bims-glucam 2026-06-28 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–06–28
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Depletion Induced Senescence-Associated β-Galactosidase Activity and Impaired Functional Properties of Ea.hy926 Endothelial Cells.
Mechanistic Integration of Beta-Alanine-Carnosine Buffering and Glutamine Metabolism in Exercise-Induced Muscle-Brain Crosstalk: Implications for Aging, Neurodegeneration, and Cognitive Decline.
Oxidative Stress Induced Senescent Macrophage-Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming.
Deciphering glutamine metabolic reprogramming: a novel therapeutic target ALDH18A1 in triple-negative breast cancer.
Regulation of Tumor-Immune Cell Communications via Enantioselectively Targeting SLC G-Quadruplexes.
Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
Tumor-immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy.
Amino Acid Metabolic Reprogramming in Immunotherapy for Hepatocellular Carcinoma: Adaptive Resistance, Patient Stratification, and Longitudinal Monitoring.
Metabolic reprogramming regulates macrophage polarization to impact ovarian cancer progression.
De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders.
Addressing the elephant in the room: A comprehensive framework to resolve selectivity, multicollinearity, and scalability challenges in Raman chemometric models for mammalian cell culture applications.
SP1-mediated NAT10 upregulation drives oral squamous cell carcinoma progression via ac4C-dependent SLC1A5 modification.
Multi-Omics Analysis Reveals Chronic Cisplatin Exposure Is Associated with Metabolic Rewiring Toward Glutathione Metabolism to Support Redox Adaptation in High-Grade Serous Ovarian Cancer.
Nutritional Amino Acid Supplementation Reduces Severity and Enhances Recovery of Radiation-Induced Oral Mucositis: A Triple-Blind Randomized Clinical Trial.
[YTHDF1 enhances the expression of exogenous proteins in the CHO-K1-GS‒/‒ cell line].
Metabolic Assessment in Human Pluripotent Stem Cell-Derived Cerebral Organoids Using HR-MAS NMR Spectroscopy.
Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.
Characterization of the lysosomal arginine transporter SLC7A14.
Prolonged In Vitro Exposure to Methylmalonic Acid Induces Inflammation, Glutamate Metabolism Disruption, and Alters Functional Gene Expression in C6 Astroglial Cells.
Slc44a2 Deficiency Unveils an IFN-I-Dependent Feedback Control of pDC Egress.
Polystyrene Microplastics Activate Noncanonical TGF‑β Signaling and Metabolomic Reprogramming to Promote Epithelial-Mesenchymal Transition and Fibrosis in the Kidney.

Cells. 2026 Jun 20. pii: 1116. [Epub ahead of print]15(12):

Glutamine Depletion Induced Senescence-Associated β-Galactosidase Activity and Impaired Functional Properties of Ea.hy926 Endothelial Cells.

Jamil Haider, Xiaoyan Huang, Chunyu Xu, TinChung Leung.

  Glutamine is a conditionally essential amino acid that is important for endothelial homeostasis, while endothelial cell dysfunction is associated with altered glutamine metabolism and shifts toward stress-responsive pathways. We investigated the role of glutamine and senescence-associated beta-galactosidase (SA-β-gal) activity in Ea.hy926 endothelial cells (ECs), together with supportive functional activity assays. We found that glutamine depletion induced a progressive decline in endothelial function. Specifically, glutamine-depleted ECs exhibited increased SA-β-gal activity, accompanied by impaired proliferative capacity, disrupted cellular morphogenesis, increased promyelocytic cell adhesion, and diminished ability to promote host tissue proliferation and EC morphogenesis in a zebrafish xenograft model. These findings suggest that glutamine availability is crucial for maintaining endothelial integrity and functional competence.

Keywords:  Ea.hy926 endothelial cell; glutamine; senescence-associated beta-galactosidase activity; zebrafish

DOI:  https://doi.org/10.3390/cells15121116
Mol Neurobiol. 2026 Jun 20. pii: 710. [Epub ahead of print]63(1):

Mechanistic Integration of Beta-Alanine-Carnosine Buffering and Glutamine Metabolism in Exercise-Induced Muscle-Brain Crosstalk: Implications for Aging, Neurodegeneration, and Cognitive Decline.

Rui Wang, Yan Guo, Juan Li, Tian Peng, Xinghao Wang.

  Aging is marked by a gradual deterioration in muscular performance, cognitive abilities, and metabolic flexibility, phenomena that are intricately linked through the muscle-brain axis. Recent research indicates that particular amino acids, notably beta-alanine (BA) and glutamine, may not function in isolation but instead converge mechanistically to modulate this axis through synergistic influences on intracellular pH regulation, nitrogen metabolism, and redox equilibrium. BA, through its involvement in the biosynthesis of carnosine, augments intracellular buffering capacity and maintains pH stability during metabolic stress scenarios such as exercise and age-related mitochondrial dysfunction. This buffering capability holds particular significance for pH-sensitive enzymes implicated in glutamine metabolism, such as glutamine synthetase and glutaminase, thereby potentially safeguarding glutamine turnover and nitrogen flux in acidic environments. Simultaneously, glutamine operates as a pivotal metabolic substrate that connects skeletal muscle and the brain by facilitating energy homeostasis, immune modulation, antioxidant protection, and neurotransmitter recycling through the glutamate-glutamine axis. Within this cohesive framework, the regulation of pH mediated by carnosine and the metabolic pathways reliant on glutamine collectively enhance mitochondrial functionality, neuroplasticity, and the mitigation of neuroinflammation. Physical exercise further intensifies these interactions by influencing both the availability of carnosine and the dynamics of glutamine, thereby strengthening their significance in the communication between muscle and brain. This review consolidates the prevailing evidence regarding BA and glutamine within a unified mechanistic paradigm, emphasizing their synergistic contributions to the regulation of metabolic resilience and neuroprotection in the context of aging and neurodegenerative disorders. In aggregate, this integrative viewpoint offers a more robust biological justification for the targeted modulation of these amino acids as complementary agents within the muscle-brain axis. Future investigations should prioritize personalized interventions that integrate amino acid supplementation and exercise regimens within the paradigm of predictive, preventive, and personalized medicine to enhance the trajectories of healthy aging.

Keywords:  Aging-related cognitive disorders; Beta-alanine; Endurance exercise; Glutamine; Muscle–brain axis

DOI:  https://doi.org/10.1007/s12035-026-05985-8
Aging Cell. 2026 Jul;25(7): e70592

Oxidative Stress Induced Senescent Macrophage-Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming.

Shimeng Wang, Jingtian Mu, Wei Zhao, Can Hu, Xueke Shi, Hongmei Zhou, Junjiang Liu, Fanglong Wu.

  Oxidative stress drives tumor microenvironment (TME) remodeling by inducing metabolic reprogramming and cellular senescence. Glutamine, a key substrate supporting oxidative stress defense, has been implicated in TME remodeling and metastasis, yet its specific role in initiating tumor invasion remains unclear. Here, oxidative stress induced the generation of senescent macrophages in the TME, and clinical samples showed that their accumulation positively correlates with malignancy. We established cisplatin- and radiation-induced senescent macrophage models that exhibited distinct senescence-associated secretory phenotypes (SASP) and enhanced squamous cell carcinoma (SCC) migration and invasion. Integrated metabolomic and transcriptomic analyses revealed the glutamine-glutamate pathway as a central metabolic hub, with glutaminase 2 upregulated to drive glutaminolysis and strongly associated with IL-1β expression. Mechanistically, IL-1β secreted by senescent macrophages promoted tumor invasion by downregulating IL-1R2 and activating NF-κB signaling in SCC cells. Targeting the glutamine metabolism-regulated IL-1β/IL-1R2 axis effectively suppressed SCC invasion. These findings uncover a novel metabolic mechanism linking glutamine metabolism to SASP regulation and suggest a therapeutic strategy to limit SCC invasion.

Keywords:  glutamine metabolism reprogramming; oxidative stress; senescence‐associated secretory phenotype; senescent macrophages; squamous cell carcinoma

DOI:  https://doi.org/10.1111/acel.70592
Sci Rep. 2026 Jun 20.

Deciphering glutamine metabolic reprogramming: a novel therapeutic target ALDH18A1 in triple-negative breast cancer.

Shuixian Li, Shenghan Gao, Jinsong Hu, Shuhan Lyu, Ju Yang, Chenyang Zhang, Chenshuo You, Xiuping Liu, Jigang Wang, Guoyuan Liu.

  Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis, highlighting an urgent need to identify novel metabolic vulnerabilities and prognostic biomarkers to improve patient outcomes. While glutamine metabolism has been implicated in cancer, the specific roles of glutamine metabolism-related genes (GMRGs) in TNBC remain poorly understood. Herein, through an integrating analysis encompassing multi-omics bioinformatics, consensus clustering and tumor microenvironment (TME) analysis, we established a glutamine metabolism-based prognostic classification for TNBC patients, which correlates with distinct survival outcomes and TME features. Furthermore, we identified ALDH18A1, one of the GMRGs that encodes P5CS for proline synthesis, as a novel prognostic biomarker and oncogenic driver. ALDH18A1 is overexpressed in TNBC and associated with larger tumor size, lymph node metastasis and poor survival, as well as an immunosuppressive TME. In vitro experiments confirmed ALDH18A1 activated the AKT/mTOR signaling pathway, promoted the proliferation, migration and invasion of TNBC cells, and increased proline synthesis. Computational drug screening predicted six compounds with potential efficacy against ALDH18A1-high tumors. Collectively, our findings demonstrate that reprogramming of glutamine metabolism plays a crucial role in the malignant progression of TNBC and provide translational insights for precision metabolomic-immunotherapeutic strategies in ALDH18A1-high TNBC.

Keywords:  ALDH18A1; Drug sensitivity prediction; Glutamine metabolism; Prognostic biomarkers; Triple-negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-026-56978-5
J Am Chem Soc. 2026 Jun 20.

Regulation of Tumor-Immune Cell Communications via Enantioselectively Targeting SLC G-Quadruplexes.

Yue Sun, Heying Yuan, Hualong Song, Chuanqi Zhao, Miles Postings, Peter Scott, Wenxuan Hu, Na Zhang, Jinsong Ren, Xiaogang Qu.

Compelling evidence shows that amino acids can influence tumor-immune cell communication. Their transfer across the plasma membrane involves multiple amino acid transporters within the solute carrier (SLC) family. Here, we present a new strategy to modulate SLC function by targeting the SLC G-quadruplexes (G4s). We first screen eight SLC genes in the promoter region and identify G4s, including one in the promoter region of glutamine transporter SLC38A2. Then, we design a CRISPR-chiral metallohelix system that selectively targets and stabilizes the SLC38A2 G4 in tumor cells, demonstrating evident enantioselectivity with the Λ-enantiomer being more effective. This leads to SLC38A2 downregulation, which shifts glutamine uptake from tumor cells to dendritic cells (DCs), thereby redirecting glutamine metabolism to activate DCs. Furthermore, we construct a CRISPR-DHX36 system to unwind the SLC38A2 G4 in DCs and upregulate SLC38A2 expression, further augmenting glutamine uptake to compete with tumor cells. The dual CRISPR system with the ability to "fold" and "unfold" the G4 motif in different cell types leads to a marked enhancement of CD8+ T cell activation and killing ability. Therefore, our work sheds new light on cancer immune regulation by modulating the metabolic communication between cancer cells and immune cells.

DOI: https://doi.org/10.1021/jacs.6c07127
bioRxiv. 2026 Jun 10. pii: 2026.06.06.727699. [Epub ahead of print]

Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.

Kyoungmin Kim, Tanvi Shankar, Yaqi Gao, Ian K Williamson, Nathaniel Snyder, Evan P Kransdorf, Ralph DeBerardinis, Heinrich Taegtmeyer, Brandon Faubert, Anja Karlstaedt.

Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits α-ketoglutarate dehydrogenase (α-KGDH) and is associated with reduced cardiac contractile function.
Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress.
Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation.
Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.

DOI: https://doi.org/10.64898/2026.06.06.727699
Front Cell Dev Biol. 2026 ;14 1823145

Tumor-immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy.

Beatrice Foglia, Jessica Nurcis, Marta Signorini, Stefania Cannito.

  Cancer remains one of the leading causes of death worldwide, with nearly 20 million new cases and 9.7 million deaths reported in 2022. Projections estimate that annual incidence may increase to 35 million by 2050, underscoring cancer as both a biomedical challenge and a global socioeconomic burden. A key hallmark of malignancy that sustains this progression is metabolic reprogramming. Within the nutrient- and oxygen-deprived tumor microenvironment, cancer cells rewire their metabolism to generate the energy and biosynthetic intermediates necessary for unchecked proliferation, invasion, and metastasis. This metabolic adaptation, however, extends beyond tumor growth. By competing for critical nutrients such as glucose and glutamine, cancer cells establish a metabolic tug-of-war with immune cells, impairing their activation and antitumor functions. In addition, cancer cells produce oncometabolites that act as signaling molecules, fostering immune suppression. Together, nutrient competition and oncometabolite signaling contribute to immune evasion and therapeutic resistance. In this review, we examine the dynamic metabolic dialogue between tumors and the immune system, focusing on how cancer cells induce immune metabolic rewiring, how immune cells respond or succumb to these changes, and the therapeutic opportunities emerging from targeting metabolic vulnerabilities on both sides of the tug-of-war.

Keywords:  immune targeted therapies; immunity; metabolic reprogramming; oncometabolites; tumor microenvironment; tumor–stroma interaction

DOI:  https://doi.org/10.3389/fcell.2026.1823145
Crit Rev Oncol Hematol. 2026 Jun 26. pii: S1040-8428(26)00344-6. [Epub ahead of print] 105457

Amino Acid Metabolic Reprogramming in Immunotherapy for Hepatocellular Carcinoma: Adaptive Resistance, Patient Stratification, and Longitudinal Monitoring.

Hongyang He, Zhiheng Qiao, Xiaocan Gai, Guoliang Ji, Shumin Liu.

   BACKGROUND: Immunotherapy has become an important component of systemic treatment for advanced hepatocellular carcinoma (HCC), yet durable benefit remains limited to a subset of patients because of marked response heterogeneity and acquired resistance.
PROBLEM: Current biomarkers are often static, single-time-point indicators that incompletely capture evolving tumor-immune metabolic interactions before and during therapy. In HCC, amino acid availability, nitrogen handling, and suppressive metabolite production are shaped by tumor-intrinsic programs, immune-cell competition, and liver-specific metabolic physiology.
MAIN BODY: This review frames amino acid metabolic reprogramming as a mechanistically and translationally informative axis for HCC immunotherapy. We discuss three clinically relevant domains. First, pretreatment amino acid states may inform patient stratification by reflecting nutrient competition, immune readiness, and transcriptomic signatures linked to glutamine, tryptophan-kynurenine, lysine, and arginine/nitrogen metabolism. Second, adaptive resistance is highlighted as the domain with the strongest mechanistic support, in which therapy pressure rewires amino acid transport, catabolism, and cross-compartment metabolic exchange to create immunosuppressive niches, reinforce suppressive myeloid and regulatory T-cell states, and impair effector T-cell function. Third, longitudinal monitoring through circulating metabolites, paired tissue profiling, spatial multi-omics, and computational integration is evaluated according to mechanistic resolution and clinical scalability.
CONCLUSION: Amino acid metabolism should be viewed not merely as a descriptive hallmark, but as a clinically organizing and potentially actionable framework for organizing patient stratification, adaptive resistance, and longitudinal monitoring in HCC immunotherapy. Prioritizing reproducible, actionable on-treatment resistance states may help move the field beyond static biomarkers toward earlier therapeutic adaptation.

Keywords:  Adaptive resistance; Amino acid metabolism; Hepatocellular carcinoma; Immunotherapy; Longitudinal monitoring

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105457
Discov Oncol. 2026 Jun 27.

Metabolic reprogramming regulates macrophage polarization to impact ovarian cancer progression.

Meng Zhang, Haizhou Fang, Shuangshuang Yang, Jinxi Yue, Lianlin Zeng, Hong Zhang.

  Metabolic reprogramming and macrophage polarization exhibit a tightly regulated reciprocal interplay, wherein the modulation of energy metabolic pathways and signaling networks directly dictates the functional phenotype and immune responses of macrophages, thereby exerting a critical influence on ovarian cancer progression and therapeutic outcomes. This manuscript elucidates the regulatory mechanisms by which diverse metabolic pathways-including glycolysis, oxidative phosphorylation, and glutamine metabolic reprogramming-orchestrate macrophage polarization. Special emphasis is placed on the functional role of tumor-associated macrophages (TAMs) within the ovarian cancer immune microenvironment, as well as the molecular mechanisms underlying their metabolic regulation. Based on the latest research advances, this study analyzes how metabolic reprogramming modulates the M1/M2 polarization balance to influence tumor immune escape and treatment resistance. Additionally, it summarizes emerging nanoscale strategies for the precise treatment of ovarian cancer via metabolic modulation of macrophage polarization. The overarching aim of this research is to clarify the pivotal role of metabolic regulation in macrophage polarization, thereby providing novel insights and therapeutic strategies for the management of ovarian cancer.

Keywords:  Macrophage polarization; Metabolic pathways; Metabolic reprogramming; Nanotherapy; Ovarian cancer

DOI:  https://doi.org/10.1007/s12672-026-05495-y
Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00665-0. [Epub ahead of print]45(7): 117587

De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.

Julia L Weber, Tien Bui, Keomonyroth Nuon, Adam J Fike, Sophia M Crocker, Kristen N Bricker, Anju Maharjan, Wujuan Zhang, Aaron R Goldman, Sathi Babu Chodisetti, Ziaur S M Rahman.

  Whether and how pyrimidine metabolites promote systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in systemic lupus erythematosus (SLE)-prone B cells. Temporal inhibition of pyrimidine synthesis dampens SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC), and antibody responses. Uridine monophosphate synthase (UMPS) conditional deletion, however, reveals a B cell-intrinsic requirement of de novo pyrimidine synthesis in foreign antigen-driven and SLE-prone GC, PC, and antibody responses and kidney immune complex deposition. Metabolomics, mitochondrial stress test, metabolic flow cytometry, glycolytic rate assay, and RNA sequencing highlight the importance of pyrimidine synthesis in promoting aerobic glycolysis and oxidative phosphorylation in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator, cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promote pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.

Keywords:  CAD; CP: Immunology; UMPS; autoantibody; autoimmunity; germinal center; mTORC1; plasma cell; pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117587
JIMD Rep. 2026 Jul;67(4): e70105

Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders.

Yasuaki Yasuda, Yoko Nakajima, Yuta Sudo, Takuma Ishihara, Tetsuya Ito.

  Hyperammonemic crisis (HAC) remains a major risk factor for urea cycle disorders (UCD), and practical outpatient predictors are limited. We tested whether short-term changes in plasma glutamine (ΔGln) and ammonia (ΔNH3) predict HAC and whether effects differ by onset type. In a retrospective cohort (2014-2024) of 18 patients with UCD (neonatal-onset [NO] nine; late-onset [LO] nine), HAC was defined as ammonia (NH3) > 150 μg/dL (88.1 μmol/L). For each patient, ΔGln and ΔNH3 were calculated between sequential outpatient samples. Investigation 1 compared the changes observed between 31-60 days and 8-30 days before HAC, with stable period changes. Investigation 2 compared changes at 61-90 and 31-60 days before HAC with stable period changes. Associations were evaluated using generalized linear mixed-effects models with onset-specific effects. In NO, larger ΔGln during Investigation 1 was associated with higher HAC risk (p < 0.001) whereas ΔNH3 was not associated with HAC (p = 0.361). The probability of HAC in NO was estimated to reach 67.1% at ΔGln +500 μmol/L. In LO, neither ΔGln nor ΔNH3 during Investigation 1 showed a significant association with HAC, and the estimated probabilities remained low across the observed ranges. During Investigation 2, no significant associations between biomarkers and HAC were observed in either group. Progressive increases in plasma glutamine levels within the 31-60 and 8-30 days pre-HAC window may serve as early markers of HAC risk in NO-UCD, supporting the utility of longitudinal monitoring. These trends were not associated with LO-UCD, suggesting the need for alternative surveillance strategies tailored to the onset phenotype.

Keywords:  ammonia; biomarker; glutamine; hyperammonemia; neonatal‐onset; urea cycle disorders

DOI:  https://doi.org/10.1002/jmd2.70105
J Pharm Biomed Anal. 2026 Jun 23. pii: S0731-7085(26)00293-1. [Epub ahead of print]280 117625

Addressing the elephant in the room: A comprehensive framework to resolve selectivity, multicollinearity, and scalability challenges in Raman chemometric models for mammalian cell culture applications.

Srikanth Rapala, Bingyu Kuang, Gregory D Doddridge, Karna Shah, Andy Kwok, Lingling Xia, Sankaran Anantharaman, Brian Lowry, Sarah W Harcum, Nicholas Abu-Absi.

  Raman spectroscopy offers significant potential for real-time bioprocess monitoring, but adoption in biologics manufacturing remains limited due to challenges in developing robust chemometric models. Key barriers include poor selectivity between structurally similar metabolites, multicollinearity among correlated analytes that confound model predictions, and insufficient training data ranges for critical quality attributes (CQAs). To overcome these barriers, a novel workflow called Spiking and Pure Analyte Characterization for Raman Chemometrics (SPARC) was developed. SPARC addresses these challenges through three innovations: using pure analytes to identify signature spectral regions for enhanced selectivity, spiking pure analytes into cell culture samples to mitigate multicollinearity, and using purified and enriched CQA material to spike into cell culture samples to broaden the CQA training data range. These protocols were implemented on the ambr250 high-throughput (HT) system, using an integrated liquid handler for automated spiked sample preparation. SPARC successfully modeled six analytes: glucose, lactate, glutamine, glutamate, monoclonal antibody (mAb), and CQA: High Molecular Weight (HMW) species. Pure analyte characterization identified 8-22 signature spectral regions per analyte using Variable Importance in Projection (VIP) scores. Cross-scale validation demonstrated successful model transfer from the ambr250 system (single-flow-cell probe) to 3 L bioreactors (dedicated in-situ immersion probe). SPARC consistently outperformed baseline methods with significant reductions in prediction errors: glucose (48%), lactate (49%), glutamine (69%), glutamate (57%), mAb (77%) and uniquely enabled modeling of HMW species where baseline methods failed. SPARC provides a systematic workflow for implementing Raman chemometrics in cell culture that overcomes technical barriers, automates data generation, and accelerates model development.

Keywords:  Ambr250 high-throughput (HT) system; Bench-scale bioreactor; Bioprocess monitoring; Chemometric modeling; Chinese hamster ovary (CHO) cell culture; Process Analytical Technology (PAT); Raman spectroscopy

DOI:  https://doi.org/10.1016/j.jpba.2026.117625
Cytotechnology. 2026 Aug;78(4): 140

SP1-mediated NAT10 upregulation drives oral squamous cell carcinoma progression via ac4C-dependent SLC1A5 modification.

Lang Xu, Zhongwei Huang.

  Oral squamous cell carcinoma (OSCC) is a prevalent malignancy in the head and neck region, accounting for 90% of all oral cancer cases. Despite advances in surgery and chemoradiotherapy, the molecular mechanisms driving OSCC progression remain incompletely understood, limiting the development of effective targeted therapies. Emerging evidence suggests that transcription factor Specificity protein 1 (SP1) and acetyltransferase N-acetyltransferase 10 (NAT10) may contribute to cancer progression, but their role in OSCC and potential regulation of the amino acid transporter solute carrier family 1 member 5 (SLC1A5) remain unclear. This study aimed to systematically investigate the SP1-NAT10-SLC1A5 regulatory network in OSCC development. The mRNA and protein expression levels were determined by reverse transcription-quantitative PCR (RT-qPCR) and western blotting, respectively. Cell proliferation was assessed using MTT and EdU assays, apoptosis was analyzed by flow cytometry, and cell invasion was evaluated using transwell assay. Enzymatic activity kits were employed to quantify key parameters of glutamine (Gln) metabolism. RNA immunoprecipitation (RIP) assay was used to detect the binding of NAT10 and SLC1A5 mRNA. Dual-luciferase reporter assay was performed to validate the direct regulatory interaction between SP1 and the NAT10 promoter region, followed by chromatin immunoprecipitation (ChIP) assay to assess SP1 occupancy on the NAT10 promoter. A mouse xenograft model was established for in vivo analysis. NAT10 expression was elevated in OSCC tissues and cells. NAT10 inhibition suppressed OSCC cell proliferation, invasion, and Gln metabolism and promoted apoptosis. Additionally, NAT10 mediated the ac4C modification of SLC1A5. Overexpression of SLC1A5 attenuated the effects of NAT10 suppression in OSCC cells. SP1 was identified as the upstream activator of NAT10 expression through transcriptional regulation analysis. Moreover, NAT10 inhibition impeded OSCC growth in vivo by regulating SLC1A5. SP1-induced NAT10 upregulation promoted OSCC advancement through ac4C-mediated SLC1A5 modification, providing new insights into OSCC treatment.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-01010-x.

Keywords:  NAT10; Oral squamous cell carcinoma; SLC1A5; SP1; ac4C

DOI:  https://doi.org/10.1007/s10616-026-01010-x
Cancers (Basel). 2026 Jun 15. pii: 1945. [Epub ahead of print]18(12):

Multi-Omics Analysis Reveals Chronic Cisplatin Exposure Is Associated with Metabolic Rewiring Toward Glutathione Metabolism to Support Redox Adaptation in High-Grade Serous Ovarian Cancer.

Ashlyn Conant, Kayla Sanchez, Shreya Patil, Ethan Nyein, Tise Suzuki, Gary Yu, Marlon Maus, Salvador Soriano, Christian Hurtz, Juli J Unternaehrer.

   BACKGROUND: Platinum-based chemotherapy is the frontline treatment for high-grade serous ovarian cancer (HGSOC); however, the development of therapy resistance greatly limits clinical response. Increasing evidence suggests that platinum agent-driven metabolic programming, particularly within redox-associated pathways, may contribute to chemoresistance.
METHODS: A syngeneic pair of patient-derived HGSOC cell lines representing cisplatin-sensitive (SE) and cisplatin-resistant (CR) states were evaluated using a multi-omics approach. Differential metabolite abundance and gene expression were assessed, followed by gene set and pathway enrichment analyses to identify coordinated metabolic shifts. In silico analysis of an additional sensitive and resistant HGSOC cell line validated the glutathione pathway upregulation seen in the patient-derived model. The functional contribution of the glutathione pathway on cisplatin resistance was evaluated following glutathione inhibition.
RESULTS: Chronic cisplatin exposure induced extensive metabolic rewiring in CR cells, characterized by enrichment of glutathione metabolism at both the metabolite and gene levels. Increased reduced glutathione was observed alongside upregulation of key enzymes involved in its de novo biosynthesis, recycling, and utilization, consistent with enhanced detoxification capacity relating to cisplatin-induced oxidative stress. Additionally, taurine was highly enriched, further highlighting a metabolic shift towards enhanced antioxidant mechanisms. CR cells also demonstrated an increase in NADPH-generating pathways, including amino acid metabolism and fatty acid β oxidation, to support redox balance and biosynthetic demands of increased glutathione metabolism. Transcriptional remodeling of the γ-glutamyl cycle further indicated a shift toward increased glutathione turnover, suggesting that the coordinated changes seen may define a metabolic state enhanced in oxidative stress tolerance and therapeutic resistance. These transcriptional changes were also seen in another model of platinum sensitivity/resistance, indicating a conserved response associated with platinum-induced resistance. Finally, concurrent cisplatin treatment and glutathione inhibition significantly increased sensitivity within the CR cells.
CONCLUSIONS: These findings suggest that cisplatin-resistant cells, previously exposed to a platinum-based agent, may undergo distinct metabolic rewiring towards antioxidant pathways to survive chronic chemotherapeutic stress. Targeting components of these systems may represent a viable strategy to overcome platinum resistance and improve therapeutic outcomes.

Keywords:  ROS buffering; beta oxidation; glutathione; metabolism; ovarian cancer; redox-maintenance; taurine; therapy resistance

DOI:  https://doi.org/10.3390/cancers18121945
J Oral Rehabil. 2026 Jun 25.

Nutritional Amino Acid Supplementation Reduces Severity and Enhances Recovery of Radiation-Induced Oral Mucositis: A Triple-Blind Randomized Clinical Trial.

Fatma E A Hassanein, Doha E Ahmed, Sarah Elkot, Asmaa Abou-Bakr.

   BACKGROUND: Radiation-induced oral mucositis (RIOM) is a common and debilitating complication of radiotherapy for head and neck cancer (HNC), frequently leading to severe pain, impaired oral intake, and treatment interruption. Nutritional interventions that support mucosal integrity may reduce mucosal injury and improve recovery.
OBJECTIVE: To evaluate the effects of oral L-arginine and L-glutamine supplementation on the severity and recovery of radiation-induced oral mucositis and their association with salivary inflammatory and regenerative biomarkers.
METHODS: In this triple-blind, parallel-arm randomized clinical trial, 84 patients receiving radiotherapy for HNC were allocated to oral L-arginine, L-glutamine, or maltodextrin control three times daily from Week 2 of radiotherapy until treatment completion. RIOM severity was assessed using the WHO scale at Weeks 2, 5, and 7. Salivary interleukin-6 (IL-6), nitric oxide (NO), and epidermal growth factor (EGF) were measured. Longitudinal changes were analysed using linear mixed-effects models, and associations with mucositis severity were evaluated using correlation and receiver operating characteristic analyses.
RESULTS: At Week 5, severe mucositis occurred in 92.9% of controls compared with 17.9% and 3.6% in the arginine and glutamine groups (p < 0.001). Intervention groups showed lower IL-6 and NO levels and higher EGF levels (p < 0.001). Biomarkers were significantly correlated with mucositis severity, and IL-6 demonstrated excellent discrimination of severe mucositis (AUC = 0.988).
CONCLUSIONS: Oral arginine and glutamine supplementation was associated with reduced severity and enhanced recovery of RIOM. Nutritional amino acid supplementation may represent a useful adjunct in supportive oral care and oral rehabilitation for patients undergoing radiotherapy.
TRIAL REGISTRATION: The study was prospectively registered at ClinicalTrials.gov (Identifier: NCT07020754) on June 6, 2025.

Keywords:  L‐arginine; L‐glutamine; epidermal growth factor; head and neck cancer; interleukin‐6; nitric oxide; radiation‐induced oral mucositis; salivary biomarkers

DOI:  https://doi.org/10.1111/joor.70246
Sheng Wu Gong Cheng Xue Bao. 2026 May 25. pii: 1000-3061(2026)05-2219-14. [Epub ahead of print]42(5): 2219-2232

[YTHDF1 enhances the expression of exogenous proteins in the CHO-K1-GS‒/‒ cell line].

Yongfang Chen, Wenjing Jin, Xinyu Ma, Ruofei Feng, Yanmei Yang.

  YTH domain family protein 1 (YTHDF1) is an RNA-binding protein and belongs to the reader modified by N6-methyladenosine (m6A). It recognizes and binds to m6A modifications on RNA through specific domains, thereby performing corresponding biological functions. This study aims to explore the effects of YTHDF1 on the expression levels of exogenous proteins in the Chinese hamster ovary (CHO) cell line and evaluate its application potential in the optimization of the expression system of CHO cells. Firstly, the glutamine synthetase (GS) gene of CHO-K1 cells was knocked out by CRISPR/Cas9 to obtain the CHO-K1-GS‒/‒ cell line. The enhancement effects of YTHDF1 overexpression on the expression of exogenous proteins in CHO-K1-GS‒/‒ cells were further analyzed. Western blotting, qPCR, and fluorescence microscopy observations showed that the overexpression of YTHDF1 significantly up-regulated the expression levels of human serum albumin, single-chain antibody, and green fluorescent protein in cells. Moreover, this process did not have a significantly negative impact on the long-term proliferation and survival rate of the cells. In addition, the experiment with the translation inhibitor cycloheximide (CHX) confirmed that YTHDF1 mainly enhanced the protein expression by promoting translation in cells. This study demonstrates that YTHDF1 can enhance the cell's ability to synthesize exogenous proteins by promoting the translation process of mRNA. This strategy provides a new theoretical basis and technical direction for constructing efficient cell lines for producing biopharmaceuticals.

Keywords:  CHO-K1- GS ‒/‒ cells; YTHDF1; cell line development; expression of exogenous protein; translation efficiency

DOI:  https://doi.org/10.13345/j.cjb.250823
NMR Biomed. 2026 Aug;39(8): e70343

Metabolic Assessment in Human Pluripotent Stem Cell-Derived Cerebral Organoids Using HR-MAS NMR Spectroscopy.

Maria Alejandra Castilla Bolanos, Vorapin Chinchalongporn, Rajshree Ghosh Biswas, Colleen Bailey, Maggie Wu, Ronald Soong, Fermisk Saleh, Andre Simpson, Carol Schuurmans, Jamie Near.

  Brain metabolism is vital to healthy brain function and is often altered in disease; yet direct investigation in patients is challenging. Although animal models are commonly used for studying brain metabolism, their use is under increasing scrutiny due to concerns of animal welfare and model validity. Human pluripotent stem cell (hPSC)-derived cerebral organoids (COs) present a unique opportunity to model human brain developmental and neuropathological processes, allowing for detailed metabolic characterization via multiple approaches. Here, we applied high-resolution magic-angle spinning (HR-MAS) proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze metabolite levels in hPSC-derived COs, establishing a pipeline to study neurometabolic pathways in these engineered human brain tissues. We identified and quantified 17 metabolites in hPSC-derived COs at different stages of maturity. The high spectral quality (linewidth < 4 Hz, SNR > 65) allowed detection of metabolite levels in 85- to 312-day-old hPSC-derived COs, which exhibited a metabolic profile similar to human fetal brain, with key distinguishing features relative to human adult brain, including: elevated lactate levels; approximately equimolar glutamate and glutamine levels; low N-acetylaspartate levels; and an abundance of hypotaurine. In summary, this study presents direct metabolic assessment in intact COs via HR-MAS 1H-NMR spectroscopy. Our approach provides a platform for investigating human brain metabolism and its alteration in human brain models of neurodegeneration.

Keywords:  NMR spectroscopy; cerebral organoids; human brain model; human pluripotent stem cells; metabolism

DOI:  https://doi.org/10.1002/nbm.70343
Front Oncol. 2026 ;16 1849057

Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.

Nazia Nazam, Shaikh Sadiya, Saba Khan, Aroonima Misra, Niti Sureka, Kirti Panwar, Neelam Sahani, Sufian Zaheer.

  Radioresistance remains a major barrier to effective cancer therapy, contributing to tumor persistence, recurrence, and poor clinical outcomes. Increasing evidence identifies mitochondria as central regulators of radiation response through their multifaceted roles in cellular bioenergetics, redox homeostasis, mitochondrial DNA (mtDNA) maintenance, apoptotic signaling, and mitochondrial dynamics. Radioresistant tumor cells undergo profound metabolic reprogramming characterized by enhanced oxidative phosphorylation (OXPHOS), glycolytic plasticity, glutaminolysis, and pentose phosphate pathway activation, enabling sustained ATP generation, antioxidant defense, and efficient DNA repair under radiation stress. In parallel, mitochondrial reactive oxygen species (ROS) signaling is tightly modulated by antioxidant systems including glutathione, superoxide dismutase, catalase, and NRF2-driven pathways, thereby limiting radiation-induced oxidative injury. Alterations in mitochondrial fusion and fission dynamics, particularly Drp1-mediated fission, further support tumor survival by promoting mitophagy, metabolic adaptation, and resistance to apoptosis. Additionally, enhanced mtDNA repair and mitochondrial biogenesis preserve mitochondrial integrity in irradiated cancer cells. Dysregulation of mitochondria-mediated intrinsic apoptotic pathways, including aberrant expression of Bcl-2 family proteins, further facilitates evasion of radiation-induced cell death. This review comprehensively examines the molecular mechanisms by which mitochondria contribute to tumor radioresistance and critically discusses emerging mitochondria-targeted therapeutic strategies aimed at improving radiosensitivity. These include OXPHOS inhibitors, glycolytic and glutaminase inhibitors, ROS-modulating agents, mitochondrial dynamics regulators, nanoparticle-based mitochondrial targeting systems, and combinatorial approaches integrating radiotherapy with immunotherapy or DNA damage response inhibitors. By integrating mechanistic insights with emerging preclinical and clinical evidence, this review highlights mitochondria as actionable therapeutic vulnerabilities and underscores the translational potential of mitochondrial-targeted radiosensitization strategies for improving outcomes in resistant malignancies.

Keywords:  cancer; mitochondria; radioresistance; radiosensitization; radiotherapy

DOI:  https://doi.org/10.3389/fonc.2026.1849057
Sci Rep. 2026 Jun 26.

Characterization of the lysosomal arginine transporter SLC7A14.

Deborah Giudice, Francesca Barone, Tiziano Mazza, Mariafrancesca Scalise, Lara Console, Cesare Indiveri.

  SLC7A14 is a putative amino acid transporter whose physiological role remains poorly characterized, despite its association with retinal degeneration, auditory defects, and metabolic dysfunctions. Confocal microscopy was performed in HEK293 transiently transfected with the human SLC7A14 (hSLC7A14), demonstrating a lysosomal localization, as previously suggested. To carry on functional and kinetic characterization, the protein was overexpressed in E. coli, and purified from insoluble fraction through affinity chromatography followed by SEC with a yield of 156 mg/L of bacterial cell culture. The homogeneous hSLC7A14 showed an apparent molecular mass of 72 kDa on SDS-PAGE and was reconstituted into proteoliposomes for functional assays. hSLC7A14 showed high specificity towards arginine, not histidine or glutamine, with a measured Km of 1.2 ± 0.21 mM. The arginine transport was inhibited by cysteine and threonine, but not by other amino acids or GABA. Inhibition kinetics identified metformin as an inhibitor of the transporter showing a mixed type of inhibition with a measured Ki in the same order of that of arginine. These findings are in agreement with hSLC7A14 being a specific lysosomal arginine transporter, with potential involvement in the mTORC1 signalling. The described results represent a first step to further elucidate hSLC7A14 role in human physiology and disease. Moreover, the identification of experimental conditions for measuring specific transport activity will allow screening of ligands as inhibitors or functional modulators opening perspectives for structure/function relationship studies.

Keywords:  Arginine; Lysosomes; Metabolic dysfunction; Metformin; SLC; mTORC1

DOI:  https://doi.org/10.1038/s41598-026-57824-4
Neurotox Res. 2026 Jun 23. pii: 28. [Epub ahead of print]44(4):

Prolonged In Vitro Exposure to Methylmalonic Acid Induces Inflammation, Glutamate Metabolism Disruption, and Alters Functional Gene Expression in C6 Astroglial Cells.

Rômulo Rodrigo de Souza Almeida, Larissa Daniele Bobermin, Izaviany Schmitz, Filipe Renato Pereira Dias, Caio César Ramalho Bezerra, Mariana Rocke-Peters, Ester Rezena, Krista Minéia Wartchow, Fernanda Urruth Fontella, Diogo Onofre Souza, Moacir Wajner, Carlos-Alberto Gonçalves, Guilhian Leipnitz, André Quincozes-Santos.

  Methylmalonic acidemia is an inherited neurometabolic disorder characterized by accumulation of methylmalonic acid (MMA) in different tissues, particularly in the brain. As a result, patients frequently exhibit progressive neurological deterioration, accompanied by episodes of acute encephalopathy following metabolic decompensation. Astrocytes are glial cells that maintain the central nervous system homeostasis and may be important cellular targets of MMA-induced dysfunction. However, most in vitro experimental models for the study of methylmalonic acidemia are based on short-term exposure to the toxic metabolites that accumulate in patients. In this study, we used a prolonged experimental model, which has not been yet explored in the context of glial cells, focusing on the inflammatory response, glutamate metabolism, and putative signaling pathways that can contribute to understanding cellular damage observed in methylmalonic acidemia. It is emphasized that MMA is persistently elevated in the brain of the affected patients. Prolonged MMA exposure induced inflammation with significant increase in gene expression of cyclooxygenase 2, interleukin (IL)-1β and its receptor (IL1R1), and IL-6, accompanied by a decrease in IL-10 expression. MMA also increased glutamate uptake and the activity and gene expression of the enzyme glutamine synthetase, while it downregulated glial cell-derived neurotrophic factor (GDNF). The expression of NFκB, p38 MAPK, Nrf2, heme oxygenase 1, PGC-1α, and sirtuin 1 were also modulated by MMA treatment, indicating the critical role of these signaling pathways in the MMA-induced persistent gliotoxicity. Finally, it is conceivable that these changes may significantly contribute to clarify the pathogenesis of methylmalonic acidemia.

Keywords:  Astroglial cells; Gliotoxicity; Methylmalonic acidemia; Neuroinflammation

DOI:  https://doi.org/10.1007/s12640-026-00806-1
Adv Sci (Weinh). 2026 Jun 26. e76325

Slc44a2 Deficiency Unveils an IFN-I-Dependent Feedback Control of pDC Egress.

Ruiqun Chen, Tao Wu, Zhen Shi, Ravi Kumar Verma, Linlin Sheng, Lei Tao, Mingming Yang, Yuchen Wang, Conggang Zhang, Hao Fan, Li Wu, Ligong Chen.

  Plasmacytoid dendritic cells (pDCs) are a specialized subset of innate immune cells capable of sensing viral nucleic acids and rapidly producing large amounts of type I interferons (IFN-I). However, excessive IFN-I production can cause various immunopathogenic conditions. The capacity for IFN-I production by pDCs is tightly regulated, yet the underlying mechanisms remain incompletely understood. Here, we describe two levels of negative regulatory mechanisms controlling IFN-I production by pDCs. First, we identified SLC44A2 as a negative regulator of IFN-I production. Slc44a2 was highly expressed in resting pDCs but significantly downregulated upon activation. Deficiency of Slc44a2 led to excessive IFN-I production. Mechanistically, SLC44A2 may restrict IFN-I production by exporting threonine, asparagine, and glutamine, amino acids that we found to be essential for IFN-I production in pDCs. Second, we uncovered an IFN-I-dependent negative feedback mechanism controlling pDC egress. Excessive IFN-I restrained pDC migration by downregulating CCR2 and CCR5. This feedback was generally observed during viral infections, autoimmune diseases, and in Slc44a2-deficient mice. Taken together, these two regulatory mechanisms are essential for maintaining pDC homeostasis and preventing systemic overactivation of IFN-I responses.

Keywords:  IFN‐I; SLC44A2; negative feedback; pDC; pDC egress

DOI:  https://doi.org/10.1002/advs.76325
ACS Omega. 2026 Jun 16. 11(23): 33395-33415

Polystyrene Microplastics Activate Noncanonical TGF‑β Signaling and Metabolomic Reprogramming to Promote Epithelial-Mesenchymal Transition and Fibrosis in the Kidney.

Richa Dubey, Samiya Baby, Anamika Singh, Sukhveer Singh, Neha Singh, Priyanka Goswami, Sauhard Kushwaha, Devendri Khantwal, Vineeta Sharma, Satyakam Patnaik, Neeraj Sinha, Vikas Srivastava.

Polystyrene microplastics (PS-MPs) have been detected in human kidneys, raising concerns about their potential health risks. In this study, we investigated the effects of 1 μm PS-MPs in BALB/c mice and NRK-52E cells. After 28 days of exposure to PS-MPs (0.1, 1, and 10 mg/kg), we observed decreased body weight and elevated levels of serum creatinine and other kidney injury markers. PS-MPs accumulated in the kidney, as confirmed by MicroRaman spectroscopy, and caused significant histopathological changes and an increase in mesenchymal markers (α-SMA, fibronectin, collagen IV, and vimentin) while reducing the epithelial marker, E-Cadherin. Further mechanistic studies revealed the activation of the noncanonical TGFβ pathway involving P38MAPK, Akt, STAT3, STAT5, and NF-κB, which led to epithelial-mesenchymal transition (EMT) and the early onset of kidney fibrosis. Moreover, NMR-based metabolomics indicated changes in metabolites involved in energy and amino-acid metabolism, including decreased levels of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), phenylalanine, and increased glutamine levels. This altered metabolomic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, as well as phenylalanine metabolism, which have been previously associated with chronic kidney disease. Overall, this study indicates that exposure to PS-MPs may jeopardize renal health by altering metabolic pathways and signaling related to EMT and kidney fibrosis.

DOI: https://doi.org/10.1021/acsomega.5c10834