bims-glucam 2025-10-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–10–12
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.
Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
Restoration of Cementoblast Mineralization by Glutamine Under Inflammatory Conditions.
Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.
Glutamine prevents diarrhea in colorectal cancer patients undergoing chemotherapy or chemoradiotherapy: a meta-analysis.
Metabolic regulation of immune memory and function of microglia.
Metabolic reprogramming: the central mechanism driving inflammatory polarization in rheumatoid arthritis and the regulatory role of traditional Chinese medicine.
Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
The BAF53A-BACH1-GCLM axis regulates glutathione metabolism and enhances ferroptosis resistance in esophageal squamous cell carcinoma.
Inhibition of integrin α3 suppresses gastric cancer progression via STAT3-mediated regulation of SLC1A5-dependent glutamine uptake.
Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.
Effects of glutaminase 1 inhibitor on rotator cuff derived cells: a preliminary report in 12 patients.
Novel biomarker identification for oral squamous cell carcinoma development in nonsmoker, nondrinker, and nonchewer patients using third-generation sequencing of oral microbiome.
ALDH2 deficiency aggravates vascular injury-induced restenosis by enhancing vascular smooth muscle cell proliferation through SLC38A2-mediated upregulation of glutamine uptake.
Sirtuin 6 mediates the therapeutic effect of endometrial regenerative cell-derived exosomes in alleviation of acute transplant rejection by weakening c-myc-dependent glutaminolysis.
Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.
lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases.

Cell Death Discov. 2025 Oct 06. 11(1): 430

Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.

Ziqian Ge, Martina Wallace, Rory Turner, Maureen Yin, Mary F Rooney, Richard K Porter.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high recurrence rates and limited treatment options due to the absence of hormone receptors. Despite advancements in breast cancer research, effective therapies for TNBC remain inadequate, highlighting the need to elucidate subtype-specific metabolic vulnerabilities. TNBC cells exhibit a strong dependence on the exogenous amino acids cystine and glutamine, yet the interplay between these metabolic dependencies remains poorly understood. Here, we demonstrate that TNBC cells exhibit sensitivity to individual nutrient deprivation but can survive dual cystine and glutamine deprivation via distinct mechanisms. Exogenous glutamine primarily fuels glutamine anaplerosis, supporting TNBC cell proliferation. Notably, when exogenous glutamine is absent, restricted cystine uptake restores intracellular glutamate levels, fulfilling metabolic demands and sustaining TNBC cell growth. Under cystine deprivation, inhibition of glutaminolysis rescues TNBC cells by mitigating lipid peroxidation and reducing ROS production, whereas supplementation with the TCA cycle intermediates ɑ-ketoglutarate (ɑ-KG) and succinate induces profound cell death in both TNBC and luminal breast cancer cells under glutaminolysis blockade. Collectively, these findings highlight the metabolic interdependence of glutamine and cystine in TNBC, providing mechanistic insights into potential metabolic-targeted and dietary interventions for TNBC therapy.

DOI: https://doi.org/10.1038/s41420-025-02714-3
Immunology. 2025 Oct 08.

Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.

Sana Ahuja, Sufian Zaheer.

  Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine-tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia-inducible factor-1 (HIF-1), MYC, p53, peroxisome proliferator-activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element-binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal-tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single-cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin-modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.

Keywords:  OXPHOS; glycolysis; mediators; metabolic reprogramming; tumour microenvironment

DOI:  https://doi.org/10.1111/imm.70045
Int Dent J. 2025 Oct 07. pii: S0020-6539(25)03214-9. [Epub ahead of print]75(6): 103930

Restoration of Cementoblast Mineralization by Glutamine Under Inflammatory Conditions.

Mengjie Yin, Hantao Yao, Jingqiu Chen, Ting Li, Yilin Liao, Yaoyu Zhao, Yue Sheng, Wengwanyue Ye, Zhengguo Cao, Yaoting Ji, Hong He.

   INTRODUCTION AND AIMS: Cementoblasts are critical for cementum formation and periodontal regeneration during inflammatory diseases such as periodontitis and apical periodontitis (AP). Bacterial infection leads to metabolic changes in cementoblasts and reduces mineralization capability. This study aimed to fully elucidate the metabolic changes of cementoblasts in inflammatory mineralization and explore therapeutic strategies targeting metabolism.
METHODS: Mouse cementoblasts cell line OCCM-30 were infected with Porphyromonas gingivalis (P.g) to model microbial infection stress. Metabolic profiling was performed using Seahorse assays and untargeted metabolomics. Genetic manipulation (knockdown/overexpression of Gls) and pharmacological inhibition (AMPK inhibitor Compound C) were used to dissect the mechanisms. An AP model was induced in C57BL/6 mice, and glutamine supplementation was administered to assess therapeutic effects in vivo.
RESULTS: P.g infection suppressed glycolysis and oxidative phosphorylation but upregulated glutamine metabolism in cementoblasts. Knockdown of Gls inhibited mineralization by the cementoblasts, whereas glutamine supplementation or Gls overexpression restored mineralization ability. AMPK inhibition reduced GLS expression and mineralization by cementoblasts. In vivo, glutamine supplementation attenuated AP progression and cementum destruction.
CONCLUSION: Glutamine supplementation compensates for energy deficits in inflamed cementoblasts via the AMPK/GLS signalling pathway. Targeting this pathway offers a potential therapeutic approach for cementum remineralization and periodontal regeneration.
CLINICAL RELEVANCE: Glutamine supplementation restores mineralization by the cementoblasts under inflammatory conditions, which provides a novel theoretical foundation for the alleviation and treatment of periodontitis and apical periodontitis.

Keywords:  Cell mineralization; Cementoblast; Dental cementum; GLS; Glutamine; P. gingivalis

DOI:  https://doi.org/10.1016/j.identj.2025.103930
Biomark Res. 2025 Oct 10. 13(1): 124

Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.

Lingbo An, Zongfang Li.

  Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major cause of cancer-related mortality worldwide, with rising incidence and limited treatment options, especially for patients diagnosed at advanced stages. In recent years, metabolic reprogramming has emerged as a hallmark of cancer that enables HCC cells to survive, proliferate, and resist therapy under hostile conditions. HCC cells undergo profound remodeling of glucose, lipid, and amino acid metabolism to adapt to hypoxia and nutrient deprivation. These processes are orchestrated by key signaling cascades, including the PI3K/AKT/mTOR, Ras-Raf-MEK-ERK-cMYC, and LKB1-AMPK pathways, forming a dynamic and integrated metabolic-signaling network. This review comprehensively integrates recent advances in the understanding of metabolic pathways in HCC, with a particular focus on glycolysis, de novo lipogenesis, and glutamine metabolism. We delineate the regulatory mechanisms underlying these pathways and construct an interaction map linking metabolic circuits to clinical phenotypes such as tumor heterogeneity, metastatic potential, and immune modulation. Furthermore, we systematically evaluate the biomarker potential of metabolic intermediates, rate-limiting enzymes, and key regulators in the context of early detection, molecular classification, prognosis prediction, and therapeutic response in HCC. We also highlight cutting-edge technologies, including metabolic imaging, liquid biopsy-based biomarker detection, and metabolism-targeted therapies. The review explores their potential synergy with immunotherapy, chemotherapy, and radiotherapy, aiming to provide a comprehensive framework for individualized HCC management. Our discussion underscores the translational relevance of metabolic biomarkers and offers insights for future research and clinical innovation.

Keywords:  Combined diagnosis and treatment; Hepatocellular carcinoma; Metabolic networks; Metabolic reprogramming; Metabolic–signaling interactions; Targeted drugs

DOI:  https://doi.org/10.1186/s40364-025-00844-5
BMC Gastroenterol. 2025 Oct 06. 25(1): 697

Glutamine prevents diarrhea in colorectal cancer patients undergoing chemotherapy or chemoradiotherapy: a meta-analysis.

Lijuan Chen, Duo Wang, Chang Meng, Hongshuo Sun, Ruolin Li, Guobin Miao, Peng Liu.

   OBJECTIVE: To assess the efficacy of glutamine in preventing diarrhea associated with chemotherapy or chemoradiotherapy in colorectal cancer.
METHODS: Randomized controlled trials of glutamine in the prevention of chemotherapy-associated diarrhea of colorectal cancer were retrieved from the Cochrane Library, Pubmed, EMBASE, CNKI, and Wanfang by computer up to August 1, 2024. Results were presented using relative risk (RR) or mean difference (MD) with a 95% confidence interval (CI). Publications were reviewed in accordance with the Cochrane Handbook and the guidelines of the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA2020). This study has been registered with INPLASY (registration number: INPLASY202490057).
RESULTS: A total of 5 studies were included, and the total number of patients was 311. Meta-analysis showed that compared with the control group, glutamine supplementation significantly reduced the incidence of chemoradiation-induced diarrhea in colorectal cancer patients (RR = 0.72, 95%CI: 0.60-0.87, P < 0.01, I²=37%). Subgroup analysis found that glutamine was more effective in reducing diarrhea in patients receiving chemotherapy alone than in those undergoing chemoradiotherapy (RR = 0.65, 95%CI: 0.43-0.98, P < 0.05, I²=35%). By tumor location, glutamine reduced diarrhea in the colorectal cancer subgroup (RR = 0.65, 95%CI: 0.44-0.97, P < 0.05, I²=30%) but not in the rectal cancer subgroup (P > 0.05). D-xylose levels were significantly higher in the glutamine group (MD = 0.32, 95%CI: 0.14-0.51, P < 0.01, I²=0%), while C-reactive protein levels were significantly lower (MD = 0.52, 95%CI: 0.32-0.72, P < 0.01, I²=0%). The certainty of evidence for diarrhea was rated as low.
CONCLUSION: Glutamine supplementation is associated with a reduced incidence of diarrhea in patients with colorectal cancer, with a more pronounced efficacy observed in those receiving chemotherapy alone.

Keywords:  Colorectal cancer; Diarrhea; Glutamine

DOI:  https://doi.org/10.1186/s12876-025-04308-w
Elife. 2025 Oct 10. pii: e107552. [Epub ahead of print]14

Metabolic regulation of immune memory and function of microglia.

Nikolaos Nirakis, Sofia Dimothyra, Eleftheria Karadima, Vasileia Ismini Alexaki.

  Innate immune cells possess memory-like properties. Exposure to infections or sterile inflammation can prime them, leading to either exacerbated inflammatory responses, a process called trained immunity, or reduced responsiveness to pro-inflammatory signals, a process termed immune tolerance. Microglia, the resident innate immune cells of the central nervous system, are central players in neurodegenerative diseases. Characterizing trained immunity and tolerance in microglia is necessary for a better understanding of neurodegenerative diseases. Cell metabolic processes orchestrate microglia inflammatory responses and promote epigenetic changes shaping immune memory in microglia. Here, we review current knowledge on the role of cell metabolic pathways in microglia innate immune memory formation, focusing on glucose, glutamine, and lipid metabolism. Moreover, we address the significance of microglial immune memory in disease pathology and discuss the potential of therapeutic targeting of cell metabolic pathways in neurodegenerative disorders.

Keywords:  cell metabolism; immunology; inflammation; microglia; tolerance; training

DOI:  https://doi.org/10.7554/eLife.107552
Front Immunol. 2025 ;16 1659541

Metabolic reprogramming: the central mechanism driving inflammatory polarization in rheumatoid arthritis and the regulatory role of traditional Chinese medicine.

Jianting Wen, Jian Liu, Lei Wan, Fanfan Wang, Yang Li.

  Rheumatoid arthritis (RA) is characterized by high morbidity, disability, and mortality rates and is intricately linked to metabolic reprogramming that governs immune cell dysfunction and inflammatory polarization, thereby driving RA pathogenesis. This review systematically explored the impact of metabolic dysregulation (especially in glucose, lipid, mitochondrial, and glutamine metabolism) on shaping the inflammatory microenvironment of RA. Key metabolic axes included aerobic glycolysis (the Warburg effect), de novo fatty acid (FA) synthesis, mitochondrial bioenergetic dysfunction, and glutaminolysis. Furthermore, the review highlighted the therapeutic potential of traditional Chinese medicine (TCM) in modulating these metabolic pathways to attenuate pro-inflammatory responses and ameliorate RA progression. Through regulation of metabolic enzymes, TCM demonstrated multi-faceted efficacy in restoring metabolic homeostasis and inhibiting pathological inflammation. This review underscored that metabolic reprogramming was pivotal for identifying novel therapeutic targets; our results may provide a scientific foundation for integrating TCM into RA management strategies. These findings advocated for further exploration of metabolism-centered interventions to develop precision therapies for RA.

Keywords:  glucose metabolism reprogramming; inflammatory polarization; metabolic reprogramming; rheumatoid arthritis; traditional Chinese medicine

DOI:  https://doi.org/10.3389/fimmu.2025.1659541
Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w
PeerJ. 2025 ;13 e20156

The BAF53A-BACH1-GCLM axis regulates glutathione metabolism and enhances ferroptosis resistance in esophageal squamous cell carcinoma.

Weijuan Jiang, Jie Zhang, Canjuan Chen, Jiangwei Shi, Lihua Fan.

   Objective: Esophageal squamous cell carcinoma (ESCC), a highly lethal malignancy, exhibits poor survival rates and limited treatment options. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, emerges as a potential therapeutic target. However, the mechanisms suppressing ferroptosis in ESCC remain poorly understood.
Methods: Short hairpin RNA (shRNA) was employed to knock down BAF53A and BACH1 in ESCC cell lines, followed by assessments of cell proliferation, colony formation, and ferroptosis sensitivity. Glutathione (GSH) metabolism was evaluated by measuring GSH/GSSG and NADP+/NADPH ratios, reactive oxygen species (ROS) levels, and lipid peroxidation through flow cytometry and fluorescence imaging. Molecular interactions were evaluated using co-immunoprecipitation and chromatin immunoprecipitation sequencing (ChIP-seq) to identify transcriptional targets of the BAF53A-BACH1 complex.
Results: BAF53A was elevated in ESCC, and its depletion impaired cell proliferation and colony formation ability of cells. Knockdown of BAF53A disrupted GSH metabolism, leading to increased ROS levels, reduced GSH/GSSG and NADP+/NADPH ratios, and enhanced ferroptosis sensitivity. Mechanistically, BAF53A collaborated with BACH1 to transcriptionally activate glutamate-cysteine ligase modifier subunit (GCLM), a key enzyme in GSH biosynthesis. Overexpression of GCLM restored redox balance and cell viability in BAF53A- or BACH1-silenced cells.
Conclusions: The BAF53A-BACH1-GCLM axis constitutes a novel egulatory pathway that integrates chromatin remodeling, transcriptional regulatione, and ferroptosis resistance in ESCC. Targeting this axis may offer a promising approach to exploit metabolic vulnerabilities and enhance ferroptosis sensitivity in ESCC treatment.

Keywords:  BAF53A; Esophageal squamous cell carcinoma; Ferroptosis; Glutathione metabolism

DOI:  https://doi.org/10.7717/peerj.20156
J Gastroenterol. 2025 Oct 08.

Inhibition of integrin α3 suppresses gastric cancer progression via STAT3-mediated regulation of SLC1A5-dependent glutamine uptake.

Weiwei Zhu, Siwei Pan, Jingli Xu, Yuqi Wang, Zhenjie Fu, Xiao Han, Yanqiang Zhang, Qianyu Zhao, Ruolan Zhang, Can Hu, Zhiyuan Xu.

   BACKGROUND: Gastric cancer (GC) remains one of the most lethal malignancies, primarily due to limited treatment efficacy and its strong metastatic potential. The identification of new molecular targets is therefore crucial for enhancing therapeutic strategies and improving clinical outcomes.
METHODS: The expression of ITGA3 was investigated in clinical GC tissue samples, and its association with patient prognosis was evaluated. Both in vitro and in vivo assays were employed to investigate the functional role of ITGA3 in GC cell proliferation and invasion. To uncover the underlying molecular mechanisms, integrated proteomic and transcriptomic analyses were performed. Mechanistic validation was subsequently carried out using Western blotting, immunofluorescence, nuclear-cytoplasmic fractionation, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP) assays.
RESULTS: Elevated ITGA3 expression was strongly correlated with an unfavorable prognosis in GC patients. Functional studies revealed that ITGA3 promotes tumor cell proliferation and invasion. Multi-omics analyses revealed that ITGA3 modulates glutamine metabolism by regulating the amino acid transporter SLC1A5 and engages the JAK-STAT3 signaling pathway. Silencing ITGA3 significantly reduced STAT3 nuclear translocation, suppressing SLC1A5 transcription and decreasing glutamine uptake. Both dual-luciferase reporter and ChIP assays confirmed that STAT3 directly binds to the promoter region of SLC1A5.
CONCLUSIONS: ITGA3 acts as an oncogenic driver in GC by facilitating glutamine uptake via the STAT3-SLC1A5 signaling axis. These findings suggest that therapeutic targeting of this pathway could represent a promising approach for the clinical management of GC.

Keywords:  ChIP; Gastric Cancer; ITGA3; Proliferation; SLC1A5

DOI:  https://doi.org/10.1007/s00535-025-02305-0
Mol Cancer. 2025 Oct 08. 24(1): 247

Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  Metabolic reprogramming is one of the fundamental characteristics of thyroid cancer (TC), which meets its energy and biosynthetic demands through mitochondrial dysfunction, glycolysis activation, lipid metabolism imbalance, and glutamine dependency, thereby promoting metastasis and reshaping the immune microenvironment. Exosomes, as extracellular vesicles, play a crucial role in TC by delivering bioactive molecules such as proteins, lipids, and nucleic acids. In the tumor microenvironment (TME) of TC, exosomes secreted by both tumor and non-tumor cells interact with each other, driving metabolic reprogramming and forming a bidirectional regulatory network. This significantly alters the biological characteristics of TC cells, including proliferation, invasion, metastasis, angiogenesis, and the acquisition of drug resistance and immune tolerance, ultimately influencing the process of immune escape in TC. This review systematically summarizes how exosomes in the TME of TC promote tumor progression through metabolic reprogramming, providing new diagnostic and therapeutic strategies for patients with locally advanced, radioiodine-refractory TC.

Keywords:  Exosomes; Immune escape; Metabolic reprogramming; Thyroid cancer; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02470-z
BMC Musculoskelet Disord. 2025 Oct 08. 26(1): 935

Effects of glutaminase 1 inhibitor on rotator cuff derived cells: a preliminary report in 12 patients.

Tatsuo Kato, Yutaka Mifune, Atsuyuki Inui, Hanako Nishimoto, Shintaro Mukohara, Tomoya Yoshikawa, Issei Shinohara, Takahiro Furukawa, Shuya Tanaka, Masaya Kusunose, Yuichi Hoshino, Takehiko Matsushita, Tomoyuki Matsumoto, Ryosuke Kuroda.

   BACKGROUND: Glutaminase 1 (GLS1) degrades glutamate into glutamine and ammonia, and is required for the survival of senescent human cells. GLS1 inhibitors contribute to the improvement of various pathological conditions associated with aging. Rotator cuff tears (RCT) increase with age, and recently the Stump classification has been proposed to evaluate the fragility of the torn rotator cuff site, with Type 3 being the most fragile and a high risk of re-tear after rotator cuff repair surgery. We hypothesized that GLS1 expression is upregulated in the degenerated rotator cuff and that GLS1 inhibitors would improve rotator cuff degeneration. In this study, we evaluated the effects of GLS1 inhibitors on human rotator cuff-derived cells.
METHODS: Twelve patients who underwent surgery for RCT were included in this study. Rotator cuff tissue was harvested during arthroscopic repair for tissue and cell evaluation. Tissue evaluation involved quantitative assessment of mRNA expression of GLS1 using real-time PCR (qPCR) and immunostaining. Rotator cuff-derived cells were isolated and cultured, divided into four groups: (1) Control group (without IL-1β and GLS1 inhibitor), (2) IL-1β(-)/GLS1 inhibitor(+), (3) IL-1β(+)/GLS1 inhibitor(-), (4) IL-1β(+)/GLS1 inhibitor(+). Cell viability was evaluated by WST assay and mRNA expression was evaluated by qPCR at 48 h after treatment. The expression of p16 and Scleraxis (SCX) was also evaluated by fluorescent immunostaining.
RESULTS: Tissue evaluation showed significantly higher expression of GLS1 in Stump classification Type 3. Cell viability was significantly decreased by IL-1β loading and increased by the GLS1 inhibitor. The mRNA expression levels of GLS1, IL-6, p16 and p21 were decreased by the GLS1 inhibitor. The mRNA expression of the tendon markers, type 1 collagen, Mohawk and SCX were increased by the GLS1 inhibitor. Immunostaining revealed that the GLS1 inhibitor decreased p16 expression and increased SCX expression.
CONCLUSIONS: This study showed that GLS1 was upregulated in the degenerated rotator cuff, and that the administration of a GLS1 inhibitor decreased inflammation and aging markers while increasing cell viability and tendon markers in rotator cuff-derived cells. These results indicate that GLS1 inhibitors exert anti-inflammatory effects in rotator cuff tears, prevent age-related degeneration of the rotator cuff, and promote tendon repair.

Keywords:  Anti-aging; Anti-inflammatory; Glutaminase 1; Rotator cuff; Stump classification

DOI:  https://doi.org/10.1186/s12891-025-09105-w
J Oral Microbiol. 2025 ;17(1): 2565452

Novel biomarker identification for oral squamous cell carcinoma development in nonsmoker, nondrinker, and nonchewer patients using third-generation sequencing of oral microbiome.

Wei-Ni Lyu, Cheng-Ying Shen, Yung-Hua Lee, Shin-Kuang Chen, Eric Y Chuang, Pei-Jen Lou, Mong-Hsun Tsai.

   Background/Objective: Oral squamous cell carcinoma (OSCC) in patients without tobacco, alcohol, or betel-quid habits is poorly understood and difficult to detect early. This study aimed to identify microbial biomarkers specific to this habit-free population using third-generation sequencing (TGS).
Patients/Materials and methods: Twenty-seven habit-free OSCC patients were recruited at National Taiwan University Hospital (NTUH). Paired tumor and adjacent normal tissues were collected with informed consent and NTUH Research Ethics Committee approval (IRB 201902080RINC, 201304078RIND). Full-length 16S rRNA sequencing (PacBio Sequel IIe) was processed with DADA2 and SILVA. Biomarkers were identified using sparse partial least squares discriminant analysis (sPLS-DA) and random forest with cross-validation, and validated against three public OSCC cohorts.
Results: A three-species panel-Eikenella corrodens, Slackia exigua, and Eggerthia catenaformis-discriminated tumor from normal tissues (AUC = 0.905 training; 0.733 testing). Functional and network analyses showed tumor-enriched taxa forming pro-inflammatory clusters linked to lipid and glutamine metabolism, while commensals correlated with homeostatic pathways. Cross-cohort comparison confirmed this panel's specificity to habit-free OSCC.
Conclusions: Using TGS, we revealed distinct microbial signatures in habit-free OSCC that may aid early diagnosis and underscore the role of microbiome-host interactions in carcinogenesis.

Keywords:  Oral squamous cell carcinoma; full-length 16S rRNA; host–microbe interaction; nonsmoker nondrinker nonchewer; novel microbial biomarkers; third-generation sequencing

DOI:  https://doi.org/10.1080/20002297.2025.2565452
Metabolism. 2025 Oct 07. pii: S0026-0495(25)00280-X. [Epub ahead of print] 156411

ALDH2 deficiency aggravates vascular injury-induced restenosis by enhancing vascular smooth muscle cell proliferation through SLC38A2-mediated upregulation of glutamine uptake.

Dehui Hou, Kehui Yang, Yang Liu, Han Du, Hongwei Yue, Fengyang Xu, Wentao Sang, Xiangkai Zhao, Yijun Sun, Feng Xu, Yuguo Chen.

   BACKGROUND AND AIMS: Vascular injury-induced restenosis is an important cause of poor long-term prognosis in patients with coronary artery disease (CAD). Although aldehyde dehydrogenase 2 (ALDH2) deficiency has been linked to poor outcomes in CAD patients, the precise mechanisms through which ALDH2 influences vascular injury-induced restenosis remain elusive. Herein, we attempted to explore the role of ALDH2 in modulating vascular smooth muscle cell (VSMC) proliferation and vascular injury-induced restenosis.
METHODS AND RESULTS: Immunofluorescence and immunoblotting revealed that ALDH2 expression was significantly decreased in VSMCs in human stenotic coronary segments and injured mouse femoral and carotid arteries. Global ALDH2 knockout and VSMC-specific ALDH2 knockout exacerbated injury-induced neointima formation, whereas VSMC-specific ALDH2 overexpression reduced neointima formation. Endothelial cell (EC)-specific ALDH2 knockout had little effect on injury-induced neointima formation. Mechanistic studies revealed that ALDH2 deficiency facilitated VSMC proliferation by upregulating the expression of the glutamine transporter SLC38A2, which is a novel ALDH2 target gene. Further bioinformatics analysis, luciferase assays, and ChIP-qPCR revealed that ALDH2 deficiency increased SLC38A2 expression via activating transcription factor 4 (ATF4) and that ATF4 knockdown largely reversed the ability of ALDH2 deficiency to promote VSMC proliferation. Moreover, ALDH2 deficiency promoted the accumulation of 4-HNE adducted proteins, thereby activating ATF4, which subsequently increased SLC28A2 transcriptional activity in VSMCs. Importantly, downregulation of SLC38A2 by adeno-associated virus serotype 2 (AAV2) shRNA or by the inhibitor MeAIB has promising therapeutic potential in limiting VSMC proliferation and neointima formation. Finally, we demonstrated that VSMC proliferation was aggravated and that neointima formation occurred in ALDH2E506k mutant mice.
CONCLUSION: Our study elucidates a novel mechanism through which ALDH2 deficiency aggravates neointimal formation by enhancing VSMC proliferation through an increase in glutamine uptake, suggesting a promising translational strategy for the prevention of vascular injury-induced restenosis.

Keywords:  Aldehyde dehydrogenase 2 (ALDH2); Cell proliferation; Glutamine; Neointima; Vascular injury-induced restenosis; Vascular smooth muscle cells (VSMCs)

DOI:  https://doi.org/10.1016/j.metabol.2025.156411
Front Cell Dev Biol. 2025 ;13 1564382

Sirtuin 6 mediates the therapeutic effect of endometrial regenerative cell-derived exosomes in alleviation of acute transplant rejection by weakening c-myc-dependent glutaminolysis.

Tong Liu, Chenglu Sun, Xu Liu, Pengyu Zhao, Bo Shao, Yini Xu, Yiyi Xiao, Hongda Wang, Qiang Chen, Guangmei Yang, Hao Wang.

   Background: Despite the rapid development of immunosuppressive drugs, acute rejection (AR) remains a cause of allograft dysfunction and allograft failure. Although endometrial regenerative cell-derived exosomes (ERC-Exos) effectively alleviate AR, more research is required to fully understand the underlying mechanisms. Thus, this study aimed to determine whether sirtuin 6 (SIRT6) mediates the therapeutic effect of ERC-Exos on AR and elucidate the underlying mechanisms.
Methods: The expression of SIRT6 was verified in ERC-Exos by Western blot. ERC-Exos with extremely low expression of SIRT6 (SIRT6-KD-ERC-Exos) were obtained by transducing shRNA-SIRT6 in ERCs. C57BL/6 recipient mice were transplanted with heart grafts from BALB/c donor mice and divided into three groups: untreated, ERC-Exo-treated, and SIRT6-KD-ERC-Exo-treated groups. Recipient mice were sacrificed on post-operative day 8 for the determination of graft pathological changes, intra-graft immunocyte infiltration, splenic CD4+ T cell populations, and serum cytokine levels in vivo. The proportion of CD4+ T cells and their secreting cytokine levels were determined in vitro. Besides, the underlying mechanisms were also investigated in vitro.
Results: ERC-Exos expressed SIRT6, and cardiac graft survival was increased by SIRT6-expressing ERC-Exos. Graft pathological damage, intra-graft CD4+ T cell infiltration, and intra-graft inflammatory (Th1 and Th17) cell infiltration decreased, and intra-graft and serum inflammatory cytokine (interferon (IFN)-γ and interleukin (IL)-17) levels decreased in the SIRT6-expressing ERC-Exo-treated mice. Furthermore, in the recipient mice, ERC-Exo treatment markedly increased the differentiation of regulatory T cells (Tregs) while significantly decreasing that of Th1 and Th17 cells. In a similar vein, ERC-Exo therapy raised the levels of the anti-inflammatory cytokine IL-10 in vitro while decreasing those of IFN-γ and IL-17. By suppressing the expression of important proteins linked to glutaminolysis and further deactivating the mammalian target of rapamycin complex 1 (mTORC1) pathway, ERC-Exos reduced the uptake and use of glutamine in naïve CD4+ T cells, according to mechanism exploration. In contrast, SIRT6-KD-ERC-Exos considerably reversed these trends and changes both in vivo and in vitro.
Conclusion: SIRT6 is crucial in mediating ERC-Exos to remodel CD4+ T cell differentiation by weakening c-Myc-dependent glutaminolysis, thereby alleviating AR.

Keywords:  CD4 + T cell differentiation; SIRT6; acute rejection; endometrial regenerative cells; exosomes; glutaminolysis

DOI:  https://doi.org/10.3389/fcell.2025.1564382
Gene. 2025 Oct 06. pii: S0378-1119(25)00608-0. [Epub ahead of print] 149819

Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.

Yuelian Fan, Yuping Suo.

  Ovarian cancer (OVCA) is a highly malignant gynecological tumor characterized by a dismal 5-year survival rate that is closely linked to aberrant ferroptosis regulation and lipid metabolic reprogramming. This study integrated bioinformatics analyses of TCGA and The Human Protein Atlas datasets, clinical validation in 30 pairs of OVCA tissues, in vitro functional assays using HO8910 and HEYT30 cell lines, and nude mouse xenograft models to explore the role of suppressor of cytokine signaling 6 (SOCS6) in OVCA prognosis. The results revealed that SOCS6 was significantly downregulated in OVCA tissues and cell lines, and low expression was strongly correlated with poor patient prognosis. Mechanistically, SOCS6 overexpression inhibited cellular proliferation, migration, and invasion and enhanced sensitivity to the ferroptosis inducer erastin. This effect occurs by promoting the ubiquitin-proteasomal degradation of the ferroptosis antagonist SLC7A11, reducing intracellular glutathione (GSH) levels, and augmenting reactive oxygen species (ROS) and Fe2+ accumulation. Additionally, SOCS6 suppressed de novo fatty acid synthesis by downregulating the key enzymes FASN and ACC, leading to decreased triglyceride and phospholipid production. In vivo xenograft experiments confirmed that SOCS6 overexpression inhibited tumor growth and reduced the expression of SLC7A11 and lipid metabolism-related molecules. Collectively, these results establish SOCS6 as a critical molecular hub linking ferroptosis and lipid metabolism in OVCA, highlighting its potential as both a prognostic biomarker and a therapeutic target for improving clinical outcomes in OVCA.

Keywords:  Ferroptosis; Lipid metabolism; OVCA; SLC7A11; SOCS6

DOI:  https://doi.org/10.1016/j.gene.2025.149819
Mech Ageing Dev. 2025 Oct 07. pii: S0047-6374(25)00094-6. [Epub ahead of print] 112118

lncRNA EPB41L4A-AS1: A promising therapeutic target for aging and age-related diseases.

Minghui Li, Tianzi Li, Xufei Zhang, Kun Li, Ziqiang Wang.

  Aging is a natural biological process characterized by progressive cellular and functional decline, significantly increasing susceptibility to age-related diseases. Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of cellular processes implicated in aging and age-related diseases. Among these, lncRNA erythrocyte membrane protein band 4.1 like 4A antisense RNA 1 (EPB41L4A-AS1) has emerged as a key player with significant dysregulation across diverse age-related diseases including cancer, Alzheimer's disease (AD), and type 2 diabetes mellitus (T2DM). This review synthesizes current evidence showing that EPB41L4A-AS1 functions primarily as a tumor suppressor in many cancers, regulates neuronal autophagy and energy metabolism in AD, and modulates inflammatory and metabolic pathways in T2DM. Mechanistically, EPB41L4A-AS1 exerts its effects-via miRNA sponging, regulating key signaling pathways (NF-κB, Rho/ROCK), influencing histone modifications, and modulating cellular metabolism (glycolysis, glutaminolysis, NAD+/ATP synthesis). The compelling evidence positions EPB41L4A-AS1 as a promising, multi-faceted therapeutic target for mitigating the burden of age-related diseases.

Keywords:  Aging; Alzheimer's disease; EPB41L4A-AS1; T2DM; age-related diseases; cancer; lncRNA

DOI:  https://doi.org/10.1016/j.mad.2025.112118