bims-glucam 2026-03-15 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–03–15
25 papers selected by
Sreeparna Banerjee, Middle East Technical University

CENPF Promotes Gastric Cancer Proliferation through c-Myc-Mediated GLS1 Upregulation and Glutamine Metabolism.
Exosomes From Cancer-Associated Fibroblasts Promote Colorectal Cancer Progression and Glutamine Metabolism Through METTL1-Mediated m7G Modification of SLC1A5 mRNA.
Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.
Wogonin-derived chemotype enables discovery of novel GLS1 inhibitors with potent antitumor activity.
Ageing promotes metastasis via activation of the integrated stress response.
Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics.
Metabolic networks in the tumor microenvironment: roles of amino acid and lipid metabolism pathways in cancer progression and therapy.
Glutaminase 1 in Vascular Disease: Linking Metabolic Reprogramming to Atherosclerosis Progression and Stability.
The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.
Role of glutamine in promoting the proliferation and chondrogenic differentiation of ATDC5 cells: based on transcriptomic analysis.
Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
MYC-Mediated Functional Manifestation of IDH1 Mutations in Intrahepatic Cholangiocarcinoma Confers Sensitivity to (+)-JQ1.
A mGluR1-targeted radiotheranostic strategy visualizes lesions and potentiates antitumor efficacy in melanoma and pancreatic cancer.
GFPT2 drives sunitinib resistance of renal cell carcinoma via enzyme-dependent and -independent manners.
IFNγ Increases Intracellular Amino Acid Content in Human Alveolar Epithelial Cells: Role of the STAT/IRF1 Axis in the Stimulation of Transmembrane Transport.
Epigenomic and Metabolic Interplay in the Development of Metastatic Brain Tumors.
Clear Cell Foci as Precursors of Hepatocyte Nuclear Factor 1-alpha-inactivated Hepatocellular Adenoma in a Metabolic Syndrome Mouse Model.
Glutamine alleviates Staphylococcus aureus-induced mastitis by modulating macrophage polarisation.
AXIN1 Mutated Hepatocellular Carcinoma.
Bioinformatics Analysis Reveals ALDH5A1: A Novel Molecular Brake on Th17 Cell Pathogenicity in Systemic Lupus Erythematosus.
Circular RNAs: Key Regulators of Tumor Metabolic Reprogramming and Clinical Translation.
Translational regulation by oxidative desulfuration of tRNA modifications.
L-Glutamine attenuates peritoneal fibrosis developed in 5-Fluorouracil-treated mice.
Accurate Measurements of Solvent Exchange in Asparagine and Glutamine Side-Chain NH2 Groups of Proteins by z-Exchange NMR Spectroscopy.
Unlocking the Silent Proteome: Chemoselective Asn/Gln Activation for Multidimensional Protein Diversification.

Oncol Res. 2026 ;34(3): 22

CENPF Promotes Gastric Cancer Proliferation through c-Myc-Mediated GLS1 Upregulation and Glutamine Metabolism.

Min Dong, Zongchang Song, Xiaohui Lu, Minxue Lu, Chen Zhong.

   Background: Gastric cancer (GC) remains highly lethal, with metabolic reprogramming as a key hallmark. This study explores Centromere Protein F (CENPF)'s role in GC pathogenesis, specifically its regulation of glutamine metabolism.
Methods: The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD), GSE19826, and GSE27342 datasets were analyzed by bioinformatics to identify key candidate genes in GC. The function of CENPF was assessed by flow cytometry, colony formation assays, and Cell Counting Kit-8 (CCK-8). RNA sequencing, metabolic profiling, chromatin immunoprecipitation (ChIP), western blot (WB), and luciferase reporter assay were employed to investigate the fundamental mechanisms.
Results: CENPF was upregulated in GC tumor samples and had a high diagnostic potential. CENPF knockdown declined cell proliferation, caused G2 arrest, and promoted apoptosis in GC cells. RNA sequencing revealed that CENPF was involved in glutamine metabolism. CENPF overexpression enhanced glutamine consumption and glutamate production, while glutamine deficiency reversed CENPF-mediated cell survival. CENPF stabilized cellular myelocytomatosis (c-Myc) by preventing proteasomal degradation, bound to the glutaminase (GLS) promoter, promoting glutamine metabolism. Overexpression of GLS or c-Myc rescued the CENPF knockdown's inhibitory effect on GC cell growth.
Conclusion: Our findings identify a new CENPF/c-Myc/GLS axis that affects glutamine metabolism and cell survival in GC, implying that CENPF might be a novel target for the treatment of GC.

Keywords:  Centromere protein F; cellular myelocytomatosis; gastric cancer; glutaminase; glutamine metabolism reprogramming

DOI:  https://doi.org/10.32604/or.2026.068508
J Gastroenterol Hepatol. 2026 Mar 12.

Exosomes From Cancer-Associated Fibroblasts Promote Colorectal Cancer Progression and Glutamine Metabolism Through METTL1-Mediated m7G Modification of SLC1A5 mRNA.

Shuanglong Zhang, Zhihua Chen, Chenyang Ma, Jie Hu, Suyong Lin, Ji Gao, Shaoqin Chen.

   BACKGROUND: Colorectal cancer (CRC) represents a major cause of cancer-related mortality worldwide. Exosomes derived from cancer-associated fibroblasts (CAFs-Exo) transfer oncogenic signals to cancer cells, promoting tumor growth, metastasis, and glutamine metabolism. However, the specific contribution of CAFs-Exo to the pathogenesis of CRC is still largely unexplored.
METHODS: The conditioned medium of CAFs (CAF-CM) and CAFs-Exo were used to treat CRC cells. The effects on cell behaviors were evaluated by measuring cell viability, proliferation, migration, invasion, and sphere formation. The influence on glutamine metabolism was assessed by detecting glutamine consumption and glutamine and α-ketoglutarate production. MeRIP, RIP, RNA pull-down, and mRNA stability assays were used to assess the METTL1/SLC1A5 mRNA interaction. Animal experiments were used to evaluate the function of CAFs-Exo in vivo.
RESULTS: CAF-CM promoted CRC cell proliferation, migration, invasion, sphere formation, and glutamine metabolism in vitro. CAF-CM increased METTL1 expression and m7G modification levels in CRC cells. Si-METTL1-CAF-CM exerted inhibitory effects on CRC cell malignant behaviors and glutamine metabolism. Mechanistically, METTL1 stabilized SLC1A5 mRNA by mediating its m7G modification. SLC1A5 overexpression reversed the inhibitory effects of si-METTL1-CAF-CM on CRC cell malignant behaviors and glutamine metabolism. Furthermore, CAFs-Exo increased METTL1 protein levels in CRC cells. Sh-METTL1-CAFs-Exo suppressed tumor growth and lung metastasis in vivo.
CONCLUSION: Our findings identify a novel CAFs-Exo/METTL1/SLC1A5 axis that drives CRC progression partially by reprogramming glutamine metabolism, revealing new potential therapeutic targets for CRC treatment.

Keywords:  cancer‐associated fibroblasts; colorectal cancer; exosomes; glutamine metabolism; m7G modification

DOI:  https://doi.org/10.1111/jgh.70334
Mol Biomed. 2026 Mar 10. pii: 25. [Epub ahead of print]7(1):

Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.

Mingkang Yu, Di Yang, Xiuli Chen, Yuling Yang, Bingqiang Zhang, Xinxin Jiang, Lijie Xing, Yuxuan Yang, Yani Sun, Ning Li.

  Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). Cancer cells exhibit enhanced glucose and glutamine uptake, increased glycolysis, pentose phosphate pathway activity, de novo lipogenesis, and altered amino acid metabolism. However, the metabolic crosstalk underlying cancer progression and the strategic directions for drug development remain insufficiently synthesized. This review systematically summarizes the functional mechanisms of key signaling regulators involved in cancer metabolic reprogramming, including mammalian target of rapamycin complex 1 (mTORC1), myelocytomatosis viral oncogene homolog (c-Myc), hypoxia-inducible factor-1α (HIF-1α), activating transcription factor 4 (ATF4), nuclear factor erythroid 2-related factor 2 (NRF2), and sterol regulatory element-binding protein 1 (SREBP1). Notably, we highlight the interconnections among metabolic pathways in cancer cells and the signaling hubs that orchestrate metabolic crosstalk, which together constitute an integrated network of metabolic pathways and their regulatory signals. Metabolic targets and metabolism-directed therapeutic agents with substantial developmental potential are comprehensively summarized, providing up-to-date insights and concrete directions for metabolism-targeted cancer therapy. Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.

Keywords:  Glutamine; Glycolysis; Hepatocellular carcinoma; Lipogenesis; Metabolic reprogramming; Metabolism-targeted therapy

DOI:  https://doi.org/10.1186/s43556-026-00427-2
Future Med Chem. 2026 Mar 12. 1-14

Wogonin-derived chemotype enables discovery of novel GLS1 inhibitors with potent antitumor activity.

Xuhong Li, Yan Liang, Xiaoyu Zhang, Yongsheng Wu, Tizhi Wu, Yucheng Tian, Cheng Tang, Zhixia Qiu, Hongxi Wu, Jinlei Bian, Zhiyu Li, Xi Xu, Jubo Wang.

   AIMS: This study evaluates LX-191, a wogonin-derived glutaminase-1 (GLS1) inhibitor featuring a non-BPTES chemotype, designed to overcome the limitations of existing GLS1-targeted therapies.
MATERIALS AND METHODS: Following targeted screening to identify the flavone-based inhibitor LX-191, we assessed its GLS1 inhibitory potency and antiproliferative effects in A549 and HCT116 cells. In vivo therapeutic efficacy was evaluated using an A549 xenograft model, alongside mechanistic studies to determine its impact on oncogenic signaling.
RESULTS: LX-191 effectively inhibited GLS1 (IC50 = 15.17 μM) and demonstrated potent antiproliferative activity in A549 and HCT116 cells. In A549 xenografts, LX-191 achieved 50.3% tumor growth inhibition at 10 mg/kg, outperforming CB-839 (21.6%) under identical conditions. Mechanistically, LX-191 attenuated glutamine metabolism while concurrently suppressing signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) signaling, leading to G1 phase cell cycle arrest and induction of autophagy.
CONCLUSIONS: The findings establish LX-191 as a promising flavone-based, non-BPTES lead for GLS1 inhibition, exhibiting multi-pathway antitumor activity both in vitro and in vivo. This work provides a tractable lead compound for the development of next-generation GLS1 therapeutics.

Keywords:  Glutamine metabolism; anti-tumor; glutaminase 1 inhibitor; natural product derivatives; wogonin

DOI:  https://doi.org/10.1080/17568919.2026.2642584
Nature. 2026 Mar 11.

Ageing promotes metastasis via activation of the integrated stress response.

Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.

Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.

DOI: https://doi.org/10.1038/s41586-026-10216-0
World J Stem Cells. 2026 Feb 26. 18(2): 113694

Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics.

Daniyaer Dilimulati, Diyaer Dilimulati, Lei Cui.

   BACKGROUND: Adipose-derived stem cells (ADSCs) hold significant therapeutic potential for regenerative medicine, particularly in wound healing, owing to their multipotency, paracrine activity, and relative abundance. However, the clinical application of ADSC-based therapies is substantially limited by the harsh microenvironment of acute wounds, characterized by hypoxia, nutrient deprivation, and oxidative stress, which leads to massive apoptotic cell death post-transplantation. Preconditioning strategies to enhance cellular resilience have thus gained considerable interest. Recent insights from cancer biology highlight the crucial role of metabolic reprogramming, orchestrated by hypoxia-inducible factor-1α (HIF-1α), in promoting survival under stress. Our previous work demonstrated that preconditioning with α-ketoglutarate (α-KG) enhances ADSC survival and accelerates wound healing, purportedly through HIF-1α upregulation. Nevertheless, the precise metabolic mechanisms by which α-KG preconditioning confers cytoprotection remain incompletely elucidated.
AIM: To investigate the mechanistic role of HIF-1α in mediating the enhanced survival and regenerative capacity of α-KG-preconditioned ADSCs in an acid burn wound model. Specifically, we sought to determine whether HIF-1α activation drives complementary adaptations in glutamine and glycogen metabolism to maintain redox and energy homeostasis, respectively, under the multifactorial stress conditions of a wound.
METHODS: Human ADSCs were isolated from lipoaspirates and preconditioned with dimethyl-α-KG. In vitro, cells were subjected to single or combined stressors (hypoxia, glucose deprivation, H2O2-induced oxidative stress). Genetic modulation was performed using lentiviral shRNAs targeting HIF-1α, GLS1, and PYGL, or an overexpression vector for GLS1. Metabolic profiling included assessments of glycolytic flux, glucose oxidation, fatty acid β-oxidation, oxygen consumption, and glycogen content. Redox status was evaluated via glutathione (GSH) (GSH/GSH disulfide) ratios and reactive oxygen species (ROS) levels. In vivo, a murine acid burn wound model was established, and pre-labeled ADSCs were implanted. Cell survival was tracked via flow cytometry (Annexin V-PI) and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Wound healing was assessed histologically.
RESULTS: α-KG preconditioning significantly enhanced the survival of ADSCs both in vitro under stress and in vivo in burn wounds. This was concomitant with HIF-1α stabilization. Mechanistically, HIF-1α orchestrated a dual metabolic adaptation: (1) It promoted glutaminolysis via GLS1, increasing glutamate and GSH synthesis, which enhanced antioxidant capacity and reduced ROS levels; and (2) It simultaneously stimulated glycogen storage (Gys1 upregulation) and mobilization (Pygl upregulation), preserving energy (ATP:AMP ratio) during glucose deprivation. Genetic inhibition of GLS1 abrogated the ROS detoxification benefit, while PYGL knockdown abolished the energy maintenance advantage, both reducing survival. Crucially, combined inhibition of both pathways completely negated the prosurvival effect of α-KG, confirming their synergistic role. In vivo, α-KG-preconditioned ADSCs accelerated wound closure, improved re-epithelialization, and enhanced angiogenesis compared to controls, effects that were HIF-1α-dependent.
CONCLUSION: This study demonstrates that α-KG preconditioning significantly enhances ADSC survival and therapeutic efficacy in burn wound healing through HIF-1α-mediated metabolic reprogramming. HIF-1α activation coordinately upregulates glutamine-driven GSH synthesis for redox homeostasis and glycogen storage for bioenergetic resilience, providing a dual mechanism of cytoprotection. These findings establish metabolic preconditioning as a potent, translatable strategy to improve the efficacy of stem cell-based therapies not only in wound healing but potentially in other ischemic and inflammatory conditions characterized by poor cell survival.

Keywords:  Adipose-derived stem cells; Alpha-ketoglutarate; Glycogen metabolism; Hypoxia-inducible factor 1-alpha; Oxidative stress; Redox homeostasis; Wound healing

DOI:  https://doi.org/10.4252/wjsc.v18.i2.113694
Exp Mol Med. 2026 Mar 13.

Metabolic networks in the tumor microenvironment: roles of amino acid and lipid metabolism pathways in cancer progression and therapy.

Yulseung Sung, Dae Kyoung Kim, Jun Se Kim, Seong-Jang Kim, Jae Ho Kim, Jung Min Han.

Metabolic rewiring, a defining hallmark of cancer, sustains cell proliferation and biosynthesis while coordinating adaptive interactions within the tumor microenvironment (TME). Recent advances reveal that metabolism in the TME-comprising stromal, immune and endothelial components forms a complex metabolic network in which intercellular competition, cooperation and plasticity profoundly influence tumor progression and therapeutic responses. Here we integrate emerging evidence on the organizational principles of amino acid and lipid metabolism within the TME, emphasizing how nutrient fluxes shape immune evasion, therapeutic resistance and metabolic symbiosis. We highlight key mechanisms through which cancer and nonmalignant cells engage in reciprocal nutrient manipulation, focusing on glutamine, arginine, tryptophan, branched-chain amino acids and lipids. The dual roles of these metabolites in immune regulation and tumor growth reveal the limitations of traditional single-pathway targeting and advocate for a network-centric therapeutic approach. We further discuss how metabolite-derived signaling and epigenetic regulation reinforce cell state transitions and immune suppression. Current and emerging therapeutic strategies, including multitarget combinations and immune-metabolic synergies, are evaluated alongside translational challenges. Finally, we underscore the need for spatial metabolomics, liquid biopsy platforms and artificial intelligence-driven modeling to map nutrient competition and cooperative exchange within the TME, offering new opportunities for precision metabolic interventions.

DOI: https://doi.org/10.1038/s12276-026-01697-0
J Cardiovasc Transl Res. 2026 Mar 11. pii: 41. [Epub ahead of print]19(1):

Glutaminase 1 in Vascular Disease: Linking Metabolic Reprogramming to Atherosclerosis Progression and Stability.

Xi-Long Zheng, Hao Yin, Zhihan Tang, Zhixin Shan, Xiaoyan Dai.

  Glutaminase-1 (GLS1) converts glutamine to glutamate, fueling anaplerosis, redox defense, and biosynthesis. We synthesize animal, cellular, and human (bulk/single-cell) data to define cell- and stage-specific roles of GLS1 in atherosclerosis and to outline translational opportunities. In early disease, GLS1 drives vascular smooth muscle proliferation, endothelial sprouting, and inflammatory macrophage activation, promoting plaque growth and neovascularization. In advanced plaques, GLS1 sustains fibrous-cap VSMC survival, endothelial barrier function, and macrophage efferocytosis, limiting necrosis and enhancing stability; excessive glutamate may favor calcification. We also connect GLS1 to vascular senescence and ferroptosis. We propose precision use of GLS1 modulation: a proof-of-concept strategy is short-term telaglenastat (CB-839) after angioplasty to curb neointimal hyperplasia, guided by glutamine-PET and biomarkers to avoid destabilizing mature plaques. GLS1 emerges as a tunable metabolic checkpoint whose effects depend on cell state and disease stage; judicious, time-limited modulation could complement lipid-lowering and anti-inflammatory therapies in cardiovascular disease.

Keywords:  Atherosclerosis; Endothelial Cell; Ferroptosis; Glutaminase-1; Macrophage; Senescence; Vascular Smooth Muscle Cell

DOI:  https://doi.org/10.1007/s12265-026-10743-1
Front Immunol. 2026 ;17 1779543

The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.

Peng Su, Ying Yang, Hong Zheng.

  As a pivotal contributor to tumor metabolism following glucose and glutamine, serine plays a crucial role in the metabolic network of tumors via its de novo synthesis pathway (SSP). The SSP is aberrantly activated in a variety of malignant tumors and promotes tumor progression through multi-dimensional mechanisms. On the one hand, it provides the material basis and one-carbon units required for the synthesis of nucleotides, proteins and phospholipids to support the rapid proliferation of tumor cells. On the other hand, it maintains cellular redox homeostasis by generating glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, it regulates the tumor immune microenvironment through metabolic reprogramming, inducing macrophage polarization and modulating T-cell function, thereby shaping an immunosuppressive microenvironment. The activity and stability of key enzymes in the SSP are precisely regulated by transcription factors (such as c-Myc, HIF-1α, and NRF2), epigenetic modifications (including m5C and m6A), and post-translational modifications (such as methylation, ubiquitination, and deacetylation). Meanwhile, the SSP forms an interactive network with tumor signaling pathways including Akt, mTOR, and EGF-ERK, collectively driving metabolic reprogramming. Therapeutic strategies targeting the SSP have emerged as a research hotspot, encompassing dietary intervention, the development of inhibitors targeting key enzymes such as phosphoglycerate dehydrogenase (PHGDH), as well as combination therapies with radiotherapy, chemotherapy and immunotherapy. Notably, these strategies have shown promising potential in reversing drug resistance to BRAF inhibitors, sorafenib, 5-fluorouracil (5-FU) and other agents, providing novel strategies for pan-cancer therapy. Through a systematic and comprehensive analysis of the multi-dimensional functions, heterogeneous regulation and roles in therapeutic resistance of the SSP across cancer types, this review aims to elucidate the conserved principles and cancer-specific characteristics of the SSP as a metabolic hub. Additionally, we discuss the prospects and unique challenges of precise intervention strategies targeting the SSP in overcoming tumor heterogeneity and drug resistance.

Keywords:  metabolic reprogramming; phosphoglycerate dehydrogenase (PHGDH); serine metabolism; serine synthesis pathway (SSP); targeted therapy; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1779543
Mol Biol Rep. 2026 Mar 12. pii: 483. [Epub ahead of print]53(1):

Role of glutamine in promoting the proliferation and chondrogenic differentiation of ATDC5 cells: based on transcriptomic analysis.

Rui-Hao Zhang, Wen-Huan Yuan, Ze-Long Wang, Qi-Rui Yang, Yi Sun, Quan-Nian Shao, Wen-Ji Wang, Jing Wang.



Keywords:  ATDC5 cells; Chondrogenesis; Glutamine; Osteoarthritis; PI3K-AKT signalling pathway

DOI:  https://doi.org/10.1007/s11033-026-11619-y
Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00189-8. [Epub ahead of print] 218426

Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.

Emma Martell, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Charul Jain, Christopher M Anderson, Tanveer Sharif.

  Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.

Keywords:  Cancer metabolism; brain tumors; epigenetics; metabolic therapy; tumor signaling

DOI:  https://doi.org/10.1016/j.canlet.2026.218426
Int J Biol Sci. 2026 ;22(5): 2247-2264

MYC-Mediated Functional Manifestation of IDH1 Mutations in Intrahepatic Cholangiocarcinoma Confers Sensitivity to (+)-JQ1.

Fangyanni Wang, Xinyu Liu, Ning Zhang, Ruirui Kong.

  Intrahepatic cholangiocarcinoma (ICC) is one of most aggressive malignancies attributable to limited treatment options. IDH1 is commonly mutated and frequently cooccurred with other genetic alterations in ICC. The mechanism by which they affect ICC patient prognosis and therapeutic resistance remains incompletely understood. We aimed to investigate the function of MYC in IDH1mutant ICC progression and develop the novel therapeutic strategies. We well-established spontaneous ICC mouse models using transposon-based Idh1 and Kras mutations system in liver-specific knockout Trp53 mice. We generated multiple independent primary ICC cells and organoids derived from tumor tissues and established subcutaneous allograft ICC tumors. Together, multiple models in our studies were utilized to elucidate the role of MYC in IDH1-mutant ICC progression and to investigate therapeutic strategies. We demonstrated that the IDH1 mutations correlated with a favorable outcome in ICC patients and murine models. However, MYC overexpression drove the malignant phenotypic manifestation of Idh1 mutations, reversing this phenotype. Mechanistically, Idh1-mutant ICC reprogrammed glutamine metabolism to regulate Myc expression. Notably, ICC with concurrent IDH1 mutations and MYC amplification exhibited sensitivity to the MYC inhibitor (+)-JQ1, but remained resistant to the IDH1 mutation inhibitor AG120. This study identified MYC as a critical pathogenic driver of malignant progression in IDH1-mutant ICC. MYC overexpression conferred resistance to IDH1 mutation inhibitor, while creating a therapeutic vulnerability to MYC-targeted agents. The selective efficacy of (+)-JQ1 against IDH1-mutant ICC identified MYC inhibition as a promising precision medicine strategy for this molecular subset.

Keywords:  (+)-JQ1; ICC; IDH mutation; MYC; glutaminolysis

DOI:  https://doi.org/10.7150/ijbs.123085
Mol Ther. 2026 Mar 10. pii: S1525-0016(26)00118-8. [Epub ahead of print]

A mGluR1-targeted radiotheranostic strategy visualizes lesions and potentiates antitumor efficacy in melanoma and pancreatic cancer.

Lin Xie, Masayuki Hanyu, Masayuki Fujinaga, Yiding Zhang, Tomomi Kokufuta, Katsushi Kumata, Wakana Mori, Kazui Nakamoto, Takayuki Ohkubo, Hidekatsu Wakizaka, Katsuyuki Minegishi, Lulu Zhang, Rui Luo, Feng Wang, Nobuki Nengaki, Kotaro Nagatsu, Ming-Rong Zhang.

  Targeting metabotropic glutamate receptor 1 (mGluR1), an oncoprotein involved in glutamine metabolism that is frequently overexpressed in most cancers, is a promising strategy for cancer treatment and management. Here, we engineered a radiotheranostic strategy to target mGluR1 by integrating positron emission tomography (PET)-guided targeted α-particle therapy (TAT) with a small-molecule pair, β+-emitting 11C-IMTM and α-emitting 211At-AMTM, to identify and eradicate refractory cancers, including melanoma and pancreatic cancer. 11C-IMTM PET clearly visualized the primary and metastatic melanoma burden; α-particles from 211At-AMTM anchored to mGluR1 downregulated this oncoprotein, which was subsequently internalized to trigger cancer cell senescence via the p21/caveolin-1 pathway. In mice with localized and metastatic melanoma, a single dose of 211At-AMTM induced a >86% reduction in tumor volume and a 2-fold increase in survival. Moreover, 46.67% (7/15) of the tumor-bearing mice exhibited complete elimination of pancreatic cancer without significant toxicity. This mGluR1-targeted radiotheranostic strategy, 11C-IMTM PET-guided 211At-AMTM TAT, represents an effective approach for the diagnosis and treatment of melanoma and pancreatic cancer and provides unique insights into the clinical development and application of approaches targeting cancer-specific metabolic vulnerabilities.

Keywords:  (11)C-IMTM; (211)At-AMTM; melanoma; metabotropic glutamate receptor 1; oncoprotein; pancreatic cancer; positron emission tomography; radiopharmaceutical; radiotheranostics; targeted α-particle therapy

DOI:  https://doi.org/10.1016/j.ymthe.2026.02.032
Int J Biol Sci. 2026 ;22(5): 2324-2342

GFPT2 drives sunitinib resistance of renal cell carcinoma via enzyme-dependent and -independent manners.

Songbo Wang, Jiajun Xing, Xiaoyi Wang, Zengjun Wang, Pengfei Shao, Chenkui Miao.

  Intrinsic resistance to sunitinib in advanced renal cell carcinoma (RCC) remains a major barrier to improving patient survival outcomes. However, the molecular mechanisms driving this resistance remain incompletely elucidated. In this study, we first observed elevated glutamine levels in sunitinib-resistant RCC models; notably, glutamine deprivation substantially impaired the growth and proliferation of RCC cells. We further demonstrated that abnormal upregulation of GFPT2-a key enzyme in glutamine metabolism-was associated with reduced sunitinib sensitivity and enhanced drug resistance in RCC. Mechanistically, we uncovered that GFPT2 modulates cellular O-GlcNAcylation levels, which in turn enhances the stability and nuclear translocation of YAP1-ultimately contributing to reduced sunitinib sensitivity. In addition, we also identified an additional non-metabolic role of GFPT2: it directly interacts with the Kelch domain of KEAP1, thereby reducing NRF2 binding to this domain and suppressing NRF2 ubiquitination-dependent degradation. Consequently, this regulatory cascade dysregulates the transcription of downstream antioxidant genes (e.g., HMOX1 and NQO1), ultimately driving NRF2-dependent sunitinib resistance in RCC. Critically, this KEAP1-NRF2 axis-mediated mechanism operates independently of GFPT2's metabolic role in regulating O-GlcNAcylation. Collectively, our findings demonstrate that GFPT2 modulates sunitinib sensitivity and drives drug resistance in RCC via dual mechanisms: a metabolic pathway (O-GlcNAcylation-YAP1) and a non-metabolic pathway (KEAP1-NRF2). Targeting the non-metabolic functions of GFPT2 thus holds promise for enhancing sunitinib sensitivity in RCC while potentially mitigating treatment-related side effects.

Keywords:  GFPT2; O-GlcNAcylation; Renal cell carcinoma; TKI resistance; non-metabolic function

DOI:  https://doi.org/10.7150/ijbs.118985
Int J Mol Sci. 2026 Feb 26. pii: 2220. [Epub ahead of print]27(5):

IFNγ Increases Intracellular Amino Acid Content in Human Alveolar Epithelial Cells: Role of the STAT/IRF1 Axis in the Stimulation of Transmembrane Transport.

Amelia Barilli, Rossana Visigalli, Eleonora Crescini, Giulia Recchia Luciani, Valeria Dall'Asta, Bianca Maria Rotoli.

  Interferon-γ (IFNγ), a key inflammatory cytokine that orchestrates immune responses, also emerges as a regulator of cellular metabolism; however, in alveolar epithelial cells its impact on amino acid homeostasis remains poorly defined. Here, we investigated the effects of IFNγ on intracellular amino acid content and transmembrane transport in human alveolar epithelial A549 cells, focusing on the contribution of the JAK/STAT/IRF1 signaling axis. To this end, A549 WT and IRF1 knockout (IRF1 KO) cells were used to investigate IRF1 contribution, and baricitinib to evaluate the role of the JAK/STAT pathway. HPLC analysis reveals that in WT, but not in IRF1 KO cells, IFNγ markedly increases the intracellular concentration of many amino acids, including glutamine, glutamate, and several neutral and cationic amino acids, without affecting the cell volume, thus indicating true metabolic accumulation. The measurement of the transmembrane uptake of specific radiolabeled amino acids demonstrates a concomitant increase in transport Systems ASC, A, L, and y+ activity; an upregulation of the related transporters ASCT2, SNAT2, LAT1, and CAT1 has also been observed by means of qPCR analysis. Moreover, conditioned medium from SARS-CoV-2 spike-activated macrophages recapitulates IFNγ-driven amino acid remodeling in a JAK/STAT/IRF1-dependent manner. Overall, our findings identify IFNγ as a potent regulator of intracellular amino acid availability in alveolar epithelial cells through the modulation of the activity of membrane transporters. The observed IFNγ-reprogramming is IRF1 dependent, ascribing a crucial role to this transcription factor in linking inflammation and amino acid metabolism.

Keywords:  System ASC; alveolar epithelial cells; amino acid transport; interferon-γ

DOI:  https://doi.org/10.3390/ijms27052220
Oncol Res. 2026 ;34(3): 7

Epigenomic and Metabolic Interplay in the Development of Metastatic Brain Tumors.

Vishal Rastogi, Deepak Verma, Saurabh Verma, Prakash Haloi, Shruti Kapoor, Havagiray R Chitme, Nethaji Muniraj, Priyanka Saroj.

  Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment. Hypoxia-inducible factor-1α (HIF1α) enhances glycolytic flux, lactate accumulation, and histone lactylation, collectively supporting metastatic colonization and immune evasion. Key metabolites including acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate (α-KG), fumarate, and 2-hydroxyglutarate (2-HG)-directly modify chromatin states by regulating histone acetyltransferases, DNA/histone methyltransferases, and α-KG dependent dioxygenases such as Ten-Eleven Translocation (TET) enzymes and lysine demethylases (KDMs). These metabolic shifts result in aberrant DNA methylation, histone lysine residue at position 27 on Histone H3 (H3K27) trimethylation, and depletion of 5-hydroxymethylcytosine (5hmC), all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System (CNS) tumors. Additionally, the blood-brain barrier (BBB) and blood-tumor barrier (BTB) impose nutrient restrictions and induce metabolic dependency on glutamine, acetate, and lactate shuttling, thereby reshaping epigenetic enzyme activity. We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity, stemness, and therapeutic resistance. Understanding these coupled pathways reveals vulnerable nodes such as HIF1α signaling, α-KG-dependent demethylation, and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors. The present review aims to provide in-depth insights into epigenetic regulation, including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming, highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.

Keywords:  Metabolic reprogramming; brain tumor; epigenetic alteration

DOI:  https://doi.org/10.32604/or.2026.072620
Acta Histochem Cytochem. 2026 Feb 27. 59(1): 59-68

Clear Cell Foci as Precursors of Hepatocyte Nuclear Factor 1-alpha-inactivated Hepatocellular Adenoma in a Metabolic Syndrome Mouse Model.

Orgil Jargalsaikhan, Mayuko Ichimura-Shimizu, Wenhua Shao, Hirohisa Ogawa, Shotaro Tachibana, Shinichiro Yamada, Mitsuko Sutoh, Hirosuke Tawara, Shogo Kawashima, Takeo Minamikawa, Koichi Tsuneyama.

  Clear cell foci (CCF) are frequently observed in metabolic dysfunction-associated steatohepatitis (MASH) and are considered potential precursor lesions of hepatocyte nuclear factor 1α-inactivated hepatocellular adenoma (H-HCA). To clarify their chronological development, we examined 55 male TSOD mice at 24, 32, 40, and 48 weeks of age using histology and immunohistochemistry for glutamine synthetase (GS), liver fatty acid-binding protein (L-FABP), β-Klotho, and fibroblast growth factor 21 (FGF21). CCF first appeared at 24 weeks and increased markedly with age (from 11% to 81%). All CCF were positive for β-Klotho, and a subset showed FGF21 expression, indicating that CCF represent a hepatocellular state associated with metabolic dysregulation. H-HCA, characterized by GS negativity and reduced L-FABP expression, emerged at 40 weeks and reached an incidence of 29% at 48 weeks. Notably, multiple H-HCA were partially or completely surrounded by β-Klotho-positive CCF, suggesting a morphologic continuum from CCF to H-HCA. Raman spectroscopic analysis demonstrated that CCF exhibit prominent autofluorescence and possess spectral characteristics distinct from both background hepatocytes and tumor tissue, supporting the concept that CCF represent a unique hepatocellular state. These findings indicate that metabolic abnormalities in TSOD mice promote the sequential formation of CCF and H-HCA, establishing this model as a useful platform for studying adenoma development in metabolic liver disease.

Keywords:  Tsumura Suzuki Obese Diabetes mouse; clear cell foci; glutamine synthetase; hepatocellular adenoma; liver fatty acid–binding protein

DOI:  https://doi.org/10.1267/ahc.25-00053
PLoS Pathog. 2026 Mar 11. 22(3): e1014053

Glutamine alleviates Staphylococcus aureus-induced mastitis by modulating macrophage polarisation.

Chunhui Feng, Miao Liu, Zhaoqi He, Yixiao Liu, Weijie Yuan, Pingan Xie, Caijun Zhao, Xiaoyu Hu, Yunhe Fu, Fanglei Han, Yue Zhang, Peng Luyuan.

Mastitis, a major dairy industry challenge, is often caused by Staphylococcus aureus (S. aureus). Previous research linked gut microbiota disruption-induced by vancomycin in mice-to reduced microbial glutamine and increased mastitis susceptibility. This study hypothesizes that oral glutamine may regulate macrophage function and mitigate S. aureus mastitis. Our results showed that glutamine attenuated S. aureus-induced mastitis, protected the blood-milk barrier function, increased M2-type macrophages in the mammary gland, and increased the concentration of its metabolite α-Ketoglutaric acid (αKG) in both serum and mammary gland. In addition, the addition of αKG in mice significantly increased the transformation of M2-type macrophages and attenuated S. aureus-induced mastitis. Further studies revealed that αKG could initiate autophagy via oxidative phosphorylation, which in turn regulated the expression of Suppressor of cytokine signaling (SOCS3), a negative feedback inhibitor of the JAK/STAT signalling pathway. In vitro experiments verified that αKG enhances autophagy in macrophages, activates the JAK-STAT pathway, thereby promoting M2 polarization and alleviating S. aureus mastitis. This study revealed the key role of glutamine and its metabolite αKG in the mammary gland's resistance to pathogenic infections, and reveal the mechanism by which they regulate macrophage polarization, providing theoretical guidance for solving the prevention and treatment problems of mastitis. This highlights a potential dietary intervention for mastitis management in dairy cows, bridging gut health and infection resistance.

DOI: https://doi.org/10.1371/journal.ppat.1014053
Am J Surg Pathol. 2026 Mar 10.

AXIN1 Mutated Hepatocellular Carcinoma.

Michael Torbenson, Chantal E McCabe, Jessica D Hohenstein, Daniel O'Brien, Zongming E Chen, Tsung-Teh Wu, Sanjay Kakar, Nguyen H Tran, Chen Wang.

  CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change.

Keywords:  APC; AXIN1; CTNNB1; beta catenin; glutamine synthetase; hepatocellular carcinoma

DOI:  https://doi.org/10.1097/PAS.0000000000002528
FASEB J. 2026 Mar 31. 40(6): e71642

Bioinformatics Analysis Reveals ALDH5A1: A Novel Molecular Brake on Th17 Cell Pathogenicity in Systemic Lupus Erythematosus.

Hui Yu, Sensen Su, Zhanchuan Ma, Zheng Xu, Huanfa Yi.

  Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with diverse clinical manifestations, in which aberrant Th17 cell differentiation plays a critical pathogenic role and contributes to the persistent challenges in its treatment. We performed a bioinformatics analysis using RNA sequencing (RNA-seq) data obtained from the GEO database, with the aim to identify genes with altered expression during SLE progression that may be associated with Th17 cell differentiation. Our analysis identified 12 glutamine metabolism-related genes (GlnMRGs) and constructed a nomogram to indicate the risk of SLE. Among the GlnMRGs, ALDH5A1 is the highest-scoring gene in the random forest (RF) model. In patients with SLE, the expression of ALDH5A1 in the peripheral blood was reduced, and it was inversely correlated with the Th17 immune score (r = -0.51) and negatively correlated with SLEDAI score (r = -0.2066, p < 0.001). Additionally, single-cell RNA sequencing (scRNA-seq) confirmed that the expression of ALDH5A1 was downregulated specifically in Th17 cells. To validate these conclusions, we performed verification in SLE patients and pristane-induced mouse models. Additionally, we performed in vitro assays using small interfering RNA (siRNA) and overexpression plasmids. The functional findings confirmed that Aldh5a1 knockdown aggravated the activation, proliferation, and Th17 differentiation of CD4+ T cells, while overexpression of Aldh5a1 suppressed this phenomenon. Collectively, our findings suggest that ALDH5A1 may influence Th17 differentiation and play a role in the pathogenesis of SLE.

Keywords:  CD4+ T cells; SLE; Th17 differentiation; genes related to glutamine metabolism

DOI:  https://doi.org/10.1096/fj.202503998R
Oncol Res. 2026 ;34(3): 1

Circular RNAs: Key Regulators of Tumor Metabolic Reprogramming and Clinical Translation.

Yimao Wu, Yitong Liu, Ruowei Sun, Yiyuan Zhang, Qian Zhang, Chen Li, Mengyao Li.

  Tumor metabolic reprogramming is a core hallmark of cancer, characterized by pathways such as aerobic glycolysis, aberrant lipid metabolism, and glutaminolysis that support rapid proliferation and immunosuppressive microenvironments. Circular RNAs (circRNAs) are highly stable, evolutionarily conserved non-coding RNAs that have emerged as critical modulators of these metabolic shifts. This review aims to systematically elucidate the roles and mechanisms of circRNAs in reprogramming tumor metabolism, and to discuss their clinical potential as biomarkers and therapeutic targets. Through mechanisms including miRNA sponging, protein interactions, regulation of mitochondrial dynamics, and modulation of metabolic enzymes, circRNAs influence key metabolic pathways by targeting glycolytic enzymes, lipid synthesis regulators, and glutaminolysis-related molecules to either facilitate or inhibit their expression. This review systematically summarizes the unique contributions of circRNAs to tumor metabolic reprogramming, highlighting key mechanisms such as regulation of peptide-encoding protein translation, mitochondrial localization function, gene promoter-targeted transcriptional regulation, and cross-pathway metabolic mediation, which underscore their distinct biological advantages and regulatory roles in tumor metabolism. The stability and tissue specificity of circRNAs make them promising diagnostic biomarkers, while their role in drug resistance mediated by metabolic reprogramming highlights their potential as therapeutic targets. Strategies such as circRNA inhibitors, mimics, and nanoparticle-based delivery systems are being explored to modulate tumor metabolism. Despite challenges including complex regulatory networks and limited manipulation tools, advances in high-throughput technologies and clinical trials hold promise for translating circRNA research into novel cancer therapies.

Keywords:  Biomarkers; circRNAs; glutaminolysis; lipid metabolism; metabolic reprogramming; therapeutic targets; tumor metabolism

DOI:  https://doi.org/10.32604/or.2026.075012
Nat Commun. 2026 Mar 10. pii: 2125. [Epub ahead of print]17(1):

Translational regulation by oxidative desulfuration of tRNA modifications.

Yufeng Mo, Kensuke Ishiguro, Kenjyo Miyauchi, Yuriko Sakaguchi, Yosei Hanzawa, Naho Akiyama, Ayaka Murayama, Kodai Machida, Hiroaki Imataka, Akio Yamashita, Takayuki Ohira, Mikako Shirouzu, Tsutomu Suzuki.

Modifications in the anticodon region of transfer RNA (tRNA) are essential for accurate and efficient protein synthesis. 5-Methyl-2-thiouridine derivatives (xm5s2U) are major modifications at the wobble position of tRNA anticodons decoding purine-ending two-codon sets. Although the thiocarbonyl group of xm5s2U enhances decoding efficiency, it is chemically susceptible to oxidative desulfuration, yielding 4-pyrimidinone derivatives (xm5h2U). Here, we identify xm5h2U derivatives in human cells and mouse tissues and confirm their cellular formation by spike-in experiments. Desulfurized tRNAs carrying 5-methoxycarbonylmethyl-4-pyrimidinone (mcm5h2U) show impaired codon recognition in a human reconstituted in vitro translation system. The mcm5h2U modification reduces aminoacylation of tRNAs for lysine, glutamate, and glutamine, but not arginine. Cryogenic electron microscopy reveals the structural basis of altered AAA/AAG decoding by mcm5h2U at the ribosomal A-site. These findings reveal a mechanism by which oxidative desulfuration of tRNA modifications dynamically regulates codon recognition and protein synthesis under oxidative stress conditions in human and mammalian cells.

DOI: https://doi.org/10.1038/s41467-026-70126-7
Exp Biol Med (Maywood). 2026 ;251 10755

L-Glutamine attenuates peritoneal fibrosis developed in 5-Fluorouracil-treated mice.

Juliana Francisca Grossi Heleno, Leticia Cristine Cardoso Dos Santos, Igor Campos Fontes, Mirielly Ranny Almeida Paiva Silva, Lucas Barbosa Correia, Nayma Drielly Granato Silva, Pedro Henrique Dias Moura Prazeres, Pedro Pires Goulart Guimarães, Derek W Gilroy, Silvia Passos Andrade, Paula Peixoto Campos.

  Peritoneal fibrosis is an adverse effect of cancer therapy leading to progressive organ failure. L-Glutamine supplementation has been shown to attenuate fibrosis and improve wound healing in several types of tissue injuries. The aim of this study was to evaluate the effects of this supplementation on key components of the peritoneal fibrovascular tissue induced by implants in mice treated with 5-Fluorouracil (5-FU) C57BL/6 mice received three intraperitoneal doses of immunosuppressant (60, 40, and 40 mg/kg) on non-consecutive days prior to implantation of polyether-polyurethane sponges into the peritoneal cavity. The group treated with L-Glutamine received 150 mg/kg/day for 7 days (oral gavage) starting 24 h after implantation and the control group received filtered water. Eight days after implantation, implants were removed and processed for inflammatory, angiogenic, and fibrogenic markers. Flow cytometry results showed that L-Glutamine decreased (48%) the frequency/influx of total intra-implant cells. The remaining cell population in the treated group had more neutrophils, lymphocytes, and macrophages than in the control. Immunohistochemistry analysis showed fewer Caspase-3-positive cells in the treated group. Myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activities, TNF-α levels, and mast cell numbers were decreased in the implants of the L-Glutamine-treated group compared with the control. Similarly, angiogenesis (VEGF levels and number of blood vessels) was attenuated by L-Glutamine. Supplementation also decreased the amount of intra-implant collagen and TGF-β1 levels. These results indicate that L-Glutamine attenuates critical inflammatory-angiogenesis and profibrotic pathways involved in fibrosis development in immunosuppression conditions, supporting its potential as an adjunct therapeutic strategy for managing peritoneal healing in cancer.

Keywords:  angiogenesis; fibrogenesis; immunonutrient; inflammation; repair

DOI:  https://doi.org/10.3389/ebm.2026.10755
J Phys Chem Lett. 2026 Mar 11.

Accurate Measurements of Solvent Exchange in Asparagine and Glutamine Side-Chain NH2 Groups of Proteins by z-Exchange NMR Spectroscopy.

Vitali Tugarinov, G Marius Clore.

NMR methodology is developed for accurate measurements of solvent exchange rates in asparagine and glutamine side-chain NH2 groups of proteins by z-exchange spectroscopy. A rigorous model of solvent exchange in NH2 groups of proteins dissolved in a 50%/50% (v/v) mixture of H2O/D2O solvents, that incorporates the independently measured rates of hindered rotation around the carboxamide C'-N bond, allowed determining solvent exchange rates for side-chain amides of the model proteins ubiquitin and GB1, as well as a subset of NH2 groups of a buried cavity mutant of T4 lysozyme. In agreement with earlier findings, the amide protons at E (anti) positions usually exchange faster with the solvent than their Z (syn) counterparts. The temperature dependence of the rates of hindered rotation and solvent exchange in ubiquitin showed that the two processes are enthalpically driven and characterized by very similar activation enthalpies of ∼70 kJ/mol.

DOI: https://doi.org/10.1021/acs.jpclett.6c00464
J Am Chem Soc. 2026 Mar 13.

Unlocking the Silent Proteome: Chemoselective Asn/Gln Activation for Multidimensional Protein Diversification.

Benjamin Emenike, Zachary E Paikin, John M Talbott, Anna Lidskog, Bao Quang Gia Le, Jagannath Swaminathan, Eric V Anslyn, Monika Raj.

Amides are ubiquitous in pharmaceuticals, natural products, and biomolecules, owing to their exceptional stability and hydrogen-bonding capacity. Among the amino acids, asparagine (Asn) and glutamine (Gln) contain neutral primary amide side chains and constitute over 8% of the human proteome. Despite their abundance, these residues have remained largely inaccessible to selective chemical modification due to their low intrinsic reactivity and the propensity of proteinogenic side chains to poison transition-metal catalysts via chelation. Here, we report a general strategy that converts the primary amides of Asn and Gln into bioorthogonal nitrile handles, which can be further diversified through carbometalation with aryl boronic acids to yield aryl ketone products. This transformation proceeds with exceptional chemoselectivity, enabling the modification of native peptides and proteins. We demonstrate its broad utility in the synthesis of unnatural amino acids, late-stage diversification of peptides, fluorosequencing of Asn residues, and site-selective protein modification, culminating in the synthesis of a functional antibody-fluorophore conjugate. The versatility and selectivity of this approach expand the accessible chemical space of biomolecules and provide a powerful route for uncovering previously uncharacterized Asn/Gln sites within the chemically silent proteome.

DOI: https://doi.org/10.1021/jacs.5c22184