bims-glucam 2026-01-25 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–01–25
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine enhances endothelial cell survival and vasodilation by increasing glutathione to reduce oxidative stress.
E2F7 targets S100A2 to suppress CD8+T cell activity in lung adenocarcinoma by regulating glutamine metabolism.
Exploring key genes in NAFLD linked to glutamine metabolism: A comprehensive analysis combining multi-omics, machine learning and SHAP.
Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.
Correction to: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.
Mechanistic study of glutamine metabolic reprogramming driving non-small cell lung cancer progression via the FGF17-FGFR4 axis mediating epithelial-mesenchymal transition.
Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.
Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential.
Identification and evaluation of glutamine-related gene characteristics based on multi-omics to predict the prognosis of patients with colorectal cancer.
Correction: Mesoporous multimetallic PdPtBi nanozymes target redox imbalance and glutamine deprivation for immuno-chemodynamic therapy.
IGF2BP3-dependent glutamine/BCAA metabolic rewiring rejuvenates aged human adipose-derived stem cells for enhanced tissue regeneration.
ppAT drives glutamine-dependent purine biosynthesis and malignant progression in hepatocellular carcinoma.
Glutamate enhances the production of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 in keloid fibroblasts.

Physiol Rep. 2026 Jan;14(2): e70737

Glutamine enhances endothelial cell survival and vasodilation by increasing glutathione to reduce oxidative stress.

Marzyeh Kheradmand, Gurneet Sangha, Claire M Sissons, Michael Sun, Xinyao Zhou, Lauren V Smith, Meagan Bauer, Chengpeng Chen, Alisa Morss Clyne.

  Cardiovascular disease is exacerbated by diabetes through hyperglycemia-induced endothelial dysfunction, which arises from oxidative stress. Glutamine is postulated to decrease oxidative stress; however, its effect on endothelial dysfunction in hyperglycemia is unknown. Therefore, we investigated how glutamine affects endothelial function in normal and high glucose. Human coronary artery endothelial cells were treated with 0, 0.5, or 2 mM glutamine in 5.5 or 15 mM glucose for 24 h. We then assessed cell proliferation, oxidative stress, cell survival, and endothelial nitric oxide synthase (eNOS) activity. Our data showed that independent of glucose concentration, glutamine increased proliferation by up to 3.5-fold. Furthermore, glutamine metabolism through glutaminase-1 reduced oxidative stress and cell death by up to 70% and 94%, respectively, by doubling glutathione and NADPH. Glutamine also increased ex vivo vasodilation in isolated murine carotid arteries without altering eNOS activity or nitric oxide in vitro, suggesting that the enhanced vasodilation results from reduced oxidative stress. These findings indicate that glutamine mitigates endothelial cell oxidative stress by enhancing reducing capacity, which may protect against diabetic cardiovascular disease.

Keywords:  cardiovascular disease; glutamine; hyperglycemia; oxidative stress

DOI:  https://doi.org/10.14814/phy2.70737
J Mol Med (Berl). 2026 Jan 19. 104(1): 31

E2F7 targets S100A2 to suppress CD8+T cell activity in lung adenocarcinoma by regulating glutamine metabolism.

Xianchao Chen, Jinping Li, Qiang Zou, Bo Tang, Yun Huang, Bin Liao.

  Malignant cells within the tumor microenvironment have developed numerous strategies to resist the CD8+T cell-driven immune response. This study focuses on the mechanism of E2F7/S100A2 axis modulating CD8+T cell activity in lung adenocarcinoma (LUAD). Bioinformatics analysis was used to screen for the gene of interest, S100A2, and its regulatory transcription factor E2F7. Expression analysis of S100A2, E2F7, CD8, and PD-L1 at mRNA and protein levels was conducted via qRT-PCR, western blot, or immunohistochemistry. The interaction between S100A2 and E2F7 was validated using dual-luciferase reporter assays and chromatin immunoprecipitation. The interaction between LUAD cells and CD8+T cells was explored to understand immune escape mechanisms. Glutamine metabolism (glutamine/glutamate/α-KG/NADPH/GSH levels) and cytotoxicity (LDH/ELISA) were assessed. The impact of the E2F7/S100A2 axis in vivo was examined with LUAD xenograft mouse model. S100A2 was upregulated in LUAD tissues and cells and negatively correlated with CD8+T cell infiltration. Enhanced S100A2 expression could modulate glutamine metabolism to dampen the cytotoxic effects of CD8+T cells. E2F7 transcriptionally activated S100A2. In animal models, E2F7 knockdown impeded tumorigenesis and encouraged CD8+T cell infiltration, but these tumor-suppressive effects were rescued by S100A2 overexpression. This research suggests that E2F7 targets S100A2 to repress the activity of CD8+T cells in LUAD by modulating glutamine metabolism, highlighting the potential of targeting the E2F7/S100A2 axis or glutamine metabolic pathways to diminish immune evasion and enhance treatment efficacy in LUAD patients. KEY MESSAGES: S100A2 is upregulated in LUAD and inversely links to CD8+T cell infiltration. Enhanced S100A2 expression could manipulate glutamine metabolism. Enhanced S100A2 expression could dampen the cytotoxicity of CD8+T cells. S100A2 is transcriptionally activated by E2F7. Targeting E2F7/S100A2 axis may diminish LUAD immune evasion.

Keywords:  CD8+T cells; E2F7; Glutamine metabolism; Lung adenocarcinoma; S100A2

DOI:  https://doi.org/10.1007/s00109-026-02637-1
Asia Pac J Clin Nutr. 2026 Feb;35(1): 81-90

Exploring key genes in NAFLD linked to glutamine metabolism: A comprehensive analysis combining multi-omics, machine learning and SHAP.

Changan Chen, Wenfeng Liu, Yongtao Lan, Fuxiong Li, Xiaoman Li.

   BACKGROUND AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver condition glob-ally, with an escalating incidence and a strong association with various metabolic disorders, thus presenting a significant public health challenge. Currently, there is a scarcity of effective preventive or therapeutic methods for NAFLD. This study used multi-omics, machine learning (ML), and SHAP comprehensive analysis to explore NAFLD-related metabolites and genes, hoping to provide new insights.
METHODS AND STUDY DESIGN: We initially conducted MR analysis on 1,400 serum metabolites and two NAFLD datasets, identifying gluta-mine as causally linked to NAFLD. In single-cell RNA sequencing, hepatocytes were categorized into high-synthesis and low-synthesis glutamine groups for cell communication analysis. We extracted differentially expressed genes from these two groups and performed GO and KEGG enrichment analysis. Further screening of these genes was followed by the application of LASSO regression to identify hub genes for ML. We constructed the ML model using Catboost, NGboost, and XGboost algorithms. Finally, we employed the SHAP method to interpret the model, identifying key genes with significant model contributions.
RESULTS: MR analysis demonstrated that the glutamine-to-alanine ratio and levels of 1-linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6) were associated with a reduced incidence of NAFLD. We identified 19 hub genes for ML, with validation set AUCs of 0.83 for Catboost, 0.82 for NGboost, and 0.86 for XGboost. The SHAP analysis highlighted ASL, LGALS1, and GLUL as genes with the contributed significantly to the models.
CONCLUSIONS: Our MR findings suggest that specific metabolites may lower the risk of NAFLD. A comprehensive analysis underscores the significant role of glutamine metabolism and related genes in NAFLD pathogenesis, offering new potential targets for NAFLD diagnosis and treatment.

Keywords:  SHAP; glutamine metabolism ; machine learning; multi-omics; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.6133/apjcn.202602_35(1).0008
J Adv Res. 2026 Jan 18. pii: S2090-1232(26)00072-X. [Epub ahead of print]

Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.

Xiaoyu Guo, Zongang Liu, Xiaoman Li, Bingzheng Zhou, Jingyi Chen.

   BACKGROUND: Ovarian cancer (OC) is a leading cause of gynecologic cancer-related mortality, primarily due to frequent therapy resistance and disease recurrence. Growing evidence indicates that metabolic reprogramming serves as a critical adaptive mechanism, allowing cancer cells to survive therapeutic stress.
AIM OF REVIEW: This review aims to decode the interplay between nutrient adaptation and therapy resistance in OC. It examines how alterations in key metabolic pathways contribute to treatment resilience and disease progression, and explores the potential of targeting metabolic vulnerabilities to improve therapeutic outcomes.
KEY SCIENTIFIC CONCEPTS OF REVIEW: We discuss how OC cells utilize metabolic pathways-including glycolysis, OXPHOS, glutamine metabolism, and lipid utilization-to promote survival, DNA repair, and immune evasion. Metabolic plasticity enables shifts between nutrient sources, driving resistance to platinum-based agents, PARP inhibitors, and anti-angiogenic therapies. These adaptations vary across subtypes, such as high-grade serous and clear cell carcinomas, and are influenced by specific mutations. Targeting metabolic enzymes-such as GLS, CPT1, OXPHOS complexes, or NAD+ synthesis-offers a promising strategic direction. Metabolic profiling may allow stratification of OC patients and pave the way for precision medicine approaches to overcome treatment resistance.

Keywords:  Glycolysis; Ovarian cancer; Oxidative phosphorylation (OXPHOS); Therapy resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jare.2026.01.047
Arch Pharm Res. 2026 Jan 19.

Correction to: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.

Huiya Ying, Yixiao Wang, Dandan Zhu, Jun Xu, Xiangting Zhang, Hong Pan, Yuan Zeng, Xiao Wu, Weimin Cai, Ruoru Zhou, Ziqiang Xia, Fujun Yu.

DOI: https://doi.org/10.1007/s12272-026-01592-2
Front Mol Biosci. 2025 ;12 1728698

Mechanistic study of glutamine metabolic reprogramming driving non-small cell lung cancer progression via the FGF17-FGFR4 axis mediating epithelial-mesenchymal transition.

Qinghua Kong, Xiaoyan Wang, Wei Ding.

   Introduction: The reprogramming of glutamine metabolism holds a pivotal position in the energy provision and biosynthesis of tumors. However, the regulatory mechanism of this phenomenon in non-small cell lung cancer (NSCLC) is still not well-understood. NSCLC is a type of malignancy that has a high incidence and mortality rate globally. There is an urgent need to elucidate the role of glutamine metabolism in its pathological mechanism. This clarification may provide theoretical guidance for developing new therapeutic approaches.
Methods: Core targets of glutamine metabolism were screened by integrating single-cell transcriptomic and RNA sequencing data from public databases. Target expression was validated in clinical samples by immunohistochemistry (IHC) and Western blot (WB), and its association with clinical features was analyzed. Lentiviral gene silencing was employed to establish glutamine-deprived cell models and xenograft mouse models. To evaluate the effects of the target on cell proliferation, redox balance, and migratory/invasive behavior in cell culture and animal models, we utilized Transwell assays, colony formation assays, redox detection kits, and Seahorse metabolic flux analysis. Subsequently, WB and IHC served to elucidate the downstream pathways and potential synergistic effects of the drugs.
Results: Analysis of the single-cell atlas revealed a marked increase in epithelial (Epi) cell populations in the tumor milieu of NSCLC. By integrating weighted gene co-expression network analysis (WGCNA) with RNA sequencing, fibroblast growth factor 17 (FGF17) was pinpointed as a crucial regulatory factor. High FGF17 expression showed a strong association with poor prognosis in patient (p = 0.0078). Consistent clinical data further demonstrated that FGF17 upregulation was associated with higher TNM stages and the presence of lymph node metastasis. Functional and mechanistic analyses revealed that silencing FGF17 suppressed the FGFR4/MEK5/ERK5 signaling cascade, disturbed NRF2-dependent redox homeostasis, and consequently impaired epithelial-mesenchymal transition (EMT), leading to a marked reduction in cancer cell motility and invasiveness. In vivo, targeting FGF17 was shown to synergistically enhance cisplatin antitumor activity and reverse the EMT phenotype.
Conclusion: As a critical driver of glutamine metabolic reprogramming, FGF17-activated under conditions of GLUL overexpression-stimulates the FGFR4/MEK5/ERK5/NRF2 signaling cascade to maintain redox homeostasis and promote invasion, thereby accelerating NSCLC progression. Targeted intervention of the pathway reverses malignant phenotypes and enhances chemosensitivity. These findings highlight FGF17 as a potential therapeutic target for NSCLC and provide new insights into tumor metabolism and EMT, thereby may paving the way for novel combination therapies.

Keywords:  FGF17; GLUL; MEK5/ERK5; epithelial–mesenchymal transition (EMT); non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.3389/fmolb.2025.1728698
Front Genet. 2025 ;16 1752384

Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.

MingWei Zhan, BinBin Zhao, Haote Chen, Junjie Wu, Run Shi, Feng Gao, Lin Zhao, Jingyu Zhu.

  Clear cell renal cell carcinoma (ccRCC), rooted in VHL loss and dysregulated HIF signaling, is defined by a sweeping metabolic overhaul: intensified glycolysis, a "downshifted" TCA cycle, the buildup of lipid droplets and cholesteryl esters, and a pronounced dependence on glutamine and one-carbon metabolism-all tightly intertwined with an immunosuppressive microenvironment. Drawing on single-cell and spatial multi-omics, metabolomic and lipidomic profiling, and imaging-based evidence, this article maps the critical nodes of carbon, lipid, amino-acid, and one-carbon pathways, and their crosstalk with ferroptosis. It highlights how metabolic heterogeneity-exemplified by the DCCD spectrum-shapes prognosis and therapeutic response. The review further synthesizes how metabolic-immune coupling, including lipid metabolic rewiring in TAMs and MDSCs, and lactate/lipid stress in CD8+ T cells, contributes to immune-therapy resistance. On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.

Keywords:  DCCD; belzutifan; clear cell renal cell carcinoma (ccRCC); ferroptosis; glutamine metabolism; immunometabolism; lipid droplets/PLIN2; one-carbon metabolism

DOI:  https://doi.org/10.3389/fgene.2025.1752384
Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01629-8. [Epub ahead of print]45(1): 116857

Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.

Sneha Shah, Daniel Barnes, Botao Liu, Tenzin Tseyang, Thang Do, Jodi L Bubenik, Suna Jung, Mina N Anadolu, Maria P Ivshina, Verónica Martínez-Cerdeño, Elizabeth Berry-Kravis, Maurice S Swanson, Jessica B Spinelli, Joel D Richter.

  Metabolic homeostasis gone awry is a contributor to, if not an underlying cause of, several neurologic disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in FMR1 and consequent loss of the encoded protein FMRP, which results in downstream molecular, neurologic, and mitochondrial deficits that are linked to cognitive impairment. In the human postmortem brain, many metabolites and solute carrier proteins are coordinately dysregulated, which also occurs during the differentiation of human induced pluripotent stem cells (iPSCs) into excitatory neurons. Metabolic tracing in FXS neurons demonstrates a dearth of glutamine deamidation to glutamate, which reduces anaplerosis into the TCA cycle, potentially hindering the bioenergetic and biosynthetic functions of mitochondria. Mechanistically, aberrant expression of glutaminase isoforms in FXS is responsible for reduced glutaminolysis, thereby altering glutamate levels, which may contribute to FXS.

Keywords:  CP: metabolism; CP: neuroscience; Fragile X syndrome; glutamate transporters; glutaminase; human neurons; iPSC; metabolomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116857
Biochem Pharmacol. 2026 Jan 18. pii: S0006-2952(26)00051-1. [Epub ahead of print] 117720

Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential.

Wenli Xie, Yanlei Dong, Jiao Lv, Xiangyu Wang.

  Macrophage migration inhibitory factor (MIF) is a versatile cytokine that links inflammation to tumor metabolism. It signals through CD74, along with co-receptors C-X-C chemokine receptor 2, 4, and 7 (CXCR2/CXCR4/CXCR7), activating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase (ERK) pathways. MIF also engages the mechanistic target of rapamycin complex 1 (mTORC1)/activating transcription factor 4 (ATF4) module to reprogram metabolic processes. This review explains how MIF promotes glucose uptake and aerobic glycolysis (the Warburg effect) and coordinates lipid regulators-sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs)-to enhance lipid uptake, de novo lipogenesis, acyl-chain remodeling, β-oxidation flexibility, and cholesterol/membrane homeostasis. It also reshapes amino acid transport, glutamine utilization, redox balance, and sensitivity to ferroptosis. The focus is on receptor-specific entry points, module-level outcomes, and how the tumor microenvironment affects nutrient competition and immune suppression. To avoid over-interpretation, evidence is graded by strength: [1] direct target engagement with pathway pharmacodynamics; [2] pathway-level signals alone; and [3] scaffold-level plausibility. Validation uses a standard set of assays, including orthogonal biophysical methods, receptor-proximal pharmacodynamic readouts, and isotope-tracing flux measurements. The review critically assesses current small-molecule classes targeting the catalytic pocket or trimer/interface to identify design principles for next-generation, receptor-focused modulators suitable for combination therapy. Finally, it proposes an imaging- and flux-based translational approach to select patients, confirm on-target action, and rationally pair MIF-axis blockade with metabolic or immunotherapeutic strategies-aiming to transform correlative data into mechanism-based clinical trials.

Keywords:  Amino acid transport; CD74; Lipid metabolism; Macrophage migration inhibitory factor; Tumor metabolism

DOI:  https://doi.org/10.1016/j.bcp.2026.117720
J Transl Med. 2026 Jan 20.

Identification and evaluation of glutamine-related gene characteristics based on multi-omics to predict the prognosis of patients with colorectal cancer.

Mingming Yin, Di Zhang, Tianbing Wang, Lifeng Xu, Rong Jin, Xiangyang Wang, Yi Man, Kai Xu, Qiang Ruan, Ting Wang, Kai Guo, Haoyi Zheng, Zheng Zhou, Guosheng Gu, Wenyong Wu.



Keywords:  Colorectal cancer; Glutamine metabolism-related genes; PCOLCE2; Prediction model; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s12967-025-07261-0
J Nanobiotechnology. 2026 Jan 19. 24(1): 42

Correction: Mesoporous multimetallic PdPtBi nanozymes target redox imbalance and glutamine deprivation for immuno-chemodynamic therapy.

Guanhua Qiu, Jie Long, Feng Lin, Zeyan Yu, Renchuan Liang, Jiaxin Luo, Xuezhong Mo, Duo Wang, Lei Jiao, Yunxi Huang.

DOI: https://doi.org/10.1186/s12951-026-04033-w
Cell Discov. 2026 Jan 20. 12(1): 5

IGF2BP3-dependent glutamine/BCAA metabolic rewiring rejuvenates aged human adipose-derived stem cells for enhanced tissue regeneration.

Zichao Li, Lin Feng, Xinxin Wei, Huichen Li, Yifu Zhu, Hongtao Wang, Jiaqi Liu, Liang Luo, Zhao Zheng, Baoqiang Song, Liangliang Shen, Dahai Hu.

Aging impairs the regenerative capacity and differentiation potential of human adipose-derived stem cells (hASCs), but the mechanisms underlying their functional decline remain unclear. Through systematic functional assays and in vivo experiments, we first confirmed age-associated reductions in hASC self-renewal, lineage plasticity, and tissue repair efficacy. By integrating multiomics profiling and functional validation, we identified a metabolically active ACTA2+TAGLN+ subpopulation that was enriched mainly in infant-derived hASCs (I-hASCs) and characterized by increased catabolism of branched-chain amino acids (BCAAs) and glutamine. Mechanistically, the RNA-binding protein IGF2BP3, which is predominantly expressed in the ACTA2+TAGLN+ subpopulation, sustains hASC stemness by stabilizing BCAT1 and GLS mRNAs via METTL3-mediated m6A modification, thereby preserving redox homeostasis and mitochondrial energy production. Furthermore, age-related attenuation of the IGF2BP3-m6A-BCAT1/GLS axis contributed to metabolic reprogramming, driving senescence-associated functional collapse in elderly-derived hASCs (E-hASCs). Strikingly, rescue experiments demonstrated that genetic restoration of BCAT1/GLS or supplementation with BCAAs/glutamine significantly rejuvenated E-hASCs, restoring their proliferation, differentiation, and in vivo wound-healing capacities. These findings identify IGF2BP3 as a central regulator of hASC aging by linking m6A epitranscriptomic modifications to metabolic reprogramming and establish the IGF2BP3-m6A-BCAT1/GLS axis as a druggable node in aged hASCs. This study proposed two therapeutic strategies: nutrient supplementation to rescue metabolic deficits and m6A modulation to stabilize key mRNAs, providing a clinically feasible protocol to optimize elderly-derived hASCs for tissue regeneration.

DOI: https://doi.org/10.1038/s41421-025-00860-7
BMC Cancer. 2026 Jan 21.

ppAT drives glutamine-dependent purine biosynthesis and malignant progression in hepatocellular carcinoma.

Junbin Zhou, Cainiao Dong, Shengqian Xu, Jun Wang, Hailin Ye, Xiaopeng Fan, Shimiao Li, Shi Wang.



Keywords:  Glutamine dependency; HCC; PpAT; Purine synthesis; Therapeutic target

DOI:  https://doi.org/10.1186/s12885-025-15512-y
Front Mol Biosci. 2025 ;12 1720876

Glutamate enhances the production of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 in keloid fibroblasts.

Yan Chen, Yaohan Xu, Jiahe Zhang, Chenxi Feng, Jie Chen, Yinjing Song, Jing Pan, Jiang Zhu, Hao Cheng.

   Introduction: Keloids are fibroproliferative skin scars characterized by excessive extracellular matrix deposition and a high rate of recurrence. Despite extensive research, their pathogenesis remains incompletely understood and effective curative therapies are lacking.
Methods: RNA sequencing (RNA-seq) and metabolomics were performed to compare gene expression and metabolite profiles between human keloid tissues and normal skin. Single-cell RNA sequencing, immunohistochemistry, and immunofluorescence were used to determine the cellular localization of key genes. In vitro, human fibroblasts were stimulated with glutamate, followed by RNA-seq, quantitative RT-PCR, and ELISA to evaluate inflammatory gene expression and cytokine secretion.
Results: Transcriptomic analysis revealed significant enrichment of the neuroactive ligand-receptor interaction pathway in keloid tissue, with marked upregulation of the glutamate receptor subunit GRIN2D. Single-cell and histological analyses demonstrated that GRIN2D is predominantly expressed in fibroblasts. Metabolomic profiling showed significantly increased levels of glutamate and glutamine in keloid tissues. Glutamate stimulation of fibroblasts significantly enhanced the expression and secretion of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 (IL-8).
Discussion: These results underscore the crucial role of glutamate metabolism in promoting the infammatory functions of fbroblasts. They suggest that glutamate contributes to keloid progression and provides a theoretical basis for targeting glutamte signaling pathway in keloid treatment.

Keywords:  GRIN2D; fibroblast; glutamate; inflammation; keloid

DOI:  https://doi.org/10.3389/fmolb.2025.1720876