bims-glucam 2026-05-31 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–05–31
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University

Single-cell RNA sequencing reveals that host Glutamine Metabolism Inhibition Enhances Macrophage Phagocytosis of Mycobacterium tuberculosis.
Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells.
Impaired redox adaptation through SLC38A5-dependent glutamine metabolism contributes to melatonin-mediated anoikis sensitivity and metastasis suppression in bone cancer.
A Boronic Acid-Based Glutamine Analog Forms a Covalent Adduct with Kidney-Type Glutaminase and Suppresses Triple-Negative Breast Cancer Cell Proliferation.
Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.
B cells just got a workout.
HIF-1α Drives Distinct Aspects of Hypoxia-Induced Glucose Metabolism in Intestinal Epithelial Cells.
[Glutamine at the heart of macrophage energy metabolism in atherosclerosis].
Eubacterium rectale Mitigates Inflammatory Bowel Disease via Modulation of Glutamine Metabolism Through the GLS2 and NF-κB Pathway.
Cancer metabolism: from the Warburg effect to precision therapy.
Pirfenidone Sensitizes Hepatic Stellate Cells to Ferroptosis by Reprogramming Glutamine and Serine Metabolism for GSH Depletion.
Heavy water labeling reveals metabolic flexibility of amino acid and polyamine pathways in mammalian cells.
NMR-based metabolomics analysis in breast cancer patients from Saudi Arabia: a pilot study.
SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.
Metabolism and Metabolic Reprogramming in Laryngeal Squamous Cell Carcinoma.
Metabolic characterization of the tumor microenvironment orchestrates therapeutic strategies and clinical outcomes in pancreatic cancer.
Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.
Glutamate-cysteine ligase catalytic related glutathione metabolism inhibited high mobility group box 1 release by regulating epithelium ferroptosis in asthma.
Dehydration promotes intracellular lipid synthesis and accumulation.
Glutathione precursors: a new opportunity for dietary interventions in obesity and metabolic health?
The activation of the metabolic oxaloacetate-pyruvate axis restores influenza A virus replication during impaired glycolysis.

bioRxiv. 2026 May 15. pii: 2026.05.14.725218. [Epub ahead of print]

Single-cell RNA sequencing reveals that host Glutamine Metabolism Inhibition Enhances Macrophage Phagocytosis of Mycobacterium tuberculosis.

Yingli Shi, Lesly Rodriguez Vicens, Micheal Teve, Barbara Slusher, William R Bishai, Sadiya Parveen-Nesson.

Macrophages are crucial for host defense against the pathogen. However, pathogens such as Mycobacterium tuberculosis (Mtb) have evolved mechanisms to alter macrophage physiology and exploit these cells as their primary niche. Mtb -infected macrophages upregulate several metabolic pathways including glutamine metabolism. We previously showed that inhibiting glutamine metabolism with the pleiotropic glutamine metabolism antagonist prodrug JHU083 has dual antibacterial and immunomodulatory effects in a mouse model of tuberculosis. In the present study, using single-cell RNA sequencing and LS-MS/MS metabolomics, we showed that JHU083-mediated glutamine metabolism inhibition increased the population of interstitial macrophages in Mtb -infected lungs. JHU083 treatment also increased inflammatory signatures while lowering immunosuppressive markers on these macrophages. Metabolically, these macrophages exhibited marked depletion of complex lipids, accumulation of free fatty acids, and increased expression of transcripts associated with the β-oxidation pathway. Additionally, JHU083-treatment also improved phagocytic activity of macrophages, as measured by using fluorescent E. coli as a bait. In conclusion, JHU083-mediated glutamine metabolism inhibition metabolically reprograms macrophages, increasing both their lipid utilization as well as phagocytic activity, potentially driving their antimycobacterial activity that we had observed earlier.

DOI: https://doi.org/10.64898/2026.05.14.725218
Commun Biol. 2026 May 26.

Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells.

Hiroki Furukawa, Keitaro Umezawa, Yuchen Sun, Hinata Chiba, Marin Kubonishi, Hayato Naito, Yuri Miura, Kousei Ito, Shigeki Aoki.

KRAS inhibitors are reshaping the cancer-treatment landscape; however, durable responses remain limited by drug-tolerant persister cells that survive initial therapy and drive relapse. We show that KRAS-mutant pancreatic and lung cancer cells enter a reversible drug-tolerant (TR) state upon KRAS inhibition, marked by proliferative arrest and extensive metabolic adaptation. Integrated proteomic and metabolomic analyses reveal lysosome-linked remodeling and relatively broad metabolic reprogramming in TR cells. Dual blockade of glutamine metabolism and lysosome-associated processes selectively compromises TR-cell viability under KRAS inhibition, which is rescued by α-ketoglutarate (α-KG). N-acetyl-L-cysteine phenocopies the rescue, and α-KG supplementation lowers intracellular reactive oxygen species levels, supporting a model in which α-KG acts predominantly as a redox-supportive metabolite rather than a Tricarboxylic Acid Cycle intermediate, in the TR state, with lysosome-associated processes contributing to redox balance. These findings define drug-tolerant redox vulnerability and provide a rationale for co-targeting glutamine metabolism and lysosome-associated processes during KRAS inhibitor therapy.

DOI: https://doi.org/10.1038/s42003-026-10374-x
Int J Biol Sci. 2026 ;22(10): 5246-5262

Impaired redox adaptation through SLC38A5-dependent glutamine metabolism contributes to melatonin-mediated anoikis sensitivity and metastasis suppression in bone cancer.

Bao Tran Nguyen, Wei-Cheng Chen, Yi-Chin Fong, Chih-Yuan Ko, Hsien-Te Chen, Chin-Jung Hsu, Kieu Thanh Huynh, Wei-Chien Huang, Shun-Fa Yang, Chih-Hsin Tang.

  Malignant bone cancer, primarily osteosarcoma and chondrosarcoma, are highly aggressive neoplasms originating from bone tissue and characterized by a strong propensity for lung metastasis. Tumor cells evade anoikis through reactive oxygen species (ROS)-mediated redox homeostasis, which modulates signaling cascades that promote proliferation, survival, and metastatic invasion into distant sites. Melatonin, synthesized primarily by the pineal gland, has been implicated in cancer prevention and therapy due to its inhibitory effects on bone cancer growth and progression. Little is known about the mechanisms underlying anoikis resistance in bone cancer cells or whether melatonin can therapeutically modulate this process. We demonstrated that glutamine metabolism is essential for bone cancer cells to maintain anoikis resistance. Melatonin treatment disrupted glutamine metabolism and altered redox homeostasis, as evidenced by increased ROS accumulation and reduced NADPH/NADP⁺ ratios under anchorage-independent conditions. Notably, solute carrier family 38 member 5 (SLC38A5), a glutamine transporter, was identified as a critical regulator of bone cancer progression, with higher SLC38A5 expression correlating with poorer clinical outcomes. Melatonin suppressed SLC38A5 expression and attenuated anoikis resistance through inhibition of the PI3K-Akt signaling pathway. Consistently, reduced SLC38A5 expression was associated with decreased lung metastasis in melatonin-treated groups in an orthotopic mouse model. Collectively, our findings reveal a previously unrecognized role of melatonin in modulating glutamine-dependent redox balance and anoikis resistance in bone cancer. This study highlights SLC38A5-mediated glutamine metabolism as a critical determinant of metastatic potential and supports melatonin and SLC38A5 as promising therapeutic targets for osteosarcoma and chondrosarcoma.

Keywords:  ROS; SLC38A5; anoikis resistance; bone cancer; glutamine metabolism; metastasis

DOI:  https://doi.org/10.7150/ijbs.133256
Biomedicines. 2026 May 13. pii: 1100. [Epub ahead of print]14(5):

A Boronic Acid-Based Glutamine Analog Forms a Covalent Adduct with Kidney-Type Glutaminase and Suppresses Triple-Negative Breast Cancer Cell Proliferation.

Thiruselvam Viswanathan, Dinesh Devadoss, Achyuta Nagaraj, Barry P Rosen, Hitendra S Chand, Venkadesh Sarkarai Nadar.

  Background: Cancer cells exhibit metabolic reprogramming characterized by increased dependence on glutamine to sustain rapid proliferation and biosynthetic demands. Kidney-type glutaminase (KGA), which catalyzes the first and rate-limiting step of glutamine metabolism, represents a promising therapeutic target, particularly in triple-negative breast cancer (TNBC), an aggressive sub-type lacking effective targeted therapies. This study evaluated 2-amino-4-boronobutyric acid (ABBA), a boronic acid-containing glutamine analog, as a potential KGA inhibitor with anticancer activity. Methods: KGA inhibition was assessed using a fluorometric enzymatic assay. Cytotoxic effects were examined in multiple TNBC cell lines. Covalent docking and molecular simulation analysis were performed to characterize interactions between ABBA and the KGA active site. Results: ABBA potently inhibited KGA activity, with an IC50 of approximately 1.0 μM, demonstrating greater efficacy than several non-proteinogenic amino acid analogs. ABBA induced dose-dependent cytotoxicity across multiple TNBC cell lines, with pronounced sensitivity observed in basal sub-type cells and cellular sensitivity correlated with KGA expression levels. Expression of γ-glutamyl transpeptidase 1 (GGT1) was negligible, and, excluding any off-target effects, the observed anticancer effects are primarily attributed to KGA inhibition. Docking analysis indicated that ABBA forms a reversible covalent adduct with the catalytic Ser286 residue of KGA in a boronate tetrahedral geometry resembling transition-state mimics, while molecular simulation demonstrated stabilization of the complex through hydrogen bonding and electrostatic interactions. Conclusions: ABBA is a potent boron-based glutaminase inhibitor with therapeutic potential for targeting glutamine metabolism in TNBC. Further structural optimization and in vivo evaluation are warranted to advance ABBA toward therapeutic development.

Keywords:  2-amino-4-boronobutyric acid; boronic compounds; glutaminase inhibitor; non-proteinogenic amino acids; triple-negative breast cancer

DOI:  https://doi.org/10.3390/biomedicines14051100
Nutrients. 2026 May 18. pii: 1596. [Epub ahead of print]18(10):

Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.

Hong Chen, Xiaoying Wu, Manting Zhu, Ying Cheng, Qing Feng.

  Objectives: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. Methods: The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. Results: Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis-manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. Conclusions: Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC.

Keywords:  AMPK; NSCLC; PDZD8; ferritinophagy; ferroptosis; glutamine starvation

DOI:  https://doi.org/10.3390/nu18101596
Cell. 2026 May 28. pii: S0092-8674(26)00513-1. [Epub ahead of print]189(11): 3181-3183

B cells just got a workout.

Maria E Moreno-Fernandez, Senad Divanovic.

In this issue of Cell, Mao et al. reveal that B cells play an unexpected, immune-independent role in exercise physiology by facilitating multi-organ communication. Secreting TGF-β1, they transcriptionally reprogram hepatic glutamine metabolism via GLS2 and SLC7A5, preserving skeletal muscle glutamate levels, which sustain mitochondrial function, Ca2⁺ signaling, and ATP production, enhancing exercise capacity.

DOI: https://doi.org/10.1016/j.cell.2026.04.046
J Biol Chem. 2026 May 25. pii: S0021-9258(26)02065-X. [Epub ahead of print] 113193

HIF-1α Drives Distinct Aspects of Hypoxia-Induced Glucose Metabolism in Intestinal Epithelial Cells.

Sarah J Kierans, Ciarán Kennedy, Rory Turner, Darragh Flood, Emily DeMichele, Martina Wallace, Cormac T Taylor.

  The hypoxia-inducible factor-1α (HIF-1α) has canonically been described as a primary regulator of glucose metabolism in hypoxic cells through transcriptional upregulation of all 10 glycolytic enzymes. Here, using 13C-glucose and 13C-glutamine tracing in intestinal epithelial cells with defined HIF1A genetic perturbations, we demonstrate that hypoxia-induced glycolysis can occur independently of HIF-1-driven transcription. While hypoxia modulates glucose-derived carbon flux into anabolic branches of glycolysis independent of HIF-1α, HIF-1α plays an important role in modulating glucose and glutamine utilisation within the TCA cycle. These alterations in substrate utilisation highlight the layered regulatory framework whereby HIF-1α regulates distinct aspects of glucose and glutamine metabolism in intestinal epithelial cells to impact the rate of intestinal epithelial cell growth and promote metabolic adaptation to hypoxia.

Keywords:  HIF-1; Hypoxia; TCA cycle; glucose metabolism; glycolysis; metabolomics

DOI:  https://doi.org/10.1016/j.jbc.2026.113193
Med Sci (Paris). 2026 May;42(5): 436-439

[Glutamine at the heart of macrophage energy metabolism in atherosclerosis].

Coraline Borowczyk, Thibault Barouillet, Florent Murcy, Laurent Yvan-Charvet.

DOI: https://doi.org/10.1051/medsci/2026076
NPJ Sci Food. 2026 May 26.

Eubacterium rectale Mitigates Inflammatory Bowel Disease via Modulation of Glutamine Metabolism Through the GLS2 and NF-κB Pathway.

Lu Han, Yiyi Jin, Wen Lin, Zide Liu, Chunyan Zeng, Youxiang Chen.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory intestinal disorder with complex etiology, closely associated with gut microbiota dysbiosis. This study demonstrates that Eubacterium rectale (ER), a beneficial commensal bacterium, alleviates dextran sulfate sodium (DSS)-induced colitis in mice, as evidenced by improved clinical symptoms, restored intestinal barrier integrity, and reduced pro-inflammatory cytokine levels. Mechanistic investigations revealed that ER specifically upregulates the expression of glutaminase 2 (GLS2), ameliorates DSS-induced disturbances in glutamine (Gln) metabolism within intestinal epithelial cells, and subsequently inhibits the NF-κB signaling pathway to exert anti-inflammatory effects. Further validation showed that GLS2 deficiency abolishes the anti-inflammatory effects of ER. Collectively, this work identifies a therapeutically relevant mechanism: ER mitigates colitis via the GLS2/NF-κB axis. These insights pave the way for developing ER-derived live biotherapeutic products for IBD.

DOI: https://doi.org/10.1038/s41538-026-00876-7
Front Immunol. 2026 ;17 1793553

Cancer metabolism: from the Warburg effect to precision therapy.

Canxuan Wang, Jing Wang, Lele Miao, Li Wei, Xinyuan Liu, Yan Lu, Longquan Xiang, Miaomiao Zhang.

  Tumor cells undergo metabolic reprogramming to enable proliferation, survival, and metastasis, making tumor metabolism a key target in cancer research. This study examines current breakthroughs in metabolic reprogramming, including the metabolism of glucose, glutamine, fatty acids, and other nutrients. It describes how these metabolic changes affect anti-tumor immunity and the tumor microenvironment. The molecular processes of metabolic control are investigated. Furthermore, the review discusses practical applications resulting from this study, such as metabolism-based therapy techniques and diagnostic tools. Finally, it discusses future research objectives and difficulties, emphasizing the possibility of targeting tumor metabolism to improve precision cancer therapy.

Keywords:  clinical application; metabolic reprogramming; targeted therapy; tumor metabolism; tumor micro-environment

DOI:  https://doi.org/10.3389/fimmu.2026.1793553
Antioxidants (Basel). 2026 Apr 26. pii: 552. [Epub ahead of print]15(5):

Pirfenidone Sensitizes Hepatic Stellate Cells to Ferroptosis by Reprogramming Glutamine and Serine Metabolism for GSH Depletion.

Jia Li, Li Wang, Yakun Li, Junyu Wang, Manon Buist-Homan, Klaas Nico Faber, Han Moshage.

  Pirfenidone (PFD) shows therapeutic potential for liver fibrosis, but its molecular mechanisms are not fully elucidated. Activation of hepatic stellate cells (HSCs) is central to liver fibrosis, making their targeted elimination a prime therapeutic strategy. Since amino acid metabolism governs both HSC activation and ferroptosis, we investigated whether PFD acts by reprogramming these metabolic pathways. Analysis of primary rat HSCs revealed that their in vitro activation induced fibrotic markers, including collagen type I and α-smooth muscle actin, as well as key metabolic enzymes. Specifically, we observed upregulation of glutaminase 1, initiating glutaminolysis to produce glutamate; serine hydroxymethyltransferase 2, which generates glycine from serine; and pyrroline-5-carboxylate synthase, the rate-limiting enzyme for de novo proline synthesis. Treatment with PFD suppressed HSC activation by reducing protein levels of these enzymes, an effect consistent with PFD's inhibition of activating transcription factor 4 nuclear accumulation. This created a dual metabolic vulnerability, limiting amino acid precursors for both collagen synthesis and the master antioxidant glutathione (GSH). Consequently, while PFD alone was not cytotoxic, GSH depletion sensitized activated HSCs to ferroptosis. Co-treatment with the ferroptosis inducer erastin triggered a synergistic increase in reactive oxygen species, labile iron, and lipid peroxidation, culminating in cell death. This synergistic lethality was abrogated by the ferroptosis inhibitor ferrostatin-1 and the antioxidant N-acetylcysteine, confirming ferroptosis as the specific cell death modality. Our study uncovers a dual anti-fibrotic mechanism for PFD: PFD inhibits collagen synthesis by limiting key amino acid precursors and depletes GSH. This compromises antioxidant defenses, creating vulnerability to ferroptosis. Our findings establish a rationale for using PFD in combination therapies designed to eliminate activated HSCs.

Keywords:  ferroptosis; hepatic stellate cell; liver fibrosis; metabolic reprogramming; pirfenidone

DOI:  https://doi.org/10.3390/antiox15050552
Commun Chem. 2026 May 29.

Heavy water labeling reveals metabolic flexibility of amino acid and polyamine pathways in mammalian cells.

Alan Gonzalez-Ibarra, Missael Arroyo-Negrete, Wioleta Banaszuk-Krupa, Katarzyna Socała, Nikola Gapińska, Piotr Wlaź, Julio Cesar Torres-Elguera, Tomasz Sawoszczuk, Marek Tchórzewski, Maria Hatzoglou, Dawid Krokowski.

Amino acid and polyamine metabolism underpins many cellular processes, such as cell growth, stress adaptation, and signaling. However, the usage of specific metabolic pathways is highly context-dependent, and there are many compensatory mechanisms in place for the biosynthesis of amino acids. Here, we establish low-dose heavy water (D₂O) labeling as a tracer to monitor amino acid and polyamine metabolism in mammalian systems. Using targeted HPLC-MS of primary amines, we quantified deuterium incorporation in mouse embryonic fibroblasts, pancreatic β-cell-derived MIN6 cells, and mouse tissues, which we then benchmarked with orthogonal tracers (13C-glucose and 15NH₄⁺). We demonstrated D₂O labels nonessential amino acids and polyamines. We validated specificity, as inhibition of key metabolic steps altered deuterium incorporation into Ala/Ser/Gly and polyamines and revealed differential engagement of branched-chain amino acid metabolism. We found that glutamine starvation induces integrated stress response-linked remodeling, increasing deuterium incorporation into Glu and glycolytic amino acids while identifying changes in amino acids efflux. Finally, in vivo short-term D₂O exposure distinguishes tissue-specific biosynthetic capacities. Collectively, these data challenge the assumption of uniform alanine labeling by D2O and demonstrate that D₂O provides a sensitive readout of metabolic flexibility, transport crosstalk, and pathway regulation across cell types and tissues.

DOI: https://doi.org/10.1038/s42004-026-02081-9
Sci Rep. 2026 May 24.

NMR-based metabolomics analysis in breast cancer patients from Saudi Arabia: a pilot study.

Muhammad Ikram Ullah, Shazia Rashid, Aisha Tahir, Ayman Ali Mohammed Alameen, Aisha Farhana, Tarig Mohamed Fadl Elmula, Ziad H Al-Oanzi.

  In breast cancer (BC), metabolomic profiles have largely focused on Western and East Asian groups, with limited data from the Middle East. Population-specific studies are required to better understand metabolite alterations due to regional, environmental and genetic heterogeneity. This exploratory pilot study aimed to evaluate serum metabolic alterations in breast cancer patients and their associations with disease stage using NMR-based metabolomics in the Saudi Arabian cohort. A total of 30 female breast cancer patients and 30 healthy controls were included. Patient samples showed higher levels of ketoglutarate, glutamine, lipids, and branched-chain amino acids, while acetate, creatine, and glucose were lower in the patient group (all FDR q < 0.05). Ketoglutarate (AUC = 0.85), glutamine (AUC = 0.84), and lipids (AUC = 0.82) demonstrated discriminatory ability. A combined model incorporating acetate and ketoglutarate achieved an AUC of 0.91. With advancing disease stage, lactate (p-trend = 0.005), leucine (p-trend = 0.044), and glutamate (p-trend = 0.033) showed decreasing trends. Lactate, choline, and glucose were each independently associated with more advanced disease in multivariable models. Unsupervised principal component analysis (PCA), supervised partial least squares-discriminant analysis (PLS-DA), and orthogonal PLS-DA (OPLS-DA) showed metabolic separation between patients and controls. Permutation testing indicated that class separation exceeded random classification; however, overfitting remains possible due to reliance on internal validation. The negative Q² value (- 0.577) indicates poor predictive generalizability. In conclusion, this study identifies candidate metabolite signatures associated with breast cancer in a Saudi cohort. These findings require validation in independent cohorts before clinical application.

Keywords:  Breast cancer; Candidate metabolites; Metabolomics; NMR spectroscopy

DOI:  https://doi.org/10.1038/s41598-026-54381-8
Cancer Lett. 2026 May 26. pii: S0304-3835(26)00379-4. [Epub ahead of print] 218616

SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.

Xiaoyan He, Zhengwei Zhao, Teng Wei, Lisi Zheng, Jincui Yang, Xinrong He, Yicai Cheng, Xiaoyi Zhan, Zejuan Li, Kelin Wu, Stephanie Roessler, Yunting Jian, Chuli Fu, Guang-Rong Yan, Junyao Xu, Qiangnu Zhang.

Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses peroxisome proliferator-activated receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.

DOI: https://doi.org/10.1016/j.canlet.2026.218616
Biomedicines. 2026 Apr 22. pii: 959. [Epub ahead of print]14(5):

Metabolism and Metabolic Reprogramming in Laryngeal Squamous Cell Carcinoma.

Barbara Verro, Roberta Oliveri, Giovanni Pratelli, Marianna Lauricella, Diana Di Liberto, Anna De Blasio, Daniela Carlisi, Carmelo Saraniti.

  Laryngeal squamous cell carcinoma (LSCC) remains a major clinical challenge within head and neck oncology, with five-year survival rates showing minimal improvement over recent decades despite advances in surgical and multimodal therapeutic strategies. Increasing evidence identifies metabolic reprogramming as a central driver of tumor progression, therapeutic resistance, and immune evasion in LSCC. Beyond the classical Warburg effect, LSCC exhibits profound metabolic reprogramming, involving coordinated alterations in carbohydrate, amino acid, lipid, and iron metabolism that support adaptation to hypoxic and nutrient-deprived microenvironments. Hypoxia-inducible factors, particularly HIF-1α, coordinate these key biochemical pathways and enzymatic steps by integrating glycolysis, glutaminolysis, folate-dependent one-carbon pathways, lipid synthesis, and mitochondrial remodeling, while also influencing stromal and immune components of the tumor microenvironment. Metabolic crosstalk between tumor cells, cancer-associated fibroblasts, and immune populations promotes immunosuppression through nutrient competition and accumulation of metabolites such as lactate and lipid-derived mediators. In parallel, dysregulated iron handling and altered ferroptosis susceptibility emerge as key determinants of tumor aggressiveness and treatment response. This review synthesizes current evidence on metabolic rewiring in laryngeal squamous cell carcinoma, highlighting how alterations in metabolic pathways create targetable vulnerabilities that drive tumor biology, immune modulation, and resistance to conventional and emerging therapies. Elucidating these metabolic dependencies may support the development of metabolism-based biomarkers and therapeutic strategies in laryngeal squamous cell carcinoma, providing an integrated and translational perspective that links tumor metabolism with microenvironmental interactions and immune modulation, while highlights emerging therapeutic vulnerabilities.

Keywords:  Oncologic; Warburg effect; cancer; larynx; malignant neoplasm; metabolic networks and pathways

DOI:  https://doi.org/10.3390/biomedicines14050959
Nat Commun. 2026 May 28.

Metabolic characterization of the tumor microenvironment orchestrates therapeutic strategies and clinical outcomes in pancreatic cancer.

Rong Tang, Yangyi Li, Cong Zhou, Chunbin Zhu, Chen Chen, Liquan Jin, Yueyue Chen, Yingna Liao, Yuan Liu, Qiong Du, Yubin Lei, Zijian Wu, Jin Xu, Wei Wang, Xiaoyu Yin, Chenghao Shao, Si Shi, Xianjun Yu.

Metabolic reprogramming and immunosuppressive tumor microenvironment (TME) are hallmark features driving pancreatic ductal adenocarcinoma (PDAC) progression. Despite the therapeutic potential of targeting immunometabolism, effective strategies remain scarce in clinical practice, likely due to cell-specific metabolic heterogeneity within PDAC TME. Here, we show integration of three algorithms to estimate metabolic fluxomes and pathways using scRNA-seq data, generating a comprehensive cell type-specific metabolic atlas. Leveraging 460 PDAC samples, we establish a TME-metabolism subtyping system, classifying PDAC into three subtypes (TMS1-3) with distinct immune-metabolic profiles and clinical outcomes. TMS1, characterized by low immune infiltrates, is susceptible to ferroptosis inducers. TMS2, enriched in macrophages, responds to chemoimmunotherapy with inhibition of glutamine synthetase. TMS3, characterized by matrix remodeling, responds to glycolysis inhibitors and albumin-paclitaxel. Finally, we develop a computational classifier for subtype discrimination. Together, this study delineates the metabolic heterogeneity of the PDAC TME and proposes a classification system that suggests promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-73702-z
bioRxiv. 2026 May 11. pii: 2026.05.06.723011. [Epub ahead of print]

Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.

Shih Ming Huang, Hannah R Foster, Eun Young Lee, Jeong Hun Jo, Xinhang Dong, Byoung-Kyu Cho, Young Ah Goo, Jing W Hughes, Matthew J Merrins.

Primary cilia are antenna-like sensory and signaling organelles present on most mammalian cells, including glucose-sensing pancreatic β-cells. Here, we show that the local energetic demands of primary cilia require the ATP-producing enzyme pyruvate kinase, with loss of PKm1, but not PKm2, impairing ciliary glycolytic flux. While the entire glycolytic machinery localizes to cilia, our data indicate that mitochondria are a critical source of phosphoenolpyruvate (PEP), the high-energy glycolytic intermediate that drives the pyruvate kinase reaction. Abolishing PCK2, the mitochondrial enzyme that generates PEP, prevents cilia from sensing not only glucose but also the amino acids glutamine and leucine. Finally, by mislocalizing glycolysis, we demonstrate that primary cilia can utilize ATP generated within the cell body when glucose is limiting. These findings indicate that primary cilia, while possessing the capacity for local ATP generation, leverage a ciliary-mitochondrial signaling axis to meet their bioenergetic needs.

DOI: https://doi.org/10.64898/2026.05.06.723011
J Thorac Dis. 2026 Apr 30. 18(4): 359

Glutamate-cysteine ligase catalytic related glutathione metabolism inhibited high mobility group box 1 release by regulating epithelium ferroptosis in asthma.

Haiqin Liu, Caiming Zhong, Xuran Jiang, Yuan Yuan, Jianing Zhang, Hao Tang.

   Background: Previous research indicated that asthma patients were with abnormal glutathione (GSH) metabolism. However, the role of glutamate-cysteine ligase catalytic (GCLC), as the key enzyme for GSH synthesis, remains ambiguous in asthma pathogenesis. Our study aimed to elucidate the role of GSH metabolism and GCLC in asthma.
Methods: We collected serum from healthy controls, asthma patients, and asthma bagg albino/c (BALB/c) mouse induced by house dust mite (HDM) to analyze GSH/oxidized GSH (GSSG) ratio. In vivo, we administered L-Buthionine-(S,R)-sulfoximine (BSO) or combined with ferrostatin-1 (Fer-1) prior to asthmatic challenge to explore the role of GCLC in asthma. In vitro, MLE-12 and Beas-2B cells were stimulated with BSO alone or combination with Fer-1 or GSH to analyze ferroptosis-related indicators and oxygen species (ROS) production. The association between GCLC and high mobility group box 1 (HMGB1) was assessed by using reverse transcription polymerase chain reaction (RT-PCR), enzyme linked immunosorbent assay (ELISA) and western blot.
Results: We found that GSH/GSSG ratio decreased in asthma patients and mice. Additionally, inhibition of GCLC aggregated airway inflammation and remodeling in asthma by mediating GSH metabolism. Furthermore, fat mass and obesity-associated protein (FTO) regulated N6-methyladenosine (m6A) demethylation of GCLC. We further found that GCLC inhibited epithelial cells ferroptosis and oxidative stress, decreasing the production of T helper 2 cells (Th2) inflammation cytokines. In addition, GCLC regulated HMGB1 expression, ultimately inhibiting epithelial-mesenchymal transition (EMT).
Conclusions: In asthma, GSH metabolism is abnormal and GCLC plays a protective role. GCLC inhibits ferroptosis in airway epithelium and HMGB1 release, ultimately alleviating airway inflammation and airway remodeling. Our studies reveal that GCLC related GSH metabolism is as a new mechanism of asthma, providing a potential therapeutic target.

Keywords:  Asthma; ferroptosis; glutamate-cysteine ligase catalytic (GCLC); glutathione (GSH); high mobility group box 1 (HMGB1)

DOI:  https://doi.org/10.21037/jtd-2026-1-0009
Nat Commun. 2026 May 25.

Dehydration promotes intracellular lipid synthesis and accumulation.

Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don A Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter K Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.

Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.

DOI: https://doi.org/10.1038/s41467-026-73534-x
Curr Opin Clin Nutr Metab Care. 2026 May 26.

Glutathione precursors: a new opportunity for dietary interventions in obesity and metabolic health?

Dimitrios Draganidis, Anastasia Rosvoglou, Ioannis G Fatouros, Athanasios Z Jamurtas.

   PURPOSE OF REVIEW: Obesity is a major risk factor for the development of metabolic disorders, including insulin resistance, hepatic steatosis and metabolic syndrome. The mechanistic link between obesity and metabolic complications largely relay on chronic inflammation and redox status disturbances driven by excess adiposity and reduced glutathione (GSH) levels. This article reviews the latest evidence on the therapeutic potential of glutathione precursors N-acetylcysteine (NAC) and glycine in mitigating metabolic complications associated with obesity.
RECENT FINDINGS: NAC demonstrates promising benefits in improving insulin resistance, reducing hepatic steatosis, and mitigating cellular senescence mainly through its antioxidant and anti-inflammatory properties. Glycine, on the other hand, may support metabolic health by enhancing detoxification pathways and improving key metabolic markers in obesity. However, research on this field is limited and predominantly based on animal models and small-scale human trials.
SUMMARY: These findings highlight the need for continued investigation on the role of glutathione precursors as part of a broader strategy for the prevention and management of metabolic diseases linked to obesity. In particular, large-scale randomized controlled studies are required to validate the efficacy, safety and optimal dosages for these supplements.

Keywords:  N-acetylcysteine; glutathione; glycine; metabolic diseases; obesity

DOI:  https://doi.org/10.1097/MCO.0000000000001240
Virol J. 2026 May 24. pii: 131. [Epub ahead of print]23(1):

The activation of the metabolic oxaloacetate-pyruvate axis restores influenza A virus replication during impaired glycolysis.

Chiara Robin Bojarzyn, Nadine Bieß, Matthias Behrens, Hans-Ulrich Humpf, Stephan Ludwig, Eike R Hrincius.

Viruses strongly depend on the host cell for efficient replication and influenza A virus (IAV) amongst others also lead to remarkable changes of the host cell metabolism. The restriction of virus replication through suppression of glucose metabolism has already been described. In addition to glycolysis and glutaminolysis, viral replication also relies on the tricarboxylic acid (TCA) cycle. So far, the metabolic key intermediate of the TCA cycle, oxaloacetate (OAA), is described to enhance glycolysis and respiration flux rates under metabolic stress conditions. However, the mode of action of the metabolic fuel intermediate OAA in direct relation to influenza viral growth under strong glycolysis inhibition remains unclear. As the TCA cycle acts as a central metabolic hub linking all major metabolic pathways, the effects of OAA under glycolysis inhibition were examined in greater detail in this study. We aimed to get a better understanding of metabolic host-virus interactions and to analyze the effects of metabolic fueling intermediates on IAV replication under glycolysis inhibition. We inhibited glycolysis and supplemented IAV infected cells with the metabolic fueling intermediate OAA. Inhibition of glycolysis led to a statistically significant reduction of viral titers while OAA addition reversed the antiviral effects such as reduced viral protein accumulation, viral titers, and vRNA expression. In line with previous studies, we showed that mannose, which is closely connected to glycolysis, circumvents the virus restricting effects of glycolysis inhibition. Moreover, we demonstrated that supplementation of mannose or OAA led to a roughly comparable replication recovery under strong inhibition of glycolysis. Furthermore, mass spectrometry-based metabolomics data revealed a strong accumulation of pyruvate in OAA supplemented samples. Finally, comparing OAA and pyruvate rescuing capacities of IAV growth under glycolysis inhibition tended to show similar activities for both metabolites arguing that OAA mediated IAV rescue is achieved through its conversion to pyruvate. Summarizing, our data indicate that the TCA cycle intermediate OAA has virus supporting effects as it reversed the antiviral effects of glycolysis inhibition.

DOI: https://doi.org/10.1186/s12985-026-03201-6