bims-glucam 2026-04-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–04–12
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Role of glutamine metabolism reprogramming in ferroptosis of lens epithelial cells under high-glucose conditions.
PHGDH is a targetable driver of PDAC progression.
Glutamine addiction is a therapeutic target to block emergency myelopoiesis.
Dependency of Non-Small Cell Lung Cancer Cells on Glutamine and Glucose Levels in the Presence of Metformin.
Combating VEGFA-siRNA-Induced Metabolic Reprogramming via Glucose Utilization Deprivation.
Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans.
Expanding the Chemoproteomic Toolkit to Asparagine and Glutamine.
Enhancing Immunotherapy in Diffuse Large B-Cell Lymphoma: The Synergistic Potential of Metabolic Checkpoint Inhibitors and Immunomodulation.
NRF2/SLC7A11 axis-mediated metabolic reprogramming drives Benzo[a]pyrene-induced malignant transformation: Evidence from lung organoid and 16HBE cell models.
Structural and functional study suggests DnfC is a putative glutamine amidotransferase in the dirammox pathway.
Protocol for stable isotope tracing of primary human peripheral blood mononuclear cells.
Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.
Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones.
Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.
NMR-Based Metabolomics Profiling Reveals Dose-Dependent Cardiotoxic Effects of Favipiravir in Rats.
Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.
Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
Metabolic profiling of a polycystic ovary syndrome-like organoid model reveals the critical role of glutamine in local endometrial dysregulation related to implantation failure.

Free Radic Biol Med. 2026 Apr 06. pii: S0891-5849(26)00293-5. [Epub ahead of print]250 422-435

Role of glutamine metabolism reprogramming in ferroptosis of lens epithelial cells under high-glucose conditions.

Chunqiao Jiang, Zili Xu, Yao Lu, Lingling Du.

  The actual pathways through which glucose elevation fosters the growth of diabetic cataracts (DC) are poorly comprehended. This paper demonstrates the active role played by re-programming of glutamine metabolism in facilitating ferroptosis in lens epithelial cells (LECs). Glutaminase 2 (GLS2) was found as a core in the bioinformatics analysis of diabetes and cataract -related datasets. In in-vitro tests, it was proven that high - glucose (HG) conditions trigger ferroptosis in LECs. The ferroptosis process shows features such as the loss of glutathione, over-accumulation of iron, lipid peroxidation, and mitochondrial impairment. From a mechanical point of view, HG was reported to aid in ferroptosis in LECs through a synergistic elevation of the metabolic pathway which contains glutamine transporter solute carrier family 1 member 5 (SLC1A5), GLS2, and glutamic-oxaloacetic transaminase 1 (GOT1). Genetic or pharmacological inhibition of SLC1A5, GLS2 or GOT1 was effective in preventing glutamine degradation, glutamate production and ferroptosis induced by the high-glucose-level. Connection between inhibitors and target proteins in molecular docking experiments was proven to be stable. This same metabolic response was also observed in diabetic rat lenses and showed both ferroptosis markers and epithelial destruction. This paper shows that the stimulation of ferroptosis in lens epithelial cells is triggered by high glucose through the mediation of glutamine catabolic pathway SLC1A5/GLS2/GOT1, establishing a new pathogenic pathway and a new therapeutic omission.

Keywords:  Diabetic cataract; Ferroptosis; GLS2; Glutamine metabolism; Lens epithelial cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.009
bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]

PHGDH is a targetable driver of PDAC progression.

Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.

Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

DOI: https://doi.org/10.64898/2026.03.11.711147
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714544. [Epub ahead of print]

Glutamine addiction is a therapeutic target to block emergency myelopoiesis.

Oakley C Olson, Ruiyuan Zhang, Melissa A Proven, James C Swann, Kexuan Huang, William E Lowry, Emmanuelle Passegue.

Inflammation-driven emergency myelopoiesis (EM) contributes to the progression of many solid cancers and inflammatory diseases, yet therapeutic strategies to selectively suppress EM without compromising hematopoiesis remain lacking. Here, we use functional and single-cell transcriptomic analyses to determine metabolic programs organizing the hematopoietic hierarchy, myeloid lineage commitment, and myeloid differentiation. We identify de novo glutamine biosynthesis as a stem cell-specific survival mechanism allowing independence from exogenous glutamine. We show that myeloid differentiation is characterized by Myc-driven upregulation of mitochondrial respiration, which is hyperactivated during EM and renders myeloid progenitors dependent on glutaminolysis to fuel the TCA cycle. Both genetic and pharmacologic targeting of glutaminase suppresses EM and impairs breast tumor progression by reducing intratumoral neutrophil infiltration. Our study defines a central role for Myc-glutaminolysis in driving EM, identifies glutaminolysis as a therapeutic target to normalize maladaptive EM, and highlights myeloid overproduction as a systemic problem requiring HSPC targeting.

DOI: https://doi.org/10.64898/2026.03.26.714544
Eurasian J Med. 2026 Mar 04. 58(2): 1-6

Dependency of Non-Small Cell Lung Cancer Cells on Glutamine and Glucose Levels in the Presence of Metformin.

Şahika Cıngır Köker, İrem Doğan Turaçlı.

BACKGROUND: Metabolic shift is one of the hallmarks of cancer cells. Due to mutations in oncogenes such as Kirsten Rat Sarcoma Viral Oncogene (KRAS), cancer cells can adapt to stress-induced conditions. One of the adaptations that is commonly observed in non-small cell lung cancer (NSCLC) cells is glutaminolysis, where they exhibit high dependency on the presence of glutamine. Metformin is used for its anti-tumor effects, which inhibit mitochondrial complex I. This study aimed to investigate how glucose and glutamine availability affect the proliferation of three KRAS mutant NSCLC cells under metformin pressure.
METHODS: Using gene expression datasets, it was observed that glutamine was the second most affected metabolite upon metformin-treated A549 cells. Based on this, several 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were done by using high and low glucose conditions having different concentrations of glutamine at different time points. Moreover, metformin was added to the setup to observe the flexibility of the cancer cells in terms of metabolic switches.
RESULTS: Addition of glutamine resulted in a decrease in metformin's antiproliferative effect especially in high glucose conditions at later time points. A significantly higher proliferation rate in low glucose conditions compared to high glucose conditions was observed, which is especially pronounced with the addition of glutamine. These observations were supported by the gene expression analysis of the GSE dataset, which revealed upregulation of apoptosis related genes and downregulation of proliferation-related genes in metformin-treated A549 cells.
CONCLUSION: Taken together, the results highlight the importance of targeting different metabolites and metabolic pathways in cancer therapy. Cite this article as: K.ker ŞC, Tura.lı İD. Dependency of non-small cell lung cancer (NSCLC) cells on glutamine and glucose levels in the presence of metformin. Eurasian J Med. 2026, 58(2), 1018, doi:10.5152/eurasianjmed.2026.251018.

DOI: https://doi.org/10.5152/eurasianjmed.2026.251018
Adv Sci (Weinh). 2026 Apr 09. e19290

Combating VEGFA-siRNA-Induced Metabolic Reprogramming via Glucose Utilization Deprivation.

Lulu Zheng, Shuai Guo, Yingjixing Luo, Pengfei Wu, Haiyin Yang, Yingqiu Xie, Yuchuan Fan, Qing Liu, Bo Hu, Jia Huang, Yuanyu Huang.

  Vascular endothelial growth factor (VEGF) inhibitors suppress tumor energy supply, but their efficacy is often limited by the restoration of tricarboxylic acid (TCA) cycle activity and enhanced glycolysis. Here, a synergistic strategy is established using an in-house-designed ionizable lipid nanoparticle (LNP) to co-encapsulate VEGFA-targeting siRNA (siVEGFA) and glucose oxidase (GOx), thereby enhancing siRNA efficacy by depleting both aerobic and anaerobic glucose utilization. At the cellular level, the optimal formulation, iVG128, inhibits energy production, suppresses microvessel formation, and induces mitochondrial ultrastructural changes, leading to persistent suppression of the TCA cycle. In both CT26 cell-derived and patient-derived xenograft tumor models, iVG128 shows potent antitumor activity, achieving 2.6-fold higher efficacy than Sorafenib, significantly prolonging survival. Untargeted metabolomics indicates that iVG128 eliminates the glutamine-driven compensation induced by VEGF inhibition, thereby exacerbating metabolic stress and promoting apoptosis. Transcriptomic profiling reveals that VEGFA silencing induces adaptive gene programs related to PDH inhibition, hypoxia signaling, and glutamine metabolism, and these responses are largely suppressed by iVG128. Collectively, iVG128 represents a versatile nanoplatform for co-delivering enzymatic and RNA therapeutics, offering an effective strategy for cancer treatment through energy source depletion.

Keywords:  VEGFA siRNA; glucose oxidase; glutamine metabolism; lipid nanoparticle; tumor metabolic reprogramming

DOI:  https://doi.org/10.1002/advs.202519290
bioRxiv. 2026 Mar 13. pii: 2026.03.12.711193. [Epub ahead of print]

Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans.

Matthew H Ward, Nathan Scherer, Leah P Shriver, Gary J Patti.

Leptospirosis, caused by pathogenic Leptospira spp. such as L. interrogans , is a bacterial zoonosis of increasing prevalence with no consistently effective treatments in severe cases. We sought to characterize metabolic mechanisms that support L. interrogans infection in the host setting, with the ultimate goal of revealing unexplored therapeutic opportunities. We first established and validated a culture medium, which we refer to as supplemented Human Plasma-Like Medium (sHPLM). sHPLM more closely resembles the physiological environment of the human host than standard culture media, such as the EMJH (Ellinghausen-McCullough-Johnson-Harris) medium typically used for Leptospira culture. To better understand bacterial metabolism, we pioneered metabolomics in sHPLM-cultured Leptospira . Specifically, we developed a liquid chromatography mass spectrometry (LC/MS) metabolomics-based workflow for both medium analysis and stable isotope tracing with L. interrogans cultures. The application of these innovations revealed that the amino acid glutamine is a major nitrogen source for L. interrogans . A small-molecule inhibitor blocking glutamine utilization, JHU-083, effectively impaired the proliferation of sHPLM cultures. Further, adding glutamine to non-physiological EMJH medium rapidly induced a short-term proliferative boost in L. interrogans and increased biofilm formation. RNA-sequencing after glutamine exposure revealed transcriptional trends for increases in biosynthesis to support these phenotypes. Although ammonium has long been thought to be the sole nitrogen source for L. interrogans, our results demonstrate that glutamine provides a second source of nitrogen for biosynthesis and may act as a metabolite signal to alter L. interrogans physiology in ways that could influence infection. This work highlights that studying L. interrogans under physiological conditions is key to understanding mechanisms supporting infection and points to nitrogen assimilation as a potential target for therapies.
Author Summary: Leptospirosis is a potentially fatal disease transmitted through water and soil contaminated with pathogenic Leptospira bacteria. Much research is currently focused on the idea that an improved understanding of how Leptospira infects hosts and causes disease may inspire the development of improved therapeutics, which are urgently needed. Focusing on Leptospira interrogans , a clinically important pathogenic species, we determined that conventional growth media are inadequate for understanding how the bacterium behaves when inside hosts. Instead, we designed an optimized formulation to mimic human blood, and we applied an underutilized technique for measuring the biochemical reactions that enable pathogen survival. These two innovations revealed that L. interrogans uses glutamine, an abundant nutrient in host blood and tissues, as a source of nitrogen for the production of biomolecules that are required for replication and infection. This discovery is notable as nitrogen demands were previously thought to be met using ammonium. Treating L. interrogans with inhibitors of both glutamine and ammonium metabolism blocked bacterial replication. We also discovered that L. interrogans increases its growth rate, upregulates its expression of biosynthetic pathways when exposed to glutamine, and increases its formation of biofilm. Our results reveal the importance of glutamine in supporting the lifecycle of leptospirosis-causing bacteria.

DOI: https://doi.org/10.64898/2026.03.12.711193
ACS Chem Biol. 2026 Apr 09.

Expanding the Chemoproteomic Toolkit to Asparagine and Glutamine.

Benjamin Emenike, John M Talbott, Zachary E Paikin, Christian M Beusch, Sohail Khoshnevis, David E Gordon, Monika Raj.

Chemoproteomic strategies have revolutionized proteome annotation by targeting nucleophilic and redox-active side chains. However, the primary amides of asparagine (Asn) and glutamine (Gln) have long lacked robust chemical tools for proteome-wide interrogation. We report a chemoselective palladium-mediated dehydration that converts Asn/Gln amides to nitriles under mild aqueous conditions. This transformation enables the first proteome-wide mapping of chemically addressable Asn/Gln sites in lysates and living cells. Leveraging this reactivity, we establish an inverse chemoproteomic framework in which reduced nitrile formation reports PTM-mediated protection of Asn/Gln sites, including those impacted by deamidation and N-glycosylation. This approach reveals sites masked by post-translational modifications (PTMs), specifically those associated with deamidation and N-glycosylation. In yeast, this framework expanded the known N-glycoproteome, identifying numerous candidates missed by traditional glycopeptide enrichment due to low abundance or noncanonical motifs. Furthermore, comparative profiling in Candida albicans captured the dynamic remodeling of glycosylation patterns during morphogenesis. This dehydration-to-nitrile platform establishes a scalable handle on the amide proteome to map residue accessibility and PTM-linked site dynamics across biological states.

DOI: https://doi.org/10.1021/acschembio.6c00173
Onco Targets Ther. 2026 ;19 581821

Enhancing Immunotherapy in Diffuse Large B-Cell Lymphoma: The Synergistic Potential of Metabolic Checkpoint Inhibitors and Immunomodulation.

Meghana K Rajendraprasad, John C Riches.

  For many patients with diffuse large B-cell lymphoma (DLBCL), frontline chemoimmunotherapy is curative; nonetheless, up to 40% of patients develop relapse or refractory disease. Immunotherapeutic approaches, such as immunomodulatory drugs, bispecific antibodies and chimeric antigen receptor T-cell therapy, have improved outcomes for relapsed/refractory DLBCL over the past ten years. However, treatment failure is still frequent because of tumor antigen loss, T-cell dysfunction, and an immunosuppressive tumor microenvironment (TME). DLBCL is a highly metabolically active cancer that impairs efficient anti-tumor immune responses by depleting vital nutrients and producing immunosuppressive metabolites such lactate, adenosine, and kynurenine. Targeting metabolic checkpoints, such as glutamine metabolism, indoleamine 2,3-dioxygenase, adenosine signaling, and lactate transport, may remodel the TME and improve the effectiveness of immunotherapy, according to new research. The immune metabolic interaction that restricts long-lasting responses is the main topic of this study, which summarizes current immunotherapeutic strategies in DLBCL. To improve T-cell fitness and overcome immunotherapy resistance, we critically assessed the preclinical and early clinical data supporting metabolic checkpoint inhibition. We also emphasize translational issues and potential future paths for logical combination treatments. Importantly, this review distinguishes itself from existing literature by specifically focusing on the integration of metabolic checkpoint inhibition with established immunotherapies in DLBCL, an area that remains underexplored. While preclinical data are promising, clinical evidence for many metabolic checkpoint inhibitors in DLBCL remains limited, and further prospective clinical studies are required to validate their therapeutic potential.

Keywords:  CAR-T cells therapy; DLBCL; immunomodulatory drugs bispecific antibodies; metabolic checkpoints

DOI:  https://doi.org/10.2147/OTT.S581821
Free Radic Biol Med. 2026 Apr 03. pii: S0891-5849(26)00292-3. [Epub ahead of print]250 321-333

NRF2/SLC7A11 axis-mediated metabolic reprogramming drives Benzo[a]pyrene-induced malignant transformation: Evidence from lung organoid and 16HBE cell models.

Yong Wang, Hongyue Kong, Yu Zhang, Jiawen Su, Jiajun Wei, Ying Guo, Xiao Yu, Jisheng Nie, Jin Yang.

  To elucidate the molecular mechanisms underlying Benzo[a]pyrene (BaP)-induced lung carcinogenesis, we constructed lung organoid and BaP-induced malignant transformation cell model (16HBE-T). Single-cell sequencing analysis confirmed that organoids were primarily composed of basal cells and secretory cells. Following BaP exposure, the lung organoids exhibited G1-phase cell cycle arrest. The expression of CYP1A1 (Log2FC = 10.24) and CYP1B1 (Log2FC = 6.27) were significantly upregulated, while that of SCGB1A1 (Log2FC = -0.26) was downregulated, indicating early-stage lung epithelial injury. Mfuzz soft clustering analysis and FindMarker function were employed to characterize gene expression patterns and identify differentially expressed genes (DEGs). GO, KEGG, GSEA and WikiPathway enrichment analyses revealed that these DEGs were enriched in redox-related metabolic processes (including cysteine/glutamate metabolism and glutathione biosynthesis), NRF2 signaling pathways, and carcinogenesis-associated pathways. Among the DEGs, 9 DEGs were associated with oxidative stress and amino acid metabolism, with SLC7A11 showing the most prominent upregulation (Log2FC = 3.40). The AddModuleScore function indicated that NRF2 exhibited the most significant transcriptional activity. In 16HBE-T cells, the protein expression of SLC7A11 and NRF2 increased by 35.74% and 82.85%, respectively. Knockdown of SLC7A11 significantly inhibited the migration, invasion, and colony-forming abilities of 16HBE-T cells. Meanwhile, intracellular glutamate and cysteine levels decreased, whereas glutamine levels increased. ChIP-PCR verified that NRF2 could directly bind to two specific regions (460-565 bp and 1488-1623 bp) within the SLC7A11 promoter to regulate amino acid metabolism. Collectively, our findings demonstrate that NRF2-regulated SLC7A11-mediated amino acid metabolic reprogramming plays a pivotal role in BaP-induced cellular malignant transformation.

Keywords:  Amino acid metabolic reprogramming; Lung organoid; Malignant transformation cell model; NRF2; Oxidative stress; SLC7A11

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.008
Biochem Biophys Res Commun. 2026 Apr 01. pii: S0006-291X(26)00479-1. [Epub ahead of print]816 153715

Structural and functional study suggests DnfC is a putative glutamine amidotransferase in the dirammox pathway.

Xiao-Kang Wang, Ya-Ling Qin, Ruo-Xi Zhao, Yu-Bo Zhang, Lu Guo, Cheng-Ying Jiang, Ji-Guo Qiu, Shuang-Jiang Liu, De-Feng Li.

  Microbial ammonia oxidation is essential for biogeochemical nitrogen cycling and wastewater treatment. Besides the well-studied nitrification and anaerobic ammonia oxidation, a novel ammonia oxidation process referred to as direct ammonia oxidation (dirammox) was recently discovered in heterotrophic nitrifier Alcaligenes members, where ammonia was converted to glutamine and oxidized to hydroxylamine and then to N2 via a gene cluster, dnfABC. Two possible ammonia oxidation mechanisms were proposed, 1) glutamine is converted to some unknown compounds by potential glutamine amidotransferase DnfC and then oxidized to hydroxylamine by oxidase DnfAB, and 2) glutamine is oxidized to l-glutamic acid γ-hydroxamate (L-GlnγHXM) by DnfAB and then hydrolyzed to hydroxylamine by DnfC. Here, we determined the crystal structure of DnfC and identified a conserved catalytic pocket essential for hydroxylamine production and far larger than that required to accommodate a glutamate molecule. We found that the L-GlnγHXM hydrolysis activity is not necessary for hydroxylamine production in E. coli cells harboring dnfABC. Our structural and functional study of DnfC suggested that glutamine was converted to a so-far unknown compound and sequentially oxidized to hydroxylamine and N2.

Keywords:  Alcaligenes; Amidotransferase; Dinitrogen formation; Direct ammonia oxidation (Dirammox); DnfC; Heterotrophic nitrification

DOI:  https://doi.org/10.1016/j.bbrc.2026.153715
STAR Protoc. 2026 Apr 06. pii: S2666-1667(26)00103-6. [Epub ahead of print]7(2): 104450

Protocol for stable isotope tracing of primary human peripheral blood mononuclear cells.

Samantha N Hart, Holden Williams, William B Inabnet, Joshua P Steiner, Varun Jain, Philip A Kern, Cecily R Wood, Barbara S Nikolajczyk, Lance A Johnson.

  Stable isotope tracing gives direct insight into the rate of metabolic reactions occurring in cells by analyzing the incorporation of labeled carbons into metabolic pathways. Here, we present a protocol for stable isotope tracing of primary human peripheral blood mononuclear cells (PBMCs). We describe the steps for culturing and exposing PBMCs to stable isotopes U13C glucose and U13C glutamine. We then detail procedures for derivatization, metabolite purification, and tracing analysis via single-quadrupole gas chromatography-mass spectrometry (GC-MS).

Keywords:  Immunology; Metabolism; Metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2026.104450
J Nanobiotechnology. 2026 Apr 09.

Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.

Xinxin Zhao, Dongmei Lv, Min Wang, Qinyu Guo, Yidi Gao, Wenxiang Fang, Wenlong Zhang, Peipei Wu.

  The systemic progression of lung cancer involves a complex interplay between local tumor microenvironment (TME) dynamics and host-level metabolic decline, culminating in cachexia. Extracellular vesicles (EVs), have emerged as critical mediators in this process. This review constructs a comprehensive model of the "EV-metabolic axis" in lung cancer, framing EVs as natural nanocarriers within a systemic communication network that orchestrates a dual pathological process. Locally, EVs remodel the TME to support tumor growth, metastasis, and therapeutic resistance by transferringdiverse metabolic cargoes. Systemically, they transmit catabolic signals to distant adipose and muscle tissues, driving the severe tissue wasting characteristic of cachexia. This integrated perspective reveals the EV-metabolic axis as a central, targetable node in lung cancer pathology. From a nanomedicine perspective, targeting EV biogenesis, cargo loading, or uptake offers a novel, multifaceted therapeutic strategy to simultaneously inhibit tumor growth and mitigate cachexia, heralding a paradigm shift in future lung cancer treatment Scheme 1. This schematic illustrates the tripartite "EV-Metabolic Axis" framework linking local tumor metabolism, systemic EV trafficking, and cachexia development in lung cancer. In the Local Metabolic Axis, primary tumors and stromal cells (CAFs, TAMs, BMSCs) secrete extracellular vesicles (EVs) that reprogram glucose, lipid, and amino acid metabolism via cargoes such as miRNAs, metabolic enzymes, and cytokines - promoting glycolysis, glutamine addiction, ferroptosis resistance, and epithelial-mesenchymal transition (EMT). In the Circulatory System EV Transport Axis, EVs (40-150 nm exosomes, 50-1000 nm ectosomes) traverse biological barriers via membrane fusion, receptor-mediated endocytosis, or ligand-receptor binding, acting as natural nano-carriers. In the Systemic Cachexia Axis, circulating EVs deliver catabolic signals (e.g., miR-21, IL-6, HSP70/90, TGF-β, PTHrP) to distant organs - triggering adipose tissue browning, lipolysis, myofibrillar atrophy, and mitochondrial dysfunction - culminating in cancer-associated cachexia. This integrated axis positions EVs as both biomarkers and therapeutic targets across the nano-bio interface.

Keywords:  Extracellular vesicles; Lung cancer cachexia; Metabolic remodeling; Nanomedicine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12951-026-04367-5
bioRxiv. 2026 Mar 10. pii: 2026.03.07.710331. [Epub ahead of print]

Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones.

Xingyu Ma, Anne A Leaman, Zeng Lin, Huapeng Li, Zhengjun Cai, Kaiwaan Dalal, Md Shahadat Hossain, Venkatesh P Thirumalaikumar, Zhihong Wang, Valerie P O'Brien, W Andy Tao, Qingfei Zheng.

Histamine is a key signaling molecule in pathophysiology that can exhibit significant regulatory roles in diverse health and disease status. Besides the well-studied noncovalent interactions between histamine and its receptors, protein histaminylation is a recently discovered mode of action, through which histamine regulates cellular signaling pathways in a covalent-interaction manner. Histaminylation is an emerging protein post-translational modification, where an isopeptide bond is formed between the histamine primary amine and γ-carboxyl group of glutamine through a transamidation reaction catalyzed by transglutaminase 2 (TGM2). However, due to the lack of efficient pan-specific antibodies targeting histaminylated glutamine, the histaminylation proteome in cells remains poorly explored. Here, we report the design and development of a novel N τ -propargylated histamine probe as well as its successful application in chemical proteomic profiling of the histaminylation proteome in cancer cells. Notably, new TGM2-catalyzed epigenetic marks on core histones, e . g ., H2AXQ84 and Q104 histaminylation, have been identified from cancer cells and verified in this study.

DOI: https://doi.org/10.64898/2026.03.07.710331
Cancer Discov. 2026 Apr 07.

Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.

Nianxin Zhou, Fan Fei, Lin Tang, Peidong Zhang, Wei Wang, Bohao Zheng, Qiuhong Shen, Jing Yue, Liang Huang, Yiwei Du, Xiaoling Liao, Liang Ouyang, Gang Yuan, Jeremy N Rich, Shengtao Zhou, Linjie Zhao.

Despite successful immuno-oncology therapies in other cancers, they largely failed in glioblastoma(GBM). Here, natural killer (NK) cells from glioma patients show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. Abundance of NDUFA9+ NK cells informed patient outcome. Ndufa9 knockout in NK cells compromised mitochondrial function, anti-tumor efficacy, and memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. Decreased α-ketoglutarate(α-KG)/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming through inducing transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell-based immunotherapy for GBM patients.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0643
Magn Reson Chem. 2026 Apr 05.

NMR-Based Metabolomics Profiling Reveals Dose-Dependent Cardiotoxic Effects of Favipiravir in Rats.

Ali Erdoğan, Akın Mumcu, Zeynep Rozerin Çevik, Ömer Lütfi Özkan, Berat Doğan.

  Metabolomics is a powerful tool for assessing drug safety and understanding the biochemical effects of pharmaceutical compounds. Favipiravir, a drug widely used during the COVID-19 pandemic, has been associated with damage to various organs, including the heart. However, a comprehensive analysis of its metabolic impact on cardiac tissue has not yet been performed. This study utilized high-resolution 1H NMR-based metabolomics to investigate metabolic alterations in rat heart tissue following favipiravir treatment. For this purpose, 60 male Wistar Albino rats were randomly assigned to three groups: control, low-dose favipiravir (200 mg/kg), and high-dose favipiravir (300 mg/kg), with 20 rats in each group. Treatments were administered via oral gavage, and heart tissue samples were collected for 1H NMR analysis after the treatment period. Bioinformatics analysis results showed significant dose-dependent changes in key metabolites in the favipiravir-treated groups. Decreased levels of ATP, citrate, and valine accompanied by increased levels of lactate and AMP suggest a disruption in mitochondrial energy production and a shift towards anaerobic glycolysis. At the higher dose, more pronounced disruptions were noted, including decreases in glutamate, glutamine, aspartate, tyrosine, 3-methylhistidine, and asparagine, suggesting a broader metabolic dysfunction. These findings offer valuable insights into the cardiotoxic effects of favipiravir and highlight the utility of NMR metabolomics in identifying drug-induced metabolic disturbances.

Keywords:  COVID‐19; NMR spectroscopy; favipiravir; heart; metabolomics

DOI:  https://doi.org/10.1002/mrc.70104
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00192-9. [Epub ahead of print]

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.

Chao Qin, Zhenhao An, Shu Feng, Wen Fu, Xinchi Xie, Ali Can Savas, Taolin Xie, Charles Brenner, Takeshi Saito, Pinghui Feng.

  Rapid cancer cell proliferation requires extensive macromolecular biosynthesis, yet how distinct anabolic pathways are coordinated remains incompletely understood. Here, we report that the trifunctional carbamoyl-phosphate synthase, aspartate transcarbamoylase, and dihydroorotase (CAD) activates key glycolytic enzymes to support biosynthesis and cancer cell proliferation. When cancer proteomics datasets were queried, a CAD activation signature was identified in diverse tumors. Metabolomics analysis revealed that CAD fuels central carbon metabolism, specifically the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP). Mechanistically, CAD deamidates and activates glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzymes of the PPP and SSP, respectively, which are fully recapitulated by the glutaminase domain of CAD. Functional interrogation of cancer-associated CAD mutations and human hepatocellular carcinoma tumors predicts the metabolic signature endowed by G6PD and PHGDH deamidation. Simultaneous inhibition of G6PD and PHGDH effectively impeded tumor formation. This work identifies CAD as a central carbon metabolism signaling node and a potential therapeutic target.

Keywords:  CAD; Cancer metabolism; G6PD; PHGDH; central carbon metabolism; deamidation; pyrimidine synthesis; the pentose phosphate pathway; the serine synthesis pathway

DOI:  https://doi.org/10.1016/j.molcel.2026.03.016
Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.

Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.

  Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.

Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite

DOI:  https://doi.org/10.1016/j.canlet.2026.218488
Front Cell Dev Biol. 2026 ;14 1751258

Metabolic profiling of a polycystic ovary syndrome-like organoid model reveals the critical role of glutamine in local endometrial dysregulation related to implantation failure.

Haoxuan Yang, Jing Zhang, Su Long, Yuhuan Xue, Jinfeng Tan, Ge Chen, Yongqi Luo, Ricardo Azziz, Chichiu Wang, Wenming Xu, Xiaomiao Zhao.

  Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by reproductive and metabolic disturbances, which causes a chronic lack of ovulation that leads to increased incidence of atypical endometrial hyperplasia and carcinogenesis. Increasing evidence indicates that metabolic changes may play a crucial role in PCOS pathogenesis; however, the metabolic profile of fluid in PCOS-related endometrium has not yet been characterized. In this study, we successfully constructed three cases of endometrial organoids derived from clinically healthy endometrium. We established a high-androgen model by adding different ratios of estradiol and testosterone to simulate PCOS-like characteristics. Through scanning electron microscopy and immunofluorescence detection, we found that extra androgen treatment-induced cellular damage led to cellular fragments and apoptosis. The intra-organoid fluid (IOF) and extra-organoid fluid (EOF) of the organoids were separated and analyzed by high-throughput quantitative metabolomics. The results showed that amino acid metabolism, specifically glutamine metabolic changes, was the major metabolic pathway altered in the EOF; meanwhile, changes in fatty acids were the main metabolites in the IOF among the groups. Specifically, the in vitro model confirmed that glutamine enhances endometrial stromal cell decidualization with altered mitochondrial function during the implantation process, which may provide the basis for metabolic marker screening and for identifying potential metabolic targets for intervention in female infertility related to PCOS.

Keywords:  endometrial organoids (EOs); extra-organoid fluid (EOF); intra-organoid fluid (IOF); metabolomics; polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.3389/fcell.2026.1751258