bims-glucam 2025-09-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–09–21
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.
Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.
Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.
Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
Cartilage Redox Balance Is Influenced by Substrate Availability.
State of the Art of IDH Inhibitors: Emerging Questions and Perspectives.
Role of tumor microenvironment in cancer promotion, development of drug resistance and cancer treatment.
Specific inhibition of glutamine synthase involved in the metabolic pathway of amino acids is associated with anti-arthritic effects of sinomenine hydrochloride.
Dual roles of amino acid metabolic reprogramming in chronic airway diseases and lung cancer: therapeutic opportunities and challenges.
SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.
P2X7R-NF-κB-PDI signal pathway regulates LPS-induced impaired GSH synthesis by modulating ATF4-mediated xCT upregulation, S-nitrosylation of ASCT2 and GSHS expressions in the mouse hippocampus.
Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.
Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity.
Pantothenate kinase 4 controls lipid synthesis for T-cell proliferation by modulating coenzyme A and glutaminolysis.
Changes in Redox Balance and Mitochondrial Activity in the Retinas of Cystine/Glutamate Antiporter Knockout Mice.
CTNNB1 mutations in serum amyloid A-positive hepatocellular neoplasm/inflammatory hepatocellular adenoma arising in alcoholic cirrhosis.

Blood. 2025 Sep 19. pii: blood.2024027496. [Epub ahead of print]

Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.

Flor Navarro, Teresa Lozano, Andrea Fuentes-García, Inés Sánchez-Moreno, Marta Larrayoz, Pedro Justicia, Beatriz Perucha, Maialen Martinez-Tabar, Rebeca Martinez-Turrillas, Noelia Casares, Celia Martín-Otal, Marta Gorraiz, Erin W Meermeier, Marta Chesi, Douglas Lake, Paul Leif Bergsagel, Eva Santamaría, Maria Erendira Calleja-Cervantes, Patxi San Martín-Úriz, Lorea Jordana-Urriza, Xabier Agirre, Sandra Hervas-Stubbs, Juan Roberto Rodriguez-Madoz, Jose A Martínez-Climent, Felipe Prosper, Juan J Lasarte.

Glutamine-dependence of cancer cells reduces local glutamine availability, which hinders anti-tumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of CAR T-cell therapies in cancer patients. We have seen that antigen-specific T cells are unable to proliferate or produce IFN-γ in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR-T cells selectively targeting BCMA in MM cells were sensitive to glutamine deprivation. However, CAR-T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-γ, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed CART cell metabolic fitness of CART cells by upregulating the mTORC1 gene signature, modifying the Solute Carrier transporter (SLC) repertoire, and improving both basal oxygen consumption rate and glycolytic function thereby enhancing CART cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of BCMA-CART cells in syngeneic and genetically-engineered mouse models of MM, which prolonged mouse survival. In patients, reduced expression of Asct2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance anti-tumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.

DOI: https://doi.org/10.1182/blood.2024027496
Semin Oncol. 2025 Sep 12. pii: S0093-7754(25)00105-8. [Epub ahead of print]52(6): 152413

Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.

Chou-Yi Hsu, Yasmeen Kateb Ahmed, Shaker Mohammed, Mohammad A Alghamdi, Hasan S Al-Ghamdi, Jaafaru Sani Mohammed, Mohammed Abed Jawad, Salim B Alsaadi.

  Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.

Keywords:  Bioenergetics; Melanoma; Metabolism; Pathogenesis; Therapy

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152413
Asian Pac J Cancer Prev. 2025 Sep 01. pii: 91865. [Epub ahead of print]26(9): 3157-3174

Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.

Ahmed S Alhallaq, Nadeen S Sultan.

  Metabolic reprogramming induced by the glutamine/glutamate (Gln/Glu) metabolic pathway is a key mechanism in ATP production, precursor biosynthesis, and redox homeostasis, promoting prostate cancer (PCa) growth and proliferation. This evolutionarily acquired hallmark of cancers enables malignant cells to adapt their bioenergetic and biosynthetic pathways in response to microenvironmental stresses. Therefore, Gln/Glu metabolism orchestrates epigenetic regulation, metastatic capacity, and oxidative homeostasis in PCa, supporting the survival of PCa tumors. Fluctuations in Glu metabolite levels and oxygen tension shape the PCa epigenome by facilitating Glu-derived α-ketoglutarate (α-KG) activation of TET and KDM enzymes, which drive histone and DNA demethylation. Furthermore, tumor progression toward metastatic castration-resistant PCa is characterized by heightened Gln/Glu dependency and increased Gln uptake. Within the tumor microenvironment (TME), a dynamic tug-of-war occurs between tumor and immune cells, competing for Gln metabolites. Gln/Glu converges on critical oncogenic signaling axes, including NF-κB/Nrf2, c-Myc/androgen receptor, MAPK/ERK, and PI3K/AKT/mTOR. Additionally, extracellular Glu release via SLC7A11 and PSMA triggers metabotropic glutamate receptor (mGluR) signaling, further potentiating oncogenic programs. Targeting this Gln/Glu metabolic network thus presents a promising therapeutic approach against PCa. In this review, we summarize the role of Gln/Glu in PCa progression based on the compartmentalization of the Gln/Glu metabolic pathway to elucidate why PCa cells manifest dependence on Gln/Glu. Eventually, we highlight potential therapeutic targets that can be exploited for PCa treatment.

Keywords:  Glutamine; Metabolic Reprogramming; Prostate Cancer; Tumor Microenvironment; glutamate

DOI:  https://doi.org/10.31557/APJCP.2025.26.9.3157
Cancer Med. 2025 Sep;14(18): e71244

Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.

Jilsy M J Punnasseril, Abdul Auwal, Vinod Gopalan, Alfred King-Yin Lam, Farhadul Islam.

   BACKGROUND: Cancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.
METHODS: An extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.
RESULTS: The rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nucleotide metabolism. Modifications in glucose metabolism in cancer cells involve changes in glucose uptake, glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. Similarly, alterations in amino acid metabolism in cancer cells relate to upregulated amino acid transport and glutaminolysis. Cancer cells also have increased lipid intake from the extracellular microenvironment, upregulated lipogenesis, and enhanced lipid storage and mobilization from intracellular lipid droplets. These rapidly proliferating cells also achieve their increased demand for nucleotides by changing the expression of enzymes in the salvage and de novo nucleotide pathways. Consequently, these metabolic processes are targets for developing cancer therapeutics. However, it is important to note that the metabolic changes in cancer cells can also contribute to resistance against various cancer therapies.
CONCLUSION: This review will explore the various ways in which cancer cells reprogram metabolic processes to sustain rapid proliferation and survival. The information presented in this report could help in the therapeutics designed to target them, and the challenges of cancer drug resistance arising from these metabolic adaptations.

Keywords:  Warburg effect; cancer metabolism; drug resistance; glucose metabolism; nucleotide metabolism; therapeutics

DOI:  https://doi.org/10.1002/cam4.71244
Cartilage. 2025 Sep 19. 19476035251377532

Cartilage Redox Balance Is Influenced by Substrate Availability.

Jingyi Wang, Corinne R Henak.

  PurposeThe mechanobiological response of cartilage redox balance might change in response to altered substrate availability. The purpose of this study is to investigate effects of key metabolic substrates (glucose, glutamine, and oxygen) on the mechanoresponsiveness of cartilage redox balance using a label-free imaging technique that measures autofluorescence from endogenous redox cofactors.FindingsCompared with room oxygen tension, low oxygen tension had higher autofluorescence intensity in green (FAD) channel after a single sub-failure tensile load. Cartilage explants cultured in high glucose medium with glutamine supply had higher autofluorescence intensity in both channels (FAD and NADH/NADPH) compared with low glucose with glutamine group or high glucose without glutamine group, while no difference was observed between the latter 2 groups.ConclusionsLow oxygen tension or high glucose culture medium with glutamine supply increases the mechanoresponsiveness of cartilage redox balance induced by sub-failure mechanical loading. Glutamine appears to partially serve as a glucose substitute in this process.

Keywords:  cartilage; glucose; glutamine; optical redox imaging; oxygen tension

DOI:  https://doi.org/10.1177/19476035251377532
Anticancer Agents Med Chem. 2025 Sep 16.

State of the Art of IDH Inhibitors: Emerging Questions and Perspectives.

João A L de Lima, Lídia Moreira Lima.

  Isocitrate Dehydrogenases (IDH) are ubiquitous enzymes essential for cellular metabolism, including the Krebs cycle, glutamine metabolism, lipogenesis, and redox balance. Mutations in IDH1 and IDH2 are implicated in several tumors - gliomas, Acute Myeloid Leukemia (AML), cholangiocarcinoma - altering enzyme activity and causing the overproduction of 2-hydroxyglutarate (2-HG). This oncometabolite disrupts α-KGdependent proteins, impairing key processes such as differentiation, division, and DNA repair. Understanding these genetic, biochemical, and clinical aspects has made IDH enzymes promising therapeutic targets, prompting the development of targeted inhibitors for tumors harboring IDH1 or IDH2 point mutations. Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML. However, resistance due to secondary mutations, especially in the allosteric binding site, remains a major obstacle. In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors. Still, many clinical factors must be considered. This review explores the current landscape of IDH-targeted therapies, emphasizing the need for novel inhibitors and highlighting innovative strategies, including the design of smaller, more potent molecules with favorable pharmacokinetics and the potential of drug repositioning. We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.

Keywords:  IDH inhibitors; IDH mutations.; enasidenib; isocitrate dehydrogenase; ivosidenib; target therapy

DOI:  https://doi.org/10.2174/0118715206382095250908095950
J Egypt Natl Canc Inst. 2025 Sep 15. 37(1): 59

Role of tumor microenvironment in cancer promotion, development of drug resistance and cancer treatment.

Duaa E Fathah, Samina Ejaz.

  Cancer is a multifactorial disease and the second leading cause of death worldwide after cardiovascular disease. Initially, it was considered a genetic disease or gene expression disorder, but now it is regarded as a tumor microenvironment (TME) disease. The TME consists of cancer cells, endothelial cells, fibroblasts, and immune cells that interact with each other. These interactions support tumor growth by providing nutrients via altered metabolic mechanisms such as glutamine metabolism, aerobic glycolysis, and fatty acid metabolism. The by-products of these altered metabolic pathways interfere with the function of surrounding cells and thus lead to cancer progression. The role of metabolic crosstalk highlights the intricate relationship between the cancer cells and their TME. This review comprehensively analyzes recent studies to enhance understanding of the metabolic crosstalk in TME. It highlights how tumor-associated macrophages and fibroblasts reprogram lipid and glucose metabolism to create an immunosuppressive environment. This review also provides information about the role of hypoxia-induced HIF-1α signaling in the promotion of lactate accumulation. This factor in turn ensures tumor cells' survival and makes them resistant to anti-cancer drugs. Further, we have discussed therapeutic approaches targeting TME, including use of PD-1, PD-L1 inhibitors, CAR-T cell therapy, and oncolytic viruses to improve patient outcomes. Besides this, clinical studies involving the estimation of lactate, GLUT1, and HIF-1α levels may help to recognize high-risk patients and develop guidance for personalized metabolism-targeting therapies. In the long run, such studies can ultimately improve patient outcomes and thus reduce disease burden.

Keywords:  Angiogenesis; CAR-T cell therapy; Cancer; PD-1/PD-L1; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43046-025-00317-8
Front Cell Dev Biol. 2025 ;13 1658089

Specific inhibition of glutamine synthase involved in the metabolic pathway of amino acids is associated with anti-arthritic effects of sinomenine hydrochloride.

Gejing Li, Zhaoli Su, Yuanyuan Tang, Hong Huang, Junlan Zhang, Ye Lin, Qin Zhang, Xiong Cai.

  Sinomenine (SIN) is the key bioactive alkaloid isolated from Sinomenium acutum which has been prescribed commonly in Chinese medicine for managing rheumatic disorders. Despite its clinical relevance, the metabolic mechanisms underlying its therapeutic effects remain insufficiently explored, particularly in relation to amino acid dysregulation in rheumatoid arthritis (RA). The anti-arthritic efficacy of sinomenine hydrochloride (SH) was tested in adjuvant-induced arthritis in rats utilizing clinical scoring and histological analysis. Plasma metabolomics was employed to identify SH-mediated changes in amino acid-related metabolic profiles. Key metabolic pathways and targets were examined using computational docking and surface plasmon resonance (SPR) assay. The interaction of SH and molecular targets was further validated in RA fibroblast-like synoviocytes (RA-FLS). SH at dose of 100 mg/kg significantly alleviated disease progression of AIA, as evidenced by reduced paw edema and inhibited histopathological changes. Metabolomic analyses identified 94 potential plasma biomarkers linked to pathways of valine/leucine/isoleucine biosynthesis, glycine/serine/threonine metabolism, phenylalanine metabolism, and alanine/aspartate/glutamate metabolism. Molecular docking and SPR identified that SH specifically targeted the glutamine synthase (GS/GLUL) (KD = 7.12 μM). Experimental validation confirmed that SH (50-200 μM) significantly inhibited GS activity and GLUL expression and consequently decreased glutamine levels in RA-FLS. In conjunction SH exerts significant anti-arthritic effects, partly by modulating the metabolic profiles of related amino acids via selective inhibition of GS-mediated de novo Gln synthesis.

Keywords:  adjuvantinduced arthritis; glutamine synthetase; metabolomics; rheumatoid arthritis; sinomenine hydrochloride

DOI:  https://doi.org/10.3389/fcell.2025.1658089
World J Surg Oncol. 2025 Sep 18. 23(1): 335

Dual roles of amino acid metabolic reprogramming in chronic airway diseases and lung cancer: therapeutic opportunities and challenges.

Xiurong Wang, Huaming Zhang.

  Amino acid metabolic reprogramming has emerged as a pivotal mechanism underlying the pathogenesis of chronic airway diseases and lung cancer. This review comprehensively examines the dynamic regulation and clinical implications of key amino acid pathways-including arginine, glutamine, and tryptophan metabolism-in chronic obstructive pulmonary disease (COPD), asthma, and lung malignancies. Our findings reveal a key difference in metabolic dysregulation between chronic airway diseases and lung cancer: while it drives persistent inflammation, oxidative stress, and tissue damage in chronic conditions, cancer cells exploit these same pathways to support their uncontrolled growth and create an immunosuppressive tumor microenvironment. Crucially, shared metabolic nodes reveal actionable targets for dual-purpose therapeutic strategies. Recent advances demonstrate the translational potential of metabolic interventions. Arginase inhibitors simultaneously improve vascular function in COPD and enhance antitumor immunity, while nanoparticle-delivered glutaminase blockers attenuate pulmonary fibrosis while curbing cancer progression. However, challenges persist in achieving tissue-specific delivery, real-time metabolic monitoring, and overcoming resistance. Future directions should focus on spatiotemporally controlled metabolic modulation and the development of multi-omics-based predictive models to usher in an era of precision metabolic therapy for respiratory disorders.

Keywords:  Amino acids; Chronic airway diseases; Lung cancer; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s12957-025-03996-8
Adv Sci (Weinh). 2025 Sep 17. e10811

SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.

Dai-Wei Hu, Chih-Hao Huang, Yu-Hao He, Ya-Ling Wei, Shu-Wei Hu, Fang-Ju Cheng, Thanh Kieu Huynh, Bo-Rong Chen, Bo-Wei Wang, Li-Chi Kuan, Der-Yen Lee, Ming-Hsin Yeh, Ya-Jen Chang, Liang-Chih Liu, Mien-Chie Hung, Wei-Chien Huang.

  Early-onset breast cancer (EOBC), diagnosed before the age of 45, is associated with poor therapeutic outcomes and limited survival, yet the underlying mechanisms remain poorly defined. Identifying environmental risk factors and actionable therapeutic targets is an urgent clinical need. Notably, the largest survival gap between younger and older patients occurs in luminal breast cancer, implicating potential endocrine disruption. Here, an association is identified between elevated levels of di(2-ethylhexyl)phthalate (DEHP) in hair, a widely used endocrine-disrupting plasticizer, and earlier age at diagnosis of breast cancer. Mechanistically, DEHP exposure promotes tumor initiation by enhancing cancer stemness through mitochondrial fusion and glutamine-driven oxidative phosphorylation. DEHP upregulates the glutamine transporter SLC6A14 to enhance glutamine uptake, while suppressing mitochondrial fission factor (MFF), which exacerbates mitochondrial fusion. High SLC6A14 expression correlates with cancer stemness signatures and earlier onset in patient cohorts. Inhibition of SLC6A14 reduces stemness, impairs tumor growth, and sensitizes tumors to chemotherapy. Collectively, the findings uncover a novel environmental-metabolic axis linking plasticizer exposure to EOBC and establish SLC6A14 as a promising metabolic vulnerability. These results provide a strong preclinical rationale for targeting SLC6A14 in young breast cancer patients and offer new insights into mitigating the oncogenic impact of environmental pollutants.

Keywords:  SLC6A14; cancer stemness; early‐onset breast cancer; mitochondria dynamics; plasticizer

DOI:  https://doi.org/10.1002/advs.202510811
Neuropharmacology. 2025 Sep 17. pii: S0028-3908(25)00404-6. [Epub ahead of print] 110696

P2X7R-NF-κB-PDI signal pathway regulates LPS-induced impaired GSH synthesis by modulating ATF4-mediated xCT upregulation, S-nitrosylation of ASCT2 and GSHS expressions in the mouse hippocampus.

Ji-Eun Kim, Su Hyeon Wang, Duk-Shin Lee.

  Protein disulfide isomerase (PDI) augments lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) activation by integrating Toll-like receptor 4 (TLR4) and P2X7 receptor (P2X7R) signaling pathways in a positive feedback manner. However, it has been largely unknown whether PDI is involved in altered glutathione (GSH) biosynthesis, which is mediated by P2X7R, in response to LPS. In the present study, LPS-induced NF-κB activation increased PDI expression, but decreased solute carrier 1 A5 (ASCT2) level in the P2X7+/+ mouse hippocampus. PDI knockdown attenuated ASCT2 downregulation and S-nitrosylated (SNO-) ASCT2 level in response to LPS. This LPS-induced NF-κB-PDI activation also increased activating transcription factor 4 (ATF4) expression in astrocytes, which elicited cystine:glutamate transporter (xCT) upregulation, but decreased ASCT2 and GSH synthetase (GSHS) expression. Furthermore, S-nitrosylation of PDI modulated ATF4-mediated xCT upregulation in response to LPS. SN50 (a NF-κB inhibitor), PDI knockdown and ATF4 siRNA mitigated the decreased GSH content induced by LPS. Under physiological condition, P2X7R deletion did not affect basal PDI, ATF4, xCT and SNO-ASCT2 levels. However, it increased ASCT2 expression and decreased SNO-PDI level. P2X7R ablation ameliorated (1) PDI, ATF4 and xCT2 upregulations, (2) S-nitrosylation of ASCT2 and PDI and (3) ASCT2 downregulation in response to LPS. These findings indicate that P2X7R-NF-κB-PDI signal pathway may inhibit GSH biosynthesis in response to LPS by modulating expression/S-nitrosylation of ASCT2 and ATF4-mediated xCT regulation in response to LPS.

Keywords:  GSH synthetase; L-NAME; Nrf2; S-nitrosylation; SLC1; SLC7a11; iNOS

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110696
JCI Insight. 2025 Sep 16. pii: e192286. [Epub ahead of print]

Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice.

Seung-Chul Choi, Yong Ge, Milind V Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C Rathmell, Mansour Mohamadzadeh, Laurence Morel.

  Glutaminolysis is enhanced in T cells of lupus patients and in follicular helper T (Tfh) cells, a critical subset of CD4+ T cells that provide help to autoreactive B cells, in lupus mice. Glutaminolysis inhibitors reduced lupus activity in association with a decreased frequency of Th17 cells in mice. Here, we thought to determine the role of glutaminolysis in murine Tfh cells. The pharmacological inhibition of glutaminolysis with DON reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production and B cell differentiation markers. Accordingly, profound transcriptomic and metabolic changes, including a reduction of glycolysis, were induced by DON in lupus Tfh cells, whereas healthy Tfh cells showed minor changes. The T cell-specific genetic inhibition of glutaminolysis largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with minor changes in Tfh and B cells in healthy controls. Furthermore, we showed that T cell-specific glutaminolysis inhibition impaired T-dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results suggest that lupus Tfh cells have a greater intrinsic requirement of glutaminolysis for their helper functions.

Keywords:  Adaptive immunity; Amino acid metabolism; Autoimmunity; Immunology; T cells

DOI:  https://doi.org/10.1172/jci.insight.192286
Cell Rep Med. 2025 Sep 16. pii: S2666-3791(25)00406-9. [Epub ahead of print]6(9): 102333

Targeting AQP5-mediated arginine deprivation in gastric cancer stem cells restores NK cell anti-tumor immunity.

Rou Zhao, Baoyu He, Lunhua Huang, Yanli Wu, Ting Liu, Jilan Liu, Mingsheng Zhao, Tao Zhong, Yanhua Zhang, Xiao Zhang, Huabao Xiong, Bin Zhang, Qingli Bie.

  Natural killer (NK) cells exhibit impaired anti-tumor activity upon entering the tumor microenvironment (TME); however, the precise mechanism(s) remains elusive. In this study, we demonstrate that AQP5+ gastric cancer stem cells contribute to the dysfunction of NK cells by reprogramming the urea cycle (UC). Mechanistically, AQP5 competitively binds ATP-dependent RNA helicase A (DHX9) over karyopherin subunit beta 1 (KPNB1), inhibiting DHX9 nuclear translocation and transcriptionally down-regulating argininosuccinate synthase 1 (ASS1). Low-arginine condition in the TME reshaped by AQP5+ tumor cells weakens NK cell function by limiting NO synthesis. Notably, preclinical murine models confirm that oral arginine supplements improve the NK cell-directed killing against organoids generated by AQP5High GC (gastric cancer) tissues. Besides, AQP5+ tumor cells also redirect the UC to the TCA cycle, which stores the saved nitrogen in glutamine by promoting glutamate-ammonia ligase (GLUL) stability. This study uncovers the evidence of AQP5+ cancer stem cells impairing NK cell cytotoxicity by changing self-metabolism patterns.

Keywords:  AQP5; NK cell; TCA cycle; cancer stem cell; urea cycle

DOI:  https://doi.org/10.1016/j.xcrm.2025.102333
Signal Transduct Target Ther. 2025 Sep 18. 10(1): 302

Pantothenate kinase 4 controls lipid synthesis for T-cell proliferation by modulating coenzyme A and glutaminolysis.

Jeong-Ryul Hwang, Chi Thi Ngoc Nguyen, Gwanghoon Ko, Jung-Ah Kang, Yeongseon Byeon, Seowoo Park, Ryunha Chang, Dawoon Jung, Mi Yeon Jeon, Young Hoon Sung, Cho-Rong Lee, Ki-Hoan Nam, Je Kyung Seong, Sankar Ghosh, Yun Pyo Kang, Sung-Gyoo Park.

During T-cell-mediated inflammatory responses, T cells are activated upon recognizing specific antigens presented by antigen-presenting cells. This recognition initiates signaling through the TCR and CD28, leading to their activation and subsequent clonal expansion. Within the signaling cascades triggered by TCR and CD28 engagement, the CD28-PI3K pathway serves as a central regulator of metabolic reprogramming in T cells, supporting the biosynthetic needs essential for their effective proliferation. In this study, we found that the regulation of PANK4 plays a role in TCR/CD28-mediated CD4+ T-cell proliferation by regulating de novo lipid synthesis. The CD28 signaling pathway negatively regulates PANK4 through direct binding with PDK1, thereby controlling de novo lipid synthesis for CD4+ T-cell proliferation. Interestingly, we found that Pank4-deficient CD4+ T cells enhance coenzyme A synthesis and glutaminolysis, whereby glutamine contributes carbon for fatty acid synthesis and provides nitrogen for coenzyme A biosynthesis. The regulatory role of PANK4 in CD4+ T-cell proliferation was confirmed in models of experimental colitis and influenza A virus infection, where Pank4-deficient CD4+ T cells exhibited greater expansion than their wild-type counterparts when co-transferred. Our findings suggest that PANK4 regulation of de novo lipid synthesis is crucial for TCR/CD28-induced CD4+ T-cell proliferation and represents a potential target for modulating general CD4+ T-cell responses.

DOI: https://doi.org/10.1038/s41392-025-02385-7
Invest Ophthalmol Vis Sci. 2025 Sep 02. 66(12): 31

Changes in Redox Balance and Mitochondrial Activity in the Retinas of Cystine/Glutamate Antiporter Knockout Mice.

Luis J Knight, Renita M Martis, Paul J Donaldson, Monica L Acosta, Julie C Lim.

Purpose: The cystine/glutamate antiporter (xCT) mediates glutamate export and cyst(e)ine import. In the retina, we previously demonstrated that xCT is important in glutamate/glutamine cycling between photoreceptor and Müller cells. This study investigates the contribution of xCT to cyst(e)ine import and glutathione homeostasis and its impact on mitochondrial function.
Methods: C57BL/6J wild type (WT) and xCT knockout (KO) retinas were analyzed at six weeks and nine months. Mass spectrometry and silver-intensified immunogold labeling were used to measure cysteine (CSH) and glutathione (GSH) in the retinal layers, whereas high-resolution respirometry measured mitochondrial activity and reactive oxygen species (ROS) levels.
Results: While CSH and GSH were similar between WT and KO whole retinas at both ages, localized reduction of CSH and GSH were evident in the photoreceptors. ROS levels increased in six-week KO compared to WT retinas, and these levels were sustained at nine months. At six weeks, but not nine months, loss of xCT resulted in increased mitochondrial complex I activity and reduced mitochondrial ROS levels.
Conclusions: As early as six weeks of age, the loss of xCT resulted in localized changes in CSH and GSH levels, suggesting that xCT plays a role in GSH homeostasis. An increase in overall ROS levels was detected, but this was not attributed to the mitochondria. Changes detected in six-week KO retinas were comparable to those seen in nine-month WT retinas, suggesting that loss of xCT may accelerate changes associated with aging. The lack of differences between WT and xCT KO retinas at nine months indicate adaptations to these early changes over time.

DOI: https://doi.org/10.1167/iovs.66.12.31
Hum Pathol. 2025 Sep 12. pii: S0046-8177(25)00223-0. [Epub ahead of print]164 105936

CTNNB1 mutations in serum amyloid A-positive hepatocellular neoplasm/inflammatory hepatocellular adenoma arising in alcoholic cirrhosis.

Motoko Sasaki, Yasunori Sato, Yasuni Nakanuma.

   BACKGROUND: Serum amyloid A-positive hepatocellular neoplasm (SAA-HN) arising in alcoholic cirrhosis is now regarded as a specific type of inflammatory hepatocellular adenoma (IHCA) associated with advanced liver disease. Since recent studies reported various glutamine synthetase (GS) expression patterns corresponding to CTNNB1 mutations in β-catenin mutated HCA, SAA-HN/IHCAs were herein re-evaluated for CTNNB1 mutations.
METHODS: GS expression was examined in 33 SAA-HN/IHCAs (23 patients) and 15 IHCAs (14 patients) from our archives and classified into patterns (P) 1-3 (P1, a diffuse homogeneous pattern suggesting an exon 3-non-S45 mutation; P2, diffuse heterogeneous, suggesting an exon 3-S45 mutation; P3, rim and focal heterogeneous, suggesting exon-7/8 mutations) and P4 (negative). Hotspot genetic mutations in CTNNB1, exons-3, 7, and 8 were examined by direct sequencing.
RESULTS: Thirty-three SAA-HN/IHCAs were classified into 3 P1, one P3, and 29 P4 and 15 HCAs into 3 P1, 1 P2, 2 P3, and 9 P4. A genetic analysis revealed 3 SAA-HN/IHCAs with CTNNB1, exon-3 mutations and 1 exon-7 mutation, consistent with GS expression patterns P1 and P3, respectively. Two SAA-HN/IHCAs were associated with CTNNB1, exon-8 mutation, and both were regarded as P4 based on GS expression patterns. No significant differences were observed in clinicopathological features between SAA-HN/IHCAs with and without CTNNB1 mutations (p > 0.05).
CONCLUSIONS: Some SAA-HN/IHCAs may be b-IHCA, exon-3 or exon-7/8 mutations. Careful evaluation of immunoreactivity for GS and a genetic analysis of CTNNB1 mutations are crucial for the accurate diagnosis of b-IHCA, exon-3 mutation, for which the risk of malignant transformation is high, and better clinical management.

Keywords:  Alcoholic cirrhosis; Glutamine synthetase; Serum amyloid A; Serum amyloid A-positive hepatocellular neoplasm/inflammatory hepatocellular adenoma (SAA-HM/IHCA); b-HCA; b-IHCA

DOI:  https://doi.org/10.1016/j.humpath.2025.105936