potential, and resistance to conventional therapies. One of the characteristic traits of CSCs is their metabolic flexibility, with the ability to adapt energy production and biosynthesis in the context of low oxygen, limited nutrients, and therapy-driven stress. This adaptability allows them to survive, advances tumor development, and results in relapse after treatment.CSCs can switch between glycolysis and oxidative phosphorylation (OXPHOS) dynamically in different biological contexts. CSCs mainly produce ATP and synthesize nucleotides, amino acids, and lipids through glycolysis in hypoxia. OXPHOS is important for the maintenance of quiescent cells, for reducing reactive oxygen species (ROS) production, and supports long-term survival and tumor initiation. In addition to glucose, CSCs utilize lipid and amino acid metabolism. Fatty acid oxidation provides energy during stress, while glutamine, serine, and glycine support biosynthesis, redox homeostasis, and epigenetic control, collectively enhancing survival and therapy resistance. CSCs also rely on lipid and amino acid metabolism, in addition to glucose. Fatty acid oxidation is a source of energy during stress, and glutamine-, serine-, and glycine-derived metabolic products contribute to promoting biosynthesis for redox homeostasis, epigenetic regulation, and survival/therapy resistance. The tumor microenvironment (TME) dictates CSCs' metabolism through cross talk with fibroblasts, immune cells, and components of the extracellular matrix. Metabolic interplay, e.g., reverse Warburg effect, allows CSC to consume stromal metabolites, facilitating the promotion of tumor and resistance to therapy. Targeting of CSC metabolism, via glycolytic and mitochondrial inhibitors, lipid metabolism originated blockers, or amino acids modulators can perturb the survival of CSCs and increase tumor sensitivity to classical therapies. In this aspect, the application of combinatorial therapy was able to provide additional benefit by addressing both proliferative and quiescent CSC.In conclusion, metabolic reprogramming underpins CSC survival, drives therapy resistance, and promotes tumor progression. Exploiting these metabolic adaptations provides a promising strategy for achieving long-lasting and effective cancer therapies.

Keywords:  Cancer stem cells; Glycolysis; Metabolic reprogramming; Metabolic targeting; Reverse Warburg effect; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-3-032-21861-2_8
bioRxiv. 2026 May 15. pii: 2026.05.02.722336. [Epub ahead of print]

Glutamine-dependent downregulation of FLT3-ITD is a mechanism of FLT3 inhibitor resistance in FLT3-ITD AML in hypoxia.

Giovannino Silvestri, Aditi Chatterjee, Blair P Rendina, Eli E Bar, Maria R Baer.

FLT3 inhibitors have improved outcomes in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), but responses are not durable. Notably, FLT3 inhibitors clear blasts from the blood, but not the bone marrow, a hypoxic niche. We investigated effects of hypoxia and the key nutrient glutamine on FLT3 inhibitor response. FLT3-ITD AML cell lines and patient blasts were cultured with FLT3 inhibitors under normoxia (21%) or hypoxia (<1% O₂) with or without glutamine or the glutaminase inhibitor telaglenastat (CB-839). Cytotoxicity was measured in WST-1 assays and drug combination effects by Chou-Talalay analysis. Protein expression was measured by immunoblotting, turnover and proteasomal degradation by cycloheximide chase with and without MG-132, and mRNA expression by RT-qPCR. Effect of the ubiquitin ligase c-CBL was tested by siRNA knockdown. FLT3 inhibitor IC₅₀s were 3-5-fold higher in hypoxia than normoxia, associated with FLT3-ITD and p-STAT5 downregulation and accelerated FLT3-ITD proteasomal degradation (half-life, 1.0 vs. 2.5 hours). c-CBL expression increased in hypoxia, and c-CBL knockdown restored FLT3-ITD expression and FLT3 inhibitor sensitivity. Glutamine deprivation or telaglenastat treatment abrogated c-CBL upregulation in hypoxia and preserved FLT3-ITD and p-STAT5 expression and FLT3 inhibitor sensitivity. Telaglenastat synergized with FLT3 inhibitors in hypoxia, supporting clinical testing.

DOI: https://doi.org/10.64898/2026.05.02.722336
Cytotechnology. 2026 Jun;78(3): 115

Metabolic crosstalk in the bladder tumor microenvironment: lactate shuttling, amino acid dependency, and immunosuppression.

Huaiquan Lu, Jing He, Hua Wang, Weiping Li, Pengcheng Chang, Wenhui Li.

  The bladder tumor microenvironment is a complex ecosystem composed of tumor cells, stromal cells, immune cells, and the extracellular matrix. Metabolic reprogramming and intercellular metabolic crosstalk within this microenvironment play a central role in tumor progression and immune evasion. This review systematically elucidates the three-dimensional interaction network among lactate shuttling, amino acid dependency, and immune checkpoint regulation in the bladder cancer microenvironment. It untangles how metabolites such as lactate, tryptophan, and glutamine directly suppress effector T-cell function and promote the activation of immunosuppressive cells, including regulatory T cells and tumor-associated macrophages, through mechanisms involving nutrient deprivation, signal transduction, and epigenetic modifications. Studies have revealed that lactate, transported via the MCT1/MCT4/CD147 complex, establishes a lactate-glutamine metabolic cycle between tumor and stromal cells. This cycle not only supports tumor proliferation but also significantly inhibits the immune response by acidifying the microenvironment and activating key signaling pathways. Concurrently, metabolic imbalances of amino acids such as arginine, cysteine, and serine contribute to immune cell dysfunction and synergize with the expression of immune checkpoint molecules to reinforce an immunosuppressive state. Clinical data indicate that metabolism-related biomarkers, including high MCT4 expression and elevated urinary lactate concentration, are closely associated with poor prognosis and resistance to immunotherapy. Furthermore, bladder cancers of different molecular subtypes and stages exhibit significant metabolic heterogeneity, underscoring the need to develop precise metabolic intervention strategies. Future research should integrate single-cell multi-omics and spatial metabolomics technologies to construct high-resolution microenvironmental maps, develop non-invasive monitoring systems based on metabolic biomarkers, and promote the clinical translation of combination treatment plans targeting metabolic crosstalk. These efforts will provide new avenues for achieving precise and personalized therapy for bladder cancer.

Keywords:  Tumor Microenvironment; Bladder tumor; Metabolic crosstalk

DOI:  https://doi.org/10.1007/s10616-026-00988-8
Cancer Treat Res. 2026 ;195 175-191

Targeting Metabolism in Cancer Therapy: Inhibitors and Approaches.

Bhabani Shankar Nayak, Bangmayee Dash, Sisir Nandi, Nebojša Pavlović, Mohamed Dkhi.

  Cancer cells show different abnormal metabolic pathways that promote their development and viability. A novel therapeutic strategy has emerged for the treatment of cancer by inhibiting major metabolic pathways, such as the glycolysis pathway, pentose phosphate pathway (PPP), fatty acid synthesis, glutaminase inhibitors, and metabolism associated with mitochondrial pathways. Metabolic reprogramming supports the formation of tumors and metabolic liabilities, which are used to treat various cancers. Metabolic research on cancer metabolism was based on Otto Warburg's research work, which is related to aerobic glycolysis. In combination with chemotherapies, the reprogramming of cancer metabolism has been efficacious in treating neoplastic cells. The success of the novel treatment demonstrates an emerging therapeutic approach towards cancer and its management, some of which are being examined in preclinical models. A number of metabolic molecules have been used to target the progression of preclinical observation, which are associated with nucleic acid synthesis and other major biochemical processes. With the advancement of multi-omics, single-cell, and other spatial technologies, we can easily track metabolism more accurately.

Keywords:  Cancer metabolism; Glutaminase inhibitors; Glycolytic inhibitors; Mitochondrial inhibitors; PPP inhibitors

DOI:  https://doi.org/10.1007/978-3-032-21861-2_9
Npj Imaging. 2026 May 21.

Metabolotheranostics of pancreatic cancer by targeting choline, glutamine, and glucose transporters with photoimmunotherapy.

Puneet Khandelwal, Jiefu Jin, James D Barnett, Yelena Mironchik, Balaji Krishnamachary, Saleem Yousf, Raj Kumar Sharma, Hisataka Kobayashi, Zaver M Bhujwalla.

Altered choline, glutamine, and glucose metabolism form a triumvirate of metabolic reprogramming in most cancers that significantly influences growth, progression, and response to treatment. Photoimmunotherapy (PIT) is a highly target-specific treatment where a targeting antibody (Ab) is conjugated to a photosensitizing dye, IR700, that damages the target only when exposed to near-infrared (NIR) light irradiation. The requirement of an extracellular target has restricted PIT targeting to cell surface receptors and antigens. Here, for the first time, we exploited the extracellular domain of three metabolic transporters, CTL1 for choline, ASCT2 for glutamine, and GLUT1 for glucose for PIT, to demonstrate metabolotheranostics of cancer cells. We analyzed the TCGA database to establish increased expression of the three transporters in human pancreatic ductal adenocarcinoma (PDAC). For the PIT studies, we used two patient-derived PDAC cell lines selected for differences in transporter expression and demonstrated an expression-dependent reduction of cell viability following PIT. A single CTL1-PIT treatment of Pa04C tumors resulted in the eradication of four out of five established tumors. In PDAC, the PIT of metabolic transporters would be most effective in the intraoperative setting, where it could significantly impact cancer cells that may have invaded critical structures.

DOI: https://doi.org/10.1038/s44303-026-00175-6
Cell Rep Methods. 2026 May 22. pii: S2667-2375(26)00162-1. [Epub ahead of print] 101462

Atomic elementary flux modes explain the steady state flow of metabolites in large-scale flux networks.

Justin G Chitpin, Theodore J Perkins.

  Steady state fluxes are a measure of cellular activity under homeostatic conditions, but understanding how individual substrates are metabolized remains a challenge in large-scale networks. Pathway-based approaches such as elementary flux mode (EFM) analysis are limited to small networks due to the combinatorial explosion of pathways and ambiguity of decomposing fluxes onto EFMs. Here, we present an alternative approach explaining metabolic fluxes in terms of the steady state flow of their atomic constituents. We refer to these pathways as atomic elementary flux modes (AEFMs) and show that computations involving AEFMs are orders of magnitude faster than standard EFMs. Using our approach, we enumerate carbon and nitrogen AEFMs in five genome-scale metabolic models and compute the AEFM decomposition of fluxes estimated in a HepG2 liver cancer cell line. Our results systematically characterize carbon and nitrogen remodeling and, on the HepG2 network, predict glutamine metabolism through a recently discovered non-canonical tricarboxylic acid (TCA) cycle.

Keywords:  CP: computational biology; CP: metabolism; Markov chain; elementary flux mode; flow decomposition; flux network; metabolic pathway; steady state flux

DOI:  https://doi.org/10.1016/j.crmeth.2026.101462
Biomed Pharmacother. 2026 May 20. pii: S0753-3322(26)00523-8. [Epub ahead of print]200 119487

ER-phagy drives resistance to mitochondria-targeted therapy in breast cancer.

Aleksandra Bogucka, Daria Korewo-Labelle, Mariola Gimła, Elwira Smolińska-Fijołek, Anna Herman-Antosiewicz, Natalia Sowa-Rogozińska, Krzysztof Urbanowicz, Agnieszka Pyrczak-Felczykowska.

  Endoplasmic reticulum stress and ER-phagy are emerging regulators of cancer cell adaptation to metabolic and oxidative stress, yet their integration with mitochondrial dysfunction remains poorly understood. Here, we identify ER-phagy as a previously unrecognized adaptive response to ISOXUS, an isoxazole derivative of usnic acid with selective anticancer activity. ISOXUS, a mitochondrial respiratory complex II inhibitor, induces bioenergetic collapse, reactive oxygen species accumulation, and extensive ER-derived vacuolization. Using integrated transcriptomic and metabolomic analyses, we demonstrate that ISOXUS selectively triggers ER-phagy in mitochondria-dependent MCF-7 breast cancer cells, but not in more glycolytic triple-negative MDA-MB-231 cells, revealing a cell-type-specific stress adaptation program. ER-phagy induction is associated with upregulation of the ER-phagy receptor FAM134B and depends on ER stress signalling, as pharmacological ER stress inhibition suppresses this process. Multi-omics profiling uncovers coordinated repression of mitochondrial gene expression together with activation of ER-centered metabolic pathways, including amino acid metabolism, the tricarboxylic acid cycle, and one-carbon folate metabolism. Notably, we also identify UFMylation-related genes (CDK5RAP3, DDRGK1) as novel candidates involved in ER-phagy induced by ISOXUS. Moreover, mitochondrial inhibitors, rotenone and oligomycin, unexpectedly promote, while antioxidant a-tocopherol blocks ISOXUS-induced ER-phagy, and all compounds partially improve cell viability under ISOXUS treatment, implicating ROS-driven ER-phagy as a cytoprotective mechanism. Integrated analyses further reveal activation of the integrated stress response (ISR), dominated by the PERK-ATF4 axis, driving glutamine-dependent metabolic reprogramming and suppression of apoptosis-related pathways. The late-stage autophagy inhibition lowered the glutathione synthesis after ISOXUS treatment. Collectively, our findings uncover a previously unappreciated mitochondria-ER-ISR axis that governs metabolic adaptation to ISOXUS and identifies ER-phagy as a potential therapeutic vulnerability in breast cancer.

Keywords:  Breast cancer; Cancer resistance; ER stress; ER-phagy; ISOXUS; Integrated Stress Response; Metabolic adaptation; Mitochondrial complex II inhibition; Usnic acid derivative

DOI:  https://doi.org/10.1016/j.biopha.2026.119487
Cell Commun Signal. 2026 May 22.

Checkpoint kinase 2 coordinates autophagy activation and Aurora kinase A degradation to regulate primary cilia for cell invasion.

Chia-Yih Wang, Yu-Ying Chao, Ting-Yu Chen, Ruei-Ci Lin, Hui-Man Tsai, Hsiao-Han Huang, Zi-Rong Chen, Fu-I Lu, Yu-Chi Su, Bon-Chu Chung.

   BACKGROUND: Checkpoint kinase 2 (CHEK2) is a tumor suppressor that safeguards genome integrity in the nucleus. It is also localized at the mother centriole. But the role of CHEK2 in this structure remains unclear. The primary cilium acts as a sensory organelle that regulates various aspects of cell behavior. However, the connection between CHEK2 and primary cilia has not been elucidated.
METHODS: We investigated the role of CHEK2 in primary cilia regulation using both cultured cells and a zebrafish model. Pharmacological inhibition and genetic manipulation of CHEK2 were employed across systems, and rescue experiments were performed to validate the specificity of the findings. The primary cilia were observed using fluorescence or electron microscopy.
RESULTS: Here, we demonstrated that in response to nutrient deprivation, CHEK2 became activated to maintain primary cilia in both in vitro and in vivo loss-of-function and rescue studies. We found that CHEK2 maintained primary cilia by destabilizing Aurora Kinase A to prevent axoneme degradation and by activating AMPK to promote autophagy. Both pathways were essential for trophoblast ciliation, migration, and invasion. Moreover, in pancreatic ductal adenocarcinoma cells, glutamine deprivation activated CHEK2, which in turn coordinated autophagy induction and Aurora A degradation to sustain primary cilia and enhance invasive ability.
CONCLUSIONS: In summary, our study uncovers a novel role of CHEK2 in mediating cell invasion under metabolic stress by promoting autophagy and stabilizing axoneme to maintain primary cilia.

Keywords:  Aurora A; Autophagy; Axoneme; Nutrient deprivation; Pancreatic cancer; Trophoblast invasion

DOI:  https://doi.org/10.1186/s12964-026-02953-6
JPEN J Parenter Enteral Nutr. 2026 May 19.

Nutrition and pharmacologic support to address metabolic demands following trauma: a narrative review.

Megan A Ralfe, Andrew B Schneider, Lauren Raff, Linda E Sousse.

  Severe traumatic injury triggers a profound hypermetabolic and hypercatabolic response, marked by increased resting energy expenditure, accelerated protein breakdown, muscle wasting, and heightened risk of malnutrition, infection, and mortality. Timely and targeted nutritional intervention is therefore essential to support immune function, promote wound healing, and facilitate recovery. Herein, we examine the metabolic demands of patients with severe trauma and synthesize current clinical guidelines and evidence-based strategies for nutritional management. This review outlines the neuroendocrine, inflammatory, and metabolic mechanisms that drive hypercatabolism following major trauma. It evaluates methods for estimating energy expenditure and their limitations, and discusses recommended caloric and protein targets, as well as timing of initiation and preferred routes of nutritional support. Additionally, our review examines the evidence for adjunctive immunonutrition, including supplementation of glutamine, omega-3 fatty acids, arginine, and ghrelin. In summary, early and individualized nutritional therapy is critical to mitigating hypercatabolism and improving clinical outcomes in trauma patients. Although foundational guidelines have been established, high-quality randomized controlled trials remain necessary to better define the role of specific immunonutrients across diverse trauma populations.

Keywords:  enteral formulas, nutrition; enteral nutrition, nutrition; nutrition assessment, nutrition; parenteral nutrition, nutrition; trauma, research and diseases

DOI:  https://doi.org/10.1002/jpen.70108
Redox Biol. 2026 May 15. pii: S2213-2317(26)00213-2. [Epub ahead of print]94 104215

The Glutamate-Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers.

Rui Wang, Yanfei Li, Dafa Shi, Hongying Huang, Zhongruowen Ren, Yuxi Ge, Yongmin Chang, Gen Yan.

  Glutamate is the most abundant excitatory neurotransmitter in the central nervous system and a key non-essential amino acid in the body. It plays a central role in maintaining the excitatory-inhibitory balance of the nervous system, regulating systemic metabolic homeostasis, and participating in immune modulation. Additionally, it serves as a precursor for glutathione synthesis. Glutathione is a vital antioxidant and detoxifying molecule in organisms, capable of directly scavenging reactive oxygen species or toxic metabolites. Dysfunction of glutathione is associated with oxidative stress-related diseases. Given the critical roles of glutamate and glutathione in physiological and pathological states, we aim to systematically elucidates the metabolic interplay between glutamate and glutathione, referred to here as the Glutamate-Glutathione axis, as an integrative conceptual framework grounded in established biochemistry. By detailing the metabolic interplay of glutamate and glutathione, this review explores their mutually influential mechanisms. Furthermore, it summarizes the relevant signaling pathways and regulatory mechanisms within the Glutamate-Glutathione axis, clarifying its pivotal role in disease pathogenesis, with a particular focus on neuropsychiatric disorders and cancer. Finally, we aim to review non-invasive methods for detecting glutamate and glutathione using magnetic resonance imaging and presents our specialized sequence. This approach aims to provide a valuable non-invasive imaging tool for early diagnosis, efficacy evaluation, and therapeutic target development in related diseases. By integrating foundational metabolic networks, molecular regulatory mechanisms, disease associations, and clinical detection techniques, this review aim to establish the research framework of the Glutamate-Glutathione axis, fostering deeper integration and advancement from bench to bedside in this field.

Keywords:  Cancer; Glutamate; Glutathione; MEGA-PRESS; Neuropsychiatric disorders

DOI:  https://doi.org/10.1016/j.redox.2026.104215
bioRxiv. 2026 May 08. pii: 2026.05.05.722979. [Epub ahead of print]

Conserved principles of central carbon partitioning in Hippo-Yorkie-driven Drosophila gut tumors.

Younshim Park, Mujeeb Qadiri, John M Asara, Yanhui Hu, Norbert Perrimon.

Central carbon metabolism undergoes extensive remodeling in cancers, yet the extent to which the resulting network architectures and operating principles are conserved across species and oncogenic contexts in vivo remains unclear. Here, central carbon metabolism was evaluated in Hippo/Yki-driven Drosophila gut tumors, as Hippo-YAP/TAZ signaling links nutritional cues to metabolic state and contributes to epithelial tumorigenesis and therapy resistance. Using integrated steady-state metabolomics, transcriptomics and [U- 13 C 6 ]glucose tracing, we defined how Hippo pathway activation reorganizes nutrient utilization and carbon flux in vivo and assessed how the resulting Yki-driven metabolic network aligns with mammalian cancer metabolism. Yki tumors exhibited a Warburg-like state with increased glycolytic throughput and enhanced conversion of glucose-derived carbon to lactate, accompanied by transcriptional upregulation of key glycolytic and lactate-production enzymes. Glucose carbon was also redirected into redox-supporting and anabolic nodes, including activation of the glycerol-3-phosphate shuttle and increased labeling of alanine and serine. Mitochondrial metabolism was reorganized into a non-canonical, segmented TCA network centered on α-ketoglutarate, which accumulated and acted as a drain into glutamate/glutamine and 2-hydroxyglutarate rather than supporting complete oxidative turnover. Despite reduced abundance of pentose phosphate intermediates, non-oxidative PPP carbon rearrangements and ribose labeling were maintained, enabling robust glucose contribution to pyrimidine nucleotide pools, including strongly labeled dTTP. Together, these data establish a comprehensive map of Yki-driven central carbon partitioning in vivo and highlight conserved principles of tumor carbon allocation shared across oncogenic contexts and mammalian cancer metabolism.

DOI: https://doi.org/10.64898/2026.05.05.722979
Neurochem Res. 2026 May 18. pii: 160. [Epub ahead of print]51(3):

xCT (Slc7a11) Regulation: Lessons from Cancer Research.

Sravika Chirla, Rahul Pandit, Zila Martinez-Lozada.

  The cystine/glutamate antiporter, also known as system Xc-, has two roles: (1) imports cystine used to form glutathione (GSH), (2) regulates the extracellular concentration of glutamate. These roles are essential for brain function, as GSH is the most important antioxidant in the brain, and glutamate is the main excitatory neurotransmitter. This antiporter is composed of two subunits: xCT (encoded by the gene Slc7a11) and a heavy chain, CD98 (encoded by the gene Slc3a2). xCT is the subunit responsible for cystine/glutamate transport, while CD98 is responsible for the translocation of system Xc- to the membrane. The antioxidant function of xCT has been highlighted by the discovery of ferroptosis, a distinctive form of programmed cell death triggered by lipid peroxidation and the accumulation of reactive oxygen species. In addition, numerous types of cancers have been shown to overexpress xCT to evade ferroptosis. The mechanisms by which healthy cells regulate xCT expression, the mechanisms responsible for xCT overexpression in cancer cells, and whether different types of cancers employ identical mechanisms to upregulate xCT have not been systematically studied. To answer these questions, we conducted a systematic review to consolidate the regulatory mechanisms governing xCT expression. We found that xCT expression is regulated at nearly all known levels, including epigenetic, transcriptional, post-transcriptional, translational, post-translational, and by protein-protein interactions, with some cell-type- and context-specific mechanisms. Overall, our work highlights the role of xCT and the breadth of axes through which its expression can be modulated.

Keywords:  Cancer; Cystine/glutamate antiporter; Glutamate transport; Slc7a11; xCT

DOI:  https://doi.org/10.1007/s11064-026-04776-w