bims-glucam 2026-10-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–10–04
twenty-six papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Metabolism in Health and Diseases.
Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines.
MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation.
Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.
Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.
HDAC4 Promotes Cancer Stemness in Nonsmall Cell Lung Cancer by Upregulating SLC38A2 Expression via HIF-1α to Enhance Glutamine Metabolism.
Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
DLST-driven metabolic alterations link skin to blood glucose: A translational study from mouse to human.
Endothelial SLC25A13 links glutamine metabolism to angiogenesis.
The Activation of the Transcription Factor NRF2 in Epithelial Cells Lining the Kidney Cysts in Tuberous Sclerosis Complex (TSC): The Interplay of Fumarate Hydratase 1, KEAP1, and NRF2 in Kidney Cystogenesis.
RNA modifications and metabolism in cancer: mechanisms, cross-talk and therapeutic implications.
Sensitive and derivatization-free amino acid analysis using liquid chromatography-Raman spectroscopy.
Metabolites and cancer metastasis.
A Thieno[3,2-D] pyrimidine class of p110α/GDH1 dual inhibitor SBS-873 suppresses TNBC growth by inhibiting PI3K/mTOR signaling and inducing ferroptosis through glutathione depletion.
MtROS-Drp1-mediated mitochondria fission contributes to microglia BV2 cell apoptosis induced by titanium dioxide nanoparticles.
Excess glutamine in embryo culture media alters mitochondrial and autophagy-related dynamics associated with impaired postnatal development.
EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.
Spatial N-Glycan Imaging and Machine Learning Classify Hepatocellular Carcinoma and Predict Glutamine Synthetase Status.
High-Density Type I Collagen Promotes IFN-γ+ CD8+ T Cell Exhaustion via SAT1-ASS1-Mediated Glutamine Accumulation and Ferroptosis in Triple-Negative Breast Cancer.
Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
Combined glutamine, dietary fiber, and oligosaccharide supplementation attenuates fasting-associated intestinal dysbiosis and stress responses in rats.
ASNS-dependent asparagine availability supports intestinal ILC2 responses and type 2 immunity under nutrient-limited conditions.
Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming.
Salivary metabolic profile in patients with oral squamous cell carcinoma and potentially malignant disorders.
GSLR Drives Lung Adenocarcinoma as a Critical Regulator of Energy Homeostasis Through Creatine Kinase B Activation.
Glutaminolysis Blockade-Empowered Bimodal Nanodepot for Spatially Complementary Sono-Thermal Ablation via PANoptosis and STING Activation Against Large Tumors.

MedComm (2020). 2026 Oct;7(10): e71035

Glutamine Metabolism in Health and Diseases.

Yi Ding, Fan Tong, Jing Zeng, Chun-Ping Cui.

  Glutamine, the most abundant nonessential amino acid in the blood and tissues, plays essential roles in cellular proliferation, immune regulation, acid-base homeostasis, and metabolic balance. Although traditionally classified as a nonessential amino acid, glutamine becomes conditionally essential under pathological conditions and physiological stress due to its critical role in supporting cellular adaptation. Under diverse pathological states, glutamine metabolism undergoes extensive reprogramming, and cancer cells exhibit a particularly high dependence on glutamine to sustain proliferation, redox balance, and biosynthetic demands. In this review, we summarize the multifaceted functions of glutamine metabolism in physiological and pathological processes. We first discuss the fundamental pathways of glutamine synthesis, transport, and utilization, followed by an overview of its regulatory roles in cellular responses to oxidative, nutritional, thermal, mechanical, DNA damage, and osmotic stresses. We further highlight the involvement of glutamine metabolism in cancer progression, immune regulation, metabolic plasticity, and therapeutic resistance. Finally, we summarize emerging glutamine-targeted therapeutic strategies, including metabolic inhibitors, combination therapies, and advanced technologies for metabolic imaging and single-cell analysis. This review provides a comprehensive perspective on glutamine metabolism and highlights its potential as a therapeutic target for cancer and other metabolic disorders.

Keywords:  cell metabolism; cellular homeostasis; glutamine; pathological conditions; therapeutic target

DOI:  https://doi.org/10.1002/mco2.71035
JACS Au. 2026 Sep 28. 6(9): 5243-5253

Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines.

Xiwen Xiao, Hibiki Okuno, Saki Inoue, Naoki Zenmyo, Yuya Matsumoto, Emi Mishiro-Sato, Keiko Kano, Kazuaki Yoshimune, Shohei Uchinomiya, Akio Ojida.

  Aberrant metabolic activity is a hallmark of cancer and is recognized as a promising target for cancer therapy. However, covalent inhibitors that irreversibly modulate cancer-associated metabolic states remain largely unexplored. Here, we report the development of covalent inhibitors targeting glutaminase 1 (GLS1), a rate-determining enzyme in the glutamine metabolism. To develop covalent inhibitors of GLS1, we systematically evaluated the reactivity of N-heteroaryl nitriles and identified 2-cyanopyrimidine as a lysine-reactive electrophile suitable for selective covalent protein targeting. A covalent inhibitor bearing a 2-cyanopyrimidine irreversibly binds GLS1 in cancer cells with excellent proteome-wide selectivity. This mode of action effectively suppresses glutamine metabolism and induces death of glutamine-dependent cancer cells, highlighting the therapeutic potential of covalent targeting of GLS1.

Keywords:  covalent inhibitor; cyanopyrimidine; glutaminase 1; glutamine metabolism; lysine-reactive warhead

DOI:  https://doi.org/10.1021/jacsau.6c00924
Cancer Res. 2026 Sep 29.

MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation.

Zeyu Yan, Dan Wu, Jingyun Wu, Caiyu Shi, Mengmeng Feng, Yu Li, Gang Wang, Xinwei Liu, Jibin Li, Guoqing Qi, Xianli He, Tingting Ren, Jinliang Xing.

Tumor cells commonly exhibit a preferential uptake of glutamine to support the heightened metabolic demands. However, the therapeutic potential of targeting glutamine metabolism is severely limited by the heterogeneous responses of cancer cells to glutamine deprivation. In this study, we identified a ribophagy-adenosine-MYC positive feedback loop that was activated and determined cell fate under glutamine deprivation. In sensitive cells, highly expressed MYC acted as a scaffold to recruit Unc-51 like autophagy activating kinase 1, which phosphorylated ribosomal protein L12 to initiate ribophagy. This process drove extensive rRNA catabolism and a burst of reactive oxygen species, ultimately leading to cell death. Moreover, adenosine generated during this cascade enhanced MYC expression via its 3'-UTR region, locking the loop into a self-reinforcing hyperactivated state. In contrast, tolerant cells exhibited lower MYC expression, which constrained the loop to a low-activity and subcritical steady state, thereby enabling survival under glutamine deprivation. Consequently, MYC-high tumors were vulnerable to glutaminase inhibition alone (CB-839), while MYC-low tumors required combination therapy with CB-839 and a pro-oxidant (elesclomol) to achieve tumor eradication. This study establishes MYC expression as a key determinant of sensitivity to glutamine deprivation, reveals the central role of ribophagy within the glutamine deprivation-triggered positive feedback loop, and uncovers a non-canonical, scaffold-like function of MYC in rRNA catabolism. These findings highlight a potential combination strategy to overcome a major bottleneck in targeting glutamine metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0575
Front Cell Dev Biol. 2026 ;14 1915673

Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.

Yuwei Huang, Huanhuan Wang, Shuang Zhang, Zhenyang Jiang, Ruolin Shen, Weiqin Chang, Xin Jiang.

   Background: As a conditionally essential amino acid that is required by tumor cells, glutamine serves as a key metabolic hub in tumor cells, functioning both as a carbon source for the tricarboxylic acid cycle and lipid synthesis and as a nitrogen source for amino acid and nucleotide biosynthesis. Cancer cells reprogram glutamine metabolism to enhance its uptake and utilization, thereby supporting anabolic demands, maintaining redox homeostasis, and ensuring genomic stability. The efficacy of radiotherapy against malignancies largely depends on tumor cell radiosensitivity, which is influenced by DNA damage repair capacity, microenvironmental hypoxia, and cancer stem cells. Growing evidence indicates that glutamine metabolism significantly modulates tumor radiosensitivity by regulating the supply of key substrates for DNA damage repair, affecting repair protein function through post-translational modifications, and altering chromatin architecture.
Methods: We performed a comprehensive literature search across PubMed and Web of Science, focusing on studies investigating the interplay among glutamine metabolism, DNA damage response, and tumor radiosensitivity. Based on critical analysis and synthesis of the retrieved literature, we propose an integrated framework linking metabolic rewiring to DNA repair modulation in the context of radiotherapy.
Results: This review identifies three principal mechanisms by which glutamine metabolism may regulate the DNA damage response in tumors: (1) supplying essential substrates for DNA repair, including purines and pyrimidines derived from glutamine-dependent biosynthesis; (2) modulating the activity and function of DNA repair proteins through O-GlcNAcylation and PARylation as critical post-translational modifications, as well as regulating chromatin accessibility via histone modifications; and (3) maintaining redox homeostasis and counteracting iron-dependent lipid peroxidation to modulate ferroptosis susceptibility following irradiation. Notably, targeted inhibition of glutamine metabolism significantly enhances tumor radiosensitivity and suppresses tumor growth, demonstrating the therapeutic potential of metabolic intervention.
Conclusion: Glutamine metabolism plays a multifaceted role in regulating the DNA damage response and tumor radiosensitivity. Targeting glutamine metabolic pathways, particularly through substrate supply deprivation, post-translational modification interference, or chromatin remodeling modulation, may represent a rational strategy for radiosensitization. This review provides a theoretical basis for the development of novel combination regimens integrating glutamine metabolism inhibitors with radiotherapy.

Keywords:  DNA damage response; DNA repair; double-strand breaks; genome stability; glutamine metabolism; radiotherapy

DOI:  https://doi.org/10.3389/fcell.2026.1915673
Front Immunol. 2026 ;17 1961819

Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.

Xiyu Liu, Jiaxin Lei, Xinhang Jiang, Lingyi Li, Longhao Yu, Gengxue Wang, Kaixun Guo, Zhenke Wen, Yan Wang.

   Background: Cancer stem cells (CSCs) are critical drivers of tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, how CSCs remodel the immunosuppressive tumor microenvironment (TME) of NSCLC remains largely unclear.
Methods: Flow cytometry was performed to evaluate the immunomodulatory effects of NSCLC CSCs on T cell differentiation. RNA-sequencing-based metabolic profiling was conducted to identify pivotal metabolic pathways activated in CSCs. Mitochondrial reactive oxygen species (ROS) encapsulated in CSC-derived exosomes were quantified, and the molecular mechanism by which exosomal ROS modulates intracellular nitric oxide (NO) production and FoxP3 post-translational modifications in T cells was further explored. Patient-derived organoids (PDOs) were utilized as a preclinical model to verify the therapeutic potential of glutamine metabolism targeting.
Results: NSCLC CSCs potently induced tumor immunosuppression by promoting regulatory T (Treg) cell differentiation. Mechanistically, hyperactive glutamine metabolism in CSCs substantially increased mitochondrial ROS generation. Exosomal ROS secreted by CSCs was transferred to T cells, thereby elevating intracellular NO synthesis. Increased NO further triggered S-nitrosylation and deubiquitination of FoxP3, which ultimately stabilized FoxP3 expression and facilitated Treg cell differentiation. In NSCLC PDO models, pharmacological inhibition of glutamine metabolism reversed the immunosuppressive T cell phenotype and efficiently suppressed PDO growth.
Conclusion: NSCLC CSCs mediate TME immunosuppression via a glutamine metabolism-dependent regulatory axis. Exosomal ROS-initiated FoxP3 post-translational modification is a novel mechanism underlying CSC-driven Treg differentiation. This study reveals an unreported immune evasion pathway in NSCLC and identifies glutamine metabolism as a viable therapeutic target for overcoming tumor immunosuppression.

Keywords:  CSCs; Foxp3; S-nitrosylation; deubiquitination; regulatory T cell

DOI:  https://doi.org/10.3389/fimmu.2026.1961819
Anal Cell Pathol (Amst). 2026 ;2026(1): e2525721

HDAC4 Promotes Cancer Stemness in Nonsmall Cell Lung Cancer by Upregulating SLC38A2 Expression via HIF-1α to Enhance Glutamine Metabolism.

Changxian Chen, Xiaoming Jiang, Zhenwu Yao, Jiaxue Sun, Liju Zhang, Mingyu Xu, Weimin Bao, Weijun Liu.

   BACKGROUND AND PURPOSE: The malignant progression of nonsmall cell lung cancer (NSCLC) is closely related to cancer stemness. Histone deacetylase 4 (HDAC4) plays a regulatory role in lung cancer, but its effect on NSCLC stemness remains unclear. This study aimed to investigate the role and mechanism of HDAC4 in NSCLC stemness.
METHODS: In this study, a tumor-bearing model was established by subcutaneously injecting A549 cells into the right dorsal side of nude mice. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry were used to measure gene and protein expression levels. Flow cytometry, sphere formation assays, and Transwell experiments were employed to assess cancer cell stemness, migration, and invasion. Additionally, a kit was used to measure changes in glutamine metabolism-related indicators.
RESULTS: In this study, we found that knocking down HDAC4 expression inhibited the expression of SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and nanog homeobox (NANOG) in A549 cells; it also reduced the proportions of CD133- and CD44-positive cells and suppressed their sphere formation, cell migration, and invasion abilities. Furthermore, HDAC4 knockdown inhibited glutamine uptake, glutamate production, α-ketoglutarate levels, and glutaminase (GLS) activity. Notably, treatment with the additional glutamine metabolism inhibitor CB-839 attenuated the promoting effects of HDAC4 overexpression on the stemness, migration, and invasion of A549 cells. In addition, HDAC4 promoted the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and solute carrier family 38 member 2 (SLC38A2); after overexpressing HIF-1α, the inhibitory effect of HDAC4 knockdown on SLC38A2 expression in A549 cells was weakened.
CONCLUSION: Our study reveals a critical mechanism by which HDAC4 enhances glutamine metabolism through upregulation of HIF-1α expression to promote SLC38A2 expression, thereby driving NSCLC stemness and progression.

Keywords:  HDAC4; HIF-1α; NSCLC; SLC38A2; cancer stemness; glutamine metabolism

DOI:  https://doi.org/10.1155/ancp/2525721
Sci Adv. 2026 Oct 02. 12(40): eaei2831

Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.

Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.

Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.

DOI: https://doi.org/10.1126/sciadv.aei2831
Mol Metab. 2026 Sep 28. pii: S2212-8778(26)00123-7. [Epub ahead of print] 102439

DLST-driven metabolic alterations link skin to blood glucose: A translational study from mouse to human.

Nsrein Ali, Syeda Tayyiba Rahat, Diana Motei, Mira Mäkelä, Subodh Sharma, Mikko Tulppo, Juhani Juntilla, J Kalervo Hiltunen, Anni I Nieminen, Steffen Ohlmeier, Seppo Vainio.

  To investigate the link between skin features and diabetes, we performed a multi-modal study combining a diabetic mouse model, a human pilot cohort, and keratinocyte response assays. Our goal was to identify molecular signatures in skin, cells, and sweat that correlate with glycemic control and could serve as early biomarkers of hyperglycemia. This integrative approach advances understanding of diabetes-associated dermatological changes and supports the development of targeted, non-invasive diagnostic tools for early detection. Following glucose tolerance tests, proteomic and metabolomic profiling was performed. We identified dihydrolipoyl-succinyltransferase (DLST) as a promising biomarker whose protein and transcript levels consistently correlated with glycemic status across models. In HaCaT keratinocytes, DLST was found to drive metabolic reprogramming toward glutamine utilization as part of an antioxidant protective response. Chromatin immunoprecipitation assay revealed that Sp1 binds to the DLST promoter region, while functional studies, including Sp1 overexpression and knowdown, further confirmed that Sp1 regulates DLST at transcriptional level. Furthermore, DLST knockdown reproduced metabolic shifts in glutamine pathways, findings supported by proteomic analyses and stable isotopic flux analysis. Reduced DLST expression in healthy skin corresponded with glutamine metabolism changes observed in keratinocytes upon oral glucose ingestion. While healthy skin and sweat displayed opposing metabolic trends, pre-type 2 diabetes samples showed aligned trends, suggesting sweat metabolomics could serve as an early systemic metabolic indicator. These findings identify DLST as a glucose-responsive biomarker reflecting skin and sweat responses to systemic glucose, providing a foundation for the development of targeted, non-invasive diagnostic tools for early detection of diabetes.

Keywords:  And sweat; Biomarkers; Blood glucose; DLST; Glutamate metabolism; Keratinocytes; Metabolites; Non-invasive; Proteomics; Skin; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.molmet.2026.102439
EMBO Mol Med. 2026 Sep 26.

Endothelial SLC25A13 links glutamine metabolism to angiogenesis.

Abhishek Subramanian, Anne Cuypers, Patricia Yagüe, Mathias Declercq, Joris Souffreau, Pieter-Jan Coolen, Liliana Sokol, Anh-Co Truong, Mila Borri, Koen Veys, Sabine Wyns, Els Gils, Stefan Vinckier, Katleen Brepoels, Ling Jin, Huberte Moreau, Mira Mousa, Bart Ghesquière, Baharak Hosseinkhani, Guy Eelen, Mieke Dewerchin, Massimiliano Mazzone, Peter Carmeliet.

Attention to exploring endothelial cell (EC) metabolism is increasing, but a holistic perspective on the metabolic adaptations of ECs during angiogenic proliferation is still missing. Here, we use a previously in-house developed computational EC-adapted genome-scale metabolic model that recapitulates known metabolic features in proliferating ECs to predict novel pathways central to biomass synthesis. We unveil the metabolic function of the glutamate-aspartate antiporter SLC25A13, previously overlooked in ECs, as a key regulator of glutamine utilization and provide evidence regarding its contribution to the generation of cholesterol and other biomass precursors. To our knowledge, predominant SLC25A13-linked utilization of glutamine for cholesterol synthesis has not been reported in other cell types in prior literature. Silencing of SLC25A13 in ECs reduced proliferation and vessel sprouting in vitro as well as in a choroidal neovascularization mouse model. These insights underscore the particular characteristics of EC metabolism and may warrant further evaluation of SLC25A13 as a putative new anti-angiogenic target.

DOI: https://doi.org/10.1038/s44321-026-00524-3
bioRxiv. 2026 Sep 23. pii: 2026.09.22.753536. [Epub ahead of print]

The Activation of the Transcription Factor NRF2 in Epithelial Cells Lining the Kidney Cysts in Tuberous Sclerosis Complex (TSC): The Interplay of Fumarate Hydratase 1, KEAP1, and NRF2 in Kidney Cystogenesis.

Sharon Barone, Kamyar Zahedi, Manoocher Soleimani.

Background: Tuberous Sclerosis Complex (TSC) is caused by inactivating mutations in either the TSC1 or TSC2 genes, leading to activation of the mammalian target of rapamycin complex 1 (mTORC1) and unhindered cell growth and proliferation. The epithelium of TSC renal cysts in both mice and humans is composed of proliferating A-intercalated (A-IC) cells. The exact molecular mechanism of kidney cystogenesis in TSC remains speculative.
Hypothesis: Superfluous cell proliferation driven by mTORC1 activation increases metabolic demand, causing oxidative stress and excess reactive oxygen species. If unchecked, this overwhelms antioxidant defenses and causes cell death. In TSC kidney cystogenesis, Nuclear Factor Erythroid 2-Related Factor 2 (NFE2L2), also known as NRF2, serves as the "master regulator" of antioxidant and anti-inflammatory responses, enabling cells to survive and proliferate by clearing the toxic environment and supplying nutrients and fuel.
Results: RNA-seq and proteomics, along with western blot analysis, showed robust downregulation of Fumarate Hydrase 1 (FH1) and upregulation of NRF2, STAT3, and HIF1α in kidneys from TSC mice with moderate or heavy cyst burden. Confocal microscopy and immunohistochemical staining on kidney sections, and/or western blot studies on nuclear and cytoplasmic fractions, showed nuclear localization of NRF2, STAT3, and HIF1α. In cyst-lining cells in TSC mouse models, FH1 downregulation was associated with inactivating succination of KEAP1 in immunoprecipitation experiments, promoting NRF2 nuclear localization in A-IC cells lining the cysts. NRF2 nuclear localization was associated with ectopic induction of the glutamine transporter SLC38A3 (SNAT3) on the basolateral membrane and activation of the NH 3 /NH 4 + transporters RHCG and RHBG in A-IC cells lining the cysts. Twenty-four h urine NH 3 /NH 4 + excretion rates increased significantly in Tsc1 KO vs. WT mice. The activation of NRF2, STAT3, and HIF1α can drive metabolic reprogramming and activate survival genes in proliferating cells. Together with SLC38A3 induction and upregulation of other glutamine and NH 3 /NH + transporters, these factors activate glutaminolysis and aerobic glycolysis, supplying nutrients to proliferating cystic epithelial cells and supporting cyst expansion in TSC. Consistent with this central role for glutaminolysis in kidney cystic epithelium and TSC cystogenesis, we find a significant reduction in kidney cyst burden in Tsc1 KO mice on a glutamine-free diet.
Conclusions: NRF2 plays a critical role in antioxidant defense. Along with STAT3 and HIF1α, NRF2 is a key player in metabolic reprogramming through glutaminolysis, which supplies nutrients to proliferating cystic epithelial cells and supports cyst expansion in TSC. These findings suggest that inhibiting or inactivating NRF2, alone or in combination with HIF1α or STAT3, may represent a potential treatment strategy for kidney lesions in TSC.

DOI: https://doi.org/10.64898/2026.09.22.753536
Semin Cancer Biol. 2026 Sep 30. pii: S1044-579X(26)00089-1. [Epub ahead of print] 102622

RNA modifications and metabolism in cancer: mechanisms, cross-talk and therapeutic implications.

Xin Luo, Xinzhao Zuo, Jingke He, Ping Yi.

  RNA modifications, particularly in the realm of epitranscriptomics, have emerged as crucial regulatory factors in cancer progression, influencing cancer cell behavior by reprogramming metabolic pathways. These modifications, such as N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N¹-methyladenosine (m¹A), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C) and pseudouridine (Ψ), modulate mRNA stability, splicing, translation efficiency, and non-coding RNA function, thereby fine-tuning the expression of metabolic enzymes and transporters. Importantly, these marks converge on shared metabolic enzymes, engage common effector proteins, and exhibit synergistic, antagonistic or hierarchical relationships that collectively shape the metabolic landscape of tumors. This review synthesizes current knowledge on how RNA modifications coordinate glucose, lipid, glutamine and nucleotide metabolism, with emphasis on cross-talk and functional integration among different marks. We further discuss tumor-type-specific wiring of these networks, the challenges of multi-modification detection, and the therapeutic potential of targeting the epitranscriptomic-metabolic axis in precision oncology.

Keywords:  RNA modifications; cancer metabolism; epitranscriptomic regulation; metabolic reprogramming; therapeutic targets

DOI:  https://doi.org/10.1016/j.semcancer.2026.102622
Analyst. 2026 Sep 28.

Sensitive and derivatization-free amino acid analysis using liquid chromatography-Raman spectroscopy.

Kana Matsuoka, Masahiro Ando, Takuji Nakashima, Haruko Takeyama.

Liquid chromatography-Raman spectroscopy with post-column spotting and solvent evaporation achieved nanogram-level detection of amino acids without derivatization and demonstrated the feasibility of quantification at this level for phenylalanine and glutamine. All 20 amino acids were successfully detected regardless of chromophore presence. Lysine modifications were directly discriminated via distinct vibrational fingerprints. Co-eluting compounds were resolved by MCR-ALS-based spectral deconvolution, demonstrating that LC-Raman spectroscopy can add a spectral separation axis to chromatographic analysis. Furthermore, LC-Raman spectroscopy was also applied to quantitative analysis. For phenylalanine and glutamine, the calibration curves exhibited excellent linearity (R2 = 0.9925 for phenylalanine, and R2 = 0.9994 for glutamine). The quantitative results of these amino acids in the culture medium obtained via LC-Raman spectroscopy (65.9 ± 3.5 µg mL-1 (n = 3, %RSD = 5.2%) for phenylalanine, and 576.3 ± 17.5 µg mL-1 (n = 3, %RSD = 3.0%) for glutamine) were in good agreement with those determined by conventional detectors (66.1 µg mL-1 for phenylalanine, and 584 µg mL-1 for glutamine). This label-free approach establishes LC-Raman spectroscopy as a structural detection mode for LC, enabling chromatographic analysis to be coupled directly with molecular fingerprinting.

DOI: https://doi.org/10.1039/d6an00841k
Oncogene. 2026 Sep 27.

Metabolites and cancer metastasis.

Suisui Yang, Silin Shi, Junchen Hou, Jian Zhang, Zhenyi Su.

Over the past decades, metastasis research has largely emphasized genetic and epigenetic regulators. Emerging evidence indicates that metabolites-including sugars (glucose, fructose), antioxidant vitamins, glutathione, lipids (palmitic acid, cholesterol), and amino acids (glutamine, aspartate, BCAAs)-can critically influence metastasis in a context-dependent manner by driving or restraining progression via metabolic reprogramming and signaling modulation. This review examines how cancer cells re-modulate core metabolic pathways to adapt and metastasize, summarizes how endogenous metabolites, dietary bioactive compounds, metabolic toxins, and pharmacological agents regulate metastasis, and discusses new concepts and perspectives on metabolic regulation of tumor metastasis, and outlines future directions in metabolite-driven tumor metastasis. The metabolic dependencies of metastasis provide a rational basis for intervention through integrated nutritional and therapeutic strategies.

DOI: https://doi.org/10.1038/s41388-026-03930-6
Cell Signal. 2026 Sep 26. pii: S0898-6568(26)00572-3. [Epub ahead of print]149 112913

A Thieno[3,2-D] pyrimidine class of p110α/GDH1 dual inhibitor SBS-873 suppresses TNBC growth by inhibiting PI3K/mTOR signaling and inducing ferroptosis through glutathione depletion.

Biswajit Dey, Essha Chatterjee, Sivkan Kaur Nanda, Ankush Bansode, Santanu Basak, Rahul Kumar, Hoshiyar Singh, Nandkumar Doijad, Bhagyashri N Wadje, Pankaj Kumar Singh, Pradeep Kumar Naik, Sandip B Bharate, Santosh Kumar Guru.

   BACKGROUND: Genetic alterations in phosphoinositide 3-kinase (PI3K) signaling are frequently observed in triple-negative breast cancer (TNBC), with the p110α subunit being the most mutated. Although this identifies p110α as a promising therapeutic target, selective inhibitors have demonstrated limited efficacy. Therefore, this study aimed to investigate the therapeutic potential and underlying mechanisms of SBS-873, a novel thieno[3,2-D]pyrimidine-based p110α inhibitor.
METHODS: SBS-873 antitumor activity was evaluated in vitro and in TNBC xenograft models. The docking and biochemical assays confirmed the binding affinity of the compound. Protein and mRNA expression were analyzed by Western blotting and qRT-PCR, with immunofluorescence and immunohistochemistry confirming protein levels. Metabolic function was assessed using Seahorse analysis. Oxidative stress and lipid peroxidation were measured through the reduced glutathione test and malondialdehyde assay, while gene knockout validated the mechanism.
RESULTS: SBS-873 exhibited broad antiproliferative activity across multiple cancer cell lines, with marked selectivity toward TNBC cells while sparing non-tumorigenic mammary cells. Mechanistically, SBS-873 suppressed the PI3K/AKT/mTOR signaling pathway by downregulating p110α and concurrently inhibited GDH1, a critical regulator of glutamine metabolism, redox homeostasis, and epithelial-mesenchymal transition (EMT). GDH1 inhibition resulted in glutathione depletion, GPX4 impairment, and increased lipid peroxidation, ultimately inducing ferroptotic cell death. In vivo, SBS-873 significantly reduced tumor growth in TNBC xenografts without observable toxicity, accompanied by suppression of both p110α and GDH1.
CONCLUSION: These findings identify SBS-873 as a first-in-class dual inhibitor targeting both p110α and GDH1, offering a promising therapeutic strategy that simultaneously disrupts proliferative signaling, metabolic adaptation, and metastatic potential in TNBC.

Keywords:  Ferroptosis; Glutamate dehydrogenase 1; PI3K signaling; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cellsig.2026.112913
Chem Biol Interact. 2026 Sep 30. pii: S0009-2797(26)00467-9. [Epub ahead of print]440 112359

MtROS-Drp1-mediated mitochondria fission contributes to microglia BV2 cell apoptosis induced by titanium dioxide nanoparticles.

Shouying Cao, Nan Bao, Qingqing Yue, Meng Tang, Changcun Bai.

  The widespread use of titanium dioxide nanoparticles (TiO2 NPs) has raised serious concerns regarding their biosafety, particularly their potential effects on the central nervous system. As innate immune cells in the brain, microglia serve as key targets for neurotoxicity assessment. This study aims to systematically elucidate the toxic effects of TiO2 NPs on BV2 cells and their underlying molecular mechanisms. The results showed that TiO2 NPs were spherical, with an average particle size of approximately 10 nm, and primarily existed in the anatase phase. TiO2 NPs significantly inhibited BV2 cell viability in a concentration-dependent manner and induced apoptosis as well as autophagosome formation. Mechanistically, TiO2 NPs exposure triggered mitochondrial network fragmentation, membrane depolarization, and bursts of both intracellular and mitochondrial ROS. Notably, the mitochondrial-targeted antioxidant mito-TEMPO effectively attenuated these deleterious effects. Western blot analysis further revealed that TiO2 NPs activated the mitochondria-dependent apoptotic pathway, upregulated the mitochondrial fission protein Drp1, downregulated the fusion protein OPA1, and promoted autophagic flux. Metabolomic analysis identified 206 significantly differentially expressed metabolites, primarily enriched in pathways such as the tricarboxylic acid cycle, glutamine metabolism, glutathione metabolism, and purine metabolism, revealing the metabolic basis of energy metabolism disruption and exacerbated oxidative stress. In summary, these findings demonstrate that TiO2 NPs induce oxidative stress, which drives mitochondrial dynamic imbalance (fission/fusion disruption) and dysfunction, subsequently triggering metabolic reprogramming, apoptosis, and autophagy in BV2 cells. This study provides important experimental evidence and novel mechanistic insights into the neurotoxic potential of TiO2 NPs.

Keywords:  Apoptosis; Autophagy; BV2 cells; Mitochondrial dynamics; Non-targeted metabolomics; Titanium dioxide nanoparticles

DOI:  https://doi.org/10.1016/j.cbi.2026.112359
Front Cell Dev Biol. 2026 ;14 1920196

Excess glutamine in embryo culture media alters mitochondrial and autophagy-related dynamics associated with impaired postnatal development.

Norermi Firzana Alfian, Yui Maruhashi, Masahiro Horizoe, Wasim Bari, Shiori Ishiyama, Kazuki Mochizuki, Satoshi Kishigami.

  The preimplantation period is a critical nutrient-sensing window influencing metabolic disease risk, as established by the developmental origins of health and disease theory (DOHaD). In this study, we examined the postnatal consequences of increased glutamine concentration, an important energy source, by altering embryonic metabolic development. In vivo-fertilised ICR mouse embryos were cultured in modified Chatot-Ziomek-Bavister medium with 1 mM L-glutamine (Gln) and bovine serum albumin (BSA) as the control and compared with elevated Gln media (2 mM) with bovine serum albumin (+Gln) or without BSA (+Gln-BSA). Early embryonic developmental analysis showed that both +Gln and +Gln-BSA presented reduced blastocyst cell number, primarily in trophectoderm cells, associated with increased apoptosis. Embryos showed altered metabolic homeostasis, including reduced mitochondrial membrane potential and mitochondrial morphology, altered autophagy-related activity (indicated by discrepancies between the DAPGreen assay and LC3-positive autophagosomes), and reduced heterochromatin methylation signals (H3K27me3). Offspring derived from these embryos subsequently exhibited irregular body weight trajectories, reduced survival, and impaired glucose tolerance. These findings indicate that in vitro exposure to elevated glutamine during early development is associated with altered mitochondrial dynamics and autophagy-related responses, interrupting intracellular mechanisms with lifelong metabolic consequences.

Keywords:  DOHaD; autophagy; embryo culture; embryogenesis; glutamine; mitochondria

DOI:  https://doi.org/10.3389/fcell.2026.1920196
Cancer Res. 2026 Oct 02.

EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.

Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine Mader, Daina Z Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois.

EZH2, the catalytic subunit of the histone methyltransferase complex PRC2, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition significantly alters chromatin landscapes and gene expression, it has limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrated that EZH2 inhibition causes the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4, EZH2 inhibition enhanced amino acid flux and promoted glutaminolysis to support TNBC cell survival. Pharmacological targeting of this metabolic axis with a glutaminase inhibitor in combination with EZH2 inhibition significantly impaired TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0801
JCI Insight. 2026 Sep 29. pii: e209628. [Epub ahead of print]

Spatial N-Glycan Imaging and Machine Learning Classify Hepatocellular Carcinoma and Predict Glutamine Synthetase Status.

Muhammed F Bayram, Jade K Macdonald, Andrew DelaCourt, Peggi M Angel, Richard R Drake, Aatur Singhi, David Geller, Satdarshan P Monga, Amit Singal, Anand Mehta.

   BACKGROUND: Hepatocellular carcinoma (HCC) exhibits molecular heterogeneity that challenges histopathologic classification and biomarker discovery. We assessed whether spatially resolved N-glycan imaging with machine learning could classify tumor regions and infer glutamine synthetase (GS) status.
METHODS: In this retrospective study, MALDI mass spectrometry imaging of N-glycans was performed on formalin-fixed, paraffin-embedded sections from two independent cohorts (discovery, n = 88; validation, n = 60) with pathologist annotation. An XGBoost classifier was trained on 90 discriminative N-glycan features using patient-grouped cross-validation. Performance was assessed by AUC for pixel- and biopsy-level discrimination of tumor from adjacent non-tumor tissue, and for GS status classification.
RESULTS: Pixel-level AUCs were 0.95 (cross-validation) and 0.89 (external validation); biopsy-level AUCs were 1.0 and 0.97, correctly identifying 97% of tumor-containing biopsies. Probability maps recapitulated pathologist-defined boundaries; UMAP embeddings captured inter- and intratumoral heterogeneity. Discriminative species (m/z 2393.846, 1905.634, 1743.579, 1809.639) reflected complex, fucosylated, branched remodeling. N-glycans bearing six GlcNAc residues were enriched in GS+ (n = 45) versus GS- (n = 17) tumors (P = 0.001) and discriminated GS status (AUC = 0.75), consistent with GLUL and MGAT5 upregulation in TCGA-LIHC.
CONCLUSION: MALDI N-glycan imaging with machine learning enables spatially resolved, objective classification of HCC and links glycan phenotypes to tumor-associated metabolic programs.
TRIAL REGISTRATION: Not applicable; retrospective analysis of archival, de-identified tissue.
FUNDING: NIH/NCI R01CA285370, 1R01CA289381, R33CA267226, R01CA282022, R21CA263464, R21CA286287, R01CA253460, S10OD030212, R01CA251155, R01CA250227, U01CA271887, P50CA295495, P30CA138313, P20GM130457, P30DK123704, P30DK120531,R24DK139775; NIH/NIA R01AG078702; Smart State Endowment, State of South Carolina; LeDucq Foundation.

Keywords:  Clinical Research; Glycobiology; Hepatology; Liver cancer; Machine learning; Oncology

DOI:  https://doi.org/10.1172/jci.insight.209628
Adv Sci (Weinh). 2026 Sep 27. e77879

High-Density Type I Collagen Promotes IFN-γ+ CD8+ T Cell Exhaustion via SAT1-ASS1-Mediated Glutamine Accumulation and Ferroptosis in Triple-Negative Breast Cancer.

Jinyan Wang, Shuangyue Pan, Lu Bai, Bin Li, Tiantian Liu, Jianing Cao, Mengdi Yang, Heda Zhang, Duancheng Guo, Wenxiang Zhi, Zhonghua Tao, Xichun Hu.

  Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by poor prognosis because of a lack of effective therapeutic agents. Changes in extracellular matrix (ECM) composition, particularly type I collagen density, significantly influence crucial cellular activities. However, the association between type I collagen density and TNBC progression remains unclear. This study finds that type I collagen density and mechanical characteristics of lesions predict the pathological grade and malignant progression of TNBC patients. The results of transcriptomics and metabolomics studies suggest that high-density type I collagen promotes TNBC ferroptosis. Further in vitro experiments indicate that high-density type I collagen promotes ferroptosis in TNBC cells through spermidine/spermine N1-acetyltransferase 1 (SAT1)/argininosuccinate synthase (ASS1)-induced glutamine (Gln) accumulation. Moreover, in vitro co-culture and in vivo experiments reveal that high-density type I collagen increases the uptake of Gln in TNBC cells, leading to Gln deprivation of IFN-γ+ CD8+ T cells in the tumor microenvironment, resulting in higher level of immunosuppression. Combination of ferrostatin 1 and anti-PD-1 therapy reverses high-density collagen-induced tumor progression of TNBC. The clinical samples further verify the role of collagen density in TNBC. This study reveals that high-density type I collagen participates in TNBC progression partly through immunosuppression induced by Gln accumulation-related ferroptosis.

Keywords:  SAT1; TNBC; Type I collagen density; ferroptosis; glutamine

DOI:  https://doi.org/10.1002/advs.77879
bioRxiv. 2026 Sep 24. pii: 2026.09.01.748489. [Epub ahead of print]

Starvation improves epithelial fitness by selectively extruding DNA damaged cells.

Lily A Gates, Dustin C Bagley, Konstantinos Kalyviotis, John Fadul, Tania Auchynnikava, Maria Voronkov, Jody Rosenblatt.

During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.

DOI: https://doi.org/10.64898/2026.09.01.748489
Front Nutr. 2026 ;13 1933552

Combined glutamine, dietary fiber, and oligosaccharide supplementation attenuates fasting-associated intestinal dysbiosis and stress responses in rats.

Yuta Murai, Takumi Iwasawa, Satoshi Takeda, Kaho Ohki, Kazunori Kato, Tomoaki Ito.

   Background: Prolonged preoperative fasting is associated with intestinal dysbiosis, impaired mucosal homeostasis, and delayed postoperative recovery. Combined nutritional supplementation with glutamine, dietary fiber, and oligosaccharides has the potential to protect intestinal function during nutritional stress. In this study, we investigated the effects of this nutritional combination in a rat model of prolonged fasting.
Methods: Male Sprague-Dawley rats received oral supplementation with a combination of glutamine, dietary fiber, and oligosaccharides (GFO) or a 15% glucose solution twice daily for 9 days and were subjected to fasting from days 6 to 9. Jejunal morphology, short-chain fatty acid (SCFA) concentrations, intestinal gene expression, and gut microbiota composition were evaluated.
Results: Fasting significantly reduced body weight, jejunal villous height, cecal weight, and the concentrations of acetate, n-butyrate, and n-valerate. Fasting was also associated with exploratory changes in gut microbiota composition and increased the expression of several Toll-like receptor (TLR), barrier, and autophagy-related genes in the jejunum. Supplementation with glutamine, dietary fiber, and oligosaccharides significantly attenuated the fasting-induced reduction in cecal weight and suppressed the upregulation of TLR5, TLR6, TLR8, CLDN1, CLDN3, OCLN, ZO-1, MUC3, ATG5, ATG12, Beclin1, p62, and LC3. Microbiota analysis showed that the relative abundance of sequences tentatively assigned to Lactobacillus reuteri in the supplemented group was comparable to that in the control group, whereas sequences tentatively assigned to Bifidobacterium animalis were detected predominantly in the supplemented group. The relative abundances of Desulfovibrio, Bilophila, and Mucispirillum schaedleri in the supplemented group appeared closer to those observed in the control group than to those in the fasting group. Furthermore, supplementation significantly increased propionate levels compared with the control group.
Conclusions: Combined supplementation with glutamine, dietary fiber, and oligosaccharides attenuated several fasting-associated intestinal stress responses and was accompanied by exploratory changes in gut microbiota composition and SCFA profiles. These intestinal effects were accompanied by exploratory changes in gut microbiota composition and SCFA profiles, together with attenuation of fasting-associated changes in intestinal stress-related markers, suggesting that this nutritional strategy may help maintain intestinal homeostasis during prolonged fasting and may have potential applications in perioperative nutritional support.

Keywords:  autophagy; glutamine dietary fiber and oligosaccharides; gut microbiota; intestinal dysbiosis; intestinal homeostasis; perioperative nutrition; prolonged fasting

DOI:  https://doi.org/10.3389/fnut.2026.1933552
Front Immunol. 2026 ;17 1878920

ASNS-dependent asparagine availability supports intestinal ILC2 responses and type 2 immunity under nutrient-limited conditions.

Wenyu Tian, Xuesong Liu, Mengqi Zheng, Jing Shen.

   Introduction: Nutrient availability critically governs group 2 innate lymphoid cell (ILC2) function and type 2 immunity. Here, we identify the non-essential amino acid asparagine (Asn) as a critical metabolite required for ILC2 survival and function.
Methods: We investigated the roles of extracellular Asn availability and asparagine synthetase (ASNS)-mediated de novo Asn biosynthesis in ILC2 responses using complementary in vitro and in vivo approaches, including amino acid restriction, ILC2-specific Asns deletion, dietary Asn restriction, and Nippostrongylus brasiliensis infection.
Results: ASNS, the rate-limiting enzyme for de novo Asn synthesis, was rapidly induced upon ILC2 activation under type 2 inflammatory conditions. When extracellular Asn was limited, ILC2s depended on ASNS-mediated Asn synthesis fueled by glutamine (Gln). Genetic ablation of Asns was well tolerated under Asnreplete conditions but severely impaired ILC2 viability and overall effector cytokine output upon Asn restriction. Dietary Asn restriction compromised ILC2s, and this effect was further aggravated by Asns deficiency. During N. brasiliensis infection, reduced intestinal Asn availability enhanced ILC2 reliance on Asns, whose deficiency impaired ILC2 abundance in the mLNs and protective anti-helminth immunity.
Discussion: These findings identify Asn as a context-dependent metabolic adaptor that supports ILC2 viability and function under nutrient-limited and type 2 inflammatory conditions.

Keywords:  anti-helminth immunity; asparagine; asparagine synthetase; group 2 innate lymphoid cell; immunometabolism

DOI:  https://doi.org/10.3389/fimmu.2026.1878920
bioRxiv. 2026 Sep 28. pii: 2026.08.23.746574. [Epub ahead of print]

Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming.

Chao He, Cristian Coarfa, Neftali Garcia, Cynthia O Lebimoyo, Haiwei Gu, Elisa Ruiz-Echartea, Xiaoli Ji, Alan W Cohen, Juan A Zuluaga, Lindsay J Celada, Scott A Ochsner, Neil J McKenna, Jennifer L Larson-Casey, Sandeep K Agarwal, Farrah Kheradmand, Yong Zhou, A Brent Carter, Ivan Rosas.

The mechanisms underlying the progression of pulmonary fibrosis in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases remain unclear. Increased extracellular matrix stiffness is a hallmark of fibrotic lung diseases. Monocyte-derived macrophages can promote fibrosis progression. However, there is limited understanding of how the mechanical properties of the fibrotic microenvironment influence macrophage phenotypes. Profibrotic macrophages are apoptosis-resistant, and this phenotype is modulated by enhanced mitochondrial bioenergetics. The objective of the study was to determine how lung tissue stiffness impacts macrophage phenotypes and fibrotic progression. We demonstrate that mechanoactivated macrophages exhibit apoptosis-resistance, increased expression of the antiapoptotic protein Bcl-xL and increased mitochondrial oxidative phosphorylation. Critically, the metabolic reprogramming observed in mechanoactivated macrophages is dependent on increased glutaminolysis. Inhibition of glutaminolysis attenuated apoptosis resistance in mechanoactivated macrophages. Moreover, inhibition of Bcl-xL in vivo protected mice against experimental pulmonary fibrosis. Lastly, mechanoactivated primary IPF macrophages produce more profibrotic cytokines and promote extracellular matrix production in precision-cut lung slices. We describe a mechanism for acquired macrophage apoptosis resistance dependent on metabolic reprogramming regulated by extracellular matrix stiffness. Our results identify mechanoactivated apoptosis-resistant macrophages as pro-fibrotic mediators, suggesting a novel therapeutic target in IPF and related fibrotic disorders.

DOI: https://doi.org/10.64898/2026.08.23.746574
Clin Oral Investig. 2026 Oct 02. pii: 495. [Epub ahead of print]30(10):

Salivary metabolic profile in patients with oral squamous cell carcinoma and potentially malignant disorders.

Lauriina Soiniemi, Eelis Hyvärinen, Jopi Mikkonen, Heli Jäsberg, Bina Kashyap, Arja Kullaa.

   OBJECTIVES: Oral Potential Malignant Lesions (OPMDs), including oral leukoplakia (OLK) and lichen planus (OLP), as well as Oral Squamous Cell Carcinoma (OSCC) are influenced by oral dysbiosis and might represent a disease continuum. Our hypothesis was that the oral salivary metabolomic reflects the association of those diseases. Hence, we aimed to study and compare salivary metabolites and metabolic pathways in OPMDs and OSCC.
MATERIAL AND METHODS: Unstimulated saliva samples were collected from 60 participants: OLK (n = 15), OLP (n = 15), OSCC (n = 15), and healthy controls (HCs; n = 15). Metabolites were quantified using NMR spectroscopy, and pathway analyses were performed with MetaboAnalyst 6.0.
RESULTS: Four metabolites (acetate, taurine, pyruvate, methylamine) were elevated, while proline was consistently decreased in all disease groups relative to HCs. Four key pathways were altered: pyruvate metabolism (in all disease groups), glutamate metabolism (in OLK and OSCC), taurine and hypotaurine metabolism (in OLP and OLK), and the glucose-alanine cycle. OLK shared more metabolic features with OSCC than with OLP.
CONCLUSIONS: Salivary metabolomic profiling reveals distinct metabolic alterations across OPMDs and OSCC, supporting their potential continuum and reflecting disease-related biochemical reprogramming. These findings highlight salivary metabolomics as a promising, non-invasive tool for understanding pathogenesis and for future development of biomarkers.
CLINICAL RELEVANCE: Divergent metabolic pathways in OLP and OLK may relate to their different pathogenesis and malignant transformation risks. Improved understanding of these pathways may support early diagnostics and targeted therapeutic strategies.

Keywords:  Metabolites; NMR spectroscopy; Oral potentially malignant lesions; Oral squamous carcinoma; Saliva

DOI:  https://doi.org/10.1007/s00784-026-07192-0
Adv Sci (Weinh). 2026 Sep 27. e77950

GSLR Drives Lung Adenocarcinoma as a Critical Regulator of Energy Homeostasis Through Creatine Kinase B Activation.

Xinyi Qian, Juze Yang, Jiayi Ren, Xiaowei Mao, Jia Li, Tengfei Sun, Liangliang Dong, Enguo Chen, Yan Lu, Pengyuan Liu.

  Lung cancer remains the leading cause of cancer-related mortality, with extremely high energy demands during progression. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in cancer metabolism; however, their role in reprogramming energy metabolism in lung cancer remains incompletely understood. In this study, we identify a glucose/glutamine sensitive lncRNA, GSLR, as a driver of lung adenocarcinoma (LUAD) progression. GSLR is markedly upregulated in LUAD, and its high expression is associated with poor patient prognosis. Nutrient restriction reduces chromatin accessibility at the GSLR locus via altered histone marks, whereas CTCF activates its transcription. Mechanistically, GSLR directly binds the RNA helicase DHX9 and recruits it to the creatine kinase B (CKB) promoter, arresting R-loop accumulation and thereby promoting CKB transcription. Elevated CKB expression sustains intracellular ATP homeostasis, thereby stabilizing mitochondrial membrane potential, preventing calcium overload, and reducing reactive oxygen species (ROS) accumulation. Collectively, our findings identify GSLR as a novel regulator of energy homeostasis that promotes lung cancer progression through the GSLR/DHX9/CKB axis. Targeting GSLR may thus represent a promising therapeutic strategy for LUAD.

Keywords:  energy homeostasis; epigenetic regulation; long non‐coding RNA; lung adenocarcinoma

DOI:  https://doi.org/10.1002/advs.77950
Adv Sci (Weinh). 2026 Sep 27. e77933

Glutaminolysis Blockade-Empowered Bimodal Nanodepot for Spatially Complementary Sono-Thermal Ablation via PANoptosis and STING Activation Against Large Tumors.

Yi-Ming Liu, Juan Qin, Si-Yuan Wu, Xue-Zhen Zhu, Yun-Fei Cai, Pei-Yao Sun, Hao Yang, Xing-Yue Wang, Shu Li, Duo Wang, Hai-Dong Zhu.

  Microwave ablation (MWA) for large hepatocellular carcinoma (HCC) is frequently compromised by non-uniform thermal distribution and immunosuppressive niche formation. To address these challenges, we engineered an injectable bimodal nanodepot (TCPD) via catalytic crosslinking of dopamine-modified hyaluronic acid by microwave thermal converter cesium-doped Prussian blue, enabling co-delivery of glutaminase 1 inhibitor Telaglenastat and sonosensitizer Chlorin e6. Under combined MWA and ultrasound irradiation, TCPD nanodepot disrupts cellular antioxidant defenses and bioenergetic pathways through glutaminolysis-TCA cycle blockade, metabolically sensitizing large tumors to spatially complementary sono-thermal ablation and enabling complete treatment coverage. This multimodal intervention induces multiple subcellular stresses, including mitochondrial and endoplasmic reticulum dysfunction, genotoxicity, and NAD+ depletion, which converge to facilitate PANoptosome assembly and immunogenic PANoptosis while activating the cGAS-STING pathway. Subsequent release of damage-associated molecular patterns and immunoregulatory cytokines promotes dendritic cell maturation, M1 macrophage polarization, and T lymphocyte infiltration, ultimately reprogramming the immunosuppressive microenvironment toward an immune‑activated niche. Integration with anti-PD-1 therapy further reinvigorates cytotoxic T lymphocytes and establishes antitumor immune memory to suppress tumor progression and metastasis, offering a multimodal therapeutic strategy for large HCC.

Keywords:  Spatially complementary sono‐thermal ablation; cGAS‐STING pathway; glutaminolysis blockade; immunogenic PANoptosis; injectable dual‐crosslinked nanodepot; microwave‐ultrasound synergy

DOI:  https://doi.org/10.1002/advs.77933