bims-glucam 2026-01-11 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–01–11
28 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.
Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
A Multifunctional PD-L1 Modulator for Metabolic Reprogramming to Induce Pyroptosis and Enhance Glutamine Inhibition-Mediated Antitumor Immunotherapy.
Maternal 3-NPA-Induced Oxidative Stress Impairs Offspring Ovarian Function via Glutamine Metabolic Dysregulation and NF-κB-Mediated Inflammation.
Comparison of Glucose and Glutamine as Energy Substrates for Astrocytes under Conditions of Oxygen Deficiency.
Cell exposure to hyaluronic acid/ε-Poly-l-Lysine physically crosslinked hydrogel disrupts glutamate metabolism and leads to cytoskeletal collapse.
Targeting Glutamine Transporters as a Novel Drug Therapy for Synovial Sarcoma.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.
Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
Amino Acid Metabolic Reprogramming in Clear Cell Renal Cell Carcinoma: Pathogenic Mechanisms and Therapeutic Targeting.
Amino acid metabolic reprogramming: future prospects for cholangiocarcinoma therapy.
Targeting the Glutaminolysis Pathway in Glaucoma-Associated Fibrosis.
‌PPIA regulates fatty acid and glutamine metabolism in lung adenocarcinoma based on multiomics prognostic model and experiment validation.
Sweet optimization: glucose-vitrified samples for hyperpolarizing glutamine in biological studies.
Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.
FOXM1/FUS facilitates triple-negative breast cancer malignant progression and glutamine metabolism through mediating SLC7A5 transcription.
The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.
Leveraging ANXA1 to enhance recombinant protein yields in CHO cells: A UPR-Mediated bioprocessing approach.
Ammonium Hydroxide Enhancement of Dietary Protein in High-Fat Diets Modulates Liver Metabolism Signaling in a Sex- and Age-Dependent Manner in C3H/HeJ Mice.
Urinary amino acid profiles emerge as promising biomarkers for predicting and assessing the prognosis of clear cell renal cell carcinoma: a retrospective case-control Study.
Immunometabolism of T cells and macrophages: Human translational perspectives.
The Arabidopsis UMAMIT30 transporter contributes to amino acid root exudation.
Perfluorooctanoic Acid Exposure Causes Macrophage Ammonia Retention and Induces Spontaneous Miscarriages.
Metabolic hijackers: how viral proteins redefine host cell landscapes.
Untargeted Serum Metabolomics Reveals Differential Signatures in Gallstone-Associated and Gallstone-Free Gallbladder Cancer Variants.
Prevalence of low bone mineral density and associated plasma metabolite alterations in thalassemia.
Unleashing the Potent Antitumor Force: A Reactive Oxygen Species (ROS) Storm Formation by Ultrasound-Activatable Metal Nanosonosensitizers.
The ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation.

Transl Cancer Res. 2025 Dec 31. 14(12): 8448-8461

Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.

Siegfried Hélage, Marie-Céline Blanc-Quintin, Nathalie Neveux, Antonin Ginguay, Jean-Pascal De Bandt, Luc Cynober, Jérôme Alexandre, François Goldwasser, Élisabeth Dion.

   Background: Glutamine, an essential nutrient for healthy cells, supports immunity and cytoprotection during anticancer treatments. However, intense glutaminolysis may promote proliferation and chemoresistance in ovarian carcinomas by activating the PI3K/AKT/mTORC1 pathway and overexpressing c-Myc. This study aimed to characterize glutamine metabolism in ovarian carcinomas and assess its impact on tumor aggressiveness and chemosensitivity, to inform nutritional supplementation or therapeutic targeting.
Methods: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
Results: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.
Conclusions: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for 18F-(2S,4R)-4-fluoroglutamine (18F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.

Keywords:  Ovarian carcinoma; chemoresistance; glutamine; glutaminolysis; metabolic imaging

DOI:  https://doi.org/10.21037/tcr-2025-1721
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01013-5. [Epub ahead of print]86(1): 6-8

Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.

Yury S Bykov, Johannes M Herrmann.

In this issue of Molecular Cell, Zhu et al.1 show that mitochondria of cancer cells rely on the import of glutamine not only to fuel metabolite synthesis via the tricarboxylic acid cycle but also to charge mt-tRNAGln to allow mitochondrial protein synthesis and respiration.

DOI: https://doi.org/10.1016/j.molcel.2025.12.014
Acta Biomater. 2026 Jan 07. pii: S1742-7061(26)00012-7. [Epub ahead of print]

A Multifunctional PD-L1 Modulator for Metabolic Reprogramming to Induce Pyroptosis and Enhance Glutamine Inhibition-Mediated Antitumor Immunotherapy.

Jialing Guo, Ligang Wu, Jieke Zhang, Xiaodi Zhang, Bin Du.

  Metabolic interference strategies offer promising interventions in tumor therapy. However, inhibiting glutamine metabolism can upregulate Programmed Cell Death Ligand 1 (PD-L1), resulting in immune evasion and limiting the efficacy of glutamine inhibitors. Here, a nano-modulator with multi-enzyme interactions, DPG@COD/CuMOF@Dz, is introduced. It combines metabolic management and immunotherapy by incorporating copper metal-organic framework nanoparticles containing cholesterol oxidase (COD) and DNAzyme (Dz), as well as particles modified with DSPE-PEG-glutamine (DPG). Once internalized, the nano-modulator releases COD, Cu²⁺, and Dz in response to the high intracellular GSH environment. Cu²⁺ activates Dz, which inhibits glutaminase production and glutamine metabolism in cancer cells. Meanwhile, COD depletes cholesterol from cancer cell membranes, decreasing PD-L1 stability and abundance. COD produces hydrogen peroxide, which combines with Cu²⁺ via Fenton-like processes to produce ·OH, raising intracellular reactive oxygen species (ROS) levels. Additionally, GLS Dz effectively suppresses glutamine metabolism, thereby diminishing intracellular glutathione (GSH) synthesis and disrupting the redox homeostasis in cancer cells. These cascading events collectively initiate pyroptosis and immunogenic cell death (ICD), which not only attenuates PD-L1-mediated immune evasion but also provokes a robust antitumor immune response. Notably, combination therapy employing the nano-modulator and an αPD-1 antibody achieved a remarkable tumor inhibition rate of 93.7%. This work presents a promising strategy to overcome the challenges associated with glutamine blockade, offering an innovative therapeutic paradigm for the treatment of breast cancer. STATEMENT OF SIGNIFICANCE: This study develops a novel nano-modulator (DPG@COD/CuMOF@Dz) that co-targets glutamine metabolism and PD-L1 stability via cholesterol depletion for enhanced cancer immunotherapy. By integrating enzymatic activity and metal-organic frameworks for synergistic redox disruption and immune activation, it overcomes limitations of conventional inhibitors and offers a "three-in-one" strategy to reverse immunosuppression. This work provides new insights into metabolic-immune crosstalk and presents a promising combinatory platform to boost immune checkpoint therapy.

Keywords:  DNAzyme; Glutamine inhibition; pyroptosis; tumor immunotherapy

DOI:  https://doi.org/10.1016/j.actbio.2026.01.004
Reprod Toxicol. 2026 Jan 07. pii: S0890-6238(26)00005-5. [Epub ahead of print] 109162

Maternal 3-NPA-Induced Oxidative Stress Impairs Offspring Ovarian Function via Glutamine Metabolic Dysregulation and NF-κB-Mediated Inflammation.

Lu Guo, Wenkai Yu, Bin Li, Xiaocheng Liu, Jiarong Zhang, Wenbin Tang.

  Oxidative stress is a well-established contributor to reproductive dysfunction, yet its intergenerational effects on offspring ovarian health remain poorly understood. This study aimed to investigate whether 3-nitropropionic acid (3-NPA)-induced maternal oxidative stress impairs ovarian development in offspring and elucidate underlying mechanisms. Female C57BL/6 mice were intraperitoneally injected 3-NPA (40mg/kg/day) for 21 days, while the control received saline. F1 offspring were assessed for ovarian function through follicle counts, serum FSH and AMH, and fertility metrics. Untargeted metabolomics and transcriptomics were performed on ovarian tissues, complemented by immunohistochemistry for glutamine metabolism enzymes of GLS1, GS, GDH and inflammatory markers (TNF-α). F1 offspring exhibited premature ovarian insufficiency (POI)-like phenotypes, including prolonged conception intervals, reduced pregnancy rates, elevated FSH, diminished primordial follicles and AMH levels, alongside impaired fertility. Maternal 3-NPA exposure induced sustained oxidative stress. Metabolomics revealed significant dysregulation of glutamine metabolism, with compensatory upregulation of GLS1/GS/GDH enzymes. Transcriptomics identified NF-κB/TNF-α pathway activation, validated by elevated ovarian TNF-α. Maternal oxidative stress triggers persistent ovarian dysfunction in offspring through glutamine metabolic disruption and NF-κB-mediated inflammation. This study provides the first evidence that 3-NPA induces intergenerational reproductive toxicity, highlighting glutamine metabolism and inflammatory pathways as potential targets for preventing oxidative stress-associated fertility decline.

Keywords:  glutamine metabolism; immune dysregulation; intergenerational effects; ovarian function; oxidative stress

DOI:  https://doi.org/10.1016/j.reprotox.2026.109162
Bull Exp Biol Med. 2026 Jan 08.

Comparison of Glucose and Glutamine as Energy Substrates for Astrocytes under Conditions of Oxygen Deficiency.

E A Turovsky, V A Babenko, E G Varlamova, E Y Plotnikov, N V Andrianova.

  We studied the effects of glucose and glutamine deficiency on the survival of astrocytes after ischemic injury and examined the mechanisms of cell death. It was found that glutamine can serve as an alternative energy substrate that maintains oxidative phosphorylation and glycolysis in astrocytes. However, the combination of glucose and glutamine reduced the ischemia-induced increase in intracellular calcium and the expression of proapoptotic proteins to a greater extent. The results of the study indicate the possibility of using glutamine to maintain the viability of brain cells under conditions of oxygen and energy substrate deprivation.

Keywords:  astrocytes; brain; energy substrates; ischemia; stroke

DOI:  https://doi.org/10.1007/s10517-026-06530-2
Int J Biol Macromol. 2026 Jan 02. pii: S0141-8130(25)10539-4. [Epub ahead of print]339(Pt 2): 149982

Cell exposure to hyaluronic acid/ε-Poly-l-Lysine physically crosslinked hydrogel disrupts glutamate metabolism and leads to cytoskeletal collapse.

Jingzhi Fan, Vahid Jahed, Liva Vita Kaufmane, Lilite Sadovska, Annija Vaska, Oleksandr Pogorielov, Rinalds Serzants, Dagnija Loca, Aija Line, Antons Sizovs, Kristaps Klavins.

  The multifunctional hydrogels made from hyaluronic acid (HA) and ε-poly-l-lysine (PLL) are interesting for soft tissue regeneration and antibacterial use. However, despite their strong antibacterial properties, the biocompatibility of physically crosslinked HA/PLL hydrogel remains inconsistent. This study investigates the molecular mechanisms underlying the cytotoxic effects of HA/PLL hydrogels, particularly their impact on cytoskeletal integrity. Using metabolomic profiling, we identified a marked accumulation of cystine and depletion of glutamate as critical factors. Tracing glutamine metabolism with 13C-labeled glutamine revealed an inhibition of glutaminase, impairing the conversion of glutamine to glutamate. Gene expression analysis further confirmed the unchanged levels of SLC7A11 gene expression and the downregulation of glutaminase. Additionally, the hydrogels significantly lowered intracellular glutathione levels, disrupting the redox balance. A reduced glutathione level can disturb disulfide bond stability. Confocal fluorescence imaging revealed a disordered and degraded actin. These findings suggest that HA/PLL hydrogels inhibit glutamine metabolism, leading to an elevated cystine/glutamate ratio, resulting in disulfide bond accumulation and subsequent cytoskeletal collapse, characteristic of disulfidptosis. This study provides novel insights into the cytotoxic pathways of HA/PLL hydrogels, with potential implications for their use in antibacterial implants and hydrogel-based therapies in tissue engineering.

Keywords:  Cystine; Cytoskeleton; Disulfidptosis; Glutamate; ε-Poly-l-lysine

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149982
Cancers (Basel). 2025 Dec 19. pii: 15. [Epub ahead of print]18(1):

Targeting Glutamine Transporters as a Novel Drug Therapy for Synovial Sarcoma.

Tran Duc Thanh, Naoki Takada, Hana Yao, Yoshitaka Ban, Naoto Oebisu, Manabu Hoshi, Nguyen Tran Quang Sang, Nguyen Van Khanh, Dang Minh Quang, Le Thi Thanh Thuy, Tran Trung Dung, Hidetomi Terai.

  Background/Objectives: Synovial sarcoma (SS) is a malignant soft tissue neoplasm with good outcomes in adolescents with localized tumors, but poor outcomes in older adults and in advanced or metastatic cases. Targeting cancer metabolism, such as glutamine metabolism, is a promising therapeutic strategy. In this study, we investigated glutamine dependency in SS and assessed the therapeutic potential of inhibiting the glutamine transporter ASCT2 using V9302. Methods: Immunohistochemistry (IHC) was used to evaluate ASCT2 expression in SS and liposarcoma (LPS) specimen. The effects of glutamine deprivation and V9302 were examined in a SS cell line (HS-SY-II), patient-derived SS cells (SSH1), and a normal cell line (HEK293). Cell viability, apoptosis, and protein expression were assessed using the CCK-8 assay, flow cytometry, and Western blotting, respectively. The therapeutic efficacy of V9302 was evaluated in a xenograft model using IHC. Results: ASCT2 expression was elevated in SS tumor tissues compared with adjacent normal tissues and LPS specimens. Both the HS-SY-II cell line and SSH1 cells exhibited strong glutamine dependency for proliferation. V9302 selectively reduced HS-SY-II cell viability by suppressing the AKT/mTOR signaling pathway and inducing apoptosis via caspase-3 activation, with minimal effects on control cells. In vivo, V9302 administration significantly inhibited tumor growth without inducing systemic toxicity, and IHC of the treated tumors confirmed the suppression of the mTOR pathway and induction of apoptosis. Conclusions: Our findings suggest that SS is a glutamine-dependent malignancy and validate ASCT2 as a promising therapeutic target. The ASCT2 inhibitor V9302 demonstrated therapeutic efficacy both in vitro and in vivo, supporting its potential as a therapeutic agent for SS.

Keywords:  AKT/mTOR pathway; ASCT2; V9302; glutamine metabolism; synovial sarcoma

DOI:  https://doi.org/10.3390/cancers18010015
Mol Carcinog. 2026 Jan 07.

Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages.

Joshua P Reddy, Rebecca A Clague, Beatriz P Peixoto, Sara Bernstein, Emma E Lauth, Clara Y Takanohashi, Sophie C Kim, Hiromi I Wettersten.

  Tumor-associated macrophages (TAMs) are critical contributors to cancer progression and are often recruited by cancer cells to support a pro-tumorigenic microenvironment. Integrin αvβ3 is a known driver and marker of cancer stem-like properties, including tumor initiation, in various epithelial cancers. We have previously shown a positive correlation between αvβ3 expression and TAM infiltration across multiple tumor types; however, the mechanistic link remains undefined. Here, we demonstrated that integrin αvβ3 expression in non-small cell lung cancer (NSCLC) cells is both necessary and sufficient to drive TAM accumulation. In orthotopic murine and human NSCLC models, ectopic integrin αvβ3 expression increased TAM infiltration independently of T cells, whereas genetic deletion of integrin β3 significantly reduced TAM numbers and tumor burden. Mechanistically, integrin αvβ3 promotes glutamine secretion from NSCLC cells, which enhances the survival and/or differentiation of bone marrow-derived macrophages. Functionally, TAMs are essential for the elevated tumor-initiating capacity of αvβ3+ cancer cells, as macrophage depletion abolished this effect. Together, our findings uncover a novel mechanism by which NSCLC cells remodel the tumor microenvironment via αvβ3-mediated glutamine secretion, promoting TAM enrichment and tumor initiation. Targeting this axis may offer therapeutic benefits in αvβ3-expressing cancers.

Keywords:  cancer metabolism; integrin αvβ3; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/mc.70077
Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
Cancer Lett. 2026 Jan 04. pii: S0304-3835(26)00007-8. [Epub ahead of print] 218244

Amino Acid Metabolic Reprogramming in Clear Cell Renal Cell Carcinoma: Pathogenic Mechanisms and Therapeutic Targeting.

Junzhe Xie, Fangjing Ni, Jialiang Shao, Dongliang Zhang, Tuanjie Guo, Xiang Wang.

  Kidney cancer is a major global health burden, with clear cell renal cell carcinoma (ccRCC) as the most common and aggressive subtype. Beyond the typical alterations of high glucose uptake and lipid accumulation, amino acid metabolism dysregulation in ccRCC is also gradually being uncovered. Pathways involving glutamine, cystine, serine, glycine, branched-chain amino acids, methionine, aspartate, arginine, proline and tryptophan are extensively rewired. These alterations enable cancer cells to sustain proliferation and biosynthesis, maintain redox balance, remodel the immune microenvironment, and develop resistance to therapy. At the same time, such reprogramming creates metabolic dependencies and vulnerabilities, including glutamine and cystine addiction as well as arginine auxotrophy. Dysregulation of key enzymes such as GLS1, ASS1 and IDO1 further highlights potential therapeutic targets. Exploiting these vulnerabilities through metabolic inhibitors or rational combinations with targeted and immunotherapy holds promise for overcoming resistance and improving outcomes in ccRCC.

Keywords:  amino acid metabolism; clear cell renal cell carcinoma; metabolic reprogramming; therapeutic vulnerability

DOI:  https://doi.org/10.1016/j.canlet.2026.218244
Cell Death Discov. 2026 Jan 09. 12(1): 13

Amino acid metabolic reprogramming: future prospects for cholangiocarcinoma therapy.

Sijia Hua, Fan Fei, Jiawen Li, Yuting Liu, Yuhong Gao, Xiang Wang, Xiulin Dong, Qiang Liu, Jianfeng Yang.

Cholangiocarcinoma (CCA) is a highly heterogeneous disease with a poor prognosis and a 5-year survival rate of less than 20% due to late diagnosis and limited therapeutic options, and the current problems in the treatment of CCA can be mainly attributed to the low rate of early diagnosis, the limited availability of targeted drugs, and the gradual increase in chemoresistance. Metabolic reprogramming in CCA causes the accumulation of large amounts of lactic acid and glycolytic intermediates, exacerbating hypoxia and the formation of an acidic environment at the tumor site, which further reduces the effectiveness of therapeutic drugs. Amino acid metabolic reprogramming promotes the proliferation, metastasis, spreading, and tumor angiogenesis of CCA cells, and some amino acid metabolites, in turn, regulate the metabolic state and gene expression of cells, which in turn regulates the cellular phenotype. Abnormal metabolism of amino acids negatively affects the progression of CCA. In the amino acid metabolism of CCA, the PI3K/AKT/mTOR and AMPK/Nrf2 pathways are two key pathways, and c-Myc plays an important role in glutamine metabolism as a transcription factor. Future studies should design targeted drugs around the abnormal accumulation process of glutamine, arginine and other amino acids to disrupt the amino acid uptake dominance in malignant tumors, as well as design novel drugs according to the changes in the tumor microenvironment.

DOI: https://doi.org/10.1038/s41420-025-02843-9
Int J Mol Sci. 2025 Dec 19. pii: 12. [Epub ahead of print]27(1):

Targeting the Glutaminolysis Pathway in Glaucoma-Associated Fibrosis.

Áine Kelly, Mustapha Irnaten, Colm O'Brien.

  Glaucoma is a group of progressive optic neuropathies and the leading cause of irreversible vision loss worldwide. It is a chronic eye disease, and its major pathological features include fibrosis of the trabecular meshwork, Schlemm's Canal and lamina cribrosa. Central to fibrosis is extracellular matrix (ECM) remodelling and metabolic reprogramming. Glutaminolysis is an alternative energy pathway that has previously been shown to be implicated in the metabolic reprogramming associated with cancer and other fibrotic diseases, facilitating ECM remodelling and cell proliferation. This paper reviews fibrosis, glutaminolysis in the setting of fibrosis, and fibrosis and glutaminolysis in the context of glaucoma. We review the evidence for fibrosis and metabolic reprogramming in oncology and systemic fibrotic diseases, which reveals a predilection for glutaminolysis. We review the current therapies that exist to target these pathways, and find glutaminolysis to be a potential target for future therapies in glaucoma.

Keywords:  bioenergetics; fibrosis; glaucoma; glutaminolysis

DOI:  https://doi.org/10.3390/ijms27010012
Sci Rep. 2026 Jan 05.

‌PPIA regulates fatty acid and glutamine metabolism in lung adenocarcinoma based on multiomics prognostic model and experiment validation.

Yuan Gan, Wanshuo Wei, Bowei Jiang, Xindan Zhang, Lin Jiang, Liangsen Teng, Xiaomei Xie, Yixin Liu, Qiumei Xie, Lihe Jiang.

  Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer worldwide, in which fatty acid metabolism plays a key role in tumor growth, metastasis, and immune evasion. PPIA has been confirmed to be closely related to tumor metabolism and immune regulation, but its specific mechanism of action is still unclear. Multi-omics data from TCGA and GEO, combined with single-cell RNA sequencing (scRNA-seq), were used to characterize metabolic heterogeneity and the immune microenvironment in lung adenocarcinoma (LUAD). Fatty acid metabolism-related genes were identified via WGCNA and univariate Cox regression, and a prognostic risk model was constructed. Virtual knockout, cell function assays, and metabolic profiling were performed to investigate the role of PPIA in metabolic reprogramming and tumor progression. In vitro, PPIA was silenced using siRNA or co-overexpressed with pCMV-C-Myc in A549 and H1975 cells. Functional validation included qRT-PCR and Western blotting, as well as CCK-8, colony formation, wound healing, and Transwell assays to assess proliferation, migration, and invasion. Metabolic assays measured glutamine uptake, α-ketoglutarate production, free fatty acid levels, and the GSH/GSSG ratio, elucidating PPIA's regulatory effects on metabolism and LUAD progression. Integrative multi-omics analysis identified a fatty acid metabolism-related gene module associated with poor prognosis in LUAD. A four-gene risk model (ERCC1, KYNU, AKR1A1, and PPIA) demonstrated strong predictive power for overall survival across multiple datasets. Single-cell analysis revealed that PPIA was highly expressed in malignant, metabolically active cell populations and strongly correlated with fatty acid and glutamine metabolism. Functional assays confirmed that PPIA silencing inhibited LUAD cell proliferation, migration, and EMT, while reducing key metabolites including glutamine uptake, α-ketoglutarate, free fatty acids, and the GSH/GSSG ratio. Mechanistically, PPIA depletion downregulated c-Myc expression, whereas c-Myc overexpression partially reversed these effects, suggesting that PPIA drives LUAD progression through the c-Myc-mediated fatty acid-glutamine metabolic axis. This study reveals that PPIA promotes the malignant progression of LUAD and affects the immune microenvironment by regulating the c-Myc-mediated fatty acid-glutamine metabolism network remodeling. A prognosis model based on fatty acid metabolism can serve as an effective tool for assessing the prognosis of LUAD patients. Due to incomplete clinical information in some datasets, comprehensive subgroup analyses could not be performed.

Keywords:  Fatty acid metabolism; Glutamine metabolism; Lung adenocarcinoma; Multiomics; Prognostic factor

DOI:  https://doi.org/10.1038/s41598-025-34313-8
Phys Chem Chem Phys. 2026 Jan 05.

Sweet optimization: glucose-vitrified samples for hyperpolarizing glutamine in biological studies.

Léa Gutierrez, Karen Dos Santos, Mehdi Soussi-Therond, Aiky Razanahoera, Daniel Abergel, Nicolas Giraud, Mathieu Baudin.

This work describes the development of a versatile formulation using glucose as a vitrification agent in dynamic nuclear polarization. Significantly high polarization levels are achieved through optimization of a sample formulation, using sodium acetate and glutamine as targets. The best optimized formulation allowed precise monitoring of the enzymatic conversion of glutamine to glutamate, paving the way for advances in cellular metabolism applications.

DOI: https://doi.org/10.1039/d5cp03827h
Mol Cancer. 2026 Jan 08.

Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.

Ran Zhou, Yuejun Li, Guanghui Li, Yan Li, Lie Luo, Bin Wang, Liping Wang.

  Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC present significant challenges to global public health. As the primary metabolic organ in the human body, the liver undergoes substantial metabolic reprogramming during carcinogenesis, affecting various metabolic pathways including those involved in carbohydrates, lipids, and amino acids. Notably, disruptions in amino acid metabolism play a critical role in the initiation and progression of HCC, helping to sustain its malignant characteristics. This review aims to provide an in-depth analysis of the alterations observed in aromatic amino acids metabolism, branched chain amino acids (BCAAs) metabolism, glutamine metabolism, and other amino acid metabolism processes, including serine, arginine, and methionine, along with the expression patterns of associated metabolic enzymes. Furthermore, it discusses potential therapeutic approaches and their clinical relevance, offering insights and strategies for improving HCC diagnosis and treatment in the future.

Keywords:  Amino acid metabolism; Hepatocellular carcinoma; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s12943-025-02492-7
J Mol Histol. 2026 Jan 06. 57(1): 23

FOXM1/FUS facilitates triple-negative breast cancer malignant progression and glutamine metabolism through mediating SLC7A5 transcription.

Shuangjian Li, Qian Zhao.

  Triple-negative breast cancer (TNBC) is highly malignant with rising incidence and mortality. Solute carrier family 7 member 5 (SLC7A5) is an amino acid transporter, and its mechanism in TNBC is still unclear. The public databases (TIMER2.0, TCGA, GEPIA, Kaplan-Meier Plotter, linkedomics, RBPmap, and RBPDB) were used to analyze the expression and correlation of genes and prognosis correlation. Gene and protein expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. 3-(4, 5)-Dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT), terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining, flow cytometry, transwell, sphere/tube formation, and metabolic kits were used to assess cell viability, apoptosis, invasion, stemness, angiogenesis, and glutamine (Gln) metabolism. The binding of forkhead box M1 (FOXM1) to the SLC7A5 promoter was determined by dual-luciferase reporter assay/chromatin immunoprecipitation (ChIP). RNA binding protein immunoprecipitation (RIP), RNA pull-down, and actinomycin D (Act D) experiments evaluated fused in sarcoma (FUS)-SLC7A5 interaction. In vivo, the mouse xenografts were established to validate the effects of FOXM1/SLC7A5 axis. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) assays were used for histological morphology analysis and the protein expression of Ki67 and SLC7A5. SLC7A5 was up-regulated in TNBC and correlated with poor prognosis. Its knockdown repressed TNBC cell viability, invasion, stemness, angiogenesis, and Gln metabolism (as evidenced by reduced Gln, α-ketoglutarate (α-KG), and adenosine 5'-triphosphate (ATP) levles). FOXM1 transcriptionally activated SLC7A5; SLC7A5 overexpression reversed the suppressive effects of FOXM1 knockdown on TNBC malignancy and metabolism. Additionally, FUS bound to and stabilized SLC7A5 mRNA. In vivo, SLC7A5 counteracted the FOXM1 knockdown-mediated inhibition of tumor growth and the reduction in SLC7A5 and Ki67 protein expression. In conclusion, SLC7A5 promotes TNBC malignancy and metabolism. Its expression is transcriptionally driven by FOXM1 and post-transcriptionally stabilized by FUS. Targeting the FOXM1/SLC7A5 axis presents a novel therapeutic strategy for TNBC.

Keywords:  Forkhead box M1; Fused in sarcoma; Solute carrier family 7 member 5; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s10735-025-10674-2
Front Immunol. 2025 ;16 1735873

The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.

Shaofan Hu, Hui Heng, Fang Yang, Meng Wang, Guoxiang Liu, Yuancai Xiang, Hongming Miao.

  Metabolic reprogramming is a defining hallmark of tumors, and plays a pivotal role in sustaining malignant growth by rewiring core bioenergetic and biosynthetic pathways. Beyond supporting tumor cell proliferation, survival, and metastasis, it profoundly shapes the tumor microenvironment through nutrient competition, accumulation of immunosuppressive metabolites, and modulation of immune cell function, thereby facilitating immune evasion and therapy resistance. This review comprehensively elaborates on metabolic reprogramming in colorectal cancer, covering key alterations in glucose metabolism (Warburg effect), tricarboxylic acid cycle remodeling, lipid biosynthesis/oxidation, cholesterol metabolism, and amino acid (glutamine, methionine, tryptophan, arginine) metabolism. It further dissects how these metabolic shifts impact the tumor microenvironment in colorectal cancer, including their effects on effector immune cells (CD8+ T cells, NK cells), immunosuppressive populations (Tregs, MDSCs, M2-TAMs), and antigen-presenting cells. Additionally, this review highlights the role of the gut microbiota and their metabolites (e.g., SCFAs, secondary bile acids and indoles) in remodeling the immune microenvironment via metabolic crosstalk. Overall, this work provides a comprehensive understanding of CRC metabolic reprogramming and its microenvironmental impacts, offering critical insights to guide the development of novel metabolism-targeted therapeutic strategies for CRC.

Keywords:  colorectal cancer (CRC); gut microbiota; immune evasion; metabolic reprogramming; metabolism-targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1735873
Synth Syst Biotechnol. 2026 Jun;12 197-208

Leveraging ANXA1 to enhance recombinant protein yields in CHO cells: A UPR-Mediated bioprocessing approach.

Qi Zhao, Hui-Jie Zhang, Ming-Ming Han, Jumai Abiti, Yan-Ju Dong, Jia-Ning Wang, Jiang-Tao Lu, Wen Wang, Xi Zhang, Shao-Lei Geng, Le-Le Qiu, Xiao-Yin Wang, Zi-Chun Hua, Tian-Yun Wang, Yan-Long Jia.

  Chinese hamster ovary (CHO) cells undergo endoplasmic reticulum stress (ERS) during intensive recombinant protein production, triggering the unfolded protein response (UPR) to balance cell survival and protein output. Nevertheless, key regulatory components of this process remain incompletely characterized. In this study, we demonstrate that Annexin A1 (ANXA1) functions as a UPR suppressor in CHO cells. Employing the PiggyBac transposon system, we generated a stable ANXA1-knockdown cell line exhibiting a 4.5-fold increase in recombinant antibody expression and a 4.2-fold increase in specific productivity. Pharmacological inhibition using AC2-26 similarly enhanced recombinant protein expression in low-productivity cell populations. Mechanistically, ANXA1 depletion remodeled the UPR by activating the PERK-eIF2α-ATF4 and IRE1-XBP1 branches. This activation upregulaed ATF4, Bip, and XBP1s; suppressed CHOP; reduced apoptosis; and enhanced autophagic flux. Metabolic profiling revealed increased glucose and lactate utilization, while glutamine consumption and ammonia flux remained unchanged. Collectively, these findings establish that ANXA1 depletion enhances recombinant protein biosynthesis through coordinated pro-survival mechanisms. Targeting ANXA1 thus represents an innovative cell engineering strategy for optimizing CHO cell platforms in industrial biopharmaceutical manufacturing.

Keywords:  Annexin A1 (ANXA1); Chinese hamster ovary (CHO) cells; Genetic engineering; Recombinant preotein expression; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.synbio.2025.12.001
Int J Mol Sci. 2025 Dec 30. pii: 403. [Epub ahead of print]27(1):

Ammonium Hydroxide Enhancement of Dietary Protein in High-Fat Diets Modulates Liver Metabolism Signaling in a Sex- and Age-Dependent Manner in C3H/HeJ Mice.

Benjamin R Barr, Indhu Subramaniyan, Li Li, Danielle E Levitt, Lauren S Gollahon.

  (1) Lifestyle changes to modify unhealthy dietary patterns with the goal of preventing MASLD have proven challenging. Here, dietary proteins and their modification with ammonium hydroxide enhancement (AHE) provide molecular evidence that this novel approach may attenuate the development of MASLD without undue dietary adjustments, potentially bypassing non-compliance. (2) High-fat diets containing dietary beef (HFB) or casein (HFC) + AHE (HFBN and HFCN, respectively) were fed to 256 C3H/HeJ female and male mice long term. At 6, 12, or 18 months, hepatic samples were analyzed with targeted metabolomics (glucose, lactate, alanine, glutamine, carnitine) and Western analysis (β-catenin, glutamine synthetase, CYP3A4). RNA sequencing was performed on samples collected at 18 months (n = 3; male HFC n = 2). (3) Metabolomics results showed that at 18 months, hepatic glutamine was greater in HFBN versus HFCN in females, whereas in males, hepatic glutamine, glucose and lactate were lower in HFBN versus HFCN. Additionally, diets with AHE decreased β-catenin and CYP3A4 protein expression in males. Ingenuity pathway analysis (IPA) of RNA-seq data predicted that HFBN activates PPARα signaling in the liver in both sexes compared to HFCN. Inflammatory activity showed predicted activation for females in the HFBN:HFCN comparison. In males, the inflammatory pathway molecular mechanisms of cancer was predicted as deactivated in HFBN:HFCN. (4) Dietary protein source impacts outcomes, and these outcomes improved with AHE. The HFBN diet improves signaling associated with lipid utilization for females and males, and improved inflammatory signaling for males compared with HFCN. Further exploration of AHE as a dietary intervention in high-fat diets is warranted.

Keywords:  HCC; MASH; MASLD; ammonium hydroxide enhancement; diet-induced obesity; dietary intervention; dietary protein; metabolites

DOI:  https://doi.org/10.3390/ijms27010403
Int J Surg. 2025 Dec 03.

Urinary amino acid profiles emerge as promising biomarkers for predicting and assessing the prognosis of clear cell renal cell carcinoma: a retrospective case-control Study.

Hanfeng Wang, Pengfei Li, Gang Guo, Liangyou Gu, Xu Zhang, Fan Zhang.

   BACKGROUND: Clear cell renal cell carcinoma (ccRCC) stands as one of the most frequently encountered urological malignancies. The development of a highly sensitive and specific non-invasive biomarker for early detection and accurate prognostic stratification of ccRCC patients remains an ongoing challenge. This study was designed to comprehensively assess the predictive and prognostic values of urinary amino acid profiles in ccRCC patients, aiming to identify potential biomarkers for clinical application.
MATERIALS AND METHODS: Between March and August 2022, a cohort of ccRCC patients and healthy controls were enrolled consecutively. Urine specimens were subjected to quantitative analysis using isobaric tags for relative and absolute quantitation-liquid chromatography-tandem mass spectrometry method. The clinical characteristics were collected retrospectively. Subsequently, univariate and multivariable regression analyses were performed to identify potential associations between amino acid profiles and tumor characteristics.
RESULTS: A total of 52 ccRCC patients and 52 matched healthy controls were enrolled. A logistic regression model was constructed incorporating four amino acids: α-aminoadipic acid (P = 0.010), glutamine (P = 0.023), β-Alanine (P = 0.011), and homocitrulline (P = 0.021). Receiver operating characteristic curves were generated for all ccRCC patients and healthy controls, T1-T2 stage ccRCC patients and healthy controls, and WHO/ISUP grade 1 ccRCC patients and healthy controls. The corresponding area under the curve values were 0.849, 0.855, 0.904, respectively. Kaplan-Meier survival analysis revealed that ccRCC patients with higher model scores (> 2) had significantly shorter progression-free survival (PFS) compared to those with lower scores (≤ 2). Cox regression analysis further demonstrated that the model score was an independent prognostic factor for PFS in ccRCC patients (P = 0.032).
CONCLUSIONS: Urinary amino acid profiles demonstrate substantial promise as a non-invasive humoral biomarker for the prediction and prognostic evaluation of ccRCC, especially for early-stage and low-grade tumors.

Keywords:  amino acids; biomarker; case-control study; clear cell renal cell carcinoma; iTRAQ-LC-MS/MS; prognosis

DOI:  https://doi.org/10.1097/JS9.0000000000004209
Immunobiology. 2025 Dec 27. pii: S0171-2985(25)00285-2. [Epub ahead of print]231(1): 153151

Immunometabolism of T cells and macrophages: Human translational perspectives.

Borros Arneth.

   BACKGROUND: Immunometabolism explores how immune-cell function depends on cellular energy metabolism. Recent insights demonstrate that nutrient utilization dictates activation, polarization, and tolerance.
AIMS: To systematically review human studies on T-cell and macrophage metabolism, identify converging pathways, and outline translational implications for inflammation, autoimmunity, and cancer.
METHODS: Following PRISMA 2020 guidelines, PubMed was searched (2015-2025) using predefined MeSH terms ("immunometabolism", "T lymphocytes", "macrophages", "metabolic reprogramming"). Of 999 records, 67 met inclusion criteria (human data, peer-reviewed, quantitative endpoints). Bias was assessed with ROBIS.
RESULTS: Effector T cells and M1 macrophages favor glycolysis for rapid ATP and pro-inflammatory signaling, whereas memory T cells and M2 macrophages rely on oxidative phosphorylation and fatty-acid oxidation for sustained energy and tolerance. mTORC1/AMPK signaling, glutaminolysis, and the kynurenine pathway integrate metabolic and immune cues. Metabolic dysregulation in obesity or tumor microenvironments skews these pathways, driving chronic inflammation or immune escape.
CONCLUSIONS: Human immunometabolism is defined by dynamic substrate switching. Targeting glycolysis, FAO, or tryptophan metabolism offers therapeutic leverage in cancer and autoimmune disease. Future directions include single-cell and spatial metabolomics and integrative metabolic-immune modeling.

Keywords:  Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; PRISMA review; T cells

DOI:  https://doi.org/10.1016/j.imbio.2025.153151
BMC Plant Biol. 2026 Jan 08.

The Arabidopsis UMAMIT30 transporter contributes to amino acid root exudation.

Israel D K Agorsor, Pramod Khadka, Cristian H Danna.

   BACKGROUND: Root exudation is an important trait that enables plants to shape their interactions with soil-borne organisms. Amino acids present in root exudates play important roles in bacterial chemotaxis, bacterial metabolism, and root colonization, contributing to plant nutrition and health. Notwithstanding the importance of amino acids in shaping the rhizosphere microbiome, the identities of the plant amino acid transporters that mediate their root exudation have remained elusive.
RESULTS: Here, we report that the Arabidopsis UMAMIT30 transporter, robustly expressed in root and shoot tissues, significantly contributes to amino acid root exudation. umamit30 loss-of-function mutants were compromised for amino acid root exudation as shown by the low concentration of amino acids, particularly glutamine, recovered from root exudates compared to wild-type plants. Amino acid quantification, as well as uptake and secretion assessments using radiolabelled glutamine, revealed that the shoots of umamit30 accumulate amino acids and have a reduced capacity to secrete glutamine, impacting root exudation.
CONCLUSIONS: Our results identify UMAMIT30 as a broadly specific amino acid exporter strongly expressed in Arabidopsis vasculature. Loss-of-function mutants displayed reduced amino acid levels in root exudates, with significant drops in glutamine and asparagine among others, yet exhibited no detectable growth defects under our growth conditions. UMAMIT30 disruption led to elevated shoot amino acid content and reduced glutamine efflux from shoots, suggesting a role in phloem uploading as an upstream step necessary for root exudation. Despite decreased levels of root-exuded amino acids, the plant growth-promotion conferred by the soil-borne beneficial bacterium Pseudomonas simiae WCS417r remained unmodified in umamit30 mutants.

Keywords:   Arabidopsis thaliana ; Amino acids; Beneficial microbes; Root exudation; Transporter; UMAMIT30

DOI:  https://doi.org/10.1186/s12870-025-07930-8
Adv Sci (Weinh). 2026 Jan 04. e06994

Perfluorooctanoic Acid Exposure Causes Macrophage Ammonia Retention and Induces Spontaneous Miscarriages.

Yongbo Zhao, Yijun Zhang, Hanyu Rao, Jiani Sun, Zhiyi Pan, Liping Jin, Yan Zhao.

  Spontaneous miscarriage, the most prevalent complication of early pregnancy, poses substantial risks to maternal health worldwide. Perfluorooctanoic acid (PFOA) is a ubiquitous environmental persistent organic pollutant. Human epidemiological studies have linked PFOA exposure to spontaneous miscarriages, yet the underlying mechanisms have been rarely explored. In this study, we found PFOA exposure induced embryonic absorption in pregnant mice by causing ammonia retention in macrophages. Excessive ammonia disrupted mitochondrial function and compromised lysosomal integrity, which ultimately impaired macrophage function. Furthermore, lysosomal dysfunction reduced secretion of cathepsin B (CTSB) and led to decreased macrophage infiltration and diminished trophoblast invasion. Mechanistically, PFOA exposure led to macrophages ammonia retention by promoting the glutaminolysis through the upregulation of glutaminase (GLS) expression. By downregulating the inhibitor of DNA binding protein 3 (ID3), PFOA enhanced nuclear translocation and DNA-binding affinity of transcription factor 12 (TCF12), which directly activated glutaminase (GLS) transcription to fuel glutamine catabolism. Collectively, our findings delineated a previously unrecognized pathway linking environmental PFOA exposure to spontaneous miscarriage via ammonia-driven macrophage impairment.

Keywords:  ammonia retention; macrophage; perfluorooctanoic acid; spontaneous miscarriage

DOI:  https://doi.org/10.1002/advs.202506994
J Virol. 2026 Jan 09. e0055625

Metabolic hijackers: how viral proteins redefine host cell landscapes.

Adam Hafner, Rebekah L Mokry, John G Purdy, Christiane E Wobus.

  Viruses are metabolic engineers of host cells. As obligate intracellular pathogens, they rely on host cell metabolism for efficient viral replication. The manipulation of host metabolic processes is a strategy shared among diverse virus families to secure the necessary resources for replicating new genomes, building more virus particles, and supporting cell growth and proliferation. Key metabolic pathways targeted by viruses for disruption and manipulation are glycolysis, glutaminolysis, and lipid metabolism. However, the mechanisms behind virus-induced metabolic reprogramming and the viral proteins mediating it remain poorly understood. This review explores how specific viral proteins reshape the metabolic milieu of host cells during viral infections. We also highlight common themes and outline gaps in knowledge to stimulate further investigations into how viral proteins manipulate host metabolism. Such mechanistic insights will deepen our understanding of virus-host interactions and may reveal novel therapeutic targets.

Keywords:  RNA and DNA virus proteins; cellular metabolism; glutaminolysis; glycolysis; lipid metabolism

DOI:  https://doi.org/10.1128/jvi.00556-25
J Proteome Res. 2026 Jan 06.

Untargeted Serum Metabolomics Reveals Differential Signatures in Gallstone-Associated and Gallstone-Free Gallbladder Cancer Variants.

Cinmoyee Baruah, Amit Rai, Anupam Sarma, Gayatri Gogoi, Uttam Konwar, Utpal Dutta, Subhash Khanna, Sheelendra P Singh, Pankaj Barah.

  Gallbladder cancer (GBC) is an aggressive malignancy often associated with gallstones (GBCGS), a condition distinct from gallstone disease (GSD). Both GBC and GBCGS are rare, with unclear pathogenesis and no established biomarker-based diagnostics. This pilot study aimed to identify distinct metabolic signatures in GBC and GBCGS for early diagnosis and stratification of high-risk GSD patients. Comparative untargeted serum metabolomic profiling was performed across three groups: GBC (n1 = 9), GBCGS (n2 = 11), and GSD (n3 = 10). A total of 35,385 mass features with MS/MS characteristics were detected and annotated into 736 biochemicals. Differential metabolome analyses relative to GSD identified 180 altered metabolites in GBC and 225 in GBCGS, with 138 shared by both. Correlation network and biomarker analyses subsequently identified 12 GBC-specific, 20 GBCGS-specific, and 30 shared metabolite signatures with high diagnostic efficiency, predominantly upregulated. Key metabolites identified included cholic acid, glycocholic acid, glycochenodeoxycholic acid, kynurenine, and glutamine, implicated in promoting metastasis and epithelial-to-mesenchymal transitions. Thus, serum metabolome reprogramming in GBC and GBCGS revealed a shared deregulation of metabolic pathways involving bile acids, amino acids, and their intermediates alongside distinct condition-specific biomarkers. These findings provide novel insights into the pathogenesis of GBC and GBCGS, advancing future diagnostic, prognostic, and therapeutic interventions.

Keywords:  OPLS-DA; bile acids; biomarkers; gallbladder cancer; gallstone disease; metabolic correlation networks; metabolomics; pathways

DOI:  https://doi.org/10.1021/acs.jproteome.5c00403
Sci Rep. 2026 Jan 03.

Prevalence of low bone mineral density and associated plasma metabolite alterations in thalassemia.

Pokpong Piriyakhuntorn, Adisak Tantiworawit, Piangrawee Niprapan, Chanisa Thonusin, Wichwara Nawara, Tawika Kaewchur, Nipon Chattipakorn, Siriporn C Chattipakorn.

  While metabolomics offers insights into metabolic diseases, plasma metabolites in thalassemia patients with low bone mineral density (BMD) have not been explored. This cross-sectional study investigated plasma metabolite alterations in thalassemia patients with low BMD compared to those with normal BMD and healthy controls at Chiang Mai University's Hematology Clinic. Eighty thalassemia patients and 40 age- and sex-matched controls were enrolled. BMD was measured at two skeletal sites, the lumbar spine (L1-L4) and hip, using dual-energy X-ray absorptiometry. Targeted plasma metabolomics and bone turnover markers (β-CTX-I, total PINP) were assessed. Low BMD was defined as a Z-score ≤ - 2 at any site, and its prevalence among thalassemia patients was 47.5%. Compared to those with normal BMD, thalassemia patients with low BMD showed elevated glutamate, arachidonic acid, and medium- to long-chain acylcarnitines, but reduced glutamine levels. Phosphatidylinositol and lysophosphatidylinositol were also increased. β-CTX-I and total PINP levels did not differ between thalassemia groups. A predictive model using key metabolites (glutamine, arachidonic acid, asparagine, lysoPI (18:0), myristoylcarnitine) showed fair discriminatory ability for low BMD (AUC 0.762, p = 0.007). Thalassemia with low BMD is associated with glutamate-glutamine metabolism disruptions, impaired fatty acid oxidation, and elevated phosphatidylinositol levels.

Keywords:  Bone mineral density; Metabolites; Metabolomics; Osteoporosis; Prevalence; Thalassemia

DOI:  https://doi.org/10.1038/s41598-025-34667-z
Small. 2026 Jan 08. e13649

Unleashing the Potent Antitumor Force: A Reactive Oxygen Species (ROS) Storm Formation by Ultrasound-Activatable Metal Nanosonosensitizers.

Qi Xiang, Yan Zhang, Yuhong Ren, Fuxue Luo, Yunfang Wu, Haitao Ran, Yang Cao.

  Reactive oxygen species (ROS)-mediated tumor therapy, which induces oxidative stress damage for precise oncolysis, represents a novel antitumor strategy. However, the overexpression of glutathione (GSH) in the tumor microenvironment (TME) forms a strong antioxidant barrier, rapidly scavenging ROS and repairing oxidative damage, thus limiting the efficacy of conventional ROS-based therapies. Metal nanosonosensitizers, activated by ultrasound and penetrating deeply into the TME, offer a promising solution when combined with glutaminase1 (GLS1) inhibitors to overcome GSH-mediated defenses. This study innovatively constructs a biomimetic metal nanosonosensitizer, CRIM, with a copper sulfide as core, encapsulating IR780 and IPN60090, coated with tumor cell membranes. CRIM specifically accumulates in tumor cell mitochondria, where ultrasound activation triggers efficient ROS generation while depleting GSH levels by direct consumption and indirect synthesis. This synergistic GSH depletion disrupts the tumor antioxidant system, sustaining ROS accumulation and triggering a ROS storm. The "ROS generation-GSH depletion-exacerbated oxidative stress" feedback loop induces immunogenic cell death (ICD). Additionally, copper ion released from CRIM induces cuproptosis, synergizing with ROS-mediated cytotoxicity to enhance therapeutic efficacy. This approach triggers a ROS storm via multi-pathway synergy, induces comprehensive tumor destruction, and activates systemic immunity, thereby unleashing a potent antitumor force and offering a new direction for cancer treatment.

Keywords:  antitumor therapy; glutathione; immunogenic cell death; metal nanosonosensitizers; reactive oxygen species; sonodynamic therapy

DOI:  https://doi.org/10.1002/smll.202513649
iScience. 2026 Jan 16. 29(1): 114267

The ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation.

Marisa Mitchell-Flack, Makenzie Higgins, Ying Zheng, Ada Tam, Hana Goldschmidt, Hiroshi Nishio, Bian Liu, Christopher M Cherry, Michael Patatanian, Richard Blosser, Sung Soo Mun, Aditya Suru, Richard Huganir, Hong Yu, Drew Pardoll.

  The AMPA receptor (AMPAR) is an ionotropic glutamate receptor that is essential for neuronal communication, yet its role in the immune system remains poorly understood. Here, using a CD4Cre selective deletion mouse model, we provide the first functional characterization of AMPAR deficient T cells. We demonstrate that AMPAR deletion in T cells significantly protects against severe paralysis in an experimental autoimmune encephalomyelitis (EAE) model, and this protection is associated with increased regulatory T cell (Treg) presence within the spinal cord. In vitro studies reveal that the deletion of the AMPAR intrinsically promotes Treg generation. Mechanistically, AMPAR deletion increases IL2 signaling and activates the mTORC1 pathway, supporting Treg development and function. These novel findings suggest that a function of the AMPAR in CD4 T cells is to limit immune suppression by restricting Treg differentiation. Targeting AMPARs on T cells could offer a novel therapeutic approach for the treatment of autoimmune disease.

Keywords:  Immune response; Immune system; Immunology; Stem cells research

DOI:  https://doi.org/10.1016/j.isci.2025.114267